Professor Andrew Pollard

Research Area: Immunology
Scientific Themes: Immunology & Infectious Disease

Clinical trials and epidemiological research: The Oxford Vaccine Group
Vaccines are a kyy component of global public health policy and are particularly important in the defence of the health of young children. Despite the challenges of so doing, new and improved vaccines must be evaluated in the target population of infants and young children prior to licensure. The Oxford Vaccine Group has enrolled over 10,000 children and young people into clinical trials in the Thames Valley since 2001. The clinical trials undertaken in the UK since 2001 include phase IV studies of a meningitis C vaccine and a pneumococcal conjugate vaccine; a phase II study of a new pneumococcal vaccine for infants; phase II and III studies of quadrivalent meningococcal vaccines and group B meningococcal vaccines; phase II studies of a preschool vaccine; evaluation of a novel avian and swine influenza vaccines in adults and children; study of different schedules for immunisation of the elderly against pneumococcal infection.

Epidemiological studies have included evaluation of carriage of Haemophilus influenzae type b and Streptococcus pneumonia throughout childhood in the UK and Nepal, surveillance of invasive bacterial infections in children admitted to Patan hospital in Kathmandu. Qualitative research studies have evaluated parental views about immunization, vaccine research and influenza vaccines. The group has a particular interest in the ethics of consent in childhood and is working with the Centre for Ethics on studies evaluating the process of consent in school age children.

Laboratory research programme
The laboratory research programme has used the clinical material provided by the clinical trials group to drive a series of projects evaluating the developing immune system in the infant. The group has specifically focused on the development of B cell memory after immunization with glycoconjugate vaccines and has found correlations between the generation of memory during priming and the persistence of the immune response. A major programme is focussed on the development of a novel serogroup B meningococcal vaccine from preclinical studies through to clinical trials. In a ground-breaking study, the group are developing a human typhoid model for the evaluation of typhoid vaccines. The group also undertakes sero-epidemiological studies and is examining acquisition of natural immunity to various organisms in the UK and Nepal. A bank of DNA is being collected form children enrolled in vaccine trials and several studies of the genetic control of the immune response following immunisation are currently underway.

There are no collaborations listed for this principal investigator.

Zhang Y, Brady A, Jones C, Song Y, Darton TC, Jones C, Blohmke CJ, Pollard AJ, Magder LS, Fasano A et al. 2018. Compositional and Functional Differences in the Human Gut Microbiome Correlate with Clinical Outcome following Infection with Wild-Type Salmonella enterica Serovar Typhi MBIO, 9 (3), | Read more

Zhang Y, Brady A, Jones C, Song Y, Darton TC, Jones C, Blohmke CJ, Pollard AJ, Magder LS, Fasano A et al. 2018. Compositional and Functional Differences in the Human Gut Microbiome Correlate with Clinical Outcome following Infection with Wild-Type Salmonella enterica Serovar Typhi. MBio, 9 (3), | Show Abstract | Read more

Insights into disease susceptibility as well as the efficacy of vaccines against typhoid and other enteric pathogens may be informed by better understanding the relationship between the effector immune response and the gut microbiota. In the present study, we characterized the composition (16S rRNA gene profiling) and function (RNA sequencing [RNA-seq]) of the gut microbiota following immunization and subsequent exposure to wild-type Salmonella enterica serovar Typhi in a human challenge model to further investigate the central hypothesis that clinical outcomes may be linked to the gut microbiota. Metatranscriptome analysis of longitudinal stool samples collected from study subjects revealed two stable patterns of gene expression for the human gut microbiota, dominated by transcripts from either Methanobrevibacter or a diverse representation of genera in the Firmicutes phylum. Immunization with one of two live oral attenuated vaccines against S. Typhi had minimal effects on the composition or function of the gut microbiota. It was observed that subjects harboring the methanogen-dominated transcriptome community at baseline displayed a lower risk of developing symptoms of typhoid following challenge with wild-type S. Typhi. Furthermore, genes encoding antioxidant proteins, metal homeostasis and transport proteins, and heat shock proteins were expressed at a higher level at baseline or after challenge with S. Typhi in subjects who did not develop symptoms of typhoid. These data suggest that functional differences relating to redox potential and ion homeostasis in the gut microbiota may impact clinical outcomes following exposure to wild-type S. Typhi.IMPORTANCES. Typhi is a significant cause of systemic febrile morbidity in settings with poor sanitation and limited access to clean water. It has been demonstrated that the human gut microbiota can influence mucosal immune responses, but there is little information available on the impact of the human gut microbiota on clinical outcomes following exposure to enteric pathogens. Here, we describe differences in the composition and function of the gut microbiota in healthy adult volunteers enrolled in a typhoid vaccine trial and report that these differences are associated with host susceptibility to or protection from typhoid after challenge with wild-type S Typhi. Our observations have important implications in interpreting the efficacy of oral attenuated vaccines against enteric pathogens in diverse populations.

Pollard AJ. 2018. Meningococcal Disease. Ulster Med J, 87 (2), pp. 81-82.

Martinón-Torres F, Salas A, Rivero-Calle I, Cebey-López M, Pardo-Seco J, Herberg JA, Boeddha NP, Klobassa DS, Secka F, Paulus S et al. 2018. Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study The Lancet Child & Adolescent Health, 2 (6), pp. 404-414. | Show Abstract | Read more

© 2018 Elsevier Ltd Background: Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods: The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings: 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; p < 0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%] ), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%] ), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admission to a paediatric intensive care unit. Of 2469 patients with outcome data, 57 (2·2%) deaths occurred: seven were in patients with severe focal infections and 50 in those with sepsis. Interpretation: Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients. Funding: European Union's Seventh Framework programme.

Voysey M, Pollard AJ, Perera R, Shrestha S, Thorson S, Fanshawe TR. 2018. Use of weighted multivariate estimates in trials of multi-serotype vaccines to simplify interpretation of treatment differences. PLoS One, 13 (4), pp. e0196200. | Show Abstract | Read more

BACKGROUND: Many vaccines contain multiple components. Licensed pneumococcal conjugate vaccines (PCV) contain polysaccharides from 7, 10, or 13 different serotypes of Streptococcus pneumoniae. The main outcomes in randomised trials of pneumococcal vaccines are serotype-specific antibody measures. Comparisons are made between groups for each serotype, resulting in multiple separate comparisons of treatment effects which can be complicated to interpret. We investigated methods for computing the overall difference between vaccine groups across all serotypes. METHODS: Pneumococcal antibody concentrations were obtained from a randomised controlled trial of ten-valent pneumococcal vaccine, conducted in Kathmandu, Nepal. Infants received either 2 priming doses of vaccine at 6 and 14 weeks of age followed by a booster (2+1), or 3 priming doses at 6, 10, and 14 weeks of age with no booster (3+0). The overall difference between vaccine schedules across all serotypes was computed at each visit using a multivariate linear model with equal weights for each serotype. Alternative weights were derived from invasive pneumococcal disease cases in Nepal, Bangladesh and Pakistan, and from estimates of the relative invasiveness of each serotype and used in sensitivity analyses. RESULTS: When 10 separate estimates of treatment differences were computed the ratio of antibody responses for each serotype in the 2+1 group compared with the 3+0 group at 10 months of age varied greatly, with serotype-specific GMRs ranging from 2.80 for serotype 14, to 9.14 for serotype 18C. Using equal weights for each serotype, the overall geometric mean ratio (GMR) was 5.02 (95% CI 4.06-6.22) at 10 months of age, and 1.46 (95% CI 1.14-1.88) at 3 years of age. Using weights based on disease incidence gave GMRs ranging from 5.15 to 6.63 at 10 months of age, and 1.47 to 1.78 at 3 years of age. Using weights based on relative invasiveness gave estimates of 6.81 and 1.59, at 10 months and 3 years respectively. CONCLUSION: PCV clinical trial data have a multivariate structure with correlated outcomes for different serotypes. When analysing each serotype separately, the multiple estimates of the treatment effect can complicate the interpretation of trial results. Reporting a single overall estimate which accounts for the correlation between outcomes can simplify such interpretation. Treatment effects can be weighted equally or alternative weights derived from independent data can be used. Many modern vaccines have multiple components, such as quadrivalent meningococcal group ACWY vaccine or four-component group B meningococcal vaccine, thus these methods are widely applicable.

Britto CD, Dyson ZA, Duchene S, Carter MJ, Gurung M, Kelly DF, Murdoch DR, Ansari I, Thorson S, Shrestha S et al. 2018. Laboratory and molecular surveillance of paediatric typhoidal Salmonella in Nepal: Antimicrobial resistance and implications for vaccine policy. PLoS Negl Trop Dis, 12 (4), pp. e0006408. | Show Abstract | Read more

BACKGROUND: Children are substantially affected by enteric fever in most settings with a high burden of the disease, including Nepal. However pathogen population structure and transmission dynamics are poorly delineated in young children, the proposed target group for immunization programs. Here we present whole genome sequencing and antimicrobial susceptibility data on 198 S. Typhi and 66 S. Paratyphi A isolated from children aged 2 months to 15 years of age during blood culture surveillance at Patan Hospital, Nepal, 2008-2016. PRINCIPAL FINDINGS: S. Typhi was the dominant agent and comprised several distinct genotypes, dominated by 4.3.1 (H58). The heterogeneity of genotypes in children under five was reduced compared to data from 2005-2006, attributable to ongoing clonal expansion of H58. Most isolates (86%) were non-susceptible to fluoroquinolones, associated mainly with S. Typhi H58 lineage II and S. Paratyphi A harbouring mutations in the quinolone resistance-determining region (QRDR); non-susceptible strains from these groups accounted for 50% and 25% of all isolates. Multi-drug resistance (MDR) was rare (3.5% of S. Typhi, 0 S. Paratyphi A) and restricted to chromosomal insertions of resistance genes in H58 lineage I strains. Temporal analyses revealed a shift in dominance from H58 Lineage I to H58 Lineage II, with the latter being significantly more common after 2010. Comparison to global data sets showed the local S. Typhi and S. Paratyphi A strains had close genetic relatives in other South Asian countries, indicating regional strain circulation. Multiple imports from India of ciprofloxacin-resistant H58 lineage II strains were identified, but these were rare and showed no evidence of clonal replacement of local S. Typhi. SIGNIFICANCE: These data indicate that enteric fever in Nepal continues to be a major public health issue with ongoing inter- and intra-country transmission, and highlights the need for regional coordination of intervention strategies. The absence of a S. Paratyphi A vaccine is cause for concern, given its prevalence as a fluoroquinolone resistant enteric fever agent in this setting.

Marlow R, Kuriyakose S, Mesaros N, Han HH, Tomlinson R, Faust SN, Snape MD, Pollard AJ, Finn A. 2018. A phase III, open-label, randomised multicentre study to evaluate the immunogenicity and safety of a booster dose of two different reduced antigen diphtheria-tetanus-acellular pertussis-polio vaccines, when co-administered with measles-mumps-rubella vaccine in 3 and 4-year-old healthy children in the UK. Vaccine, 36 (17), pp. 2300-2306. | Show Abstract | Read more

AIM: To evaluate the immunogenicity and safety of a reduced antigen diphtheria-tetanus-acellular pertussis-inactivated poliovirus (dTap-IPVB) vaccine (Boostrix-IPV, GSK) as a pre-school booster in 3-4 year old children as compared to dTap-IPVR (Repevax, Sanofi Pasteur), when co-administered with mumps-measles-rubella vaccine (MMRV). METHODS: This phase III, open label, randomised study was conducted in the UK between April 2011 and April 2012. Children due their pre-school dTap-IPV booster vaccination were randomised 2:1 to receive one of two different dTap-IPV vaccines (dTap-IPVB or dTap-IPVR) with blood sample for immunogenicity assessment just prior and one month after vaccination. Immune responses to diphtheria, tetanus and polio antigens were compared between the study vaccines (inferential comparison). In the absence of an accepted pertussis correlate of protection, the immunogenicity of dTap-IPVB vaccine against pertussis was compared with historical pertussis efficacy data (inferential comparison). Safety and reactogenicity of both study vaccines were evaluated. RESULTS: 387 children were randomised and 385 vaccinated: 255 in the dTap-IPVB group and 130 in the dTap-IPVR group. Prior to vaccination, ≥76.8% of children had anti-diphtheria and ≥65.5% had anti-tetanus titres above the protection threshold; for pertussis, the pre-vaccination seropositivity rate ranged between 18.1 and 70.6%. Both vaccines were immunogenic with 99.2-100% of children achieving titres above the pre-specified seroprotection/seropositivity thresholds. One serious adverse event not considered as causally related to the study vaccination by the study investigator was reported in the dTap-IPVB group. CONCLUSION: Non-inferiority of dTap-IPVB to dTap-IPVR was demonstrated. Both vaccines had a clinically acceptable safety and reactogenicity profile when co-administered with MMRV to children 3-4 years old. TRIAL REGISTRATION: NCT01245049 (ClinicalTrials.gov).

Baay MFD, Richie TL, Neels P, Cavaleri M, Chilengi R, Diemert D, Hoffman SL, Johnson R, Kirkpatrick BD, Knezevic I et al. 2018. Human challenge trials in vaccine development, Rockville, MD, USA, September 28–30, 2017 Biologicals, | Show Abstract | Read more

© 2018 The International Alliance for Biological Standardization organized the second workshop on human challenge trials (HCT) in Rockville, MD, in September 2017. The objective of this meeting was to examine the use of HCT, in response to the continuing human suffering caused by infectious diseases, preventable by the development of new and improved vaccines. For this, the approach of HCT could be valuable, as HCT can provide key safety, tolerability, immunogenicity, and efficacy data, and can be used to study host-pathogen biology. HCT can generate these data with speed, efficiency and minimal expense, albeit not with the same level of robustness as clinical trials. Incorporated wisely into a clinical development plan, HCT can support optimization or down-selection of new vaccine candidates, assuring that only the worthiest candidates progress to field testing. HCT may also provide pivotal efficacy data in support of licensure, particularly when field efficacy studies are not feasible. Many aspects of HCT were discussed by the participants, including new and existing models, standardization and ethics. A consensus was achieved that HCT, if ethically justified and performed with careful attention to safety and informed consent, should be pursued to promote and accelerate vaccine development.

Ramasamy R, Willis L, Kadambari S, Kelly DF, Heath PT, Nadel S, Pollard AJ, Sadarangani M. 2018. Management of suspected paediatric meningitis: a multicentre prospective cohort study. Arch Dis Child, pp. archdischild-2017-313913-archdischild-2017-313913. | Show Abstract | Read more

OBJECTIVE: To quantify delays during management of children with suspected meningitis. DESIGN: Multicentre prospective cohort study. SETTING: Three UK tertiary paediatric centres; June 2011-June 2012 PATIENTS: 388 children aged <16 years hospitalised with suspected meningitis or undergoing lumbar puncture (LP) during sepsis evaluation. MAIN OUTCOME MEASURES: Time of prehospital and in-hospital assessments, LP, antibiotic treatment and discharge; types of prehospital medical assessment and microbiological results. Data collected from hospital records and parental interview. RESULTS: 220/388 (57%) children were seen by a medical professional prehospitalisation (143 by a general practitioner). Median times from initial hospital assessment to LP and antibiotic administration were 4.8 hours and 3.1 hours, respectively; 62% of children had their LP after antibiotic treatment. Median time to LP was shorter for children aged <3 months (3.0 hours) than those aged 3-23 months (6.2 hours, P<0.001) or age ≥2 years (20.3 hours, P<0.001). In meningitis of unknown cause, cerebrospinal fluid (CSF) PCR was performed for meningococcus in 7%, pneumococcus in 10% and enterovirus in 76%. When no pathogen was identified, hospital stay was longer if LP was performed after antibiotics (median 12.5 days vs 5.0 days, P=0.037). CONCLUSIONS: Most children had LP after antibiotics were administered, reducing yield from CSF culture, and PCRs were underused despite national recommendations. These deficiencies reduce the ability to exclude bacterial meningitis, increasing unnecessary hospital stay and antibiotic treatment.

Norheim G, Mueller JE, Njanpop-Lafourcade B-M, Delrieu I, Findlow H, Borrow R, Xie O, Nagaputra J, Ramasamy R, Dold C et al. 2018. Natural immunity against capsular group X N. meningitidis following an outbreak in Togo, 2007. Vaccine, 36 (10), pp. 1297-1303. | Show Abstract | Read more

BACKGROUND: Capsular group X N. meningitidis (MenX) has emerged as a cause of localized disease outbreaks in sub-Saharan Africa, but the human immune response following exposure to MenX antigens is poorly described. We therefore assessed the natural immunity against MenX in individuals who were living in an area affected by a MenX outbreak during 2007 in Togo, West Africa. During 2009, 300 healthy individuals (100 aged 3-5 years, 100 aged 13-19 years and 100 aged 20-25 years) were included in the study, and serum responses were compared with sera from age-matched controls from the U.K. and Burkina Faso. METHODS: MenX serum bactericidal antibody (SBA) was measured using rabbit complement, and antibodies against MenX polysaccharide (XPS) and outer membrane vesicles (XOMVs) were quantified by ELISA. RESULTS: The proportion of Togolese individuals with an SBA titer of ≥8 against the MenX strain was 29% (95% confidence interval (CI) 18-41) among those aged 3-5 years, 34% (95% CI 9-60) among those aged 13-19 years and 32% (95% CI 24-40) among those aged 20-25 years. These were significantly higher than observed in the control populations from the U.K (range 13-16%) and Burkina Faso (range 2-6%). CONCLUSION: In Togolese individuals, the concentration of serum IgG against XPS was higher among the two older age groups as compared to the youngest age group. Antibody concentrations against MenX PS correlated significantly with SBA titers. This supports further development of a MenX PS based conjugate vaccine. Further studies are needed to verify the ability of MenX PS to induce SBA in humans.

Juel HB, Thomaides-Brears HB, Darton TC, Jones C, Jones E, Shrestha S, Sie R, Eustace A, Galal U, Kurupati P et al. 2017. Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model. Front Immunol, 8 (JAN), pp. 1916. | Show Abstract | Read more

Effective vaccines against Salmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of two Salmonella Typhi vaccines, licensed Ty21a or candidate M01ZH09, did not provide full immunity in a controlled human infection model. Here, we describe the human humoral immune responses to these oral vaccines and their functional role in protection after challenge with S. Typhi. Serum, obtained from healthy volunteers before and after vaccination with Ty21a or M01ZH09 or placebo and before and after oral challenge with wild-type S. Typhi, was assessed for bactericidal activity. Single-dose vaccination with M01ZH09 induced an increase in serum bactericidal antibodies (p = 0.001) while three doses of Ty21a did not. No association between bactericidal activity and protection against typhoid after challenge was seen in either vaccine arm. Bactericidal activity after vaccination correlated significantly with delayed disease onset (p = 0.013), lower bacterial burden (p = 0.006), and decreased disease severity scores (p = 0.021). Depletion of antibodies directed against lipopolysaccharide significantly reduced bactericidal activity (p = 0.009). We conclude that antibodies induced after ingestion of oral live-attenuated typhoid vaccines or after challenge with wild-type S. Typhi exhibit bactericidal activity. This bactericidal activity is mediated by anti-O:LPS antibodies and significantly reduces clinical symptoms but does not provide sterile immunity. This directs future vaccine studies toward other antigens or mechanisms of protection against typhoid.

Howson LJ, Napolitani G, Shepherd D, Ghadbane H, Kurupati P, Preciado-Llanes L, Rei M, Dobinson HC, Gibani MM, Teng KWW et al. 2018. MAIT cell clonal expansion and TCR repertoire shaping in human volunteers challenged with Salmonella Paratyphi A. Nat Commun, 9 (1), pp. 253. | Show Abstract | Read more

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)β clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRβ clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes. Our results demonstrate that host exposure to antigen may drive clonal expansion of MAIT cells with increased functional avidity, suggesting a role for specific vaccination strategies to increase the frequency and potency of MAIT cells to optimize effector function.

Trück J, Kelly S, Jawad S, Snape MD, Voysey M, Pollard AJ. 2018. Differences in Immunization Site Pain in Toddlers Vaccinated With Either the 10- or the 13-Valent Pneumococcal Conjugate Vaccine. Pediatr Infect Dis J, 37 (4), pp. e103-e106. | Show Abstract | Read more

BACKGROUND: Immunization site pain is a common and unpleasant experience for both children and adults. It is a source of anxiety and distress and may ultimately result in nonadherence to vaccination schedules. There is limited information on how different brands of vaccines affect the intensity of immediate pain at the time of vaccine injection. METHODS: Children in the United Kingdom (n = 178) were randomized to receive a booster dose of either the 10- or the 13-valent pneumococcal conjugate vaccine (PCV-10 or PCV-13). Immediate immunization site pain was assessed using validated pain assessment tools and crying time to investigate factors that may interfere with parental compliance to vaccination. RESULTS: Pain measurements were available for n ≥ 74 and n ≥ 78 PCV-10 and PCV-13 recipients, respectively. PCV-13 recipients had significantly higher scores on the observer-rated modified behavioral pain scale than did those receiving PCV-10. No significant differences in the induction of pain between the 2 vaccines were found when a parent-rated pain assessment tool or crying time was used. CONCLUSIONS: PCV-10 administration was associated with slightly less acute pain compared with the injection of PCV-13, but the size of the difference was small and is of unknown clinical significance.

Barton AJ, Hill J, Pollard AJ, Blohmke CJ. 2017. Transcriptomics in Human Challenge Models. Front Immunol, 8 (DEC), pp. 1839. | Show Abstract | Read more

Human challenge models, in which volunteers are experimentally infected with a pathogen of interest, provide the opportunity to directly identify both natural and vaccine-induced correlates of protection. In this review, we highlight how the application of transcriptomics to human challenge studies allows for the identification of novel correlates and gives insight into the immunological pathways required to develop functional immunity. In malaria challenge trials for example, innate immune pathways appear to play a previously underappreciated role in conferring protective immunity. Transcriptomic analyses of samples obtained in human challenge studies can also deepen our understanding of the immune responses preceding symptom onset, allowing characterization of innate immunity and early gene signatures, which may influence disease outcome. Influenza challenge studies demonstrate that these gene signatures have diagnostic potential in the context of pandemics, in which presymptomatic diagnosis of at-risk individuals could allow early initiation of antiviral treatment and help limit transmission. Furthermore, gene expression analysis facilitates the identification of host factors contributing to disease susceptibility, such as C4BPA expression in enterotoxigenic Escherichia coli infection. Overall, these studies highlight the exceptional value of transcriptional data generated in human challenge trials and illustrate the broad impact molecular data analysis may have on global health through rational vaccine design and biomarker discovery.

Wilkins AL, Kazmin D, Napolitani G, Clutterbuck EA, Pulendran B, Siegrist C-A, Pollard AJ. 2017. AS03- and MF59-Adjuvanted Influenza Vaccines in Children. Front Immunol, 8 (DEC), pp. 1760. | Show Abstract | Read more

Influenza is a major cause of respiratory disease leading to hospitalization in young children. However, seasonal trivalent influenza vaccines (TIVs) have been shown to be ineffective and poorly immunogenic in this population. The development of live-attenuated influenza vaccines and adjuvanted vaccines are important advances in the prevention of influenza in young children. The oil-in-water emulsions MF59 and adjuvant systems 03 (AS03) have been used as adjuvants in both seasonal adjuvanted trivalent influenza vaccines (ATIVs) and pandemic monovalent influenza vaccines. Compared with non-adjuvanted vaccine responses, these vaccines induce a more robust and persistent antibody response for both homologous and heterologous influenza strains in infants and young children. Evidence of a significant improvement in vaccine efficacy with these adjuvanted vaccines resulted in the use of the monovalent (A/H1N1) AS03-adjuvanted vaccine in children in the 2009 influenza pandemic and the licensure of the seasonal MF59 ATIV for children aged 6 months to 2 years in Canada. The mechanism of action of MF59 and AS03 remains unclear. Adjuvants such as MF59 induce proinflammatory cytokines and chemokines, including CXCL10, but independently of type-1 interferon. This proinflammatory response is associated with improved recruitment, activation and maturation of antigen presenting cells at the injection site. In young children MF59 ATIV produced more homogenous and robust transcriptional responses, more similar to adult-like patterns, than did TIV. Early gene signatures characteristic of the innate immune response, which correlated with antibody titers were also identified. Differences were detected when comparing child and adult responses including opposite trends in gene set enrichment at day 3 postvaccination and, unlike adult data, a lack of correlation between magnitude of plasmablast response at day 7 and antibody titers at day 28 in children. These insights show the utility of novel approaches in understanding new adjuvants and their importance for developing improved influenza vaccines for children.

Pollard AJ, Christensen H. 2017. Trends in meningococcal disease: challenges for vaccine control when disease is rare. Med J Aust, 207 (9), pp. 380-381. | Read more

Sibley A, Fitzpatrick R, Davis E, Sheehan M, Pollard AJ. 2018. The Family Context of Assent: Comparison of Child and Parent Perspectives on Familial Decision-Making Children & Society, 32 (4), pp. 266-278. | Read more

Darton TC, Jones C, Dongol S, Voysey M, Blohmke CJ, Shrestha R, Karkey A, Shakya M, Arjyal A, Waddington CS et al. 2017. Assessment and Translation of the Antibody-in-Lymphocyte Supernatant (ALS) Assay to Improve the Diagnosis of Enteric Fever in Two Controlled Human Infection Models and an Endemic Area of Nepal. Front Microbiol, 8 (OCT), pp. 2031. | Show Abstract | Read more

New diagnostic tests for enteric fever are urgently needed to assist with timely antimicrobial treatment of patients and to measure the efficacy of prevention measures such as vaccination. In a novel translational approach, here we use two recently developed controlled human infection models (CHIM) of enteric fever to evaluate an antibody-in-lymphocyte supernatant (ALS) assay, which can detect recent IgA antibody production by circulating B cells in ex vivo mononuclear cell culture. We calculated the discriminative ability of the ALS assay to distinguish diagnosed cases in the two CHIM studies in Oxford, prior to evaluating blood culture-confirmed diagnoses of patients presenting with fever to hospital in an endemic areas of Kathmandu, Nepal. Antibody responses to membrane preparations and lipopolysaccharide provided good sensitivity (>90%) for diagnosing systemic infection after oral challenge with Salmonella Typhi or S. Paratyphi A. Assay specificity was moderate (~60%) due to imperfect sensitivity of blood culture as the reference standard and likely unrecognized subclinical infection. These findings were augmented through the translation of the assay into the endemic setting in Nepal. Anti-MP IgA responses again exhibited good sensitivity (86%) but poor specificity (51%) for detecting blood culture-confirmed enteric fever cases (ROC AUC 0.79, 95%CI 0.70-0.88). Patients with anti-MP IgA ALS titers in the upper quartile exhibited a clinical syndrome synonymous with enteric fever. While better reference standards are need to assess enteric fever diagnostics, routine use of this ALS assay could be used to rule out infection and has the potential to double the laboratory detection rate of enteric fever in this setting over blood culture alone.

Voysey M, Fanshawe TR, Kelly DF, O'Brien KL, Kandasamy R, Shrestha S, Thorson S, Hinds J, Pollard AJ. 2018. Serotype-Specific Correlates of Protection for Pneumococcal Carriage: An Analysis of Immunity in 19 Countries. Clin Infect Dis, 66 (6), pp. 913-920. | Show Abstract | Read more

Background: Pneumococcal conjugate vaccines (PCVs) provide direct protection against disease in those vaccinated, and interrupt transmission through the prevention of nasopharyngeal (NP) carriage. Methods: We analyzed immunogenicity data from 5224 infants who received PCV in prime-boost schedules. We defined any increase in antibody between the 1-month postpriming visit and the booster dose as an indication of NP carriage ("seroincidence"). We calculated antibody concentrations using receiver operating characteristic curves, and used generalized additive models to compute their protective efficacy against seroincidence. To support seroincidence as a marker of carriage, we compared seroincidence in a randomized immunogenicity trial in Nepal with the serotype-specific prevalence of carriage in the same community. Results: In Nepalese infants, seroincidence of carriage closely correlated with serotype-specific carriage prevalence in the community. In the larger data set, antibody concentrations associated with seroincidence were lowest for serotypes 6B and 23F (0.50 µg/mL and 0.63 µg/mL, respectively), and highest for serotypes 19F and 14 (2.54 µg/mL and 2.48 µg/mL, respectively). The protective efficacy of antibody at these levels was 62% and 74% for serotypes 6B and 23F, and 87% and 84% for serotypes 19F and 14. Protective correlates were on average 2.15 times higher in low/lower middle-income countries than in high/upper middle-income countries (geometric mean ratio, 2.15 [95% confidence interval, 1.46-3.17]; P = .0024). Conclusions: Antibody concentrations associated with protection vary between serotypes. Higher antibody concentrations are required for protection in low-income countries. These findings are important for global vaccination policy, to interrupt transmission by protecting against carriage.

Sadarangani M, Sell T, Iro MA, Snape MD, Voysey M, Finn A, Heath PT, Bona G, Esposito S, Diez-Domingo J et al. 2017. Persistence of immunity after vaccination with a capsular group B meningococcal vaccine in 3 different toddler schedules. CMAJ, 189 (41), pp. E1276-E1285. | Show Abstract | Read more

BACKGROUND: One schedule for the capsular group B meningococcal vaccine 4CMenB is 2 doses that are administered 2 months apart for children aged 12-23 months, with a booster dose 12-24 months later. Our objective was to provide data on persistence of human serum bactericidal antibody (hSBA) titres in children up to 4 years of age after initial doses at 12-24 months, and immunogenicity of a booster dose at 48 months of age compared with vaccine-naive children. METHODS: Children previously immunized, as part of a randomized controlled trial, with 2 doses of 4CMenB vaccine at 12-24 months of age received a booster at 4 years of age. Vaccine-naive age-matched toddlers received 2 doses of 4CMenB. Human serum bactericidal antibody titres against reference strains H44/76, 5/99, NZ98/254 and M10713 were evaluated before and after innoculation with 4CMenB vaccine in 4-year-old children. RESULTS: Of 332 children in the study, 123 had previously received 4CMenB and 209 were vaccine-naive controls. Before the booster, the proportions of participants (previously vaccinated groups compared with controls) with hSBA titres of 1:5 or more were as follows: 9%-11% v. 1% (H44/76), 84%-100% v. 4% (5/99), 0%-18% v. 0% (NZ98/254) and 59%-60% v. 60% (M10713). After 1 dose of 4CMenB in previously immunized children, the proportions of participants achieving hSBA titres of 1:5 or more were 100% (H44/76 and 5/99), 70%-100% (NZ98/254) and 90%-100% (M10713). INTERPRETATION: We found that waning of hSBA titres by 4 years of age occurred after 2 doses of 4CMenB vaccine administered at 12-24 months, and doses at 12-24 months have a priming effect on the immune system. A booster may be necessary to maintain hSBA titres of 1:5 or more among those children with increased disease risk. Trial registration: ClinicalTrials.gov, no. NCT01717638.

Blohmke CJ, Hill J, Darton TC, Carvalho-Burger M, Eustace A, Jones C, Schreiber F, Goodier MR, Dougan G, Nakaya HI, Pollard AJ. 2017. Induction of Cell Cycle and NK Cell Responses by Live-Attenuated Oral Vaccines against Typhoid Fever. Front Immunol, 8 (OCT), pp. 1276. | Show Abstract | Read more

The mechanisms by which oral, live-attenuated vaccines protect against typhoid fever are poorly understood. Here, we analyze transcriptional responses after vaccination with Ty21a or vaccine candidate, M01ZH09. Alterations in response profiles were related to vaccine-induced immune responses and subsequent outcome after wild-type Salmonella Typhi challenge. Despite broad genetic similarity, we detected differences in transcriptional responses to each vaccine. Seven days after M01ZH09 vaccination, marked cell cycle activation was identified and associated with humoral immunogenicity. By contrast, vaccination with Ty21a was associated with NK cell activity and validated in peripheral blood mononuclear cell stimulation assays confirming superior induction of an NK cell response. Moreover, transcriptional signatures of amino acid metabolism in Ty21a recipients were associated with protection against infection, including increased incubation time and decreased severity. Our data provide detailed insight into molecular immune responses to typhoid vaccines, which could aid the rational design of improved oral, live-attenuated vaccines against enteric pathogens.

Iro MA, Martin NG, Absoud M, Pollard AJ. 2017. Intravenous immunoglobulin for the treatment of childhood encephalitis. Cochrane Database Syst Rev, 10 (10), pp. CD011367. | Show Abstract | Read more

BACKGROUND: Encephalitis is a syndrome of neurological dysfunction due to inflammation of the brain parenchyma, caused by an infection or an exaggerated host immune response, or both. Attenuation of brain inflammation through modulation of the immune response could improve patient outcomes. Biological agents such as immunoglobulin that have both anti-inflammatory and immunomodulatory properties may therefore be useful as adjunctive therapies for people with encephalitis. OBJECTIVES: To assess the efficacy and safety of intravenous immunoglobulin (IVIG) as add-on treatment for children with encephalitis. SEARCH METHODS: The Cochrane Multiple Sclerosis and Rare Diseases of the CNS group's Information Specialist searched the following databases up to 30 September 2016: CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, and the WHO ICTRP Search Portal. In addition, two review authors searched Science Citation Index Expanded (SCI-EXPANDED) & Conference Proceedings Citation Index - Science (CPCI-S) (Web of Science Core Collection, Thomson Reuters) (1945 to January 2016), Global Health Library (Virtual Health Library), and Database of Abstracts of Reviews of Effects (DARE). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing IVIG in addition to standard care versus standard care alone or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently selected articles for inclusion, extracted relevant data, and assessed quality of trials. We resolved disagreements by discussion among the review authors. Where possible, we contacted authors of included studies for additional information. We presented results as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). MAIN RESULTS: The search identified three RCTs with 138 participants. All three trials included only children with viral encephalitis, one of these included only children with Japanese encephalitis, a specific form of viral encephalitis. Only the trial of Japanese encephalitis (22 children) contributed to the primary outcome of this review and follow-up in that study was for three to six months after hospital discharge. There was no follow-up of participants in the other two studies. We identified one ongoing trial.For the primary outcomes, the results showed no significant difference between IVIG and placebo when used in the treatment of children with Japanese encephalitis: significant disability (RR 0.75, 95% CI 0.22 to 2.60; P = 0.65) and serious adverse events (RR 1.00, 95% CI 0.07 to 14.05; P = 1.00).For the secondary outcomes, the study of Japanese encephalitis showed no significant difference between IVIG and placebo when assessing significant disability at hospital discharge (RR 1.00, 95% CI 0.60 to 1.67). There was no significant difference (P = 0.53) in Glasgow Coma Score at discharge between IVIG (median score 14; range 3 to 15) and placebo (median 14 score; range 7 to 15) in the Japanese encephalitis study. The median length of hospital stay in the Japanese encephalitis study was similar for IVIG-treated (median 13 days; range 9 to 21) and placebo-treated (median 12 days; range 6 to 18) children (P = 0.59).Pooled analysis of the results of the other two studies resulted in a significantly lower mean length of hospital stay (MD -4.54 days, 95% CI -7.47 to -1.61; P = 0.002), time to resolution of fever (MD -0.97 days, 95% CI -1.25 to -0.69; P < 0.00001), time to stop spasms (MD -1.49 days, 95% CI -1.97 to -1.01; P < 0.00001), time to regain consciousness (MD -1.10 days, 95% CI -1.48 to -0.72; P < 0.00001), and time to resolution of neuropathic symptoms (MD -3.20 days, 95% CI -3.34 to -3.06; P < 0.00001) in favour of IVIG when compared with standard care.None of the included studies reported other outcomes of interest in this review including need for invasive ventilation, duration of invasive ventilation, cognitive impairment, poor adaptive functioning, quality of life, number of seizures, and new diagnosis of epilepsy.The quality of evidence was very low for all outcomes of this review. AUTHORS' CONCLUSIONS: The findings suggest a clinical benefit of adjunctive IVIG treatment for children with viral encephalitis for some clinical measures (i.e. mean length of hospital stay, time (days) to stop spasms, time to regain consciousness, and time to resolution of neuropathic symptoms and fever. For children with Japanese encephalitis, IVIG had a similar effect to placebo when assessing significant disability and serious adverse events.Despite these findings, the risk of bias in the included studies and quality of the evidence make it impossible to reach any firm conclusions on the efficacy and safety of IVIG as add-on treatment for children with encephalitis. Furthermore, the included studies involved only children with viral encephalitis, therefore findings of this review cannot be generalised to all forms of encephalitis. Future well-designed RCTs are needed to assess the efficacy and safety of IVIG in the management of children with all forms of encephalitis. There is a need for internationally agreed core outcome measures for clinical trials in childhood encephalitis.

Jin C, Gibani MM, Moore M, Juel HB, Jones E, Meiring J, Harris V, Gardner J, Nebykova A, Kerridge SA et al. 2017. Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet, 390 (10111), pp. 2472-2480. | Show Abstract | Read more

BACKGROUND: Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi. METHODS: In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing. FINDINGS: Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group). INTERPRETATION: Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality. FUNDING: The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).

Darton TC, Baker S, Randall A, Dongol S, Karkey A, Voysey M, Carter MJ, Jones C, Trappl K, Pablo J et al. 2017. Identification of Novel Serodiagnostic Signatures of Typhoid Fever Using a Salmonella Proteome Array. Front Microbiol, 8 (SEP), pp. 1794. | Show Abstract | Read more

Current diagnostic tests for typhoid fever, the disease caused by Salmonella Typhi, are poor. We aimed to identify serodiagnostic signatures of typhoid fever by assessing microarray signals to 4,445 S. Typhi antigens in sera from 41 participants challenged with oral S. Typhi. We found broad, heterogeneous antibody responses with increasing IgM/IgA signals at diagnosis. In down-selected 250-antigen arrays we validated responses in a second challenge cohort (n = 30), and selected diagnostic signatures using machine learning and multivariable modeling. In four models containing responses to antigens including flagellin, OmpA, HlyE, sipC, and LPS, multi-antigen signatures discriminated typhoid (n = 100) from other febrile bacteremia (n = 52) in Nepal. These models contained combinatorial IgM, IgA, and IgG responses to 5 antigens (ROC AUC, 0.67 and 0.71) or 3 antigens (0.87), although IgA responses to LPS also performed well (0.88). Using a novel systematic approach we have identified and validated optimal serological diagnostic signatures of typhoid fever.

Voysey M, Pollard AJ, Sadarangani M, Fanshawe TR. 2017. Prevalence and decay of maternal pneumococcal and meningococcal antibodies: A meta-analysis of type-specific decay rates. Vaccine, 35 (43), pp. 5850-5857. | Show Abstract | Read more

BACKGROUND: At the time of an infant's initial vaccination at age ∼2 to 3months, some infants already have maternal antibodies against vaccine antigens and these can suppress the immune response to vaccination. Modelling the effects of maternal antibody and the timing of infant doses on the antibody response to vaccination, requires estimates of the rate of maternal antibody decay. Decay rates are not well characterised in the medical literature. We investigated variation in the prevalence of maternal anti-capsular pneumococcal and meningococcal antibodies in infants in 14 countries, and estimated type-specific half-lives. METHODS: Individual participant serological data were obtained from clinical trials. Half-lives were estimated from antibody concentrations in infants who did not receive meningococcal or pneumococcal vaccines. RESULTS: The seroprevalence of maternal pneumococcal antibodies was highest for serotypes 14, and 19F (92% and 80% respectively) and lowest for serotypes 4 and 1 (30% and 34% respectively). Half-life estimates ranged from 38.7days (95% CI 36.6-41.0) for serotype 6B, to 48.3days (95% CI 46.7-50.2) for serotype 5. The overall half-life was 42.6days (95% CI 41.5-43.7). Seroprevalence was highest in Mali, Nigeria, India, and the Philippines, (all >65%) and lowest in the Czech Republic and Finland (both <45%). In studies of meningococcal vaccines, seroprevalence was 13% for group C (half-life 39.8days, 95% CI 33.4-49.4) and 43% for group A (half-life 43.1days 95% CI 39.8-47.2). CONCLUSION: Substantial proportions of infants in many countries have antibodies to vaccine serotypes of pneumococcus, however fewer infants have maternally acquired antibodies to groups A and C meningococcus. Passively-acquired antibodies to capsular polysaccharides decay with a half-life of approximately 6weeks. These estimates are useful for modelling the impact of proposed vaccination programmes, and consideration of schedules with a delayed start.

Meiring JE, Gibani M, TyVAC Consortium Meeting Group:. 2017. The Typhoid Vaccine Acceleration Consortium (TyVAC): Vaccine effectiveness study designs: Accelerating the introduction of typhoid conjugate vaccines and reducing the global burden of enteric fever. Report from a meeting held on 26-27 October 2016, Oxford, UK. Vaccine, 35 (38), pp. 5081-5088. | Show Abstract | Read more

Typhoid fever is estimated to cause between 11.9-26.9 million infections globally each year with 129,000-216,510 deaths. Access to improved water sources have reduced disease incidence in parts of the world but the use of efficacious vaccines is seen as an important public health tool for countries with a high disease burden. A new generation of Vi typhoid conjugate vaccines (TCVs), licensed for use in young children and expected to provide longer lasting protection than previous vaccines, are now available. The WHO Strategic Advisory Group of Experts on Immunization (SAGE) has convened a working group to review the evidence on TCVs and produce an updated WHO position paper for all typhoid vaccines in 2018 that will inform Gavi, the Vaccine Alliance's future vaccine investment strategies for TCVs. The Typhoid Vaccine Acceleration Consortium (TyVAC) has been formed through a $36.9 million funding program from the Bill & Melinda Gates Foundation to accelerate the introduction of TCVs into Gavi-eligible countries. In October 2016, a meeting was held to initiate planning of TCV effectiveness studies that will provide the data required by policy makers and stakeholders to support decisions on TCV use in countries with a high typhoid burden. Discussion topics included (1) the latest evidence and data gaps in typhoid epidemiology; (2) WHO and Gavi methods and data requirements; (3) data on TCV efficacy; (4) cost effectiveness analysis for TCVs from mathematical models; (5) TCV delivery and effectiveness study design. Specifically, participants were asked to comment on study design in 3 sites for which population-based typhoid surveillance is underway. The conclusion of the meeting was that country-level decision making would best be informed by the respective selected sites in Africa and Asia vaccinating children aged from 9-months to 15-years-old, employing either an individual or cluster randomized design with design influenced by population characteristics, transmission dynamics, and statistical considerations.

de Graaf H, Sukhtankar P, Arch B, Ahmad N, Lees A, Bennett A, Spowart C, Hickey H, Jeanes A, Armon K et al. 2017. Duration of intravenous antibiotic therapy for children with acute osteomyelitis or septic arthritis: a feasibility study. Health Technol Assess, 21 (48), pp. 1-164. | Show Abstract | Read more

BACKGROUND: There is little current consensus regarding the route or duration of antibiotic treatment for acute osteomyelitis (OM) and septic arthritis (SA) in children. OBJECTIVE: To assess the overall feasibility and inform the design of a future randomised controlled trial (RCT) to reduce the duration of intravenous (i.v.) antibiotic use in paediatric OM and SA. DESIGN: (1) A prospective service evaluation (cohort study) to determine the current disease spectrum and UK clinical practice in paediatric OM/SA; (2) a prospective cohort substudy to assess the use of targeted polymerase chain reaction (PCR) in diagnosing paediatric OM/SA; (3) a qualitative study to explore families' views and experiences of OM/SA; and (4) the development of a core outcome set via a systematic review of literature, Delphi clinician survey and stakeholder consensus meeting. SETTING: Forty-four UK secondary and tertiary UK centres (service evaluation). PARTICIPANTS: Children with OM/SA. INTERVENTIONS: PCR diagnostics were compared with culture as standard of care. Semistructured interviews were used in the qualitative study. RESULTS: Data were obtained on 313 cases of OM/SA, of which 218 (61.2%) were defined as simple disease and 95 (26.7%) were defined as complex disease. The epidemiology of paediatric OM/SA in this study was consistent with existing European data. Children who met oral switch criteria less than 7 days from starting i.v. antibiotics were less likely to experience treatment failure (9.6%) than children who met oral switch criteria after 7 days of i.v. therapy (16.1% when switch was between 1 and 2 weeks; 18.2% when switch was > 2 weeks). In 24 out of 32 simple cases (75%) and 8 out of 12 complex cases (67%) in which the targeted PCR was used, a pathogen was detected. The qualitative study demonstrated the importance to parents and children of consideration of short- and long-term outcomes meaningful to families themselves. The consensus meeting agreed on the following outcomes: rehospitalisation or recurrence of symptoms while on oral antibiotics, recurrence of infection, disability at follow-up, symptom free at 1 year, limb shortening or deformity, chronic OM or arthritis, amputation or fasciotomy, death, need for paediatric intensive care, and line infection. Oral switch criteria were identified, including resolution of fever for ≥ 48 hours, tolerating oral food and medicines, and pain improvement. LIMITATIONS: Data were collected in a 6-month period, which might not have been representative, and follow-up data for long-term complications are limited. CONCLUSIONS: A future RCT would need to recruit from all tertiary and most secondary UK hospitals. Clinicians have implemented early oral switch for selected patients with simple disease without formal clinical trial evidence of safety. However, the current criteria by which decisions to make the oral switch are made are not clearly established or evidence based. FUTURE WORK: A RCT in simple OM and SA comparing shorter- or longer-course i.v. therapy is feasible in children randomised after oral switch criteria are met after 7 days of i.v. therapy, excluding children meeting oral switch criteria in the first week of i.v. therapy. This study design meets clinician preferences and addresses parental concerns not to randomise prior to oral switch criteria being met. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Sheerin D, Openshaw PJ, Pollard AJ. 2017. Issues in vaccinology: Present challenges and future directions. Eur J Immunol, 47 (12), pp. 2017-2025. | Show Abstract | Read more

Vaccination is a principal and highly cost-effective means of controlling infectious diseases, providing direct protection against pathogens by conferring long-lasting immunological memory and inducing population-level herd immunity. Despite rapid ongoing progress in vaccinology, there remain many obstacles to the development and deployment of novel or improved vaccines; these include the underlying science of how to induce and sustain appropriate protective immune responses as well as bureaucratic, logistic and socio-political hurdles. The failure to distribute and administer existing vaccines to at-risk communities continues to account for a large proportion of infant mortality worldwide: almost 20 million children do not have access to basic vaccines and several million still die each year as a result. While emerging epidemic or pandemic diseases pose a significant threat to global health and prosperity, there are many infectious diseases which provide a continuous or cyclical burden on healthcare systems which also need to be addressed. Gaps in knowledge of the human immune system stand in the way of developing technologies to overcome individual and pathogenic variation. The challenges in tackling infectious disease and directions that the field of preventive medicine may take to improve the current picture of global health are the focus of this review.

Weissmueller NT, Marsay L, Schiffter HA, Carlisle RC, Rollier CS, Prud'homme RK, Pollard AJ. 2017. Alternative vaccine administration by powder injection: Needle-free dermal delivery of the glycoconjugate meningococcal group Y vaccine. PLoS One, 12 (8), pp. e0183427. | Show Abstract | Read more

Powder-injectors use gas propulsion to deposit lyophilised drug or vaccine particles in the epidermal and sub epidermal layers of the skin. We prepared dry-powder (Tg = 45.2 ± 0.5°C) microparticles (58.1 μm) of a MenY-CRM197 glyconjugate vaccine (0.5% wt.) for intradermal needle-free powder injection (NFPI). SFD used ultrasound atomisation of the liquid vaccine-containing excipient feed, followed by lyophilisation above the glass transition temperature (Tg' = - 29.9 ± 0.3°C). This resulted in robust particles (density~ 0.53 ±0.09 g/cm3) with a narrow volume size distribution (mean diameter 58.1 μm, and span = 1.2), and an impact parameter (ρvr ~ 11.5 kg/m·s) sufficient to breach the Stratum corneum (sc). The trehalose, manitol, dextran (10 kDa), dextran (150 kDa) formulation, or TMDD (3:3:3:1), protected the MenY-CRM197 glyconjugate during SFD with minimal loss, no detectable chemical degradation or physical aggregation. In a capsular group Y Neisseria meningitidis serum bactericidal assay (SBA) with human serum complement, the needle free vaccine, which contained no alum adjuvant, induced functional protective antibody responses in vivo of similar magnitude to the conventional vaccine injected by hypodermic needle and syringe and containing alum adjuvant. These results demonstrate that needle-free vaccination is both technically and immunologically valid, and could be considered for vaccines in development.

Cromer D, van Hoek AJ, Newall AT, Pollard AJ, Jit M. 2017. Burden of paediatric respiratory syncytial virus disease and potential effect of different immunisation strategies: a modelling and cost-effectiveness analysis for England. Lancet Public Health, 2 (8), pp. e367-e374. | Show Abstract | Read more

BACKGROUND: Vaccines and prophylactic antibodies against respiratory syncytial virus (RSV) are in development and likely to be available in the next 5-10 years. The most efficient way to use these products when they become available is an important consideration for public health decision makers. METHODS: We performed a multivariate regression analysis to estimate the burden of RSV in children younger than 5 years in England (UK), a representative high-income temperate country, and used these results to assess the potential effect of different RSV immunisation strategies (targeting vaccination for infants, or pregnant women, or prophylactic antibodies for neonates). We did a cost-effectiveness analysis for these strategies, implemented either separately or concurrently, and assessed the effect of restricting vaccination to certain months of the year. FINDINGS: We estimated that RSV is responsible for 12 primary care consultations (95% CI 11·9-12·1) and 0·9 admissions to hospital annually per 100 children younger than 5 years (95% CI 0·89-0·90), with the major burden occurring in infants younger than 6 months. The most cost-effective strategy was to selectively immunise all children born before the start of the RSV season (maximum price of £220 [95% uncertainty interval (UI) 208-232] per vaccine, for an incremental cost-effectiveness ratio of £20 000 per quality-adjusted life-year). The maximum price per fully protected person that should be paid for the infant, newborn, and maternal strategies without seasonal restrictions was £192 (95% UI 168-219), £81 (76-86), and £54 (51-57), respectively. INTERPRETATION: Nearly double the number of primary care consultations, and nearly five times the number of admissions to hospital occurred with RSV compared with influenza. RSV vaccine and antibody strategies are likely to be cost-effective if they can be priced below around £200 per fully protected person. A seasonal vaccination strategy is likely to provide the most direct benefits. Herd effects might render a year-round infant vaccination strategy more appealing, although it is currently unclear whether such a programme would induce herd effects. FUNDING: UK National Institute for Health Research.

Tran Vu Thieu N, Trinh Van T, Tran Tuan A, Klemm EJ, Nguyen Ngoc Minh C, Voong Vinh P, Pham Thanh D, Ho Ngoc Dan T, Pham Duc T, Langat P et al. 2017. An evaluation of purified Salmonella Typhi protein antigens for the serological diagnosis of acute typhoid fever. J Infect, 75 (2), pp. 104-114. | Show Abstract | Read more

OBJECTIVES: The diagnosis of typhoid fever is a challenge. Aiming to develop a typhoid diagnostic we measured antibody responses against Salmonella Typhi (S. Typhi) protein antigens and the Vi polysaccharide in a cohort of Bangladeshi febrile patients. METHODS: IgM against 12 purified antigens and the Vi polysaccharide was measured by ELISA in plasma from patients with confirmed typhoid fever (n = 32), other confirmed infections (n = 17), and healthy controls (n = 40). ELISAs with the most specific antigens were performed on plasma from 243 patients with undiagnosed febrile disease. RESULTS: IgM against the S. Typhi protein antigens correlated with each other (rho > 0.8), but not against Vi (rho < 0.6). Typhoid patients exhibited higher IgM against 11/12 protein antigens and Vi than healthy controls and those with other infections. Vi, PilL, and CdtB exhibited the greatest sensitivity and specificity. Specificity and sensitivity was improved when Vi was combined with a protein antigen, generating sensitivities and specificities of 0.80 and >0.85, respectively. Applying a dynamic cut-off to patients with undiagnosed febrile disease suggested that 34-58% had an IgM response indicative of typhoid. CONCLUSIONS: We evaluated the diagnostic potential of several S. Typhi antigens; our assays give good sensitivity and specificity, but require further assessment in differing patient populations.

Darton TC, Meiring JE, Tonks S, Khan MA, Khanam F, Shakya M, Thindwa D, Baker S, Basnyat B, Clemens JD et al. 2017. The STRATAA study protocol: a programme to assess the burden of enteric fever in Bangladesh, Malawi and Nepal using prospective population census, passive surveillance, serological studies and healthcare utilisation surveys. BMJ Open, 7 (6), pp. e016283. | Show Abstract | Read more

INTRODUCTION: Invasive infections caused by Salmonella enterica serovar Typhi and Paratyphi A are estimated to account for 12-27 million febrile illness episodes worldwide annually. Determining the true burden of typhoidal Salmonellae infections is hindered by lack of population-based studies and adequate laboratory diagnostics.The Strategic Typhoid alliance across Africa and Asia study takes a systematic approach to measuring the age-stratified burden of clinical and subclinical disease caused by typhoidal Salmonellae infections at three high-incidence urban sites in Africa and Asia. We aim to explore the natural history of Salmonella transmission in endemic settings, addressing key uncertainties relating to the epidemiology of enteric fever identified through mathematical models, and enabling optimisation of vaccine strategies. METHODS/DESIGN: Using census-defined denominator populations of ≥100 000 individuals at sites in Malawi, Bangladesh and Nepal, the primary outcome is to characterise the burden of enteric fever in these populations over a 24-month period. During passive surveillance, clinical and household data, and laboratory samples will be collected from febrile individuals. In parallel, healthcare utilisation and water, sanitation and hygiene surveys will be performed to characterise healthcare-seeking behaviour and assess potential routes of transmission. The rates of both undiagnosed and subclinical exposure to typhoidal Salmonellae (seroincidence), identification of chronic carriage and population seroprevalence of typhoid infection will be assessed through age-stratified serosurveys performed at each site. Secondary attack rates will be estimated among household contacts of acute enteric fever cases and possible chronic carriers. ETHICS AND DISSEMINATION: This protocol has been ethically approved by the Oxford Tropical Research Ethics Committee, the icddr,b Institutional Review Board, the Malawian National Health Sciences Research Committee and College of Medicine Research Ethics Committee and Nepal Health Research Council. The study is being conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained before study enrolment. Results will be submitted to international peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN 12131979. ETHICS REFERENCES: Oxford (Oxford Tropical Research Ethics Committee 39-15).Bangladesh (icddr,b Institutional Review Board PR-15119).Malawi (National Health Sciences Research Committee 15/5/1599).Nepal (Nepal Health Research Council 306/2015).

Nickless A, Galiza EP, Pollard AJ, Drysdale SB. 2017. Benchmarking of Viral Bronchiolitis Management by General Practitioners in the United Kingdom PEDIATRIC ALLERGY IMMUNOLOGY AND PULMONOLOGY, 30 (2), pp. 69-73. | Show Abstract | Read more

© Copyright 2017, Mary Ann Liebert, Inc. 2017. Viral bronchiolitis is the leading cause of hospitalization in infants in the United Kingdom (UK) with wide variation in rates of hospitalization in different geographical regions of the UK. A potential cause of these differences is variation in primary care management and referral to hospital. This study aimed to prospectively survey general practitioners (GPs) in the UK to provide a benchmark of practice against which future practice can be assessed. An electronic, structured questionnaire was sent to 1,001 geographically representative GPs in primary care centers in the UK, through the market research company MedeConnect, to assess their management of infants with viral bronchiolitis. We measured practice before the 2015 National Institute for Health and Care Excellence (NICE) bronchiolitis guideline against the guideline, to obtain a benchmark of practice. We also used a multivariate analysis to assess GP factors associated with variation in management. Thirty-nine percent of GPs did not refer to any guideline to manage infants with bronchiolitis, 33% did not routinely measure oxygen saturations, 48% prescribed an "inappropriate" (evidence of no benefit) medication, and 62% did not give written guidance to parents. GP factors influencing management included the year the GP qualified, sex, region of practice, and working at a dispensing practice. Up to 75% of GPs' management did not conform to the newly published 2015 NICE bronchiolitis guideline before its publication. There was wide variation in the management of infants with viral bronchiolitis by UK GPs. Most infants with viral bronchiolitis are not managed optimally by GPs and multiple GP factors influenced this management.

Iro MA, Snape MD, Voysey M, Jawad S, Finn A, Heath PT, Bona G, Esposito S, Diez-Domingo J, Prymula R et al. 2017. Corrigendum to "Persistence of bactericidal antibodies following booster vaccination with 4CMenB at 12, 18 or 24months and immunogenicity of a fifth dose administered at 4years of age-a phase 3 extension to a randomised controlled trial" [Vaccine 35 (2017) 395-402]. Vaccine, 35 (24), pp. 3279. | Show Abstract | Read more

© 2017 The Author(s) The authors regret that since the publication of this paper, they have discovered an error in the Conclusion of the Abstract. The corrected Conclusion is listed below. The authors would also like to correct the name of Dr. Miguel Tortajada-Girbés in The European Men B vaccine study group section. Conclusion: Waning of protective antibodies occurred 24–36 months after toddler booster regardless of age at boost. This was least marked against target strains 5/99 and M10713. A robust memory response occurred after a booster dose given at 4 years of age. The authors would like to apologise for any inconvenience caused.

Wang NY, Pollard AJ. 2018. The next chapter for group B meningococcal vaccines. Crit Rev Microbiol, 44 (1), pp. 95-111. | Show Abstract | Read more

The majority of invasive meningococcal disease (IMD) in the developed world is caused by capsular group B Neisseria meningitidis, however success with vaccination against organisms bearing this capsule has previously been restricted to control of geographically limited clonal outbreaks. As we enter a new era, with the first routine program underway to control endemic group B meningococcal disease for infants in the UK, it is timely to review the key landmarks in group B vaccine development, and discuss the issues determining whether control of endemic group B disease will be achieved. Evidence of a reduction in carriage acquisition of invasive group B meningococcal strains, after vaccination among adolescents, is imperative if routine immunization is to drive population control of disease beyond those who are vaccinated (i.e. through herd immunity). The need for multiple doses to generate a sufficiently protective response and reactogenicity remain significant problems with the new generation of vaccines. Despite these limitations, early data from the UK indicate that new group B meningococcal vaccines have the potential to have a major impact on meningococcal disease, and to provide new insight into how we might do better in the future.

Voysey M, Kelly DF, Fanshawe TR, Sadarangani M, O'Brien KL, Perera R, Pollard AJ. 2017. The Influence of Maternally Derived Antibody and Infant Age at Vaccination on Infant Vaccine Responses : An Individual Participant Meta-analysis. JAMA Pediatr, 171 (7), pp. 637-646. | Show Abstract | Read more

Importance: The design of infant immunization schedules requires an understanding of the factors that determine the immune response to each vaccine antigen. Data Sources: Deidentified individual participant data from GlaxoSmithKline clinical trials were obtained through Clinical Study Data Request. The data were requested on January 2, 2015, and final data were received on April 11, 2016. Study Selection: Immunogenicity trials of licensed or unlicensed vaccines administered to infants were included if antibody concentrations in infants were measured prior to the first dose of vaccine. Data Extraction and Synthesis: The database was examined; studies that appeared to have appropriate data were reviewed. Main Outcomes and Measures: Antigen-specific antibody concentration measured 1 month after priming vaccine doses, before booster vaccination, and 1 month after booster vaccine doses. Results: A total of 7630 infants from 32 studies in 17 countries were included. Mean (SD) age at baseline was 9.0 (2.3) weeks; 3906 (51.2%) were boys. Preexisting maternal antibody inhibited infant antibody responses to priming doses for 20 of 21 antigens. The largest effects were observed for inactivated polio vaccine, where 2-fold higher maternal antibody concentrations resulted in 20% to 28% lower postvaccination antibody concentration (geometric mean ratios [GMRs], type 1: 0.80; 95% CI, 0.78-0.83; type 2: 0.72; 95% CI, 0.69-0.74; type 3: 0.78; 95% CI, 0.75-0.82). For acellular pertussis antigens, 2-fold higher maternal antibody was associated with 11% lower postvaccination antibody for pertussis toxoid (GMR, 0.89; 95% CI, 0.87-0.90) and filamentous hemagglutinin (GMR, 0.89; 95% CI, 0.88-0.90) and 22% lower pertactin antibody (GMR, 0.78; 95% CI, 0.77-0.80). For tetanus and diphtheria, these estimates were 13% (GMR, 0.87; 95% CI, 0.86-0.88) and 24% (GMR, 0.76; 95% CI, 0.74-0.77), respectively. The influence of maternal antibody was still evident in reduced responses to booster doses of acellular pertussis, inactivated polio, and diphtheria vaccines at 12 to 24 months of age. Children who were older when first immunized had higher antibody responses to priming doses for 18 of 21 antigens, after adjusting for the effect of maternal antibody concentrations. The largest effect was seen for polyribosylribitol phosphate antibody, where responses were 71% higher per month (GMR, 1.71; 95% CI, 1.52-1.92). Conclusions and Relevance: Maternal antibody concentrations and infant age at first vaccination both influence infant vaccine responses. These effects are seen for almost all vaccines contained in global immunization programs and influence immune response for some vaccines even at the age of 24 months. These data highlight the potential for maternal immunization strategies to influence established infant programs.

Pollard AJ, Finn A, Curtis N. 2017. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child, 102 (11), pp. 1077-1081. | Show Abstract | Read more

Non-specific effects (NSE) or heterologous effects of vaccines are proposed to explain observations in some studies that certain vaccines have an impact beyond the direct protection against infection with the specific pathogen for which the vaccines were designed. The importance and implications of such effects remain controversial. There are several known immunological mechanisms which could lead to NSE, since it is widely recognised that the generation of specific immunity is initiated by non-specific innate immune mechanisms that may also have wider effects on adaptive immune function. However, there are no published studies that demonstrate a mechanistic link between such immunological phenomena and clinically relevant NSE in humans. While it is highly plausible that some vaccines do have NSE, their magnitude and duration, and thus importance, remain uncertain. Although the WHO recently concluded that current evidence does not justify changes to immunisation policy, further studies of sufficient size and quality are needed to assess the importance of NSE for all-cause mortality. This could provide insights into vaccine immunobiology with important implications for infant health and survival.

Trück J, Thompson A, Morales-Aza B, Clutterbuck EA, Voysey M, Clarke E, Snape MD, Kelly DF, Finn A, Pollard AJ. 2017. Memory B cell response to a PCV-13 booster in 3.5year old children primed with either PCV-7 or PCV-13. Vaccine, 35 (20), pp. 2701-2708. | Show Abstract | Read more

Pneumococcal protein-polysaccharide conjugate vaccines provide direct protection against Streptococcus pneumoniae through the induction of persistent anti-polysaccharide antibodies, and by priming for a rapid secondary antibody response. Memory B cells (BMEM) generated during an initial immune response are responsible for both the more rapid and quantitatively greater secondary antibody response and are also thought to contribute to the ongoing production of plasma cells providing long-term antibody persistence. We recruited 3.5-year-old children who had participated in a previous clinical trial comparing infant immunization with either a 7-valent (PCV-7) or a 13-valent pneumococcal conjugate vaccine (PCV-13) to investigate whether prior priming with pneumococcal antigens influences BMEM responses. Blood was taken before and 1month after a PCV-13 booster. BMEM were quantified using a cultured ELISpot assay for pneumococcal serotypes 1, 3, 4, 14, 19A, 23F, and with diphtheria and tetanus toxoid as controls, and then correlated with serotype-specific IgG concentrations and opsonophagocytic activity (OPA) titers. In total, blood samples from 62 participants were available for analysis. Serotype-specific BMEM frequencies were generally low at baseline (before boost) although for serotypes 14 and 3, they were significantly higher in children primed with PCV-13 than PCV-7 primed children. Following the PCV-13 booster, BMEM frequencies increased and were not different between the groups for all serotypes. A strong inverse correlation was found between antibody concentrations and OPA titers at baseline and BMEM following booster vaccination for serotype 3 but not for other serotypes suggesting that, for this serotype, pre-existing serotype-specific antibodies may inhibit BMEM formation in response to vaccination. Clinicaltrials.gov registration number: NCT01095471.

Cottineau J, Kottemann MC, Lach FP, Kang Y-H, Vély F, Deenick EK, Lazarov T, Gineau L, Wang Y, Farina A et al. 2017. Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J Clin Invest, 127 (5), pp. 1991-2006. | Show Abstract | Read more

Inborn errors of DNA repair or replication underlie a variety of clinical phenotypes. We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation. The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic. We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients. The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice. The patients' fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which was rescued by WT GINS1. The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. The levels of GINS1 activity did not influence the immunological phenotype, which was uniform. Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency.

Salerno-Goncalves R, Luo D, Fresnay S, Magder L, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM et al. 2017. Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells. Front Immunol, 8 (APR), pp. 398. | Show Abstract | Read more

Gastrointestinal infections by Salmonella enterica serovar Typhi (S. Typhi) are rare in industrialized countries. However, they remain a major public health problem in the developing world with an estimated 26.9 million new cases annually and significant mortality when untreated. Recently, we provided the first direct evidence that CD8+ MAIT cells are activated and have the potential to kill cells exposed to S. Typhi, and that these responses are dependent on bacterial load. However, MAIT cell kinetics and function during bacterial infections in humans remain largely unknown. In this study, we characterize the human CD8+ MAIT cell immune response to S. Typhi infection in subjects participating in a challenge clinical trial who received a low- or high dose of wild-type S. Typhi. We define the kinetics of CD8+ MAIT cells as well as their levels of activation, proliferation, exhaustion/apoptosis, and homing potential. Regardless of the dose, in volunteers resistant to infection (NoTD), the levels of CD8+ MAIT cells after S. Typhi challenge fluctuated around their baseline values (day 0). In contrast, volunteers susceptible to the development of typhoid disease (TD) exhibited a sharp decline in circulating MAIT cells during the development of typhoid fever. Interestingly, MAIT cells from low-dose TD volunteers had higher levels of CD38 coexpressing CCR9, CCR6, and Ki67 during the development of typhoid fever than high-dose TD volunteers. No substantial perturbations on the levels of these markers were observed in NoTD volunteers irrespective of the dose. In sum, we describe, for the first time, that exposure to an enteric bacterium, in this case S. Typhi, results in changes in MAIT cell activation, proliferation, and homing characteristics, suggesting that MAIT cells are an important component of the human host response to bacterial infection.

Iro MA, Sadarangani M, Goldacre R, Nickless A, Pollard AJ, Goldacre MJ. 2017. 30-year trends in admission rates for encephalitis in children in England and effect of improved diagnostics and measles-mumps-rubella vaccination: a population-based observational study. Lancet Infect Dis, 17 (4), pp. 422-430. | Show Abstract | Read more

BACKGROUND: Encephalitis is a serious neurological disorder, yet data on admission rates for all-cause childhood encephalitis in England are scarce. We aimed to estimate admission rates for childhood encephalitis in England over 33 years (1979-2011), to describe trends in admission rates, and to observe how these rates have varied with the introduction of vaccines and improved diagnostics. METHODS: We did a retrospective analysis of hospital admission statistics for encephalitis for individuals aged 0-19 years using national data from the Hospital Inpatient Enquiry (HIPE, 1979-85) and Hospital Episode Statistics (HES, 1990-2011). We analysed annual age-specific and age-standardised admission rates in single calendar years and admission rate trends for specified aetiologies in relation to introduction of PCR testing and measles-mumps-rubella (MMR) vaccination. We compared admission rates between the two International Classification of Diseases (ICD) periods, ICD9 (1979-94) and ICD10 (1995-2011). FINDINGS: We found 16 571 encephalitis hospital admissions in the period 1979-2011, with a mean hospital admission rate of 5·97 per 100 000 per year (95% CI 5·52-6·41). Hospital admission rates declined from 1979 to 1994 (ICD9; annual percentage change [APC] -3·30%; 95% CI -2·88 to -3·66; p<0·0001) and increased between 1995 and 2011 (ICD10; APC 3·30%; 2·75-3·85; p<0·0001). Admissions for measles decreased by 97% (from 0·32 to 0·009) and admissions for mumps encephalitis decreased by 98% (from 0·60 to 0·01) after the introduction of the two-dose MMR vaccine. Hospital admission rates for encephalitis of unknown aetiology have increased by 37% since the introduction of PCR testing. INTERPRETATION: Hospital admission rates for all-cause childhood encephalitis in England are increasing. Admissions for measles and mumps encephalitis have decreased substantially. The numbers of encephalitis admissions without a specific diagnosis are increasing despite availability of PCR testing, indicating the need for strategies to improve aetiological diagnosis in children with encephalitis. FUNDING: None.

Darton TC, Zhou L, Blohmke CJ, Jones C, Waddington CS, Baker S, Pollard AJ. 2017. Blood culture-PCR to optimise typhoid fever diagnosis after controlled human infection identifies frequent asymptomatic cases and evidence of primary bacteraemia. J Infect, 74 (4), pp. 358-366. | Show Abstract | Read more

BACKGROUND: Improved diagnostics for typhoid are needed; a typhoid controlled human infection model may accelerate their development and translation. Here, we evaluated a blood culture-PCR assay for detecting infection after controlled human infection with S. Typhi and compared test performance with optimally performed blood cultures. METHODOLOGY/PRINCIPAL FINDINGS: Culture-PCR amplification of blood samples was performed alongside daily blood culture in 41 participants undergoing typhoid challenge. Study endpoints for typhoid diagnosis (TD) were fever and/or bacteraemia. Overall, 24/41 (59%) participants reached TD, of whom 21/24 (86%) had ≥1 positive blood culture (53/674, 7.9% of all cultures) or 18/24 (75%) had ≥1 positive culture-PCR assay result (57/684, 8.3%). A further five non-bacteraemic participants produced culture-PCR amplicons indicating infection; overall sensitivity/specificity of the assay compared to the study endpoints were 70%/65%. We found no significant difference between blood culture and culture-PCR methods in ability to identify cases (12 mismatching pairs, p = 0.77, binomial test). Clinical and stool culture metadata demonstrated that additional culture-PCR amplification positive individuals likely represented true cases missed by blood culture, suggesting the overall attack rate may be 30/41 (73%) rather than 24/41 (59%). Several participants had positive culture-PCR results soon after ingesting challenge providing new evidence for occurrence of an early primary bacteraemia. CONCLUSIONS/SIGNIFICANCE: Overall the culture-PCR assay performed well, identifying extra typhoid cases compared with routine blood culture alone. Despite limitations to widespread field-use, the benefits of increased diagnostic yield, reduced blood volume and faster turn-around-time, suggest that this assay could enhance laboratory typhoid diagnostics in research applications and high-incidence settings.

Britto C, Pollard AJ, Voysey M, Blohmke CJ. 2017. An Appraisal of the Clinical Features of Pediatric Enteric Fever: Systematic Review and Meta-analysis of the Age-Stratified Disease Occurrence. Clin Infect Dis, 64 (11), pp. 1604-1611. | Show Abstract | Read more

Children bear a substantial proportion of the enteric fever disease burden in endemic areas. Controversy persists regarding which age groups are most affected, leading to uncertainty about optimal intervention strategies. We performed a systematic review and meta-analysis of studies in Asia and Africa to compare the relative proportion of children with enteric fever in the age groups <5 years, 5-9 years, and 10-14 years. Overall, studies conducted in Africa showed a relatively smaller occurrence of disease in the youngest age group, whereas in Asia the picture was more mixed with a very large degree of heterogeneity in estimates. The clinical features of enteric fever reviewed here differ between younger and older children and adults, likely leading to further uncertainty over disease burden. It is evident from our review that preschool children and infants also contribute a significant proportion of disease burden but have not been adequately targeted via vaccination programs, which have been focusing primarily on school-based vaccination campaigns.

Sadarangani M, Barlow S, Anthony M, Pollard AJ. 2017. Four Component Meningococcal Capsular Group B Vaccine in Preterm Infants. J Pediatric Infect Dis Soc, 6 (3), pp. 309-310. | Read more

Seib K, Pollard AJ, de Wals P, Andrews RM, Zhou F, Hatchett RJ, Pickering LK, Orenstein WA. 2017. Policy making for vaccine use as a driver of vaccine innovation and development in the developed world. Vaccine, 35 (10), pp. 1380-1389. | Show Abstract | Read more

In the past 200years, vaccines have had unmistakable impacts on public health including declines in morbidity and mortality, most markedly in economically-developed countries. Highly engineered vaccines including vaccines for conditions other than infectious diseases are expected to dominate future vaccine development. We examine immunization vaccine policy as a driver of vaccine innovation and development. The pathways to recommendation for use of licensed vaccines in the US, UK, Canada and Australia have been similar, including: expert review of disease epidemiology, disease burden and severity; vaccine immunogenicity, efficacy and safety; programmatic feasibility; public demand; and increasingly cost-effectiveness. Other attributes particularly important in development of future vaccines are likely to include: duration of immunity for improved vaccines such as pertussis; a greater emphasis on optimizing community protection rather than direct protection only; programmatic implementation, feasibility, improvements (as in the case of development of a universal influenza vaccine); public concerns/confidence/fears related to outbreak pathogens like Ebola and Zika virus; and major societal burden for combating hard to treat diseases like HIV and antimicrobial resistant pathogens. Driving innovation and production of future vaccines faces enormous economic hurdles as available approaches, technologies and regulatory pathways become more complex. As such, cost-mitigating strategies and focused, aligned efforts (by governments, private organizations, and private-public partnerships) will likely be needed to continue to spur major advances in vaccine technologies and development.

Fresnay S, McArthur MA, Magder LS, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM, Pollard AJ, Sztein MB. 2017. Importance of Salmonella Typhi-Responsive CD8+ T Cell Immunity in a Human Typhoid Fever Challenge Model. Front Immunol, 8 (MAR), pp. 208. | Show Abstract | Read more

Typhoid fever, caused by the human-restricted organism Salmonella enterica serovar Typhi (S. Typhi), constitutes a major global health problem. The development of improved attenuated vaccines is pressing, but delayed by the lack of appropriate preclinical models. Herein, we report that high levels of S. Typhi-responsive CD8+ T cells at baseline significantly correlate with an increased risk of disease in humans challenged with a high dose (~104 CFU) wild-type S. Typhi. Typhoid fever development was associated with higher multifunctional S. Typhi-responsive CD8+ T effector memory cells at baseline. Early decreases of these cells in circulation following challenge were observed in both S. Typhi-responsive integrin α4β7- and integrin α4β7+ CD8+ T effector memory (TEM) cells, suggesting their potential to home to both mucosal and extra-intestinal sites. Participants with higher baseline levels of S. Typhi-responsive CD8+ T memory cells had a higher risk of acquiring disease, but among those who acquired disease, those with a higher baseline responses took longer to develop disease. In contrast, protection against disease was associated with low or absent S. Typhi-responsive T cells at baseline and no changes in circulation following challenge. These data highlight the importance of pre-existing S. Typhi-responsive immunity in predicting clinical outcome following infection with wild-type S. Typhi and provide novel insights into the complex mechanisms involved in protective immunity to natural infection in a stringent human model with a high challenge dose. They also contribute important information on the immunological responses to be assessed in the appraisal and selection of new generation typhoid vaccines.

Dobinson HC, Gibani MM, Jones C, Thomaides-Brears HB, Voysey M, Darton TC, Waddington CS, Campbell D, Milligan I, Zhou L et al. 2017. Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model. Clin Infect Dis, 64 (8), pp. 1066-1073. | Show Abstract | Read more

Background: To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection. Methods: Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 × 103 colony-forming units [CFU] and group 2: 0.5-1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature ≥38°C for ≥12 hours and/or bacteremia) or at day 14 postchallenge. Results: The primary study objective was achieved following challenge with 1-5 × 103 CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24-85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia. Conclusions: Challenge with S. Paratyphi A at a dose of 1-5 × 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology. Clinical Trials Registration: NCT02100397.

O'Connor D, Clutterbuck EA, Thompson AJ, Snape MD, Ramasamy MN, Kelly DF, Pollard AJ. 2017. High-dimensional assessment of B-cell responses to quadrivalent meningococcal conjugate and plain polysaccharide vaccine. Genome Med, 9 (1), pp. 11. | Show Abstract | Read more

BACKGROUND: Neisseria meningitidis is a globally important cause of meningitis and septicaemia. Twelve capsular groups of meningococci are known, and quadrivalent vaccines against four of these (A, C, W and Y) are available as plain-polysaccharide and protein-polysaccharide conjugate vaccines. Here we apply contemporary methods to describe B-cell responses to meningococcal polysaccharide and conjugate vaccines. METHODS: Twenty adults were randomly assigned to receive either a meningococcal plain-polysaccharide or conjugate vaccine; one month later all received the conjugate vaccine. Blood samples were taken pre-vaccination and 7, 21 and 28 days after vaccination; B-cell responses were assessed by ELISpot, serum bactericidal assay, flow cytometry and gene expression microarray. RESULTS: Seven days after an initial dose of either vaccine, a gene expression signature characteristic of plasmablasts was detectable. The frequency of newly generated plasma cells (CXCR3+HLA-DR+) and the expression of transcripts derived from IGKC and IGHG2 correlated with immunogenicity. Notably, using an independent dataset, the expression of glucosamine (N-acetyl)-6-sulfatase was found to reproducibly correlate with the magnitude of immune response. Transcriptomic and flow cytometric data revealed depletion of switched memory B cells following plain-polysaccharide vaccine. CONCLUSIONS: These data describe distinct gene signatures associated with the production of high-avidity antibody and a plain-polysaccharide-specific signature, possibly linked to polysaccharide-induced hyporesponsiveness.

Defres S, Keller SS, Das K, Vidyasagar R, Parkes LM, Burnside G, Griffiths M, Kopelman M, Roberts N, Solomon T, ENCEPH UK study group. 2017. A Feasibility Study of Quantifying Longitudinal Brain Changes in Herpes Simplex Virus (HSV) Encephalitis Using Magnetic Resonance Imaging (MRI) and Stereology. PLoS One, 12 (1), pp. e0170215. | Show Abstract | Read more

OBJECTIVES: To assess whether it is feasible to quantify acute change in temporal lobe volume and total oedema volumes in herpes simplex virus (HSV) encephalitis as a preliminary to a trial of corticosteroid therapy. METHODS: The study analysed serially acquired magnetic resonance images (MRI), of patients with acute HSV encephalitis who had neuroimaging repeated within four weeks of the first scan. We performed volumetric measurements of the left and right temporal lobes and of cerebral oedema visible on T2 weighted Fluid Attenuated Inversion Recovery (FLAIR) images using stereology in conjunction with point counting. RESULTS: Temporal lobe volumes increased on average by 1.6% (standard deviation (SD 11%) in five patients who had not received corticosteroid therapy and decreased in two patients who had received corticosteroids by 8.5%. FLAIR hyperintensity volumes increased by 9% in patients not receiving treatment with corticosteroids and decreased by 29% in the two patients that had received corticosteroids. CONCLUSIONS: This study has shown it is feasible to quantify acute change in temporal lobe and total oedema volumes in HSV encephalitis and suggests a potential resolution of swelling in response to corticosteroid therapy. These techniques could be used as part of a randomized control trial to investigate the efficacy of corticosteroids for treating HSV encephalitis in conjunction with assessing clinical outcomes and could be of potential value in helping to predict the clinical outcomes of patients with HSV encephalitis.

Iro MA, Snape MD, Voysey M, Jawad S, Finn A, Heath PT, Bona G, Esposito S, Diez-Domingo J, Prymula R et al. 2017. Persistence of bactericidal antibodies following booster vaccination with 4CMenB at 12, 18 or 24months and immunogenicity of a fifth dose administered at 4years of age-a phase 3 extension to a randomised controlled trial. Vaccine, 35 (2), pp. 395-402. | Show Abstract | Read more

BACKGROUND: 4CMenB is immunogenic in infants and toddlers. We assessed persistence of human complement serum bactericidal activity (hSBA) following a fourth dose administered at 12, 18 or 24months and characterised the antibody response to a fifth dose administered at 4years of age. METHODS: A phase 3, open label, multi-centre extension to a randomised controlled trial conducted in four countries (number of centres): Czech Republic (nineteen), Italy (four), Spain (four) and the United Kingdom (four). Four-year-old children who were either 4CMenB-naïve or had previously received a variety of 3-dose infant priming schedules and a booster vaccine as toddlers (follow-on group) were recruited. Venous blood samples were obtained to determine hSBA against four reference strains; acting as targets to assess immunity to each of the vaccine antigens, NadA (5/99), fHbp (H44/76), PorA (NZ98/254), and NHBA (M10713) at baseline (prior to vaccination, all participants) and one month following a dose of 4CMenB for all vaccine-naïve and follow-on participants primed with the 2, 3, 4 schedule, and a third of follow-on participants primed with a 2, 4, 6month schedule. RESULTS: At baseline (prior to vaccination), the proportion of participants (n=468) with hSBA titers⩾5 was similar across all followon groups: 89-100% against 5/99; 12-35% for H44/76; 8-12% for NZ98/254 and 53-80% for M10713 compared with 5%, 0%, 0%; and 60% respectively, for the vaccine-naïve controls (n=206). Following a dose of 4CMenB at 4years of age, this increased to 100% (5/99), 97-100% (H44/76), 80-95 % (NZ98/254) and 84-100% (M10713) (n=210), compared with 89%, 70%, 24%, and 76% respectively for vaccine-naïve controls (n=192). CONCLUSION: Waning of protective antibodies occurred 24–36 months after toddler booster regardless of age at boost. This was least marked against target strains 5/99 and M10713. A robust memory response occurred after a booster dose given at 4 years of age.

Drury RE, O'Connor D, Pollard AJ. 2017. The Clinical Application of MicroRNAs in Infectious Disease. Front Immunol, 8 (SEP), pp. 1182. | Show Abstract | Read more

MicroRNAs (miRNAs) are short single-stranded non-coding RNA sequences that posttranscriptionally regulate up to 60% of protein encoding genes. Evidence is emerging that miRNAs are key mediators of the host response to infection, predominantly by regulating proteins involved in innate and adaptive immune pathways. miRNAs can govern the cellular tropism of some viruses, are implicated in the resistance of some individuals to infections like HIV, and are associated with impaired vaccine response in older people. Not surprisingly, pathogens have evolved ways to undermine the effects of miRNAs on immunity. Recognition of this has led to new experimental treatments, RG-101 and Miravirsen-hepatitis C treatments which target host miRNA. miRNAs are being investigated as novel infection biomarkers, and they are being used to design attenuated vaccines, e.g., against Dengue virus. This comprehensive review synthesizes current knowledge of miRNA in host response to infection with emphasis on potential clinical applications, along with an evaluation of the challenges still to be overcome.

Pollard A. 2017. Correlates of protection against Neisseria Meningitidis. Nat Rev Immunol, 17 (1), pp. 3. | Read more

Giuntini S, Lujan E, Gibani MM, Dold C, Rollier CS, Pollard AJ, Granoff DM. 2017. Serum Bactericidal Antibody Responses of Adults Immunized with the MenB-4C Vaccine against Genetically Diverse Serogroup B Meningococci. Clin Vaccine Immunol, 24 (1), pp. e00430-16-e00430-16. | Show Abstract | Read more

MenB-4C is a meningococcal vaccine for the prevention of serogroup B disease. The vaccine contains factor H binding protein (FHbp) and three other antigens that can elicit serum bactericidal antibodies (SBA). For vaccine licensure, efficacy was inferred from the SBA responses against three antigen-specific indicator strains. The relation between those results and broad protection against circulating genetically diverse strains is not known. Twenty adults were immunized with two doses of MenB-4C given 1 to 2 months apart. SBA activity against 3 reference strains and 15 serogroup B test strains (6 from college outbreaks) was measured. Compared to the preimmunization titers, 70%, 95%, and 95% of subjects had ≥4-fold increases in the titers of anti-PorA P1.4, anti-NadA, and anti-FHbp antibodies against the reference strains, respectively. In contrast, only 25 to 45% of the subjects had ≥4-fold increases in responses to 10 of the 15 test strains, including 8 that expressed one to three of the antigens in the vaccine. At 1 month, the majority of subjects with <4-fold titer increases had serum titers of ≥1:4, which are considered sufficient for protection. However, the titers against four strains declined to <1:4 by 4 to 6 months in one-third to greater than 50% of the subjects tested. Clinically relevant isolates are often more resistant to SBA than the indicator strains used to measure antigen-specific SBA. A working model is that the percentage of subjects with titers of ≥1:4 at 1 month postimmunization correlates with short-term protection against that strain, whereas the percentage of subjects with ≥4-fold titer increases represents a more robust response. (The protocol used at the Oxford Vaccine Group has been registered at ClinicalTrials.gov under registration no. NCT02398396.).

Trück J, Mitchell R, Jawad S, Clutterbuck EA, Snape MD, Kelly DF, Voysey M, Pollard AJ. 2017. Divergent Memory B Cell Responses in a Mixed Infant Pneumococcal Conjugate Vaccine Schedule. Pediatr Infect Dis J, 36 (5), pp. e130-e135. | Show Abstract | Read more

BACKGROUND: Vaccine-induced immunity against pneumococcal infection relies on the generation of high concentrations of antibody and B cell memory. Both the 10- and the 13-valent pneumococcal conjugate vaccines (PCV-10 and PCV-13) effectively reduce disease caused by vaccine serotypes. It is unknown whether the generation of B cell memory requires several doses of the same vaccine or whether different PCVs are interchangeable. METHODS: Children in the United Kingdom (n=178) who had previously received PCV-13 at 2 and 4 months were randomized 1:1 to receive a PCV-13 or PCV-10 booster at age 12 months. Peripheral blood memory B cells (BMEM) were quantified before and at 1 and 12 months after vaccination using a cultured enzyme-linked immunospot assay for pneumococcal serotypes 1, 3, 4, 9V, 14, 19A, and diphtheria and tetanus toxoid. Correlations between BMEM frequencies and simultaneously measured antibody (IgG and opsonophagocytic assay) was also assessed. RESULTS: A significant rise in postbooster BMEM frequency was seen for 5 out of 6 serotypes in the PCV-13 group and none in the PCV-10 group. In the PCV-13 group, there was a particularly large increase in serotype 3-specific BMEM associated with only a small increase in antibody. Postbooster BMEM responses correlated positively with antibody, but correlations between prebooster BMEM and subsequent BMEM and antibody responses were inconsistent. CONCLUSIONS: After priming with PCV-13 in early infancy, a booster dose of PCV-10 does not induce detectable peripheral blood BMEM responses but a PCV-13 booster does induce robust responses. Booster responses to PCVs may be dependent on homologous carrier protein priming.

Pace D, Khatami A, Attard-Montalto S, Voysey M, Finn A, Faust SN, Heath PT, Borrow R, Snape MD, Pollard AJ. 2016. Use of a booster dose of capsular group C meningococcal glycoconjugate vaccine to demonstrate immunologic memory in children primed with one or two vaccine doses in infancy. Vaccine, 34 (50), pp. 6350-6357. | Show Abstract | Read more

BACKGROUND: Use of a polysaccharide vaccine challenge to demonstrate immunologic memory after priming with capsular group C meningococcal conjugate vaccines (MenCC) risks induction of immunologic hyporesponsiveness. For this reason, MenCC vaccines are now used as probes of immunologic memory, however, no studies have demonstrated their ability to distinguish primed from unprimed children. METHODS: This study was part of a randomised controlled trial investigating the immunogenicity of a booster dose of the combined Haemophilus influenzae type b and MenC-tetanus toxoid vaccine (Hib-MenC-TT) in infants receiving reduced dose MenCC vaccine priming schedules (one MenC-CRM/MenC-TT or two MenC-CRM vaccine doses) compared with an unprimed group. Antibody kinetics were studied in a subset of 269 children by measuring changes in the MenC serum bactericidal antibody, using rabbit complement, (MenC rSBA) titres and MenC specific IgG memory B-cells before and at 6 and 28days following the 12month booster vaccination. RESULTS: At 6days after the 12monthMenCC vaccine, the rise in MenC rSBA titres and MenC specific IgG memory B-cells of the primed groups were significantly higher than the infant MenCC naïve group. Participants primed with one MenC-TT dose had the highest increase in MenC rSBA titres compared with all other groups. The MenC rSBA titres at the 28th compared with the 6th day after boosting was significantly higher in those primed with a single MenC-TT/MenC-CRM vaccine in infancy compared with those who were not primed or who were primed with two doses of the MenC-CRM vaccine. CONCLUSION: Immunologic memory can be demonstrated by a MenCC booster vaccination but is affected by the type and number of MenCC doses used for infant priming. The MenC rSBA responses can be used to demonstrate successful immunologic priming.

Drysdale SB, Pollard AJ. 2016. Intussusception risk after rotavirus vaccination in England. Vaccine, 34 (50), pp. 6114. | Read more

Iro MA, Sadarangani M, Absoud M, Chong WK, Clark CA, Easton A, Gray V, Kneen R, Lim M, Pike M et al. 2016. ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE): protocol for a multicentre randomised controlled trial. BMJ Open, 6 (11), pp. e012356. | Show Abstract | Read more

INTRODUCTION: Infectious and immune-mediated encephalitides are important but under-recognised causes of morbidity and mortality in childhood, with a 7% death rate and up to 50% morbidity after prolonged follow-up. There is a theoretical basis for ameliorating the immune response with intravenous immunoglobulin (IVIG), which is supported by empirical evidence of a beneficial response following its use in the treatment of viral and autoimmune encephalitis. In immune-mediated encephalitis, IVIG is often used after a delay (by weeks in some cases), while diagnosis is confirmed. Wider use of IVIG in infectious encephalitis and earlier use in immune-mediated encephalitis could improve outcomes for these conditions. We describe the protocol for the first ever randomised control trial of IVIG treatment for children with all-cause encephalitis. METHODS AND ANALYSIS: 308 children (6 months to 16 years) with a diagnosis of acute/subacute encephalitis will be recruited in ∼30 UK hospitals and randomised to receive 2 doses (1 g/kg/dose) of either IVIG or matching placebo, in addition to standard treatment. Recruitment will be over a 42-month period and follow-up of each participant will be for 12 months post randomisation. The primary outcome is 'good recovery' (score of 2 or lower on the Glasgow Outcome Score Extended-paediatric version), at 12 months after randomisation. Additional secondary neurological measures will be collected at 4-6 weeks after discharge from acute care and at 6 and 12 months after randomisation. Safety, radiological, other autoimmune and tertiary outcomes will also be assessed. ETHICS AND DISSEMINATION: This trial has been approved by the UK National Research Ethics committee (South Central-Oxford A; REC 14/SC/1416). Current protocol: V4.0 (10/03/2016). The findings will be presented at national and international meetings and conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT02308982, EudraCT201400299735 and ISRCTN15791925; Pre-results.

Martinón-Torres F, Png E, Khor CC, Davila S, Wright VJ, Sim KS, Vega A, Fachal L, Inwald D, Nadel S et al. 2016. Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies. Sci Rep, 6 (1), pp. 35842. | Show Abstract | Read more

Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10-8) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10-9). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10-8). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.

Kandasamy R, Voysey M, McQuaid F, de Nie K, Ryan R, Orr O, Uhlig U, Sande C, O'Connor D, Pollard AJ. 2016. Non-specific immunological effects of selected routine childhood immunisations: systematic review. BMJ, 355 pp. i5225. | Show Abstract | Read more

OBJECTIVE:  To identify and characterise non-specific immunological effects after routine childhood vaccines against BCG, measles, diphtheria, pertussis, and tetanus. DESIGN:  Systematic review of randomised controlled trials, cohort studies, and case-control studies. DATA SOURCES:  Embase, PubMed, Cochrane library, and Trip searched between 1947 and January 2014. Publications submitted by a panel of experts in the specialty were also included. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:  All human studies reporting non-specific immunological effects after vaccination with standard childhood immunisations. Studies using recombinant vaccines, no vaccine at all, or reporting only vaccine specific outcomes were excluded. The primary aim was to systematically identify, assemble, and review all available studies and data on the possible non-specific or heterologous immunological effects of BCG; measles; mumps, measles, and rubella (MMR); diphtheria; tetanus; and pertussis vaccines. RESULTS:  The initial search yielded 11 168 references; 77 manuscripts met the inclusion criteria for data analysis. In most included studies (48%) BCG was the vaccine intervention. The final time point of outcome measurement was primarily performed (70%) between one and 12 months after vaccination. There was a high risk of bias in the included studies, with no single study rated low risk across all assessment criteria. A total of 143 different immunological variables were reported, which, in conjunction with differences in measurement units and summary statistics, created a high number of combinations thus precluding any meta-analysis. Studies that compared BCG vaccinated with unvaccinated groups showed a trend towards increased IFN-γ production in vitro in the vaccinated groups. Increases were also observed for IFN-γ measured after BCG vaccination in response to in vitro stimulation with microbial antigens from Candida albicans, tetanus toxoid, Staphylococcus aureas, lipopolysaccharide, and hepatitis B. Cohort studies of measles vaccination showed an increase in lymphoproliferation to microbial antigens from tetanus toxoid and C albicans Increases in immunogenicity to heterologous antigens were noted after diphtheria-tetanus (herpes simplex virus and polio antibody titres) and diphtheria-tetanus-pertussis (pneumococcus serotype 14 and polio neutralising responses) vaccination. CONCLUSIONS:  The papers reporting non-specific immunological effects had heterogeneous study designs and could not be conventionally meta-analysed, providing a low level of evidence quality. Some studies, such as BCG vaccine studies examining in vitro IFN-γ responses and measles vaccine studies examining lymphoproliferation to microbial antigen stimulation, showed a consistent direction of effect suggestive of non-specific immunological effects. The quality of the evidence, however, does not provide confidence in the nature, magnitude, or timing of non-specific immunological effects after vaccination with BCG, diphtheria, pertussis, tetanus, or measles containing vaccines nor the clinical importance of the findings.

Finn A, Morales-Aza B, Sikora P, Giles J, Lethem R, Marlais M, Thors V, Pollard AJ, Faust S, Heath P et al. 2016. Density Distribution of Pharyngeal Carriage of Meningococcus in Healthy Young Adults: New Approaches to Studying the Epidemiology of Colonization and Vaccine Indirect Effects. Pediatr Infect Dis J, 35 (10), pp. 1080-1085. | Show Abstract | Read more

BACKGROUND: Improved understanding of Neisseria meningitidis (Nm) carriage biology and better methods for detection and quantification would facilitate studies of potential impact of new vaccines on colonization and transmission in adolescents. METHODS: We performed plate cultures on 107 oropharyngeal swabs stored frozen in skim milk tryptone glucose glycerol (STGG) broth and previously positive for Nm. We compared quantitative polymerase chain reaction (qPCR) detection of Nm in 601 STGG-swabs with culture. Using qPCR (n = 87), a log-phase broth culture standard curve and semiquantitative plate cultures (n = 68), we measured density of carriage. We compared qPCR genogrouping of DNA extracts from STGG-swabs and from plate culture lawns (n = 110) with purified isolates (n = 80). RESULTS: Swab storage resulted in only 10% loss of culture sensitivity. Direct sodC qPCR Nm detection yielded more positives (87/601, 14.5%) than culture (80/601, 13.3%). Most samples (57/110) positive by culture were also positive by qPCR and vice versa, but discrepancies (single positives) were frequent among low-density samples. sodC qPCR was positive in 79/80 isolates but in only 65 by ctrA qPCR. Density both by culture and qPCR varied across 4 orders of magnitude with the majority being low (<50 bacteria-gene copies/mL) and a minority being high (>1000). Genogrouping qPCRs yielded more positive results when performed on DNA extracts from lawn cultures. CONCLUSIONS: We provide the first description of the distribution of Nm carriage density. This could be important for understanding transmission dynamics and population-level effectiveness of adolescent vaccine programs. Storage of swabs frozen in STGG for batched laboratory analysis facilitates carriage studies and direct sodC qPCR for Nm combined with qPCR genogrouping of lawn culture extracts provides accurate, detailed description of colonization.

Carande EJ, Pollard AJ, Drysdale SB. 2016. Management of Respiratory Syncytial Virus Bronchiolitis: 2015 Survey of Members of the European Society for Paediatric Infectious Diseases. Can J Infect Dis Med Microbiol, 2016 pp. 9139537. | Show Abstract | Read more

In 1995, the European Society for Paediatric Infectious Diseases (ESPID) carried out a survey of its members to assess the variation in management of respiratory syncytial virus (RSV) bronchiolitis. The aim of the current study was to carry out a similar survey 20 years later to assess how the management had changed. An electronic, structured, English language survey, based on the United Kingdom National Institute for Health and Care Excellence (NICE) bronchiolitis draft guideline, was sent to ESPID members in March 2015. Questions asked included information on treatment practices of infants with bronchiolitis and doctor demographics. We received responses from 135 doctors (14% of the ESPID members) who worked in 115 hospitals. 56% of the doctors used a written guideline to manage bronchiolitic infants. All doctors stated that they isolated individually or in cohorts all hospitalised bronchiolitis infants. The level of oxygen saturation suggested as an indication to administer supplemental oxygen varied between <89% and <95%. We found significant reductions in the use of ribavirin, bronchodilators, and corticosteroids from 1995 to 2015 (ribavirin 57% to 13%, P < 0.0001; bronchodilators 95% to 82%, P = 0.0024; corticosteroids 81% to 45%, P < 0.0001). Although variability in management remains high, encouragingly significantly fewer doctors are prescribing ribavirin, bronchodilators, and corticosteroids compared to 20 years ago.

Stein DF, O'Connor D, Blohmke CJ, Sadarangani M, Pollard AJ. 2016. Gene expression profiles are different in venous and capillary blood: Implications for vaccine studies. Vaccine, 34 (44), pp. 5306-5313. | Show Abstract | Read more

BACKGROUND: Detailed analysis of the immunological pathways leading to robust vaccine responses has become possible with the application of systems biology, including transcriptomic analysis. Venous blood is usually obtained for such studies but others have obtained capillary blood (e.g. finger-prick). Capillary samples are practically advantageous, especially in children. METHODS: The aim of this study was to compare gene expression profiles in venous and capillary blood before, 12h and 24h after vaccination with 23-valent pneumococcal polysaccharide or trivalent inactivated seasonal influenza vaccines. RESULTS: Gene expression at baseline was markedly different between venous and capillary samples, with 4940 genes differentially expressed, and followed a different pattern of changes after vaccination. At baseline, multiple pathways were upregulated in venous compared to capillary blood, including transforming growth factor-beta receptor signalling and toll-like receptor cascades. After vaccination with the influenza vaccine, there was enrichment for T and NK cell related signatures in capillary blood, and monocyte signatures in venous blood. By contrast, after vaccination with the pneumococcal vaccination, there was enrichment of dendritic cells, monocytes and interferon related signatures in capillary blood, whilst at 24h there was enrichment for T and NK cell related signatures in venous blood. CONCLUSIONS: These data show differences between venous and capillary gene expression both at baseline, and post vaccination, which may impact on the conclusions regarding immunological mechanisms drawn from studies using these different sampling methodologies.

Kent A, Ladhani SN, Andrews NJ, Scorrer T, Pollard AJ, Clarke P, Hughes SM, Heal C, Menson E, Chang J et al. 2016. Schedules for Pneumococcal Vaccination of Preterm Infants: An RCT. Pediatrics, 138 (3), pp. e20153945-e20153945. | Show Abstract | Read more

BACKGROUND AND OBJECTIVE: Premature infants have a higher risk of invasive pneumococcal disease and are more likely to have lower vaccine responses compared with term infants. Increasingly, immunization schedules are including a reduced, 2-dose, pneumococcal conjugate vaccine priming schedule. Our goal was to assess the immunogenicity of 3 commonly used 13-valent pneumococcal conjugate vaccine (PCV13) priming schedules in premature infants and their response to a 12-month booster dose. METHODS: Premature infants (<35 weeks' gestation) were randomized to receive PCV13 at 2 and 4 months (reduced schedule); 2, 3, and 4 months (accelerated schedule); or 2, 4, and 6 months (extended schedule). All infants received a 12-month PCV13 booster. Serotype-specific pneumococcal immunoglobulin G (IgG) for PCV13 serotypes was measured by using enzyme-linked immunosorbent assay 1 month after the primary and booster vaccinations. RESULTS: A total of 210 infants (median birth gestation, 29(+6) weeks; range, 23(+2)-34(+6) weeks) were included. After the primary vaccination, 75% (95% confidence interval [CI], 62-85), 88% (95% CI, 76-95), and 97% (95% CI, 87-99) of participants had protective antibody concentrations for at least one-half the PCV13 serotypes for the reduced, accelerated, and extended schedules, respectively. After the booster vaccination, participants receiving the extended schedule had significantly lower (P < .05) geometric mean concentrations compared with reduced (for 9 of 13 serotypes) and accelerated (for 4 of 13 serotypes) schedules, but nearly all participations, regardless of schedule or serotype, had seroprotective IgG concentrations. CONCLUSIONS: A reduced priming schedule of PCV13 resulted in higher post-booster IgG concentrations but lower post-primary concentrations. The optimum vaccine schedule for preterm infants will therefore depend on when they are most at risk for invasive pneumococcal disease.

Darton TC, Jones C, Blohmke CJ, Waddington CS, Zhou L, Peters A, Haworth K, Sie R, Green CA, Jeppesen CA et al. 2016. Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a. PLoS Negl Trop Dis, 10 (8), pp. e0004926. | Show Abstract | Read more

BACKGROUND: Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. METHODS AND FINDINGS: We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. CONCLUSIONS: Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01405521) and EudraCT (number 2011-000381-35).

Martin NG, Iro MA, Sadarangani M, Goldacre R, Pollard AJ, Goldacre MJ. 2016. Hospital admissions for viral meningitis in children in England over five decades: a population-based observational study. Lancet Infect Dis, 16 (11), pp. 1279-1287. | Show Abstract | Read more

BACKGROUND: A substantial reduction in bacterial meningitis has occurred in the UK following successful implementation of immunisation programmes. Most childhood meningitis in developed countries is now caused by viruses. Long-term trends in paediatric viral meningitis in England have not previously been reported. The objective of this study is to report on epidemiological trends over time in childhood viral meningitis in England. METHODS: In this population-based observational study, we used routinely collected hospital discharge records from English National Health Service hospitals from 1968-2011 to analyse annual age-specific admission rates for viral meningitis, including specific viral aetiologies, in children younger than 15 years. FINDINGS: We analysed hospital discharge records from Jan 1, 1968, to Dec 31, 2011. Hospital admission rates for viral meningitis from Jan 1, 1968, to Dec 31, 1985, varied annually, with a mean of 13·5 admissions per 100 000 children aged less than 15 years, per year (95% CI 13·0-14·0). Admission rates declined during the late 1980s, and the mean number of admissions from 1989-2011 was 5·2 per 100 000 per year (5·1-5·3). This decrease was entirely in children aged 1-14 years. Admission rates for infants aged less than 1 year increased since 2005, to 70·0 per 100 000 (63·7-76·2) in 2011, which was driven by an increase in admission of infants aged 90 days or less. In 1968-85, the majority of cases in children were in those aged 1-14 years (22 150 [89%] of 24 920 admissions). In 2007-11, 1716 (72%) of 2382 cases were in infants. Admissions for mumps-related meningitis almost disappeared following introduction of the measles-mumps-rubella (MMR) vaccine in 1988. Admissions with a specified viral aetiology have increased since 2000. INTERPRETATION: Trends in viral meningitis admissions have changed substantially over the past 50 years, and probably reflect the impact of the MMR vaccine programme and the use of more sensitive diagnostic techniques. FUNDING: None.

Galson JD, Trück J, Clutterbuck EA, Fowler A, Cerundolo V, Pollard AJ, Lunter G, Kelly DF. 2016. Erratum to: B-cell repertoire dynamics after sequential hepatitis B vaccination and evidence for cross-reactive B-cell activation. Genome Med, 8 (1), pp. 81. | Show Abstract | Read more

© 2016 The Author(s). It has come to our attention that there was an omission in the Acknowledgements section in this article [1]. The Acknowledgements section should read: The authors are grateful to the study participants, to the doctors and nurses at the Oxford Vaccine Group for assisting with sample collection, and to the National Institute for Health Research Clinical Research Network. The authors thank Craig Waugh for help with cell sorting and the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (subsidized by Wellcome Trust grant reference 090532/Z/09/Z) for the generation of sequencing data. Purified HBsAg was provided by GlaxoSmithKline Biologicals SA, and conjugated to APC by Miltenyi Biotec.

Herberg JA, Kaforou M, Wright VJ, Shailes H, Eleftherohorinou H, Hoggart CJ, Cebey-López M, Carter MJ, Janes VA, Gormley S et al. 2016. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children. JAMA, 316 (8), pp. 835-845. | Show Abstract | Read more

IMPORTANCE: Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others. OBJECTIVE: To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children. DESIGN, SETTING, AND PARTICIPANTS: Febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets. EXPOSURES: A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis. MAIN OUTCOMES AND MEASURES: Definite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group. RESULTS: The discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller (2-transcript) signature (FAM89A and IFI44L) was identified by removing highly correlated transcripts. When this 2-transcript signature was implemented as a disease risk score in the validation group (130 children, with 23 definite bacterial, 28 definite viral, and 79 indeterminate infections; median age, 17 months; 57% male), all 23 patients with microbiologically confirmed definite bacterial infection were classified as bacterial (sensitivity, 100% [95% CI, 100%-100%]) and 27 of 28 patients with definite viral infection were classified as viral (specificity, 96.4% [95% CI, 89.3%-100%]). When applied to additional validation datasets from patients with meningococcal and inflammatory diseases, bacterial infection was identified with a sensitivity of 91.7% (95% CI, 79.2%-100%) and 90.0% (95% CI, 70.0%-100%), respectively, and with specificity of 96.0% (95% CI, 88.0%-100%) and 95.8% (95% CI, 89.6%-100%). Of the children in the indeterminate groups, 46.3% (63/136) were classified as having bacterial infection, although 94.9% (129/136) received antibiotic treatment. CONCLUSIONS AND RELEVANCE: This study provides preliminary data regarding test accuracy of a 2-transcript host RNA signature discriminating bacterial from viral infection in febrile children. Further studies are needed in diverse groups of patients to assess accuracy and clinical utility of this test in different clinical settings.

Trück J, Kelly DF, Taylor JM, Kienzler AK, Lester T, Seller A, Pollard AJ, Patel SY. 2016. Variable phenotype and discrete alterations of immune phenotypes in CTP synthase 1 deficiency: Report of 2 siblings. J Allergy Clin Immunol, 138 (6), pp. 1722-1725.e6. | Read more

Voysey M, Sadarangani M, Clutterbuck E, Bolgiano B, Pollard AJ. 2016. The impact of administration of conjugate vaccines containing cross reacting material on Haemophilus influenzae type b antibody responses in infants: A systematic review and meta-analysis of randomised controlled trials. Vaccine, 34 (34), pp. 3986-3992. | Show Abstract | Read more

BACKGROUND: Protein-polysaccharide conjugate vaccines such as Haemophilus influenzae type b (Hib), meningococcal, and pneumococcal vaccine, induce immunological memory and longer lasting protection than plain polysaccharide vaccines. The most common proteins used as carriers are tetanus toxoid (TT) and cross reacting material-197 (CRM), a mutant form of diphtheria toxoid. CRM conjugate vaccines have been reported to suppress antibody responses to co-administered Hib-TT vaccine. METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials in which infants were randomised to receive meningococcal or pneumococcal conjugate vaccines along with Hib-TT. Trials of licensed vaccines with different carrier proteins were included for group C meningococcal (MenC), quadrivalent ACWY meningococcal (MenACWY), and pneumococcal vaccines. RESULTS: Twenty-three trials were included in the meta-analyses. Overall, administration of MenC-CRM in a 2 or 3 dose schedule resulted in a 45% reduction in Hib antibody concentrations (GMR 0.55, 95% CI 0.49-0.62). MenACWY-CRM boosted Hib antibody responses by 22% (GMR 1.22, 95% CI 1.06-1.41) whilst pneumococcal CRM conjugate vaccines had no impact on Hib antibody responses (GMR 0.91, 95% CI 0.68-1.22). CONCLUSIONS: The effect of CRM protein-polysaccharide conjugate vaccines on Hib antibody responses varies greatly between vaccines. Co-administration of a CRM conjugate vaccine can produce either positive or negative effects on Hib antibody responses. These inconsistencies suggest that CRM itself may not be the main driver of variability in Hib responses, and challenge current perspectives on this issue.

Voysey M, Kandasamy R, Yu L-M, Baudin M, Sadorge C, Thomas S, John T, Pollard AJ. 2016. The predicted persistence and kinetics of antibody decline 9years after pre-school booster vaccination in UK children. Vaccine, 34 (35), pp. 4221-4228. | Show Abstract | Read more

BACKGROUND: Long term follow-up of vaccine trials is essential to establish the duration of protection. In the context of worldwide concern about rising pertussis incidence, estimates of antibody persistence after vaccination, which do not account for the rise in antibody due to natural boosting or infection, may overestimate the degree of protection afforded by pertussis vaccines. METHODS: This was a 5year follow up study of a randomised controlled trial of diphtheria, tetanus, pertussis and polio booster vaccines in UK children aged 3.5-5years. Antibody persistence was measured at 1month, 1, 3, and 5years after vaccination and the kinetics of antibody decline were modelled longitudinally. Estimates of predicted antibody persistence 9years after the pre-school booster were derived from model parameters. RESULTS: Antibody levels 9years after vaccination were predicted to be above accepted thresholds for protection for diphtheria, tetanus and polio. Antibody responses to pertussis toxoid were undetectable in 49% of children at the 5year follow up visit, and responses were predicted to be undetectable in 69% (95% CI 45-88%) of children by the time of their teenage booster at 13-14years of age. CONCLUSIONS: There is no defined correlate of protection for pertussis. However, the large proportion of participants in this study with undetectable pertussis antibody levels at both measured and predicted timepoints suggests sub-optimal immunity in adolescence. Adding pertussis to the teenage booster for UK children as is done in other countries, would enhance immunity in adolescence.

Trück J, Jawad S, Goldblatt D, Roalfe L, Snape MD, Voysey M, Pollard AJ. 2016. The Antibody Response Following a Booster With Either a 10- or 13-valent Pneumococcal Conjugate Vaccine in Toddlers Primed With a 13-valent Pneumococcal Conjugate Vaccine in Early Infancy. Pediatr Infect Dis J, 35 (7), pp. 787-793. | Show Abstract | Read more

BACKGROUND: Both the 13- and 10-valent pneumococcal conjugate vaccines (PCV-13; PCV-10) are immunogenic and effective against vaccine-type pneumococcal disease when given to young children. However, limited data are available regarding the interchangeability of these 2 vaccines. METHODS: UK children (n = 178) who had previously been vaccinated with PCV-13 at 2 and 4 months were randomized to receive either a PCV-13 or a PCV-10 booster at 12 months of age. PCV-13 vaccine-type antipolysaccharide serum immunoglobulin G (IgG) concentrations and opsonophagocytic assay titers were measured before and at 1 and 12 months following vaccination. The primary objective was to assess noninferiority of PCV-10 compared with PCV-13. RESULTS: For 8 of the PCV-10 serotypes at least 97% of participants in both groups had IgG concentrations ≥0.35 µg/mL at 1 month after vaccination; inferior responses were seen for serotypes 5 and 9V following the PCV-10 compared with the PCV-13 booster. Post booster geometric mean IgG concentrations and opsonophagocytic assay titers were significantly superior for most serotypes in PCV-13 compared with PCV-10 recipients, whereas similar or inferior responses were seen for serotypes 4, 18C, and 19F. Although some increase in antibody was seen in PCV-10 recipients against the serotypes 6A and 19A (serotypes that cross-react with 6B and 19F in PCV-10, respectively) at 1-month post booster, these responses were significantly lower than in the PCV-13 group. CONCLUSIONS: In PCV-13 primed infants, a PCV-10 booster is generally less immunogenic than a PCV-13 booster. For the 3 serotypes in PCV-10 with higher antigen content and/or conjugation to diphtheria or tetanus toxoid carrier proteins, higher or similar booster responses were seen in PCV-10 recipients. Although these findings suggest that responses are generally better with a PCV-13 booster among PCV-13 primed children, the clinical significance of these differences in immunogenicity is unclear.

Toapanta FR, Bernal PJ, Fresnay S, Magder LS, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM et al. 2016. Oral Challenge with Wild-Type Salmonella Typhi Induces Distinct Changes in B Cell Subsets in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis, 10 (6), pp. e0004766. | Show Abstract | Read more

A novel human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently established by the Oxford Vaccine Group. In this model, 104 CFU of Salmonella resulted in 65% of participants developing typhoid fever (referred here as typhoid diagnosis -TD-) 6-9 days post-challenge. TD was diagnosed in participants meeting clinical (oral temperature ≥38°C for ≥12h) and/or microbiological (S. Typhi bacteremia) endpoints. Changes in B cell subpopulations following S. Typhi challenge remain undefined. To address this issue, a subset of volunteers (6 TD and 4 who did not develop TD -NoTD-) was evaluated. Notable changes included reduction in the frequency of B cells (cells/ml) of TD volunteers during disease days and increase in plasmablasts (PB) during the recovery phase (>day 14). Additionally, a portion of PB of TD volunteers showed a significant increase in activation (CD40, CD21) and gut homing (integrin α4β7) molecules. Furthermore, all BM subsets of TD volunteers showed changes induced by S. Typhi infections such as a decrease in CD21 in switched memory (Sm) CD27+ and Sm CD27- cells as well as upregulation of CD40 in unswitched memory (Um) and Naïve cells. Furthermore, changes in the signaling profile of some BM subsets were identified after S. Typhi-LPS stimulation around time of disease. Notably, naïve cells of TD (compared to NoTD) volunteers showed a higher percentage of cells phosphorylating Akt suggesting enhanced survival of these cells. Interestingly, most these changes were temporally associated with disease onset. This is the first study to describe differences in B cell subsets directly related to clinical outcome following oral challenge with wild-type S. Typhi in humans.

Goodridge HS, Ahmed SS, Curtis N, Kollmann TR, Levy O, Netea MG, Pollard AJ, van Crevel R, Wilson CB. 2016. Harnessing the beneficial heterologous effects of vaccination. Nat Rev Immunol, 16 (6), pp. 392-400. | Show Abstract | Read more

Clinical evidence strongly suggests that certain live vaccines, in particular bacille Calmette-Guérin (BCG) and measles vaccines, can reduce all-cause mortality, most probably through protection against non-targeted pathogens in addition to the targeted pathogen. The underlying mechanisms are currently unknown. We discuss how heterologous lymphocyte activation and innate immune memory could promote protection beyond the intended target pathogen and consider how vaccinologists could leverage heterologous immunity to improve outcomes in vulnerable populations, in particular the very young and the elderly.

Blohmke CJ, Darton TC, Jones C, Suarez NM, Waddington CS, Angus B, Zhou L, Hill J, Clare S, Kane L et al. 2016. Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med, 213 (6), pp. 1061-1077. | Show Abstract | Read more

Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host-pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever.

Ewer K, Rampling T, Venkatraman N, Bowyer G, Wright D, Lambe T, Imoukhuede EB, Payne R, Fehling SK, Strecker T et al. 2016. A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA. N Engl J Med, 374 (17), pp. 1635-1646. | Show Abstract | Read more

BACKGROUND: The West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak. METHODS: In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels--1×10(10) viral particles, 2.5×10(10) viral particles, and 5×10(10) viral particles--with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glycoprotein, in 30 of the 60 participants and evaluated a reduced prime-boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability. RESULTS: No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P<0.001). Virus-specific antibody responses in participants primed with ChAd3 remained positive 6 months after vaccination (geometric mean titer, 758) but were significantly higher in those who had received the MVA booster (geometric mean titer, 1750; P<0.001). CONCLUSIONS: The ChAd3 vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875.).

Sadarangani M, Pollard AJ. 2016. Can we control all-cause meningococcal disease in Europe? Clin Microbiol Infect, 22 Suppl 5 pp. S103-S112. | Show Abstract | Read more

Invasive disease caused by Neisseria meningitidis is potentially devastating, with a case fatality rate of 5-15% and high rates of significant sequelae among survivors after septicaemia or meningitis. Capsular group C (MenC) conjugate vaccines have been highly successful in achieving control of MenC disease across Europe, and some countries have also introduced quadrivalent MenACWY conjugate vaccines to reduce disease caused by groups A, W and Y in addition to C. These vaccines putatively elicit protective levels of bactericidal antibodies in all age groups, induce immunologic memory and reduce nasopharyngeal carriage, thereby leading to herd protection. Protein-based meningococcal vaccines based on subcapsular components, and designed primarily to target capsular group B (MenB) disease, have recently been licensed. These vaccines are highly immunogenic in infants and adolescents, inducing bactericidal antibodies against strains expressing high levels of vaccine antigens which are identical to the variants present in the vaccines. Effectiveness of these vaccines at a population level will be determined by whether vaccine-induced antibodies provide cross-protection against variants of the vaccine antigens present on the surface of the diverse collection of circulating invasive strains. The level of serum bactericidal activity induced against strains also seems to depend on the level of expression of the vaccine antigens. The duration of protection and the impact on carriage of meningococci will have a major bearing on the overall effectiveness of the programme. In September 2015 the UK became the first country to introduce the multicomponent meningococcal serogroup B vaccine (4CMenB) into a national routine immunization schedule, and data on the effectiveness of this programme are anticipated in the next few years.

Milligan ID, Gibani MM, Sewell R, Clutterbuck EA, Campbell D, Plested E, Nuthall E, Voysey M, Silva-Reyes L, McElrath MJ et al. 2016. Safety and Immunogenicity of Novel Adenovirus Type 26- and Modified Vaccinia Ankara-Vectored Ebola Vaccines: A Randomized Clinical Trial. JAMA, 315 (15), pp. 1610-1623. | Show Abstract | Read more

IMPORTANCE: Developing effective vaccines against Ebola virus is a global priority. OBJECTIVE: To evaluate an adenovirus type 26 vector vaccine encoding Ebola glycoprotein (Ad26.ZEBOV) and a modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein (MVA-BN-Filo). DESIGN, SETTING, AND PARTICIPANTS: Single-center, randomized, placebo-controlled, observer-blind, phase 1 trial performed in Oxford, United Kingdom, enrolling healthy 18- to 50-year-olds from December 2014; 8-month follow-up was completed October 2015. INTERVENTIONS: Participants were randomized into 4 groups, within which they were simultaneously randomized 5:1 to receive study vaccines or placebo. Those receiving active vaccines were primed with Ad26.ZEBOV (5 × 10(10) viral particles) or MVA-BN-Filo (1 × 10(8) median tissue culture infective dose) and boosted with the alternative vaccine 28 or 56 days later. A fifth, open-label group received Ad26.ZEBOV boosted by MVA-BN-Filo 14 days later. MAIN OUTCOMES AND MEASURES: The primary outcomes were safety and tolerability. All adverse events were recorded until 21 days after each immunization; serious adverse events were recorded throughout the trial. Secondary outcomes were humoral and cellular immune responses to immunization, as assessed by enzyme-linked immunosorbent assay and enzyme-linked immunospot performed at baseline and from 7 days after each immunization until 8 months after priming immunizations. RESULTS: Among 87 study participants (median age, 38.5 years; 66.7% female), 72 were randomized into 4 groups of 18, and 15 were included in the open-label group. Four participants did not receive a booster dose; 67 of 75 study vaccine recipients were followed up at 8 months. No vaccine-related serious adverse events occurred. No participant became febrile after MVA-BN-Filo, compared with 3 of 60 participants (5%; 95% CI, 1%-14%) receiving Ad26.ZEBOV in the randomized groups. In the open-label group, 4 of 15 Ad26.ZEBOV recipients (27%; 95% CI, 8%-55%) experienced fever. In the randomized groups, 28 of 29 Ad26.ZEBOV recipients (97%; 95% CI, 82%- 99.9%) and 7 of 30 MVA-BN-Filo recipients (23%; 95% CI, 10%-42%) had detectable Ebola glycoprotein-specific IgG 28 days after primary immunization. All vaccine recipients had specific IgG detectable 21 days postboost and at 8-month follow-up. Within randomized groups, at 7 days postboost, at least 86% of vaccine recipients showed Ebola-specific T-cell responses. CONCLUSIONS AND RELEVANCE: In this phase 1 study of healthy volunteers, immunization with Ad26.ZEBOV or MVA-BN-Filo did not result in any vaccine-related serious adverse events. An immune response was observed after primary immunization with Ad26.ZEBOV; boosting by MVA-BN-Filo resulted in sustained elevation of specific immunity. These vaccines are being further assessed in phase 2 and 3 studies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02313077.

Kent A, Scorrer T, Pollard AJ, Snape MD, Clarke P, Few K, Menson E, Varghese AS, Hughes S, Ladhani SN, Heath PT. 2016. Lymphocyte subpopulations in premature infants: an observational study. Arch Dis Child Fetal Neonatal Ed, 101 (6), pp. F546-F551. | Show Abstract | Read more

BACKGROUND AND OBJECTIVES: The infant's immune system evolves over the first months and years of life. Strong correlation exists between lymphocyte count, lymphocyte subpopulations and gestational age at birth. Associations with antenatal and postnatal steroid treatment, infection and chronic lung disease have also been described. Few published studies report the effect of increasing postnatal age (PNA) and comorbidities on lymphocyte subpopulations in premature infants beyond the first 4 months of life. This study aimed to describe changes in lymphocyte subpopulations in preterm infants up to 13 months PNA. METHODS: Premature infants (23-34 weeks completed gestation) from five centres had lymphocyte subpopulations measured at 2, 5 or 7, 12 and 13 months PNA alongside their vaccine responses in a vaccination trial. RESULTS: 393 blood samples from 151 babies were analysed. There was an increase in absolute numbers of total lymphocytes (median cell count 6.21×109/L at 13 months compared with 4.9×109/L at 2 months PNA) and CD3+, CD4+, CD8+, natural killer and B cells with increasing age. At 2 months PNA, there was a positive correlation between gestation and CD3+ and CD4+ counts (r=0.32 and 0.46, respectively) and proportions (r=0.22 and 0.41, respectively), and CD4+:CD8+ ratios (r=0.57), but a negative correlation with CD8+ proportions (r=-0.32). CONCLUSIONS: This longitudinal study describes the distribution of lymphocyte subpopulations in premature infants and provides reference ranges for the major lymphocyte subsets to help guide clinicians when assessing premature infants for immunodeficiency in the first year of life. TRIAL REGISTRATION NUMBER: EudraCT 2007-007535-23.

Bambery B, Selgelid M, Weijer C, Savulescu J, Pollard AJ. 2016. Ethical Criteria for Human Challenge Studies in Infectious Diseases. Public Health Ethics, 9 (1), pp. 92-103. | Show Abstract | Read more

Purposeful infection of healthy volunteers with a microbial pathogen seems at odds with acceptable ethical standards, but is an important contemporary research avenue used to study infectious diseases and their treatments. Generally termed 'controlled human infection studies', this research is particularly useful for fast tracking the development of candidate vaccines and may provide unique insight into disease pathogenesis otherwise unavailable. However, scarce bioethical literature is currently available to assist researchers and research ethics committees in negotiating the distinct issues raised by research involving purposefully infecting healthy volunteers. In this article, we present two separate challenge studies and highlight the ethical issues of human challenge studies as seen through a well-constructed framework. Beyond the same stringent ethical standards seen in other areas of medical research, we conclude that human challenge studies should also include: (i) independent expert reviews, including systematic reviews; (ii) a publicly available rationale for the research; (iii) implementation of measures to protect the public from spread of infection beyond the research setting; and (iv) a new system for compensation for harm. We hope these additions may encourage safer and more ethical research practice and help to safeguard public confidence in this vital research alternative in years to come.

Sadarangani M, Hoe CJ, Makepeace K, van der Ley P, Pollard AJ. 2016. Phase variation of Opa proteins of Neisseria meningitidis and the effects of bacterial transformation. J Biosci, 41 (1), pp. 13-19. | Show Abstract

Opa proteins are major proteins involved in meningococcal colonization of the nasopharynx and immune interactions. Opa proteins undergo phase variation (PV) due to the presence of the 5'-CTCTT-3' coding repeat (CR) sequence. The dynamics of PV of meningococcal Opa proteins is unknown. Opa PV, including the effect of transformation on PV, was assessed using a panel of Opa-deficient strains of Neisseria meningitidis. Analysis of Opa expression from UK disease-causing isolates was undertaken. Different opa genes demonstrated variable rates of PV, between 6.4 × 10(-4) and 6.9 × 10(-3) per cell per generation. opa genes with a longer CR tract had a higher rate of PV (r(2) = 0.77, p = 0.1212). Bacterial transformation resulted in a 180-fold increase in PV rate. The majority of opa genes in UK disease isolates (315/463, 68.0%) were in the 'on' phase, suggesting the importance of Opa proteins during invasive disease. These data provide valuable information for the first time regarding meningococcal Opa PV. The presence of Opa PV in meningococcal populations and high expression of Opa among invasive strains likely indicates the importance of this protein in bacterial colonization in the human nasopharynx. These findings have potential implications for development of vaccines derived from meningococcal outer membranes.

Voysey M, Barker CIS, Snape MD, Kelly DF, Trück J, Pollard AJ. 2016. Sex-dependent immune responses to infant vaccination: an individual participant data meta-analysis of antibody and memory B cells. Vaccine, 34 (14), pp. 1657-1664. | Show Abstract | Read more

BACKGROUND: Biological sex can be an important source of variation in infection and immunity and sex-dependent differences in immune response to vaccination have been reported in some studies. METHODS: We conducted an individual participant data meta-analysis of vaccine trials from one research centre, in which vaccines were administered to children under three years of age and immunological parameters measured. Log-transformed antigen-specific antibody and memory B cell results were meta-analysed and differences between girls and boys reported as geometric mean ratios. RESULTS: Antibody and memory B cell data were available from nine trials and 2378 children. Statistically significant differences between girls and boys were observed for diphtheria toxoid, capsular group A, W, and Y meningococcal, and pneumococcal vaccines. No sex-differences were observed for responses to Haemophilus influenzae type b, capsular group C meningococcal or tetanus toxoid vaccines. CONCLUSIONS: In young children, immune responses to vaccines were consistently higher or equivalent in girls compared with boys. In no instance were responses in boys significantly higher than girls. While these data do not indicate differences in protection conferred by immunisation in boys and girls, they do support further consideration of biological sex in planning of clinical trials of vaccines.

Licciardi PV, Toh ZQ, Clutterbuck EA, Balloch A, Marimla RA, Tikkanen L, Lamb KE, Bright KJ, Rabuatoka U, Tikoduadua L et al. 2016. No long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine. J Allergy Clin Immunol, 137 (6), pp. 1772-1779.e11. | Show Abstract | Read more

BACKGROUND: A randomized controlled trial in Fiji examined the immunogenicity and effect on nasopharyngeal carriage after 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) in infancy followed by 23-valent pneumococcal polysaccharide vaccine (23vPPV; Pneumovax) at 12 months of age. At 18 months of age, children given 23vPPV exhibited immune hyporesponsiveness to a micro-23vPPV (20%) challenge dose in terms of serotype-specific IgG and opsonophagocytosis, while 23vPPV had no effect on vaccine-type carriage. OBJECTIVE: This follow-up study examined the long-term effect of the 12-month 23vPPV dose by evaluating the immune response to 13-valent pneumococcal conjugate vaccine (PCV13) administration 4 to 5 years later. METHODS: Blood samples from 194 children (now 5-7 years old) were taken before and 28 days after PCV13 booster immunization. Nasopharyngeal swabs were taken before PCV13 immunization. We measured levels of serotype-specific IgG to all 13 vaccine serotypes, opsonophagocytosis for 8 vaccine serotypes, and memory B-cell responses for 18 serotypes before and after PCV13 immunization. RESULTS: Paired samples were obtained from 185 children. There were no significant differences in the serotype-specific IgG, opsonophagocytosis, or memory B-cell response at either time point between children who did or did not receive 23vPPV at 12 months of age. Nasopharyngeal carriage of PCV7 and 23vPPV serotypes was similar among the groups. Priming with 1, 2, or 3 PCV7 doses during infancy did not affect serotype-specific immunity or carriage. CONCLUSION: Immune hyporesponsiveness induced by 23vPPV in toddlers does not appear to be sustained among preschool children in this context and does not affect the pneumococcal carriage rate in this age group.

Sadarangani M, Hoe JC, Makepeace K, van der Ley P, Pollard AJ. 2016. Phase variation of Opa proteins of Neisseria meningitidis and the effects of bacterial transformation JOURNAL OF BIOSCIENCES, 41 (1), pp. 13-19. | Show Abstract | Read more

© 2016, Indian Academy of Sciences. Opa proteins are major proteins involved in meningococcal colonization of the nasopharynx and immune interactions. Opa proteins undergo phase variation (PV) due to the presence of the 5′-CTCTT-3′ coding repeat (CR) sequence. The dynamics of PV of meningococcal Opa proteins is unknown. Opa PV, including the effect of transformation on PV, was assessed using a panel of Opa-deficient strains of Neisseria meningitidis. Analysis of Opa expression from UK disease-causing isolates was undertaken. Different opa genes demonstrated variable rates of PV, between 6.4 ×10 –4 and 6.9 ×10 –3 per cell per generation. opa genes with a longer CR tract had a higher rate of PV (r 2 =0.77, p=0.1212). Bacterial transformation resulted in a 180-fold increase in PV rate. The majority of opa genes in UK disease isolates (315/463, 68.0%) were in the ‘on’ phase, suggesting the importance of Opa proteins during invasive disease. These data provide valuable information for the first time regarding meningococcal Opa PV. The presence of Opa PV in meningococcal populations and high expression of Opa among invasive strains likely indicates the importance of this protein in bacterial colonization in the human nasopharynx. These findings have potential implications for development of vaccines derived from meningococcal outer membranes.

Nakaya HI, Clutterbuck E, Kazmin D, Wang L, Cortese M, Bosinger SE, Patel NB, Zak DE, Aderem A, Dong T et al. 2016. Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood. Proc Natl Acad Sci U S A, 113 (7), pp. 1853-1858. | Show Abstract | Read more

The dynamics and molecular mechanisms underlying vaccine immunity in early childhood remain poorly understood. Here we applied systems approaches to investigate the innate and adaptive responses to trivalent inactivated influenza vaccine (TIV) and MF59-adjuvanted TIV (ATIV) in 90 14- to 24-mo-old healthy children. MF59 enhanced the magnitude and kinetics of serum antibody titers following vaccination, and induced a greater frequency of vaccine specific, multicytokine-producing CD4(+) T cells. Compared with transcriptional responses to TIV vaccination previously reported in adults, responses to TIV in infants were markedly attenuated, limited to genes regulating antiviral and antigen presentation pathways, and observed only in a subset of vaccinees. In contrast, transcriptional responses to ATIV boost were more homogenous and robust. Interestingly, a day 1 gene signature characteristic of the innate response (antiviral IFN genes, dendritic cell, and monocyte responses) correlated with hemagglutination at day 28. These findings demonstrate that MF59 enhances the magnitude, kinetics, and consistency of the innate and adaptive response to vaccination with the seasonal influenza vaccine during early childhood, and identify potential molecular correlates of antibody responses.

Jones C, Sadarangani M, Lewis S, Payne I, Saleem M, Derrick JP, Pollard AJ. 2016. Characterisation of the Immunomodulatory Effects of Meningococcal Opa Proteins on Human Peripheral Blood Mononuclear Cells and CD4+ T Cells. PLoS One, 11 (4), pp. e0154153. | Show Abstract | Read more

Opa proteins are major surface-expressed proteins located in the Neisseria meningitidis outer membrane, and are potential meningococcal vaccine candidates. Although Opa proteins elicit high levels of bactericidal antibodies following immunisation in mice, progress towards human clinical trials has been delayed due to previous findings that Opa inhibits T cell proliferation in some in vitro assays. However, results from previous studies are conflicting, with different Opa preparations and culture conditions being used. We investigated the effects of various Opa+ and Opa- antigens from N. meningitidis strain H44/76 in a range of in vitro conditions using peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells, measuring T cell proliferation by CFSE dilution using flow cytometry. Wild type recombinant and liposomal Opa proteins inhibited CD4+ T cell proliferation after stimulation with IL-2, anti-CD3 and anti-CD28, and these effects were reduced by mutation of the CEACAM1-binding region of Opa. These effects were not observed in culture with ex vivo PBMCs. Opa+ and Opa- OMVs did not consistently exert a stimulatory or inhibitory effect across different culture conditions. These data do not support a hypothesis that Opa proteins would be inhibitory to T cells if given as a vaccine component, and T cell immune responses to OMV vaccines are unlikely to be significantly affected by the presence of Opa proteins.

Zhou L, Jones C, Gibani MM, Dobinson H, Thomaides-Brears H, Shrestha S, Blohmke CJ, Darton TC, Pollard AJ. 2016. Development and Evaluation of a Blood Culture PCR Assay for Rapid Detection of Salmonella Paratyphi A in Clinical Samples. PLoS One, 11 (3), pp. e0150576. | Show Abstract | Read more

BACKGROUND: Enteric fever remains an important cause of morbidity in many low-income countries and Salmonella Paratyphi A has emerged as the aetiological agent in an increasing proportion of cases. Lack of adequate diagnostics hinders early diagnosis and prompt treatment of both typhoid and paratyphoid but development of assays to identify paratyphoid has been particularly neglected. Here we describe the development of a rapid and sensitive blood culture PCR method for detection of Salmonella Paratyphi A from blood, potentially allowing for appropriate diagnosis and antimicrobial treatment to be initiated on the same day. METHODS: Venous blood samples from volunteers experimentally challenged orally with Salmonella Paratyphi A, who subsequently developed paratyphoid, were taken on the day of diagnosis; 10 ml for quantitative blood culture and automated blood culture, and 5 ml for blood culture PCR. In the latter assay, bacteria were grown in tryptone soy broth containing 2.4% ox bile and micrococcal nuclease for 5 hours (37°C) before bacterial DNA was isolated for PCR detection targeting the fliC-a gene of Salmonella Paratyphi A. RESULTS: An optimized broth containing 2.4% ox bile and micrococcal nuclease, as well as a PCR test was developed for a blood culture PCR assay of Salmonella Paratyphi A. The volunteers diagnosed with paratyphoid had a median bacterial burden of 1 (range 0.1-6.9) CFU/ml blood. All the blood culture PCR positive cases where a positive bacterial growth was shown by quantitative blood culture had a bacterial burden of ≥ 0.3 CFU/ ml blood. The blood culture PCR assay identified an equal number of positive cases as automated blood culture at higher bacterial loads (≥0.3 CFU/ml blood), but utilized only half the volume of specimens. CONCLUSIONS: The blood culture PCR method for detection of Salmonella Paratyphi A can be completed within 9 hours and offers the potential for same-day diagnosis of enteric fever. Using 5 ml blood, it exhibited a lower limit of detection equal to 0.3 CFU/ml blood, and it performed at least as well as automated blood culture at higher bacterial loads (≥0.3 CFU/ml blood) of clinical specimens despite using half the volume of blood. The findings warrant its further study in endemic populations with a potential use as a novel diagnostic which fills the present gap of paratyphoid diagnostics.

Fresnay S, McArthur MA, Magder L, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM, Pollard AJ, Sztein MB. 2016. Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans. J Transl Med, 14 (1), pp. 62. | Show Abstract | Read more

BACKGROUND: Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection. METHODS: Recently, a controlled human infection model was re-established in which volunteers received ~10(3) cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 1 year after challenge were exposed to three S. Typhi-infected targets, i.e., autologous B lymphoblastoid cell-lines (B-LCL), autologous blasts and HLA-E restricted AEH B-LCL cells. CMI responses were evaluated using 14-color multiparametric flow cytometry to detect simultaneously five intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a). RESULTS: Herein we provide the first evidence that S. Typhi-specific CD8+ responses correlate with clinical outcome in humans challenged with wild-type S. Typhi. Higher multifunctional S. Typhi-specific CD8+ baseline responses were associated with protection against typhoid and delayed disease onset. Moreover, following challenge, development of typhoid fever was accompanied by decreases in circulating S. Typhi-specific CD8+ T effector/memory (TEM) with gut homing potential, suggesting migration to the site(s) of infection. In contrast, protection against disease was associated with low or no changes in circulating S. Typhi-specific TEM. CONCLUSIONS: These studies provide novel insights into the protective immune responses against typhoid disease that will aid in selection and development of new vaccine candidates.

Daniels-Treffandier H, de Nie K, Marsay L, Dold C, Sadarangani M, Reyes-Sandoval A, Langford PR, Wyllie D, Hill F, Pollard AJ, Rollier CS. 2016. Impact of Reducing Complement Inhibitor Binding on the Immunogenicity of Native Neisseria meningitidis Outer Membrane Vesicles. PLoS One, 11 (2), pp. e0148840. | Show Abstract | Read more

Neisseria meningitidis recruits host human complement inhibitors to its surface to down-regulate complement activation and enhance survival in blood. We have investigated whether such complement inhibitor binding occurs after vaccination with native outer membrane vesicles (nOMVs), and limits immunogenicity of such vaccines. To this end, nOMVs reactogenic lipopolysaccharide was detoxified by deletion of the lpxl1 gene (nOMVlpxl1). nOMVs unable to bind human complement factor H (hfH) were generated by additional deletions of the genes encoding factor H binding protein (fHbp) and neisserial surface protein A (NspA) (nOMVdis). Antibody responses elicited in mice with nOMVdis were compared to those elicited with nOMVlpxl1 in the presence of hfH. Results demonstrate that the administration of human fH to mice immunized with fHbp containing OMVlpxl1 decreased immunogenicity against fHbp (but not against the OMV as a whole). The majority of the OMV-induced bactericidal immune response (OMVlpxl1 or OMVdis) was versus PorA. Despite a considerable reduction of hfH binding to nOMVdis, and the absence of the vaccine antigen fHbp, immunogenicity in mice was not different from nOMVlpxl1, in the absence or presence of hfH (serum bactericidal titers of 1:64 vs 1:128 after one dose in the nOMVdis and nOMVlpxl1-immunized groups respectively). Therefore, partial inhibition of fH binding did not enhance immunity in this model.

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Ladhani SN, Ramsay M, Borrow R, Riordan A, Watson JM, Pollard AJ. 2016. Enter B and W: two new meningococcal vaccine programmes launched ARCHIVES OF DISEASE IN CHILDHOOD, 101 (1), pp. 91-94. | Read more

Sibley A, Pollard AJ, Fitzpatrick R, Sheehan M. 2016. Developing a new justification for assent. BMC Med Ethics, 17 (1), pp. 2. | Show Abstract | Read more

BACKGROUND: Current guidelines do not clearly outline when assent should be attained from paediatric research participants, nor do they detail the necessary elements of the assent process. This stems from the fact that the fundamental justification behind the concept of assent is misunderstood. In this paper, we critically assess three widespread ethical arguments used for assent: children's rights, the best interests of the child, and respect for a child's developing autonomy. We then outline a newly-developed two-fold justification for the assent process: respect for the parent's pedagogical role in teaching their child to become an autonomous being and respect for the child's moral worth. DISCUSSION: We argue that the ethical grounding for the involvement of young children in medical decision-making does not stem from children's rights, the principle of best interests, or respect for developing autonomy. An alternative strategy is to examine the original motivation to engage with the child. In paediatric settings there are two obligations on the researcher: an obligation to the parents who are responsible for determining when and under what circumstances the child develops his capacity for autonomy and reasoning, and an obligation to the child himself. There is an important distinction between respecting a decision and encouraging a decision. This paper illustrates that the process of assent is an important way in which respect for the child as an individual can be demonstrated, however, the value lies not in the child's response but the fact that his views were solicited in the first place. This paper demonstrates that the common justifications for the process of assent are incomplete. Assent should be understood as playing a pedagogical role for the child, helping to teach him how specific decisions are made and therefore helping him to become a better decision-maker. How the researcher engages with the child supports his obligation to the child's parents, yet why the researcher engages with the child stems from the child's moral worth. Treating a child as having moral worth need not mean doing what they say but it may mean listening, considering, engaging or involving them in the decision.

Ladhani SN, Ramsay M, Borrow R, Riordan A, Watson JM, Pollard AJ. 2016. Enter B and W: two new meningococcal vaccine programmes launched. Arch Dis Child, 101 (1), pp. 91-95. | Show Abstract | Read more

In 2015, the UK became the first country in the world to have a comprehensive routine meningococcal vaccine programme targeting all of the main capsular groups of N. meningitidis. 1 An infant vaccine programme against meningococcal capsular group B Neisseria meningitidis (MenB) was launched from 1st September with an aim to reduce endemic MenB disease in early childhood. On 1st August 2015, an adolescent programme against groups A, C, W and Y meningococci (MenACWY) was rolled out to halt a growing outbreak of capsular group W disease (MenW) caused by a hypervirulent clone of N. meningitidis, in addition to maintaining control against MenC disease provided by the current adolescent programme. 2.

Lazarus R, Kelly S, Snape MD, Vandermeulen C, Voysey M, Hoppenbrouwers K, Hens A, Van Damme P, Pepin S, Leroux-Roels I et al. 2016. Antibody Persistence and Booster Responses to Split-Virion H5N1 Avian Influenza Vaccine in Young and Elderly Adults. PLoS One, 11 (11), pp. e0165384. | Show Abstract | Read more

Avian influenza continues to circulate and remains a global health threat not least because of the associated high mortality. In this study antibody persistence, booster vaccine response and cross-clade immune response between two influenza A(H5N1) vaccines were compared. Participants aged over 18-years who had previously been immunized with a clade 1, A/Vietnam vaccine were re-immunized at 6-months with 7.5 μg of the homologous strain or at 22-months with a clade 2, alum-adjuvanted, A/Indonesia vaccine. Blood sampled at 6, 15 and 22-months after the primary course was used to assess antibody persistence. Antibody concentrations 6-months after primary immunisation with either A/Vietnam vaccine 30 μg alum-adjuvanted vaccine or 7.5 μg dose vaccine were lower than 21-days after the primary course and waned further with time. Re-immunization with the clade 2, 30 μg alum-adjuvanted vaccine confirmed cross-clade reactogenicity. Antibody cross-reactivity between A(H5N1) clades suggests that in principle a prime-boost vaccination strategy may provide both early protection at the start of a pandemic and improved antibody responses to specific vaccination once available. TRIAL REGISTRATION: ClinicalTrials.gov NCT00415129.

Fitzgerald F, Yeung S, Gibb DM, Baion DE, Pollard A. 2015. Ebola vaccination. Lancet, 386 (10012), pp. 2478. | Read more

Ellul MA, Griffiths MJ, Iyer A, Avula S, Defres S, Baborie A, Vincent A, Martin NG, Sadarangani M, Pollard AJ et al. 2016. Anti-N-Methyl-D-Aspartate Receptor Encephalitis In A Young Child With Histological Evidence On Brain Biopsy Of Coexistent Herpes Simplex Virus Type 1 Infection. Pediatr Infect Dis J, 35 (3), pp. 347-349. | Show Abstract | Read more

We report a 3-year-old boy with anti-N-methyl-D-aspartate receptor encephalitis with a typical syndrome of movement disorder and encephalopathy and evidence of herpes simplex virus (HSV) type 1 infection on brain biopsy. HSV type 1 infection and anti-N-methyl-D-aspartate receptor encephalitis are temporally linked in some cases: this case suggests that prodromal HSV type-1 infection may be clinically subtle and easily missed.

Drysdale SB, Sande CJ, Green CA, Pollard AJ. 2016. RSV vaccine use--the missing data. Expert Rev Vaccines, 15 (2), pp. 149-152. | Show Abstract | Read more

Respiratory syncytial virus (RSV) infection is the most important cause of hospitalization in infants and is one of the leading global causes of infant mortality and as such its prevention through vaccination is a public health priority. While essential for the successful implementation of vaccine programs, there remains a paucity of data on the epidemiology of the virus in different settings and age groups and limited knowledge about virus transmission and the health-care costs of the disease. Such data are now needed to populate health economic models and to inform optimal approaches to disease control through vaccination.

Darton T, Jones C, Waddington C, Blohmke C, Peters A, Haworth K, Green C, Jeppesen C, Moore M, Thompson B et al. 2015. LIVE ATTENUATED ORAL VACCINE, AGE AND ANTI-VI ANTIBODY STATUS AT BASELINE SIGNIFICANTLY AFFECT ATTACK RATE IN A HUMAN SALMONELLA TYPHI CHALLENGE MODEL JOURNAL OF INFECTION, 71 (6), pp. 689-689. | Read more

Galson JD, Trück J, Fowler A, Clutterbuck EA, Münz M, Cerundolo V, Reinhard C, van der Most R, Pollard AJ, Lunter G, Kelly DF. 2015. Analysis of B Cell Repertoire Dynamics Following Hepatitis B Vaccination in Humans, and Enrichment of Vaccine-specific Antibody Sequences. EBioMedicine, 2 (12), pp. 2070-2079. | Show Abstract | Read more

Generating a diverse B cell immunoglobulin repertoire is essential for protection against infection. The repertoire in humans can now be comprehensively measured by high-throughput sequencing. Using hepatitis B vaccination as a model, we determined how the total immunoglobulin sequence repertoire changes following antigen exposure in humans, and compared this to sequences from vaccine-specific sorted cells. Clonal sequence expansions were seen 7 days after vaccination, which correlated with vaccine-specific plasma cell numbers. These expansions caused an increase in mutation, and a decrease in diversity and complementarity-determining region 3 sequence length in the repertoire. We also saw an increase in sequence convergence between participants 14 and 21 days after vaccination, coinciding with an increase of vaccine-specific memory cells. These features allowed development of a model for in silico enrichment of vaccine-specific sequences from the total repertoire. Identifying antigen-specific sequences from total repertoire data could aid our understanding B cell driven immunity, and be used for disease diagnostics and vaccine evaluation.

Snape MD, Voysey M, Finn A, Bona G, Esposito S, Principi N, Diez-Domingo J, Sokal E, Kieninger D, Prymula R et al. 2016. Persistence of Bactericidal Antibodies After Infant Serogroup B Meningococcal Immunization and Booster Dose Response at 12, 18 or 24 Months of Age. Pediatr Infect Dis J, 35 (4), pp. e113-e123. | Show Abstract | Read more

BACKGROUND: A serogroup B meningococcal vaccine (4CMenB) is licensed for infant use in countries including Canada, Australia and those of the European Union. Data on serum bactericidal antibody (hSBA) waning and the ideal timing of a "toddler" booster dose are essential to optimize vaccine utilization. METHODS: An open-labeled, multicenter phase-2b follow-on European study conducted from 2009 to 2012. Participants previously receiving 4CMenB with routine vaccines at 2, 4 and 6 or 2, 3 and 4 months (246Con and 234Con) or at 2, 4 and 6 months intercalated with routine vaccines (246Int) received a booster dose at 12, 18 or 24 months. 4CMenB-naïve "Control" participants aged 12, 18 or 24 months received 2 doses of 4CMenB 2 months apart. RESULTS: One thousand five hundred eighty-eight participants were recruited. At 12 months, before any booster doses, the proportions with hSBA titers ≥1:5 for strain 44/76-SL (testing vaccine component fHBP) were 73% (120/165) for the "246Con" group, 85% (125/147) for "246Int," 57% (51/90) for "234Con" and 13% (26/199) for Controls. For strain 5/99 (NadA) proportions were ≥96% (all 4CMenB-recipients) and 1% (Controls). For strain NZ98/254 (PorA), these were 18-35% (4CMenB-recipients) and 1% (Controls). By 24 months, 4CMenB-recipient proportions were 13-22% (44/76-SL), 82-94% (5/99) and 7-13% (NZ98/254) and in controls ≤4%. After a 12-month booster-dose, ≥95% of previously immunized participants had titers ≥1:5 (all strains). CONCLUSIONS: A 4CMenB booster-dose can overcome waning hSBA titers after early-infant immunization. Administration at 12 months could help to maintain immunity during an age of high risk, and the persistence of this response requires further study.

Blohmke CJ, O'Connor D, Pollard AJ. 2015. The use of systems biology and immunological big data to guide vaccine development. Genome Med, 7 (1), pp. 114. | Show Abstract | Read more

High-throughput technologies applied to the analysis of vaccine responses are likely to reveal the mechanisms responsible for vaccine-induced protection, aid understanding of vaccine safety and help accelerate vaccine development and clinical trials.

Gibani MM, Jin C, Darton TC, Pollard AJ. 2015. Control of Invasive Salmonella Disease in Africa: Is There a Role for Human Challenge Models? Clin Infect Dis, 61 Suppl 4 (suppl 4), pp. S266-S271. | Show Abstract | Read more

Invasive Salmonella disease in Africa is a major public health concern. With evidence of the transcontinental spread of the Salmonella Typhi H58 haplotype, improved estimates of the burden of infection and understanding of the complex interplay of factors affecting disease transmission are needed to assist with efforts aimed at disease control. In addition to Salmonella Typhi, invasive nontyphoidal Salmonella are increasingly recognized as an important cause of febrile illness and mortality in sub-Saharan Africa. Human experimental oral challenge studies with Salmonella can be used as a model to offer unique insights into host-pathogen interactions as well as a platform to efficiently test new diagnostic and vaccine candidates. In this article, we review the background and use of human challenge studies to date and discuss how findings from these studies may lead to progress in the control of invasive Salmonella disease in Africa.

Sanders H, Norheim G, Chan H, Dold C, Vipond C, Derrick JP, Pollard AJ, Maiden MCJ, Feavers IM. 2015. FetA Antibodies Induced by an Outer Membrane Vesicle Vaccine Derived from a Serogroup B Meningococcal Isolate with Constitutive FetA Expression. PLoS One, 10 (10), pp. e0140345. | Show Abstract | Read more

Invasive meningococcal disease causes over 3500 cases each year in Europe, with particularly high incidence among young children. Among serogroup B meningococci, which cause most of the cases, high diversity in the outer membrane proteins (OMPs) is observed in endemic situations; however, comprehensive molecular epidemiological data are available for the diversity and distribution of the OMPs PorA and FetA and these can be used to rationally design a vaccine with high coverage of the case isolates. The aim of this study was to determine whether outer membrane vesicles (OMVs) derived from an isolate with constitutive FetA expression (MenPF-1 vaccine) could be used to induce antibodies against both the PorA and FetA antigens. The immunogenicity of various dose levels and number of doses was evaluated in mice and rabbits, and IgG antibody responses tested against OMVs and recombinant PorA and FetA proteins. A panel of four isogenic mutants was generated and used to evaluate the relative ability of the vaccine to induce serum bactericidal activity (SBA) against FetA and PorA. Sera from mice were tested in SBA against the four target strains. Results demonstrated that the MenPF-1 OMVs were immunogenic against PorA and FetA in both animal models. Furthermore, the murine antibodies induced were bactericidal against isogenic mutant strains, suggesting that antibodies to both PorA and FetA were functional. The data presented indicate that the MenPF-1 vaccine is a suitable formulation for presenting PorA and FetA OMPs in order to induce bactericidal antibodies, and that proceeding to a Phase I clinical trial with this vaccine candidate is justified.

Angus BJ, Dobinson H, Thomaides-Brears H, Jones C, Campbell D, Voysey M, Kerridge S, Martin LB, Leroy O, Dalessio F, Pollard AJ. 2015. A NOVEL HUMAN MODEL OF SALMONELLA ENTERICA SEROVAR PARATYPHI A CHALLENGE IN HEALTHY ADULT VOLUNTEERS AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 93 (4), pp. 365-366.

Darton TC, Blohmke CJ, Giannoulatou E, Waddington CS, Jones C, Sturges P, Webster C, Drakesmith H, Pollard AJ, Armitage AE. 2015. Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans. PLoS Negl Trop Dis, 9 (9), pp. e0004029. | Show Abstract | Read more

BACKGROUND: Iron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge. METHODOLOGY/PRINCIPAL FINDINGS: Fifty study participants were challenged with Salmonella enterica serovar Typhi and monitored for evidence of typhoid fever. Serum hepcidin, ferritin, serum iron parameters, C-reactive protein (CRP), and plasma IL-6 and TNF-alpha concentrations were measured during the 14 days following challenge. We found that hepcidin concentrations were markedly higher during acute typhoid infection than at baseline. Hepcidin elevations mirrored the kinetics of fever, and were accompanied by profound hypoferremia, increased CRP and ferritin, despite only modest elevations in IL-6 and TNF-alpha in some individuals. During inflammation, the extent of hepcidin upregulation associated with the degree of hypoferremia. CONCLUSIONS/SIGNIFICANCE: We demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi.

Norheim G, Sanders H, Mellesdal JW, Sundfør I, Chan H, Brehony C, Vipond C, Dold C, Care R, Saleem M et al. 2015. An OMV Vaccine Derived from a Capsular Group B Meningococcus with Constitutive FetA Expression: Preclinical Evaluation of Immunogenicity and Toxicity. PLoS One, 10 (9), pp. e0134353. | Show Abstract | Read more

Following the introduction of effective protein-polysaccharide conjugate vaccines against capsular group C meningococcal disease in Europe, meningococci of capsular group B remain a major cause of death and can result in debilitating sequelae. The outer membrane proteins PorA and FetA have previously been shown to induce bactericidal antibodies in humans. Despite considerable antigenic variation among PorA and FetA OMPs in meningococci, systematic molecular epidemiological studies revealed this variation is highly structured so that a limited repertoire of antigenic types is congruent with the hyperinvasive meningococcal lineages that have caused most of the meningococcal disease in Europe in recent decades. Here we describe the development of a prototype vaccine against capsular group B meningococcal infection based on a N. meningitidis isolate genetically engineered to have constitutive expression of the outer membrane protein FetA. Deoxycholate outer membrane vesicles (dOMVs) extracted from cells cultivated in modified Frantz medium contained 21.8% PorA protein, 7.7% FetA protein and 0.03 μg LPS per μg protein (3%). The antibody response to the vaccine was tested in three mouse strains and the toxicological profile of the vaccine was tested in New Zealand white rabbits. Administration of the vaccine, MenPF-1, when given by intramuscular injection on 4 occasions over a 9 week period, was well tolerated in rabbits up to 50 μg/dose, with no evidence of systemic toxicity. These data indicated that the MenPF-1 vaccine had a toxicological profile suitable for testing in a phase I clinical trial.

Green CA, Yeates D, Goldacre A, Sande C, Parslow RC, McShane P, Pollard AJ, Goldacre MJ. 2016. Admission to hospital for bronchiolitis in England: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma. Arch Dis Child, 101 (2), pp. 140-146. | Show Abstract | Read more

BACKGROUND: Admission of infants to hospital with bronchiolitis consumes considerable healthcare resources each winter. We report an analysis of hospital admissions in England over five decades. METHODS: Data were analysed from the Hospital In-Patient Enquiry (HIPE, 1968-1985), Hospital Episode Statistics (HES, 1989-2011), Oxford Record Linkage Study (ORLS, 1963-2011) and Paediatric Intensive Care Audit Network (PICANet, 2003-2012). Cases were identified using International Classification of Diseases (ICD) codes in discharge records. Bronchiolitis was given a separate code in ICD9 (used in England from 1979). Geographical variation was analysed using Local Authority area boundaries. Maternal and perinatal risk factors associated with bronchiolitis and subsequent admissions for asthma were analysed using record-linkage. RESULTS: All-England HIPE and HES data recorded 468 138 episodes of admission for bronchiolitis in infants aged <1 year between 1979 and 2011. In 2011 the estimated annual hospital admission rate was 46.1 (95% CI 45.6 to 46.6) per 1000 infants aged <1 year. Between 2004 and 2011 the rates rose by an average of 1.8% per year in the all-England HES data, whereas admission rates to paediatric intensive care changed little (1.3 to 1.6 per 1000 infants aged <1 year). A fivefold geographical variation in hospital admission rates was observed. Young maternal age, low social class, low birth weight and maternal smoking were among factors associated with an increased risk of hospital admission with bronchiolitis. CONCLUSIONS: Hospital admissions for infants with bronchiolitis have increased substantially in recent years. However, cases requiring intensive care have changed little since 2004.

Ford KJ, Lang S, Pollard AJ, McCarthy ND. 2016. A quantitative review of healthcare professionals' questions to a local immunization advice service: 4299 enquiries from 3 years. J Public Health (Oxf), 38 (3), pp. 578-584. | Show Abstract | Read more

BACKGROUND: Immunization advice services can support health professionals by providing rapid access to accurate and reliable current information and advice. The Vaccine Advice for Clinicians Service (VACCSline) is a service for health professionals working within the Thames Valley Area of the UK. METHODS: We reviewed all 4299 enquiries received by VACCSline over 3 years. Queries were summarized by vaccine type and topic of enquiry. Associations with profession and workplace of the enquirer were tested using Fisher's exact tests. RESULTS: Incomplete immunization status and non-UK schedules were the most common topics of enquiry. Practice nurses were the main service users followed by doctors. Enquiries varied by professional role. Alterations to the immunization programme led to temporary changes to enquiry content and some more persistent adjustments in the balance of enquiries were identified, such as an increase in enquiries relating to vaccination in pregnancy. CONCLUSIONS: The content of enquiries to VACCSline is broad, confirming the need for immunizers to have a wide knowledge base and access to specialist advice to assist with complex scenarios. Systematic data capture provided intelligence to guide training and materials to support immunizers. A wider networked application of this approach could improve support for immunizers.

Green CA, Scarselli E, Sande CJ, Thompson AJ, de Lara CM, Taylor KS, Haworth K, Del Sorbo M, Angus B, Siani L et al. 2015. Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults. Sci Transl Med, 7 (300), pp. 300ra126. | Show Abstract | Read more

Respiratory syncytial virus (RSV) causes respiratory infection in annual epidemics, with infants and the elderly at particular risk of developing severe disease and death. However, despite its importance, no vaccine exists. The chimpanzee adenovirus, PanAd3-RSV, and modified vaccinia virus Ankara, MVA-RSV, are replication-defective viral vectors encoding the RSV fusion (F), nucleocapsid (N), and matrix (M2-1) proteins for the induction of humoral and cellular responses. We performed an open-label, dose escalation, phase 1 clinical trial in 42 healthy adults in which four different combinations of prime/boost vaccinations were investigated for safety and immunogenicity, including both intramuscular (IM) and intranasal (IN) administration of the adenovirus-vectored vaccine. The vaccines were safe and well tolerated, with the most common reported adverse events being mild injection site reactions. No vaccine-related serious adverse events occurred. RSV neutralizing antibody titers rose in response to IM prime with PanAd3-RSV and after IM boost for individuals primed by the IN route. Circulating anti-F immunoglobulin G (IgG) and IgA antibody-secreting cells (ASCs) were observed after the IM prime and IM boost. RSV-specific T cell responses were increased after the IM PanAd3-RSV prime and were most efficiently boosted by IM MVA-RSV. Interferon-γ (IFN-γ) secretion after boost was from both CD4(+) and CD8(+) T cells, without detectable T helper cell 2 (TH2) cytokines that have been previously associated with immune pathogenesis following exposure to RSV after the formalin-inactivated RSV vaccine. In conclusion, PanAd3-RSV and MVA-RSV are safe and immunogenic in healthy adults. These vaccine candidates warrant further clinical evaluation of efficacy to assess their potential to reduce the burden of RSV disease.

John T, Voysey M, Yu LM, McCarthy N, Baudin M, Richard P, Fiquet A, Kitchin N, Pollard AJ. 2015. Immunogenicity of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine compared to standard-dose diphtheria, tetanus, acellular pertussis when used as a pre-school booster in UK children: A 5-year follow-up of a randomised controlled study. Vaccine, 33 (36), pp. 4579-4585. | Show Abstract | Read more

This serological follow up study assessed the kinetics of antibody response in children who previously participated in a single centre, open-label, randomised controlled trial of low-dose compared to standard-dose diphtheria booster preschool vaccinations in the United Kingdom (UK). Children had previously been randomised to receive one of three combination vaccines: either a combined adsorbed tetanus, low-dose diphtheria, 5-component acellular pertussis and inactivated polio vaccine (IPV) (Tdap-IPV, Repevax(®); Sanofi Pasteur MSD); a combined adsorbed tetanus, low-dose diphtheria and 5-component acellular pertussis vaccine (Tdap, Covaxis(®); Sanofi Pasteur MSD) given concomitantly with oral polio vaccine (OPV); or a combined adsorbed standard-dose diphtheria, tetanus, 2-component acellular pertussis and IPV (DTap-IPV, Tetravac(®); Sanofi Pasteur MSD). Blood samples for the follow-up study were taken at 1, 3 and 5 years after participation in the original trial (median, 5.07 years of age at year 1), and antibody persistence to each vaccine antigen measured against defined serological thresholds of protection. All participants had evidence of immunity to diphtheria with antitoxin concentrations greater than 0.01IU/mL five years after booster vaccination and 75%, 67% and 79% of children who received Tdap-IPV, Tdap+OPV and DTap-IPV, respectively, had protective antitoxin levels greater than 0.1IU/mL. Long lasting protective immune responses to tetanus and polio antigens were also observed in all groups, though polio responses were lower in the sera of those who received OPV. Low-dose diphtheria vaccines provided comparable protection to the standard-dose vaccine and are suitable for use for pre-school booster vaccination.

Marshall H, Wang B, Wesselingh S, Snape M, Pollard AJ. 2016. Control of invasive meningococcal disease: is it achievable? Int J Evid Based Healthc, 14 (1), pp. 3-14. | Show Abstract | Read more

Neisseria meningitidis still leads to deaths and severe disability in children, adolescents and adults. Six different capsular groups of N. meningitidis cause invasive meningococcal disease in the form of meningitis and septicaemia in humans. Although conjugate meningococcal vaccines have been developed to provide protection against four of the capsular groups causing most diseases in humans, vaccines against capsular group B, which causes 85% of cases in Australia and the United Kingdom, have only recently been developed. A capsular group B meningococcal vaccine - 4CMenB (Bexsero) - has recently been licensed in the European Union, Canada and Australia. In Australia, a submission for inclusion of 4CMenB in the funded national immunization programme has recently been rejected. The vaccine will now be introduced into the national immunization programme in the United Kingdom following negotiation of a cost-effective price. With the current low incidence of invasive meningococcal disease in many regions, cost-effectiveness of a new capsular group B meningococcal vaccine is borderline in both the United Kingdom and Australia. Cost-effectiveness of an infant programme is determined largely by the direct protection of those vaccinated and is driven by the higher rate of disease in this age group. However, for an adolescent programme to be cost-effective, it must provide both long-term protection against both disease and carriage. The potential of vaccination to reduce the rate of severe invasive disease is a real possibility. A dual approach using both an infant and adolescent immunization programme to provide direct protection to those age groups at highest risk of meningococcal disease and to optimize the potential herd immunity effects is likely to be the most effective means of reducing invasive meningococcal disease. This commentary aims to describe the known disease burden and consequences of meningococcal disease, and the development and potential effectiveness of new capsular group B meningococcal vaccines.

Mentzer AJ, O'Connor D, Pollard AJ, Hill AVS. 2015. Searching for the human genetic factors standing in the way of universally effective vaccines. Philos Trans R Soc Lond B Biol Sci, 370 (1671), pp. 20140341-20140341. | Show Abstract | Read more

Vaccines have revolutionized modern public health. The effectiveness of some vaccines is limited by the variation in response observed between individuals and across populations. There is compelling evidence that a significant proportion of this variability can be attributed to human genetic variation, especially for those vaccines administered in early life. Identifying and understanding the determinants of this variation could have a far-reaching influence upon future methods of vaccine design and deployment. In this review, we summarize the genetic studies that have been undertaken attempting to identify the genetic determinants of response heterogeneity for the vaccines against hepatitis B, measles and rubella. We offer a critical appraisal of these studies and make a series of suggestions about how modern genetic techniques, including genome-wide association studies, could be used to characterize the genetic architecture of vaccine response heterogeneity. We conclude by suggesting how the findings from such studies could be translated to improve vaccine effectiveness and target vaccination in a more cost-effective manner.

Toapanta FR, Bernal PJ, Fresnay S, Darton TC, Jones C, Waddington CS, Blohmke CJ, Dougan G, Angus B, Levine MM et al. 2015. Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis, 9 (6), pp. e0003837. | Show Abstract | Read more

A new human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently developed. In this model, ingestion of 104 CFU of Salmonella resulted in 65% of subjects developing typhoid fever (referred here as typhoid diagnosis -TD-) 5-10 days post-challenge. TD criteria included meeting clinical (oral temperature ≥38°C for ≥12 h) and/or microbiological (S. Typhi bacteremia) endpoints. One of the first lines of defense against pathogens are the cells of the innate immune system (e.g., monocytes, dendritic cells -DCs-). Various changes in circulating monocytes and DCs have been described in the murine S. Typhimurium model; however, whether similar changes are present in humans remains to be explored. To address these questions, a subset of volunteers (5 TD and 3 who did not develop typhoid despite oral challenge -NoTD-) were evaluated for changes in circulating monocytes and DCs. Expression of CD38 and CD40 were upregulated in monocytes and DCs in TD volunteers during the disease days (TD-0h to TD-96h). Moreover, integrin α4β7, a gut homing molecule, was upregulated on monocytes but not DCs. CD21 upregulation was only identified in DCs. These changes were not observed among NoTD volunteers despite the same oral challenge. Moreover, monocytes and DCs from NoTD volunteers showed increased binding to S. Typhi one day after challenge. These monocytes showed phosphorylation of p38MAPK, NFkB and Erk1/2 upon stimulation with S. Typhi-LPS-QDot micelles. In contrast, monocytes from TD volunteers showed only a moderate increase in S. Typhi binding 48 h and 96 h post-TD, and only Erk1/2 phosphorylation. This is the first study to describe different activation and migration profiles, as well as differential signaling patterns, in monocytes and DCs which relate directly to the clinical outcome following oral challenge with wild type S. Typhi.

Darton TC, Blohmke CJ, Moorthy VS, Altmann DM, Hayden FG, Clutterbuck EA, Levine MM, Hill AVS, Pollard AJ. 2015. Design, recruitment, and microbiological considerations in human challenge studies. Lancet Infect Dis, 15 (7), pp. 840-851. | Show Abstract | Read more

Since the 18th century a wealth of knowledge regarding infectious disease pathogenesis, prevention, and treatment has been accumulated from findings of infection challenges in human beings. Partly because of improvements to ethical and regulatory guidance, human challenge studies-involving the deliberate exposure of participants to infectious substances-have had a resurgence in popularity in the past few years, in particular for the assessment of vaccines. To provide an overview of the potential use of challenge models, we present historical reports and contemporary views from experts in this type of research. A range of challenge models and practical approaches to generate important data exist and are used to expedite vaccine and therapeutic development and to support public health modelling and interventions. Although human challenge studies provide a unique opportunity to address complex research questions, participant and investigator safety is paramount. To increase the collaborative effort and future success of this area of research, we recommend the development of consensus frameworks and sharing of best practices between investigators. Furthermore, standardisation of challenge procedures and regulatory guidance will help with the feasibility for using challenge models in clinical testing of new disease intervention strategies.

Marsay L, Dold C, Green CA, Rollier CS, Norheim G, Sadarangani M, Shanyinde M, Brehony C, Thompson AJ, Sanders H et al. 2015. A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial. J Infect, 71 (3), pp. 326-337. | Show Abstract | Read more

OBJECTIVES: Outer membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines. METHODS: The OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 μg or 50 μg of MenPF-1 were delivered intra-muscularly to 52 healthy adults. RESULTS: MenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetA(on)PorA(off) compared to 51% in the strain 44/76 FetA(off)PorA(off), demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies. CONCLUSION: This study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.

Galson JD, Clutterbuck EA, Trück J, Ramasamy MN, Münz M, Fowler A, Cerundolo V, Pollard AJ, Lunter G, Kelly DF. 2015. BCR repertoire sequencing: different patterns of B-cell activation after two Meningococcal vaccines. Immunol Cell Biol, 93 (10), pp. 885-895. | Show Abstract | Read more

Next-generation sequencing was used to investigate the B-cell receptor heavy chain transcript repertoire of different B-cell subsets (naive, marginal zone (MZ), immunoglobulin M (IgM) memory and IgG memory) at baseline, and of plasma cells (PCs) 7 days following administration of serogroup ACWY meningococcal polysaccharide and protein-polysaccharide conjugate vaccines. Baseline B-cell subsets could be distinguished from each other using a small number of repertoire properties (clonality, mutation from germline and complementarity-determining region 3 (CDR3) length) that were conserved between individuals. However, analyzing the CDR3 amino-acid sequence (which is particularly important for antigen binding) of the baseline subsets showed few sequences shared between individuals. In contrast, day 7 PCs demonstrated nearly 10-fold greater sequence sharing between individuals than the baseline subsets, consistent with the PCs being induced by the vaccine antigen and sharing specificity for a more limited range of epitopes. By annotating PC sequences based on IgG subclass usage and mutation, and also comparing them with the sequences of the baseline cell subsets, we were able to identify different signatures after the polysaccharide and conjugate vaccines. PCs produced after conjugate vaccination were predominantly IgG1, and most related to IgG memory cells. In contrast, after polysaccharide vaccination, the PCs were predominantly IgG2, less mutated and were equally likely to be related to MZ, IgM memory or IgG memory cells. High-throughput B-cell repertoire sequencing thus provides a unique insight into patterns of B-cell activation not possible from more conventional measures of immunogenicity.

McArthur MA, Fresnay S, Magder LS, Darton TC, Jones C, Waddington CS, Blohmke CJ, Dougan G, Angus B, Levine MM et al. 2015. Activation of Salmonella Typhi-specific regulatory T cells in typhoid disease in a wild-type S. Typhi challenge model. PLoS Pathog, 11 (5), pp. e1004914. | Show Abstract | Read more

Salmonella Typhi (S. Typhi), the causative agent of typhoid fever, causes significant morbidity and mortality worldwide. Currently available vaccines are moderately efficacious, and identification of immunological responses associated with protection or disease will facilitate the development of improved vaccines. We investigated S. Typhi-specific modulation of activation and homing potential of circulating regulatory T cells (Treg) by flow and mass cytometry using specimens obtained from a human challenge study. Peripheral blood mononuclear cells were obtained from volunteers pre- and at multiple time-points post-challenge with wild-type S. Typhi. We identified differing patterns of S. Typhi-specific modulation of the homing potential of circulating Treg between volunteers diagnosed with typhoid (TD) and those who were not (No TD). TD volunteers demonstrated up-regulation of the gut homing molecule integrin α4ß7 pre-challenge, followed by a significant down-regulation post-challenge consistent with Treg homing to the gut. Additionally, S. Typhi-specific Treg from TD volunteers exhibited up-regulation of activation molecules post-challenge (e.g., HLA-DR, LFA-1). We further demonstrate that depletion of Treg results in increased S. Typhi-specific cytokine production by CD8+ TEM in vitro. These results suggest that the tissue distribution of activated Treg, their characteristics and activation status may play a pivotal role in typhoid fever, possibly through suppression of S. Typhi-specific effector T cell responses. These studies provide important novel insights into the regulation of immune responses that are likely to be critical in protection against typhoid and other enteric infectious diseases.

Drysdale SB, Pollard AJ. 2015. Group B meningococcal vaccine science and policy. J Infect, 71 Suppl 1 pp. S15-S20. | Show Abstract | Read more

Capsular group B Neisseria meningitidis is one of the leading causes of death in developed countries. A new vaccine (4CMenB) has recently been developed which was found to have an acceptable safety profile in clinical studies and to be immunogenic. This review examines the evidence supporting the licensure of the 4CMenB vaccine and discusses recommendations for its use.

Pace D, Khatami A, McKenna J, Campbell D, Attard-Montalto S, Birks J, Voysey M, White C, Finn A, Macloed E et al. 2015. Immunogenicity of reduced dose priming schedules of serogroup C meningococcal conjugate vaccine followed by booster at 12 months in infants: open label randomised controlled trial. BMJ, 350 (apr01 16), pp. h1554. | Show Abstract | Read more

OBJECTIVE: To determine whether the immunogenicity of a single dose infant priming schedule of serogroup C meningococcal (MenC) conjugate vaccine is non-inferior to a two dose priming schedule when followed by a booster dose at age 12 months. DESIGN: Phase IV open label randomised controlled trial carried out from July 2010 until August 2013 SETTING: Four centres in the United Kingdom and one centre in Malta. PARTICIPANTS: Healthy infants aged 6-12 weeks followed up until age 24 months. INTERVENTIONS: In the priming phase of the trial 509 infants were randomised in a 10:10:7:4 ratio into four groups to receive either a single MenC-cross reacting material 197 (CRM) dose at 3 months; two doses of MenC-CRM at 3 and 4 months; a single MenC-polysaccharide-tetanus toxoid (TT) dose at 3 months; or no MenC doses, respectively. Haemophilus influenzae type b (Hib)-MenC-TT vaccine was administered to all infants at 12 months of age. All infants also received the nationally routinely recommended vaccines. Blood samples were taken at age 5, 12, 13, and 24 months. MAIN OUTCOME MEASURE: MenC serum bactericidal antibody assay with rabbit complement (rSBA) one month after the Hib-MenC-TT vaccine. Non-inferiority was met if the lower 95% confidence limit of the difference in the mean log10 MenC rSBA between the single dose MenC-CRM and the two dose MenC-CRM groups was >-0.35. RESULTS: The primary objective was met: after a Hib-MenC-TT booster dose at 12 months of age the MenC rSBA geometric mean titres induced in infants primed with a single MenC-CRM dose were not inferior to those induced in participants primed with two MenC-CRM doses in infancy (660 (95% confidence interval 498 to 876) v 295 (220 to 398)) with a corresponding difference in the mean log10 MenC rSBA of 0.35 (0.17 to 0.53) that showed superiority of the single over the two dose schedule). Exploration of differences between the priming schedules showed that one month after Hib-MenC-TT vaccination, MenC rSBA ≥ 1:8 was observed in >96% of participants previously primed with any of the MenC vaccine schedules in infancy and in 83% of those who were not vaccinated against MenC in infancy. The MenC rSBA geometric mean titres induced by the Hib-MenC-TT boost were significantly higher in children who were primed with one rather than two MenC-CRM doses in infancy. Only priming with MenC-TT, however, induced robust MenC bactericidal antibody after the Hib-MenC-TT booster that persisted until 24 months of age. CONCLUSIONS: MenC vaccination programmes with two MenC infant priming doses could be reduced to a single priming dose without reducing post-boost antibody titres. When followed by a Hib-MenC-TT booster dose, infant priming with a single MenC-TT vaccine dose induces a more robust antibody response than one or two infant doses of MenC-CRM. Bactericidal antibody induced by a single Hib-MenC-TT conjugate vaccine dose at 12 months of age (that is, a toddler only schedule), without infant priming, is not well sustained at 24 months. Because of rapid waning of MenC antibody, programmes using toddler only schedules will still need to rely on herd protection to protect infants and young children.Trial registration Eudract No: 2009-016579-31; NCT01129518; study ID: 2008_06 (http://clinicaltrials.gov).

Weissmueller NT, Schiffter HA, Carlisle RC, Rollier CS, Pollard AJ. 2015. Needle-Free Dermal Delivery of a Diphtheria Toxin CRM197 Mutant on Potassium-Doped Hydroxyapatite Microparticles. Clin Vaccine Immunol, 22 (5), pp. 586-592. | Show Abstract | Read more

Injections with a hypodermic needle and syringe (HNS) are the current standard of care globally, but the use of needles is not without limitation. While a plethora of needle-free injection devices exist, vaccine reformulation is costly and presents a barrier to their widespread clinical application. To provide a simple, needle-free, and broad-spectrum protein antigen delivery platform, we developed novel potassium-doped hydroxyapatite (K-Hap) microparticles with improved protein loading capabilities that can provide sustained local antigen presentation and release. K-Hap showed increased protein adsorption over regular hydroxyapatite (P < 0.001), good structural retention of the model antigen (CRM197) with 1% decrease in α-helix content and no change in β-sheet content upon adsorption, and sustained release in vitro. Needle-free intradermal powder inoculation with K-Hap-CRM197 induced significantly higher IgG1 geometric mean titers (GMTs) than IgG2a GMTs in a BALB/c mouse model (P < 0.001) and induced IgG titer levels that were not different from the current clinical standard (P > 0.05), namely, alum-adsorbed CRM197 by intramuscular (i.m.) delivery. The presented results suggest that K-Hap microparticles may be used as a novel needle-free delivery vehicle for some protein antigens.

McQuaid F, Snape MD, John TM, Kelly S, Robinson H, Yu L-M, Toneatto D, D'Agostino D, Dull PM, Pollard AJ. 2015. Persistence of specific bactericidal antibodies at 5 years of age after vaccination against serogroup B meningococcus in infancy and at 40 months. CMAJ, 187 (7), pp. E215-E223. | Show Abstract | Read more

BACKGROUND: The multicomponent serogroup B meningococcal (4CMenB) vaccine induces antibodies against indicator strains of serogroup B meningococcus under various schedules. We investigated the persistence of antibodies in 5-year-old children 18-20 months after their last dose (at about 3.5 years of age). METHODS: We assessed 5-year-old children who received the 4CMenB vaccine or a recombinant protein vaccine in a previous randomized trial. We also recruited 50 vaccine-naive 5-year-olds and administered 2 doses of 4CMenB to each child. We measured serum bactericidal antibody titres against 4 indicator strains of serogroup B meningococcus matched to each individual vaccine component and against 4 mismatched strains. RESULTS: Of those who received the 4CMenB vaccine at 2, 4, 6, 12 and 40 months (n = 16), the percentage with protective antibody titres (≥ 1:4) at 60 months ranged from 44% to 88% against matched strains and from 13% to 81% against mismatched strains. Loss of protective titres was also observed for those who received the 4CMenB vaccine at 12, 40 and 42 months (n = 5) (80%-100% against matched strains, 60%-100% against mismatched strains) or at 40 and 42 months (n = 29) (31%-100% against matched strains, 41%-81% against mismatched strains). Administering the 4CMenB vaccine to 5-year-old children yielded protective titres against matched strains in 92%-100% and against mismatched strains in 59%-100%. The majority of these children reported injection-site pain (40/50 [80%] after dose 1, 39/46 [85%] after dose 2) and erythema (47/50 [94%] and 40/46 [87%], respectively); rates of fever were low (5/50 [10%] and 2/46 [4%], respectively). INTERPRETATION: Waning of immunity by 5 years of age occurred after receipt of the 4CMenB vaccine in infancy, even with an additional booster at 40 months. The 4CMenB vaccine is immunogenic and was fairly well tolerated by 5-year-old children, although injection-site pain was noteworthy. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01027351.

Takla A, Wichmann O, Carrillo-Santisteve P, Cotter S, Levy-Bruhl D, Paradowska-Stankiewicz I, Valentiner-Branth P, D'Ancona F, VENICE III NITAG Survey Group. 2015. Characteristics and practices of National Immunisation Technical Advisory Groups in Europe and potential for collaboration, April 2014. Euro Surveill, 20 (9), | Show Abstract | Read more

In many countries, national vaccination recommendations are developed by independent expert committees, so-called national immunisation technical advisory groups (NITAG). Since the evaluation of vaccines is complex and resource-demanding, collaboration between NITAGs that evaluate the same vaccines could be beneficial. We conducted a cross-sectional survey among 30 European countries in February 2014, to explore basic characteristics and current practices of European NITAGs and identify potential modes and barriers for collaboration. Of 28 responding countries, 26 reported to have a NITAG or an equivalent expert group. Of these, 20 apply a systematic approach in the vaccine decision-making process, e.g. by considering criteria such as country-specific disease epidemiology, vaccine efficacy/effectiveness/safety, health economics, programme implementation/logistics or country-specific values/preferences. However, applied frameworks and extent of evidence review differ widely. The use of systematic reviews is required for 15 of 26 NITAGs, while results from transmission modelling and health economic evaluations are routinely considered by 18 and 20 of 26 NITAGs, respectively. Twenty-five countries saw potential for NITAG-collaboration, but most often named structural concerns, e.g. different NITAG structures or countries’ healthcare systems. Our survey gathered information that can serve as an inventory on European NITAGs, allowing further exploration of options and structures for NITAG collaboration.

Jeppesen CA, Snape MD, Robinson H, Gossger N, John TM, Voysey M, Ladhani S, Okike IO, Oeser C, Kent A et al. 2015. Meningococcal carriage in adolescents in the United Kingdom to inform timing of an adolescent vaccination strategy. J Infect, 71 (1), pp. 43-52. | Show Abstract | Read more

OBJECTIVES: Recent development of serogroup B meningococcal (MenB) vaccines highlights the importance of pharyngeal carriage data, particularly in adolescents and young adults, to inform implementation strategies. We describe current UK carriage prevalence in this high risk population and compare methods of carriage detection. METHODS: In this multisite study, pharyngeal swabs were collected on 3-4 occasions over 6-12 months, from 1040 school and university students, aged 10-25 years. Meningococcal carriage was detected by standard culture combined with seroagglutination or PCR of cultured isolates, or by direct PCR from swab. The factor H binding protein (fHBP) variants present in meningococcal isolates were determined. RESULTS: Meningococcal serogroups B and Y were most common, with carriage up to 6.5% and 5.5% respectively, increasing throughout adolescence. Identification by seroagglutination was often unreliable, and the sensitivity of direct PCR detection was 66% compared to culture combined with PCR. Of MenB isolates, 89.1% had subfamily A variants of fHBP. The acquisition rate of MenB carriage was estimated at 2.8 per 1000 person-months. CONCLUSIONS: If vaccination is to precede the adolescent rise in MenB carriage, these data suggest it should take place in early adolescence. Studies assessing vaccine impact should use molecular methods to detect carriage.

Hamaluba M, Kandasamy R, Ndimah S, Morton R, Caccamo M, Robinson H, Kelly S, Field A, Norman L, Plested E et al. 2015. A cross-sectional observational study of pneumococcal carriage in children, their parents, and older adults following the introduction of the 7-valent pneumococcal conjugate vaccine. Medicine (Baltimore), 94 (1), pp. e335. | Show Abstract | Read more

Using nasopharyngeal carriage as a marker of vaccine impact, pneumococcal colonization and its relation to invasive disease were examined in children, their parents, and older adults in the United Kingdom following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) and prior to 13-valent pneumococcal conjugate vaccine (PCV13).A cross-sectional observational study was conducted, collecting nasopharyngeal swabs from children aged 25 to 55 months who had previously received 3 doses of PCV7, their parents, and adults aged ≥65 years. Pneumococcal serotyping was conducted according to World Health Organization guidelines with nontypeable isolates further analyzed by molecular serotyping. A national invasive disease surveillance program was conducted throughout the corresponding period.Pneumococcus was isolated from 47% of children, 9% of parents, and 2.2% of older adults. For these groups, the percentage of serotypes covered by PCV7 were 1.5%, 0.0%, and 15.4%, with a further 20.1%, 44.4%, and 7.7% coverage added by those in PCV13. In each group, the percentage of disease due to serotypes covered by PCV7 were 1.0%, 7.4% and 5.1% with a further 65.3%, 42.1%, and 61.4% attributed to those in PCV13.The prevalence of carriage is the highest in children, with direct vaccine impact exemplified by low carriage and disease prevalence of PCV7 serotypes in vaccinated children, whereas the indirect effects of herd protection are implied by similar observations in unvaccinated parents and older adults.

Iro MA, Khatami A, Marshall ASJ, Pace D, Voysey M, McKenna J, Campbell D, Attard-Montalto S, Finn A, White C et al. 2015. Immunological effect of administration of sequential doses of Haemophilus influenzae type b and pneumococcal conjugate vaccines in the same versus alternating limbs in the routine infant immunisation schedule: an open-label randomised controlled trial. Lancet Infect Dis, 15 (2), pp. 172-180. | Show Abstract | Read more

BACKGROUND: The use of different limbs for the administration of sequential doses of an intradermal rabies vaccine was shown to result in reduced vaccine immunogenicity. We aimed to assess whether this phenomenon also occurs with routine infant vaccines. METHODS: In this open-label, randomised, controlled study, eligible healthy infants 6-12 weeks of age recruited through five clinical trials units (four in the UK and one in Malta) were randomly assigned in a 1:1 ratio to two vaccination groups: consistent limb or alternating limb. Infants in the consistent limb group received the diphtheria-tetanus-acellular pertussis-inactived polio-Haemophilus influenzae type b combined vaccine (DTaP-IPV-Hib) at 2, 3, and 4 months of age, and the pneumococcal conjugate vaccine (PCV13) at 2, 4, and 12 months, all administered to the right leg. Infants in the alternating limb group received DTaP-IPV-Hib in the left leg at 2 months and in the right leg at 3 and 4 months; and PCV13 in the left leg at 2 months, in the right leg at 4 months, and in the left arm at 12 months. All infants in both groups received the combined H influenzae type b and capsular group C Neisseria meningitidis tetanus toxoid conjugate vaccine (Hib-MenC-TT), administered in the left leg at 12 months. Randomisation was achieved by randomly generated codes, with permuted block size of 30, and was stratified by study site. Group allocation was not masked from study staff and parents of participants after enrolment, but group allocation was masked from laboratory staff assessing blood samples. The current study was a prespecified secondary objective of a parent phase 4 trial that assessed the induction of immunity following varying schedules of vaccination with glyco-conjugate capsular group C Neisseria meningitidis (Men C) vaccines in infancy. The objective of the current study was to compare the immunogenicity and reactogenicity of vaccines delivered in either consistent or alternating limbs. Immunogenicity was assessed by comparing serum IgG geometric mean concentrations at 5, 12, 13, and 24 months, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01129518. FINDINGS: Between July 5, 2010, and Aug 1, 2013, we enrolled 509 infants and randomly allocated them to the consistent limb group (n=254) or the alternating limb group (n=255). Anti-H influenzae type b anti-polyribosylribitol phosphate IgG geometric mean concentrations were lower in the consistent limb group than in the alternating limb group at 5 months (consistent limb 0·41 μg/mL [95% CI 0·31-0·54] vs alternating limb 0·61 μg/mL [0·45-0·82]; p=0·0268) and at 12 months (0·35 μg/mL [0·28-0·43] vs 0·50 μg/mL [0·40-0·62]; p=0·0136). Anti-tetanus toxoid antibody IgG geometric mean concentrations were lower in the consistent limb group (1·63 IU/mL [95% CI 1·40-1·90]) than in the alternating limb group (2·30 IU/mL [1·97-2·68]) at 13 months (p=0·0008) and at 24 months (0·44 IU/mL [0·37-0·52] vs 0·61 IU/mL [0·51-0·73]; p=0·0074). Anti-pneumococcal IgG geometric mean concentrations were similar between both groups at all timepoints. The proportions of participants who had adverse events did not differ between the two groups. INTERPRETATION: Use of different (alternating) limbs for sequential doses of routine infant vaccines does not reduce, and might enhance, immunogenicity. The underlying mechanism for this finding warrants further research. FUNDING: NIHR Oxford Biomedical Research Centre and GlaxoSmithKline Biologicals.

Stoesser N, Sheppard AE, Shakya M, Sthapit B, Thorson S, Giess A, Kelly D, Pollard AJ, Peto TEA, Walker AS, Crook DW. 2015. Dynamics of MDR Enterobacter cloacae outbreaks in a neonatal unit in Nepal: insights using wider sampling frames and next-generation sequencing. J Antimicrob Chemother, 70 (4), pp. 1008-1015. | Show Abstract | Read more

OBJECTIVES: There are limited data on Enterobacter cloacae outbreaks and fewer describing these in association with NDM-1. With whole-genome sequencing, we tested the hypothesis that a cluster of 16 E. cloacae bacteraemia cases in a Nepali neonatal unit represented a single clonal outbreak, using a wider set of epidemiologically unrelated clinical E. cloacae isolates for comparison. METHODS: Forty-three isolates were analysed, including 23 E. cloacae and 3 Citrobacter sp. isolates obtained from blood cultures from 16 neonates over a 3 month period. These were compared with two contemporaneous community-associated drug-resistant isolates from adults, a unit soap dispenser isolate and a set of historical invasive isolates (n=14) from the same geographical locality. RESULTS: There were two clear neonatal outbreaks and one isolated case in the unit. One outbreak was associated with an NDM-1 plasmid also identified in a historical community-associated strain. The smaller, second outbreak was likely associated with a contaminated soap dispenser. The two community-acquired adult cases and three sets of historical hospital-associated neonatal isolates represented four additional genetic clusters. CONCLUSIONS: E. cloacae infections in this context represent several different transmission networks, operating at the community/hospital and host strain/plasmid levels. Wide sampling frames and high-resolution typing methods are needed to describe the complex molecular epidemiology of E. cloacae outbreaks, which is not appropriately reflected by routine susceptibility phenotypes. Soap dispensers may represent a reservoir for E. cloacae and bacterial strains and plasmids may persist in hospitals and in the community for long periods, sporadically being involved in outbreaks of disease.

Marsay L, Dold C, Green CA, Rollier CS, Norheim G, Sadarangani M, Shanyinde M, Brehony C, Thompson AJ, Sanders H et al. 2015. A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial Journal of Infection, 71 (3), pp. 326-337. | Show Abstract | Read more

© 2015 The Authors. Objectives: Outer membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines. Methods: The OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 μg or 50 μg of MenPF-1 were delivered intra-muscularly to 52 healthy adults. Results: MenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetA on PorA off compared to 51% in the strain 44/76 FetA off PorA off , demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies. Conclusion: This study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.

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Galson JD, Clutterbuck EA, Trück J, Ramasamy MN, Münz M, Fowler A, Cerundolo V, Pollard AJ, Lunter G, Kelly DF. 2015. BCR repertoire sequencing: Different patterns of B-cell activation after two Meningococcal vaccines Immunology and Cell Biology, 93 (10), pp. 885-895. | Show Abstract | Read more

© 2015 Australasian Society for Immunology Inc. All rights reserved. Next-generation sequencing was used to investigate the B-cell receptor heavy chain transcript repertoire of different B-cell subsets (naive, marginal zone (MZ), immunoglobulin M (IgM) memory and IgG memory) at baseline, and of plasma cells (PCs) 7 days following administration of serogroup ACWY meningococcal polysaccharide and protein-polysaccharide conjugate vaccines. Baseline B-cell subsets could be distinguished from each other using a small number of repertoire properties (clonality, mutation from germline and complementarity-determining region 3 (CDR3) length) that were conserved between individuals. However, analyzing the CDR3 amino-acid sequence (which is particularly important for antigen binding) of the baseline subsets showed few sequences shared between individuals. In contrast, day 7 PCs demonstrated nearly 10-fold greater sequence sharing between individuals than the baseline subsets, consistent with the PCs being induced by the vaccine antigen and sharing specificity for a more limited range of epitopes. By annotating PC sequences based on IgG subclass usage and mutation, and also comparing them with the sequences of the baseline cell subsets, we were able to identify different signatures after the polysaccharide and conjugate vaccines. PCs produced after conjugate vaccination were predominantly IgG1, and most related to IgG memory cells. In contrast, after polysaccharide vaccination, the PCs were predominantly IgG2, less mutated and were equally likely to be related to MZ, IgM memory or IgG memory cells. High-throughput B-cell repertoire sequencing thus provides a unique insight into patterns of B-cell activation not possible from more conventional measures of immunogenicity.

Green CA, Scarselli E, Voysey M, Capone S, Vitelli A, Nicosia A, Cortese R, Thompson AJ, Sande CS, de Lara C et al. 2015. Safety and immunogenicity of novel respiratory syncytial virus (RSV) vaccines based on the RSV viral proteins F, N and M2-1 encoded by simian adenovirus (PanAd3-RSV) and MVA (MVA-RSV); protocol for an open-label, dose-escalation, single-centre, phase 1 clinical trial in healthy adults. BMJ Open, 5 (10), pp. e008748. | Show Abstract | Read more

INTRODUCTION: Respiratory syncytial virus (RSV) infection causes respiratory disease throughout life, with infants and the elderly at risk of severe disease and death. RSV001 is a phase 1 (first-in-man), open-label, dose-escalation, clinical trial of novel genetic viral-vectored vaccine candidates PanAd3-RSV and modified vaccinia virus Ankara (MVA)-RSV. The objective of RSV001 is to characterise the (primary objective) safety and (secondary objective) immunogenicity of these vaccines in healthy younger and older adults. METHODS AND ANALYSIS: Heterologous and homologous 'prime'/boost combinations of PanAd3-RSV and single-dose MVA-RSV are evaluated in healthy adults. 40 healthy adults aged 18-50 years test one of four combinations of intramuscular (IM) or intranasal (IN) PanAd3-RSV prime and IM PanAd3 or IM MVA-RSV boost vaccination, starting at a low dose for safety. The following year an additional 30 healthy adults aged 60-75 years test either a single dose of IM MVA-RSV, one of three combinations of IN or IM PanAd3-RSV prime and PanAd3-RSV or MVA-RSV boost vaccination used in younger volunteers, and a non-vaccinated control group. Study participants are self-selected volunteers who satisfy the eligibility criteria and are assigned to study groups by sequential allocation. Safety assessment includes the daily recording of solicited and unsolicited adverse events for 1 week after vaccination, as well as visit (nursing) observations and safety bloods obtained at all scheduled attendances. Laboratory measures of RSV-specific humoral and cellular immune responses after vaccination will address the secondary end points. All study procedures are performed at the Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Oxford, UK. ETHICS AND DISSEMINATION: RSV001 has clinical trial authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) and ethics approval from NRES Berkshire (reference 13/SC/0023). All study procedures adhere to International Conference on Harmonisation (ICH) Good Clinical Practice guidelines. The results of the trial are to be published in peer-reviewed journals, conferences and academic forums. TRIAL REGISTRATION NUMBER: NCT01805921.

Galson JD, Trück J, Fowler A, Münz M, Cerundolo V, Pollard AJ, Lunter G, Kelly DF. 2015. In-Depth Assessment of Within-Individual and Inter-Individual Variation in the B Cell Receptor Repertoire. Front Immunol, 6 (OCT), pp. 531. | Show Abstract | Read more

High-throughput sequencing of the B cell receptor (BCR) repertoire can provide rapid characterization of the B cell response in a wide variety of applications in health, after vaccination and in infectious, inflammatory and immune-driven disease, and is starting to yield clinical applications. However, the interpretation of repertoire data is compromised by a lack of studies to assess the intra and inter-individual variation in the BCR repertoire over time in healthy individuals. We applied a standardized isotype-specific BCR repertoire deep sequencing protocol to a single highly sampled participant, and then evaluated the method in 9 further participants to comprehensively describe such variation. We assessed total repertoire metrics of mutation, diversity, VJ gene usage and isotype subclass usage as well as tracking specific BCR sequence clusters. There was good assay reproducibility (both in PCR amplification and biological replicates), but we detected striking fluctuations in the repertoire over time that we hypothesize may be due to subclinical immune activation. Repertoire properties were unique for each individual, which could partly be explained by a decrease in IgG2 with age, and genetic differences at the immunoglobulin locus. There was a small repertoire of public clusters (0.5, 0.3, and 1.4% of total IgA, IgG, and IgM clusters, respectively), which was enriched for expanded clusters containing sequences with suspected specificity toward antigens that should have been historically encountered by all participants through prior immunization or infection. We thus provide baseline BCR repertoire information that can be used to inform future study design, and aid in interpretation of results from these studies. Furthermore, our results indicate that BCR repertoire studies could be used to track changes in the public repertoire in and between populations that might relate to population immunity against infectious diseases, and identify the characteristics of inflammatory and immunological diseases.

Darton TC, Blohmke CJ, Moorthy VS, Altmann DM, Hayden FG, Clutterbuck EA, Levine MM, Hill AVS, Pollard AJ. 2015. Design, recruitment, and microbiological considerations in human challenge studies The Lancet Infectious Diseases, 15 (7), pp. 840-851. | Show Abstract | Read more

© 2015 Elsevier Ltd. Since the 18th century a wealth of knowledge regarding infectious disease pathogenesis, prevention, and treatment has been accumulated from findings of infection challenges in human beings. Partly because of improvements to ethical and regulatory guidance, human challenge studies-involving the deliberate exposure of participants to infectious substances-have had a resurgence in popularity in the past few years, in particular for the assessment of vaccines. To provide an overview of the potential use of challenge models, we present historical reports and contemporary views from experts in this type of research. A range of challenge models and practical approaches to generate important data exist and are used to expedite vaccine and therapeutic development and to support public health modelling and interventions. Although human challenge studies provide a unique opportunity to address complex research questions, participant and investigator safety is paramount. To increase the collaborative effort and future success of this area of research, we recommend the development of consensus frameworks and sharing of best practices between investigators. Furthermore, standardisation of challenge procedures and regulatory guidance will help with the feasibility for using challenge models in clinical testing of new disease intervention strategies.

McCullagh D, Dobinson HC, Darton T, Campbell D, Jones C, Snape M, Stevens Z, Plested E, Voysey M, Kerridge S et al. 2015. Understanding paratyphoid infection: study protocol for the development of a human model of Salmonella enterica serovar Paratyphi A challenge in healthy adult volunteers. BMJ Open, 5 (6), pp. e007481. | Show Abstract | Read more

INTRODUCTION: This study will develop the first human challenge model of paratyphoid infection which may then be taken forward to evaluate paratyphoid vaccine candidates. Salmonella Paratyphi A is believed to cause a quarter of the estimated 20 million cases of enteric fever annually. Epidemiological evidence also suggests that an increasing proportion of the enteric fever burden is attributable to S. Paratyphi infection meriting further attention and interest in vaccine development. Assessment of paratyphoid vaccine efficacy in preclinical studies is complicated by the lack of a small animal model and the human-restricted nature of the infection. The use of experimental human infection in healthy volunteers provides an opportunity to address these problems in a cost-effective manner. METHODS AND ANALYSIS: Volunteers will ingest virulent S. Paratyphi A bacteria (NVGH308 strain) with a bicarbonate buffer solution to establish the infectious dose resulting in an 'attack rate' of 60-75%. Using an a priori decision-making algorithm, the challenge dose will be escalated or de-escalated to achieve the target attack rate, with the aim of reaching the study end point while exposing as few individuals as possible to infection. The attack rate will be determined by the proportion of paratyphoid infection in groups of 20 healthy adult volunteers, with infection being defined by one or more positive blood cultures (microbiological end point) and/or fever, defined as an oral temperature exceeding 38 °C sustained for at least 12 h (clinical end point); 20-80 participants will be required. Challenge participants will start a 2-week course of an oral antibiotic on diagnosis of infection, or after 14 days follow-up. ETHICS AND DISSEMINATION: The strict eligibility criterion aims to minimise risk to participants and their close contacts. Ethical approval has been obtained. The results will be disseminated in a peer-reviewed journal and presented at international congresses. TRIAL REGISTRATION NUMBER: NCT02100397.

Thebault S, Waters P, Snape MD, Cottrell D, Darin N, Hallböök T, Huutoniemi A, Partinen M, Pollard AJ, Vincent A. 2015. Neuronal Antibodies in Children with or without Narcolepsy following H1N1-AS03 Vaccination. PLoS One, 10 (6), pp. e0129555. | Show Abstract | Read more

Type 1 narcolepsy is caused by deficiency of hypothalamic orexin/hypocretin. An autoimmune basis is suspected, but no specific antibodies, either causative or as biomarkers, have been identified. However, the AS03 adjuvanted split virion H1N1 (H1N1-AS03) vaccine, created to protect against the 2009 Pandemic, has been implicated as a trigger of narcolepsy particularly in children. Sera and CSFs from 13 H1N1-AS03-vaccinated patients (12 children, 1 young adult) with type 1 narcolepsy were tested for autoantibodies to known neuronal antigens including the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein 2 (CASPR2), both associated with encephalopathies that include disordered sleep, to rodent brain tissue including the lateral hypothalamus, and to live hippocampal neurons in culture. When sufficient sample was available, CSF levels of melanin-concentrating hormone (MCH) were measured. Sera from 44 H1N1-ASO3-vaccinated children without narcolepsy were also examined. None of these patients' CSFs or sera was positive for NMDAR or CASPR2 antibodies or binding to neurons; 4/13 sera bound to orexin-neurons in rat brain tissue, but also to other neurons. MCH levels were a marginally raised (n = 8; p = 0.054) in orexin-deficient narcolepsy patients compared with orexin-normal children (n = 6). In the 44 H1N1-AS03-vaccinated healthy children, there was no rise in total IgG levels or in CASPR2 or NMDAR antibodies three weeks following vaccination. In conclusion, there were no narcolepsy-specific autoantibodies identified in type 1 narcolepsy sera or CSFs, and no evidence for a general increase in immune reactivity following H1N1-AS03 vaccination in the healthy children. Antibodies to other neuronal specific membrane targets, with their potential for directing use of immunotherapies, are still an important goal for future research.

Curtis N, Pollard AJ, Finn A, Ramilo O, Dobson S. 2015. Hot topics in infection and immunity in children Journal of Infection, 71 (S1), pp. S1. | Read more

Drysdale SB, Pollard AJ. 2015. Group B meningococcal vaccine science and policy Journal of Infection, 71 (S1), pp. S15-S20. | Show Abstract | Read more

© 2015 The British Infection Association. Capsular group B Neisseria meningitidis is one of the leading causes of death in developed countries. A new vaccine (4CMenB) has recently been developed which was found to have an acceptable safety profile in clinical studies and to be immunogenic. This review examines the evidence supporting the licensure of the 4CMenB vaccine and discusses recommendations for its use.

Curtis N, Pollard AJ, Finn A, Ramilo O, Dobson S. 2015. Hot topics in infection and immunity in children PREFACE JOURNAL OF INFECTION, 71 pp. S1-S1. | Read more

Hamaluba M, Kandasamy R, Upreti SR, Subedi GR, Shrestha S, Bhattarai S, Gurung M, Pradhan R, Voysey M, Gurung S et al. 2015. Comparison of two-dose priming plus 9-month booster with a standard three-dose priming schedule for a ten-valent pneumococcal conjugate vaccine in Nepalese infants: a randomised, controlled, open-label, non-inferiority trial. Lancet Infect Dis, 15 (4), pp. 405-414. | Show Abstract | Read more

BACKGROUND: Use of pneumococcal conjugate vaccines (PCVs) in resource-poor countries has focused on early infant immunisation with little emphasis on protection in late infancy and beyond. Boosting of the immune response later in infancy might provide improved persistence of immunogenicity into early childhood, however data are scarce. The aim of this study was to investigate if a two-dose prime with booster at age 9 months compared with a three-dose prime-only PCV schedule provided non-inferior immunogenicity in early infancy and superior persistence of antibody responses in early childhood. METHODS: We did an open-label, randomised, parallel group, controlled trial in healthy infants aged 40-60 days from Kathmandu, Nepal. Participants were randomly allocated (4:4:5 ratio) to receive PCV10 in addition to routine immunisations either as a two-dose prime and boost (2+1), three-dose prime (3+0), or two doses after completion of the initial study phase (0+2). We used a computer generated randomisation list with randomly varying block sizes. We followed up participants at age 2-4 years together with a group of unvaccinated controls. Sera were analysed for opsonophagocytic activity, protein D, and PCV10 serotype-specific IgG. Laboratory staff was masked to intervention group assignment. The primary outcome measure was to determine the proportion of participants in the 2+1 group at age 10 months with specific IgG for serotypes 1, 5, and 14 of at least 0·2 μg/mL in the per-protocol population. The secondary outcomes were non-inferiority (within 10% levels) at age 18 weeks for the proportion of participants in the 2+1 group compared with the 3+0 group with serotypes 1, 5, and 14 specific IgG of at least 0·2 μg/mL; the proportion of participants with PCV10 serotype-specific IgG of at least 0·2 μg/mL and opsonophagocytic activity reciprocal titre of at least 8 at ages 18 weeks and 10 months; and nasopharyngeal pneumococcal serotype-specific carriage rates at age 9 months in each study group. In the follow-up study, the primary outcome measure was the proportion of participants with IgG of at least 0·2 μg/mL for PCV10 serotypes at age 2-4 years in children previously immunised with a 3+0 schedule compared with a 2+1 schedule. The trial is registered with Current Controlled Trials, registration number ISRCTN56766232. FINDINGS: Between May 10, 2010, and Jan 7, 2011, 390 children were randomly assigned to each group: 119 to the 2+1 group, 120 to the 3+0 group, and 151 to the 0+2 group. At age 10 months, the proportions of 2+1 participants with IgG of at least 0·2 μg/mL were 99·0% (95% CI 94·2-100·0) for serotype 1, 100% (96·2-100·0) for serotype 5, and 97·9% (92·5-99·7) for serotype 14. At age 18 weeks, non-inferiority (within 10% levels) of the 2+1 group was shown compared with the 3+0 group, and there was no difference between the 2+1 and 3+0 groups for the proportion with IgG of at least 0·2 μg/mL for any of the PCV10 serotypes. At age 10 months, proportions with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 23F, were higher in the 2+1 group than in the 3+0 group. At age 18 weeks, there were no differences in opsonophagocytic activity between the 2+1 and 3+0 groups for reciprocal titres of at least 8, but at age 10 months, proportions with an opsonophagocytic reciprocal titre of at least 8 for serotypes 1, 4, 5, 6B, 18C, 19F and 23F were higher in the 2+1 group than in the 3+0 group. At age 2-4 years, there were higher proportions in the 2+1 group versus the 3+0 group with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 18C. INTERPRETATION: Use of a 2+1 PCV schedule with booster at age 9 months in a resource-poor setting improved antibody persistence through early childhood without compromising antibody responses in early infancy. This schedule is now recommended by WHO for progressive introduction across Nepal, with PCV10 introduction having commenced on Jan 18, 2015. Concurrent pre-implementation and post-implementation surveillance is being done by a GAVI Alliance funded study. FUNDING: This study was supported by funding from the National Institute for Public Health and the Environment, The Netherlands; Oxford Vaccine Group, University of Oxford, UK; and GlaxoSmithKline Biologicals, Belgium.

Kandasamy R, Gurung M, Thapa A, Ndimah S, Adhikari N, Murdoch DR, Kelly DF, Waldron DE, Gould KA, Thorson S et al. 2015. Multi-serotype pneumococcal nasopharyngeal carriage prevalence in vaccine naïve Nepalese children, assessed using molecular serotyping. PLoS One, 10 (2), pp. e0114286. | Show Abstract | Read more

Invasive pneumococcal disease is one of the major causes of death in young children in resource poor countries. Nasopharyngeal carriage studies provide insight into the local prevalence of circulating pneumococcal serotypes. There are very few data on the concurrent carriage of multiple pneumococcal serotypes. This study aimed to identify the prevalence and serotype distribution of pneumococci carried in the nasopharynx of young healthy Nepalese children prior to the introduction of a pneumococcal conjugate vaccine using a microarray-based molecular serotyping method capable of detecting multi-serotype carriage. We conducted a cross-sectional study of healthy children aged 6 weeks to 24 months from the Kathmandu Valley, Nepal between May and October 2012. Nasopharyngeal swabs were frozen and subsequently plated on selective culture media. DNA extracts of plate sweeps of pneumococcal colonies from these cultures were analysed using a molecular serotyping microarray capable of detecting relative abundance of multiple pneumococcal serotypes. 600 children were enrolled into the study: 199 aged 6 weeks to <6 months, 202 aged 6 months to < 12 months, and 199 aged 12 month to 24 months. Typeable pneumococci were identified in 297/600 (49.5%) of samples with more than one serotype being found in 67/297 (20.2%) of these samples. The serotypes covered by the thirteen-valent pneumococcal conjugate vaccine were identified in 44.4% of samples containing typeable pneumococci. Application of a molecular serotyping approach to identification of multiple pneumococcal carriage demonstrates a substantial prevalence of co-colonisation. Continued surveillance utilising this approach following the introduction of routine use of pneumococcal conjugate vaccinates in infants will provide a more accurate understanding of vaccine efficacy against carriage and a better understanding of the dynamics of subsequent serotype and genotype replacement.

Rollier CS, Dold C, Marsay L, Sadarangani M, Pollard AJ. 2015. The capsular group B meningococcal vaccine, 4CMenB : clinical experience and potential efficacy. Expert Opin Biol Ther, 15 (1), pp. 131-142. | Show Abstract | Read more

INTRODUCTION: Capsular group B meningococcal disease is a leading cause of childhood meningitis and septicaemia. Up to 10% of sufferers die, and sequelae remain in > 30% of survivors. A vaccine, four component meningococcal group B ( 4CMenB ), designed with the aim to induce broad coverage against this highly variable bacterium, has been licensed in countries including in the European Union, Canada and Australia. AREAS COVERED: Immunogenicity and safety data, published in peer-reviewed literature between 2004 and 2014, are presented in the context of the recent recommendation for the use of the vaccine in infants in the UK. EXPERT OPINION: 4CMenB induces significant reactogenicity when administered with routine infant vaccines, in particular with respect to fever rates. Fevers can be somewhat reduced using paracetamol. The efficacy of the vaccine is unknown but has been extrapolated from effectiveness data obtained from use of one of its components in New Zealand, immunogenicity data from clinical trials and estimation of coverage from in vitro studies. These data suggest that the vaccine will prevent a proportion of invasive meningococcal disease cases in infants and young children. Implementation and well-planned post-marketing surveillance will address uncertainties over field effectiveness.

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Read RC, Baxter D, Chadwick DR, Faust SN, Finn A, Gordon SB, Heath PT, Lewis DJM, Pollard AJ, Turner DPJ et al. 2014. Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: An observer-blind, phase 3 randomised clinical trial The Lancet, 384 (9960), pp. 2123-2131. | Show Abstract | Read more

© 2014 Elsevier Ltd. Background Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. Methods In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. Findings Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed] , 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3] ) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. Interpretation Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. Funding Novartis Vaccines.

Galson JD, Clutterbuck EA, Trueck J, Muenz M, Fowler A, Cerundolo V, Pollard AJ, Lunter G, Kelly DF. 2014. Plasma cell antibody repertoire analysis following administration of meningococcal polysaccharide and protein-polysaccharide conjugate vaccines: evidence of distinct patterns of B cell activation IMMUNOLOGY, 143 pp. 62-62.

Trück J, Ramasamy MN, Galson JD, Rance R, Parkhill J, Lunter G, Pollard AJ, Kelly DF. 2015. Identification of antigen-specific B cell receptor sequences using public repertoire analysis. J Immunol, 194 (1), pp. 252-261. | Show Abstract | Read more

High-throughput sequencing allows detailed study of the BCR repertoire postimmunization, but it remains unclear to what extent the de novo identification of Ag-specific sequences from the total BCR repertoire is possible. A conjugate vaccine containing Haemophilus influenzae type b (Hib) and group C meningococcal polysaccharides, as well as tetanus toxoid (TT), was used to investigate the BCR repertoire of adult humans following immunization and to test the hypothesis that public or convergent repertoire analysis could identify Ag-specific sequences. A number of Ag-specific BCR sequences have been reported for Hib and TT, which made a vaccine containing these two Ags an ideal immunological stimulus. Analysis of identical CDR3 amino acid sequences that were shared by individuals in the postvaccine repertoire identified a number of known Hib-specific sequences but only one previously described TT sequence. The extension of this analysis to nonidentical, but highly similar, CDR3 amino acid sequences revealed a number of other TT-related sequences. The anti-Hib avidity index postvaccination strongly correlated with the relative frequency of Hib-specific sequences, indicating that the postvaccination public BCR repertoire may be related to more conventional measures of immunogenicity correlating with disease protection. Analysis of public BCR repertoire provided evidence of convergent BCR evolution in individuals exposed to the same Ags. If this finding is confirmed, the public repertoire could be used for rapid and direct identification of protective Ag-specific BCR sequences from peripheral blood.

Iro MA, Martin NG, Absoud M, Pollard AJ. 2014. Intravenous immunoglobulin for the treatment of childhood encephalitis Cochrane Database of Systematic Reviews, 2014 (11), | Show Abstract | Read more

© 2014 The Cochrane Collaboration. This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the safety and efficacy of intravenous immunoglobulin as add-on treatment for children with encephalitis.

Curtis N, Pollard AJ, Finn A. 2014. Hot topics in infection and immunity in children Journal of Infection, 69 (S1), pp. S1. | Read more

Stoesser N, Giess A, Batty EM, Sheppard AE, Walker AS, Wilson DJ, Didelot X, Bashir A, Sebra R, Kasarskis A et al. 2014. Genome sequencing of an extended series of NDM-producing Klebsiella pneumoniae isolates from neonatal infections in a Nepali hospital characterizes the extent of community- versus hospital-associated transmission in an endemic setting. Antimicrob Agents Chemother, 58 (12), pp. 7347-7357. | Show Abstract | Read more

NDM-producing Klebsiella pneumoniae strains represent major clinical and infection control challenges, particularly in resource-limited settings with high rates of antimicrobial resistance. Determining whether transmission occurs at a gene, plasmid, or bacterial strain level and within hospital and/or the community has implications for monitoring and controlling spread. Whole-genome sequencing (WGS) is the highest-resolution typing method available for transmission epidemiology. We sequenced carbapenem-resistant K. pneumoniae isolates from 26 individuals involved in several infection case clusters in a Nepali neonatal unit and 68 other clinical Gram-negative isolates from a similar time frame, using Illumina and PacBio technologies. Within-outbreak chromosomal and closed-plasmid structures were generated and used as data set-specific references. Three temporally separated case clusters were caused by a single NDM K. pneumoniae strain with a conserved set of four plasmids, one being a 304,526-bp plasmid carrying bla(NDM-1). The plasmids contained a large number of antimicrobial/heavy metal resistance and plasmid maintenance genes, which may have explained their persistence. No obvious environmental/human reservoir was found. There was no evidence of transmission of outbreak plasmids to other Gram-negative clinical isolates, although bla(NDM) variants were present in other isolates in different genetic contexts. WGS can effectively define complex antimicrobial resistance epidemiology. Wider sampling frames are required to contextualize outbreaks. Infection control may be effective in terminating outbreaks caused by particular strains, even in areas with widespread resistance, although this study could not demonstrate evidence supporting specific interventions. Larger, detailed studies are needed to characterize resistance genes, vectors, and host strains involved in disease, to enable effective intervention.

Sadarangani M, Willis L, Kadambari S, Gormley S, Young Z, Beckley R, Gantlett K, Orf K, Blakey S, Martin NG et al. 2015. Childhood meningitis in the conjugate vaccine era: a prospective cohort study. Arch Dis Child, 100 (3), pp. 292-294. | Show Abstract | Read more

Bacterial conjugate vaccines have dramatically changed the epidemiology of childhood meningitis; viral causes are increasingly predominant, but the current UK epidemiology is unknown. This prospective study recruited children under 16 years of age admitted to 3 UK hospitals with suspected meningitis. 70/388 children had meningitis-13 bacterial, 26 viral and 29 with no pathogen identified. Group B Streptococcus was the most common bacterial pathogen. Infants under 3 months of age with bacterial meningitis were more likely to have a reduced Glasgow Coma Score and respiratory distress than those with viral meningitis or other infections. There were no discriminatory clinical features in older children. Cerebrospinal fluid (CSF) white blood cell count and plasma C-reactive protein at all ages, and CSF protein in infants <3 months of age, distinguished between bacterial meningitis and viral meningitis or other infections. Improved diagnosis of non-bacterial meningitis is urgently needed to reduce antibiotic use and hospital stay.

Burton MJ, Pollard AJ, Ramsden JD, Chong LY, Venekamp RP. 2014. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev, 2014 (9), pp. CD008669. | Show Abstract | Read more

BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a rare clinical syndrome of unknown cause usually identified in children. Tonsillectomy is considered a potential treatment option for this syndrome. This is an update of a Cochrane review first published in 2010. OBJECTIVES: To assess the effectiveness and safety of tonsillectomy (with or without adenoidectomy) in children with PFAPA. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 30 October 2013. SELECTION CRITERIA: Randomised controlled trials comparing tonsillectomy (with or without adenoidectomy) with non-surgical treatment in children with PFAPA. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias.One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months.Combining the trial results suggests that patients with PFAPA experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution).There was a large overall reduction in the average number of episodes over the total length of follow-up in these studies (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years. The severity, as indicated by the length of PFAPA symptoms during these episodes, was also reduced. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group. The proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92).Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Other outcomes such as quality of life, number of days with pain after surgery and absence from school were not measured or reported. AUTHORS' CONCLUSIONS: The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate quality (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.

Trück J, Mitchell R, Thompson AJ, Morales-Aza B, Clutterbuck EA, Kelly DF, Finn A, Pollard AJ. 2014. Effect of cryopreservation of peripheral blood mononuclear cells (PBMCs) on the variability of an antigen-specific memory B cell ELISpot. Hum Vaccin Immunother, 10 (8), pp. 2490-2496. | Show Abstract | Read more

The ELISpot assay is used in vaccine studies for the quantification of antigen-specific memory B cells (B(MEM)), and can be performed using cryopreserved samples. The effects of cryopreservation on B(MEM) detection and the consistency of cultured ELISpot assays when performed by different operators or laboratories are unknown. In this study, blood was taken from healthy volunteers, and a cultured ELISpot assay was used to count B(MEM) specific for 2 routine vaccine antigens (diphtheria and tetanus toxoid). Results were assessed for intra- and inter-operator variation, and the effects of cryopreservation. Cryopreserved samples were shipped to a second laboratory in order to assess inter-laboratory variation. B(MEM) frequencies were very strongly correlated when comparing fresh and frozen samples processed by the same operator, and were also very strongly correlated when comparing 2 operators in the same laboratory. Results were slightly less consistent when samples were processed in different laboratories but correlation between the 2 measurements was still very strong. Although cell viability was reduced in some cryopreserved samples due to higher temperatures during transportation, B(MEM) could still be quantified. These results demonstrate the reproducibility of the ELISpot assay across operators and laboratories, and support the use of cryopreserved samples in future B(MEM) studies.

Weissmueller NT, Schiffter HA, Pollard AJ, Tas AC. 2014. Molten salt synthesis of potassium-containing hydroxyapatite microparticles used as protein substrate MATERIALS LETTERS, 128 pp. 421-424. | Show Abstract | Read more

The bioactivity of a material may be favorably altered by exerting control over its protein sorption propensity. Spheroidal potassium-containing calcium phosphate bioceramic microparticles were manufactured by molten salt synthesis. The effects on particle characteristics and adsorption of bovine serum albumin (BSA) of different hydroxyapatite (HA, Ca 10 (PO 4 ) 6 (OH) 2 ) to salt flux (K 2 SO 4 ) ratios were investigated. X-ray diffraction (XRD) patterns showed the emergence of minor phases in addition to the HA major phase with increased salt flux. Synthesized particles were found to increase in potassium content with increasing HA:K 2 SO 4 ratio. Conversely, the amount of BSA adsorption onto microparticles, normalized for surface area, decreased with excess K 2 SO 4 . The results indicate that K 2 SO 4 content can impact the morphology, composition, and BSA adsorption propensity of the resultant bioceramic microparticles. © 2014 Elsevier Inc. All rights reserved.

Waddington CS, Darton TC, Angus B, Pollard AJ. 2014. Reply to Farmakiotis et al. Clin Infect Dis, 59 (8), pp. 1198-1199. | Read more

Khatami A, Clutterbuck EA, Thompson AJ, McKenna JA, Pace D, Birks J, Snape MD, Pollard AJ. 2014. Evaluation of the induction of immune memory following infant immunisation with serogroup C Neisseria meningitidis conjugate vaccines--exploratory analyses within a randomised controlled trial. PLoS One, 9 (7), pp. e101672. | Show Abstract | Read more

AIM: We measured meningococcal serogroup C (MenC)-specific memory B-cell responses in infants by Enzyme-Linked Immunospot (ELISpot) following different MenC conjugate vaccine schedules to investigate the impact of priming on immune memory. METHODS: Infants aged 2 months were randomised to receive 1 or 2 doses of MenC-CRM197 at 3 or 3 and 4 months, 1 dose of MenC-TT at 3 months, or no primary MenC doses. All children received a Haemophilus influenzae type b (Hib)-MenC booster at 12 months. Blood was drawn at 5, 12, 12 months +6 days and 13 months of age. RESULTS: Results were available for 110, 103, 76 and 44 children from each group respectively. Following primary immunisations, and prior to the 12-month booster, there were no significant differences between 1- or 2-dose primed children in the number of MenC memory B-cells detected. One month following the booster, children primed with 1 dose MenC-TT had more memory B-cells than children primed with either 1-dose (p = 0.001) or 2-dose (p<0.0001) MenC-CRM197. There were no differences in MenC memory B-cells detected in children who received 1 or 2 doses of MenC-CRM197 in infancy and un-primed children. CONCLUSIONS: MenC-specific memory B-cell production may be more dependent on the type of primary vaccine used than the number of doses administered. Although the mechanistic differences between MenC-CRM197 and MenC-TT priming are unclear, it is possible that structural differences, including the carrier proteins, may underlie differential interactions with B- and T-cell populations, and thus different effects on various memory B-cell subsets. A MenC-TT/Hib-MenC-TT combination for priming/boosting may offer an advantage in inducing more persistent antibody. TRIAL REGISTRATION: EU Clinical Trials Register 2009-016579-31 ClinicalTrials.gov NCT01129518.

Ramasamy MN, Clutterbuck EA, Haworth K, Bowman J, Omar O, Thompson AJ, Blanchard-Rohner G, Yu L-M, Snape MD, Pollard AJ. 2014. Randomized clinical trial to evaluate the immunogenicity of quadrivalent meningococcal conjugate and polysaccharide vaccines in adults in the United kingdom. Clin Vaccine Immunol, 21 (8), pp. 1164-1168. | Show Abstract | Read more

Meningococcal conjugate vaccines are today successfully deployed in universal programs for children and adolescents in different geographic regions to control meningitis and septicemia. However, in adults, the advantages of these conjugates over the older polysaccharide vaccines are less clear. In this randomized clinical trial, we demonstrated that both conjugate and polysaccharide quadrivalent meningococcal vaccines elicit protective antibody responses in adults aged 18 to 70. (This study has been registered at www.clinicaltrials.gov under registration no. NCT00901940.).

Trück J, Mitchell R, Thompson AJ, Morales-Aza B, Clutterbuck EA, Kelly DF, Finn A, Pollard AJ. 2014. Effect of cryopreservation of peripheral blood mononuclear cells (PBMCs) on the variability of an antigen-specific memory B cell ELISpot: Variability of the memory B cell ELISpot assay. Hum Vaccin Immunother, 10 (8), | Show Abstract

The ELISpot assay is used in vaccine studies for the quantification of antigen-specific memory B cells (BMEM), and can be performed using cryopreserved samples. The effects of cryopreservation on BMEM detection and the consistency of cultured ELISpot assays when performed by different operators or laboratories are unknown. In this study, blood was taken from healthy volunteers, and a cultured ELISpot assay was used to count BMEM specific for 2 routine vaccine antigens (diphtheria and tetanus toxoid). Results were assessed for intra- and inter-operator variation, and the effects of cryopreservation. Cryopreserved samples were shipped to a second laboratory in order to assess inter-laboratory variation. BMEM frequencies were very strongly correlated when comparing fresh and frozen samples processed by the same operator, and were also very strongly correlated when comparing 2 operators in the same laboratory. Results were slightly less consistent when samples were processed in different laboratories although correlation between the 2 measurements was still very strong. Although cell viability was reduced in some cryopreserved samples due to higher temperatures during transportation, BMEM could still be quantified. These results demonstrate the reproducibility of the ELISpot assay across operators and laboratories, and support the use of cryopreserved samples in future BMEM studies.

Pollard AJ. 2014. Meningococcal disease prevention in India. Indian Pediatr, 51 (6), pp. 445-446.

O'Connor D, Moore CE, Snape MD, John T, Hill AVS, Pollard AJ. 2014. Exonic single nucleotide polymorphisms within TLR3 associated with infant responses to serogroup C meningococcal conjugate vaccine Vaccine, 32 (27), pp. 3424-3430. | Show Abstract | Read more

The introduction of the serogroup C meningococcal (MenC) conjugate vaccination has successfully controlled the burden of disease associated with this serogroup in many countries. However, considerable inter-individual variation is observed in immune responses to MenC vaccine, and little is understood of the determinants of this variability. Previously, we reported an association between single nucleotide polymorphisms (SNPs) in TLR3 and CD44 and the persistence of MenC vaccine immunity. Here we further examine polymorphisms within these two candidate genes and immune responses to MenC vaccine. MenC-specific IgG concentrations and serum bactericidal assay (SBA) titres were measured one month after a primary course of MenC vaccination in 318 human infants. Tagging SNPs (TagSNPs) within TLR3 and CD44 were genotyped and regional imputations carried out to screen these genes for variations associated with immunological responses to MenC vaccine. This study reports an association between an exonic variant (rs3775290, P= 0.025) in TLR3 and MenC IgG concentrations, as well as an association between three SNPs in CD44 (rs3794109, P= 0.021; rs3794110, P= 0.022; rs112762, P= 0.049) and MenC SBA titres. These data support our previous findings of an association between SNPs in TLR3 and CD44, and present novel findings implicating exonic variants in these genes with MenC vaccine responses. © 2014 Elsevier Ltd.

Pollard AJ. 2014. Meningococcal Disease Prevention in India WESTERN PERSPECTIVE INDIAN PEDIATRICS, 51 (6), pp. 445-446. | Read more

Reynolds CJ, Jones C, Blohmke CJ, Darton TC, Goudet A, Sergeant R, Maillere B, Pollard AJ, Altmann DM, Boyton RJ. 2014. The serodominant secreted effector protein of Salmonella, SseB, is a strong CD4 antigen containing an immunodominant epitope presented by diverse HLA class II alleles. Immunology, 143 (3), pp. 438-446. | Show Abstract | Read more

Detailed characterization of the protective T-cell response in salmonellosis is a pressing unmet need in light of the global burden of human Salmonella infections and the likely contribution of CD4 T cells to immunity against this intracellular infection. In previous studies screening patient sera against antigen arrays, SseB was noteworthy as a serodominant target of adaptive immunity, inducing significantly raised antibody responses in HIV-seronegative compared with seropositive patients. SseB is a secreted protein, part of the Espa superfamily, localized to the bacterial surface and forming part of the translocon of the type III secretion system (T3SS) encoded by Salmonella pathogenicity island 2. We demonstrate here that SseB is also a target of CD4 T-cell immunity, generating a substantial response after experimental infection in human volunteers, with around 0.1% of the peripheral repertoire responding to it. HLA-DR/peptide binding studies indicate that this protein encompasses a number of peptides with ability to bind to several different HLA-DR alleles. Of these, peptide 11 (p11) was shown in priming of both HLA-DR1 and HLA-DR4 transgenic mice to contain an immunodominant CD4 epitope. Analysis of responses in human donors showed immunity focused on p11 and another epitope in peptide 2. The high frequency of SseB-reactive CD4 T cells and the broad applicability to diverse HLA genotypes coupled with previous observations of serodominance and protective vaccination in mouse challenge experiments, make SseB a plausible candidate for next-generation Salmonella vaccines.

Galson JD, Pollard AJ, Trück J, Kelly DF. 2014. Studying the antibody repertoire after vaccination: practical applications. Trends Immunol, 35 (7), pp. 319-331. | Show Abstract | Read more

Nearly all licensed vaccines have been developed to confer protection against infectious diseases by stimulating the production of antibodies by B cells, but the nature of a successful antibody response has been difficult to capture. Recent advances in next-generation sequencing (NGS) technology have allowed high-resolution characterization of the antibody repertoire, and of the changes that occur following vaccination. These approaches have yielded important insights into the B cell response, and have raised the possibility of using specific antibody sequences as measures of vaccine immunogenicity. Here, we review recent findings based on antibody repertoire sequencing, and discuss potential applications of these new technologies and of the analyses of the increasing volume of antibody sequence data in the context of vaccine development.

Cited:

48

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Martin NG, Sadarangani M, Pollard AJ, Goldacre MJ. 2014. Hospital admission rates for meningitis and septicaemia caused by Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae in children in England over five decades: A population-based observational study The Lancet Infectious Diseases, 14 (5), pp. 397-405. | Show Abstract | Read more

Background: Infection with Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae causes substantial mortality and long-term morbidity in children. We know of no study to assess the long-term trends in hospital admission rates for meningitis and septicaemia caused by these pathogens in children in England. We aimed to do such a study using routinely reported data in England. Methods: In this population-based observational study, we used datasets that include routinely collected administrative statistics for hospital care: the Hospital In-Patient Enquiry (data for England from 1968 to 1985), the Hospital Episode Statistics dataset (data for England from 1989 onwards), and the Oxford record linkage study (data for Oxfordshire and surrounding areas from 1963 to 2011). We analysed annual age-specific and age-standardised admission rates in children younger than 15 years with H influenzae, meningococcal and pneumococcal meningitis, and septicaemia. Findings: We saw a reduction in hospital admission rates for childhood invasive bacterial disease after the introduction of conjugate vaccines against H influenzae, N meningitidis, and S pneumoniae in England. Annual incidence of H influenzae meningitis per 100 000 children decreased from 6·72 admissions (95% CI 6·18-7·26) in 1992 to 0·39 admissions (0·26-0·52) in 1994, after the introduction of routine H influenzae type b vaccination. We saw a small rise in admissions in the early 2000s, peaking at 1·24 admissions per 100 000 children (0·99-1·48) in 2003, which decreased to 0·28 per 100 000 children (0·17-0·39) by 2008 after the introduction of catch-up (2003) and routine (2006) booster programmes for young children. Meningococcal disease increased during the 1990s, reaching a peak in 1999, with 34·54 admissions (33·30-35·78) per 100 000 children. Hospital admissions decreased after the meningococcal serogroup C vaccine was introduced in 1999 and was 12·40 admissions (11·68-13·12) per 100 000 in 2011. Admissions for invasive pneumococcal disease increased from the 1990s reaching a peak in 2006 at 4·45 admissions for meningitis (95% CI 4·0-4·9) per 100 000 children and 2·81 admissions for septicaemia (2·45-3·17) per 100 000 children. A reduction in admissions occurred after the introduction of the pneumococcal conjugate vaccine in 2006: hospital admission rates in 2011 were 2·03 per 100 000 children for meningitis and 1·12 per 100 000 children for septicaemia. Interpretation: Vaccine-preventable invasive bacterial disease in children has decreased substantially in England in the past five decades, most notably with the advent of effective conjugate vaccines since the 1990s. Ongoing disease surveillance and continued development and implementation of vaccines against additional pneumococcal serotypes and serogroup B meningococcal disease are important. Funding: None. © 2014 Elsevier Ltd.

Cited:

33

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Andrews SM, Pollard AJ. 2014. A vaccine against serogroup B Neisseria meningitidis: dealing with uncertainty The Lancet Infectious Diseases, 14 (5), pp. 426-434. | Show Abstract | Read more

Neisseria meningitidis is an important cause of invasive bacterial infection in children worldwide. Although serogroup C meningococcal disease has all but disappeared in the past decade as a direct result of immunisation programmes in Europe, Canada, and Australia, meningitis and septicaemia caused by serogroup B meningococci remain uncontrolled. A vaccine (4CMenB) has now been licensed for use in the European Union, comprising three immunogenic antigens (identified with use of reverse vaccinology) combined with bacterial outer-membrane vesicles. The vaccine has the potential to reduce mortality and morbidity associated with serogroup B meningococci infections, but uncertainty remains about the breadth of protection the vaccine might induce against the diverse serogroup B meningococci strains that cause disease. We discuss drawbacks in the techniques used to estimate coverage and potential efficacy of the vaccine, and their effects on estimates of cost-effectiveness, both with and without herd immunity. For parents, and clinicians treating individual patients, the predicted benefits of vaccination outweigh existing uncertainties if any cases can be prevented, but future use of the vaccine must be followed by rigorous post-implementation surveillance to reassess its value to health systems with directly recorded epidemiological data. © 2014 Elsevier Ltd.

Cited:

20

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Waddington CS, Darton TC, Woodward WE, Angus B, Levine MM, Pollard AJ. 2014. Advancing the management and control of typhoid fever: A review of the historical role of human challenge studies Journal of Infection, 68 (5), pp. 405-418. | Show Abstract | Read more

Typhoid infection causes considerable morbidity and mortality worldwide, particularly in settings where lack of clean water and inadequate sanitation facilitate disease spread through faecal-oral transmission. Improved understanding of the pathogenesis, immune control and microbiology of Salmonella Typhi infection can help accelerate the development of improved vaccines and diagnostic tests necessary for disease control. S. Typhi is a human-restricted pathogen; therefore animal models are limited in their relevance to human infection. During the latter half of the 20th century, induced human infection ("challenge") studies with S. Typhi were used effectively to assess quantitatively the human host response to challenge and to measure directly the efficacy of typhoid vaccines in preventing clinical illness. Here, the findings of these historic challenge studies are reviewed, highlighting the pivotal role that challenge studies have had in improving our understanding of the host-pathogen interaction, and illustrating issues relevant to modern typhoid challenge model design. © 2014.

O'Connor D, Moore CE, Snape MD, John T, Hill AVS, Pollard AJ. 2014. Exonic single nucleotide polymorphisms within TLR3 associated with infant responses to serogroup C meningococcal conjugate vaccine. Vaccine, 32 (27), pp. 3424-3430. | Show Abstract | Read more

The introduction of the serogroup C meningococcal (MenC) conjugate vaccination has successfully controlled the burden of disease associated with this serogroup in many countries. However, considerable inter-individual variation is observed in immune responses to MenC vaccine, and little is understood of the determinants of this variability. Previously, we reported an association between single nucleotide polymorphisms (SNPs) in TLR3 and CD44 and the persistence of MenC vaccine immunity. Here we further examine polymorphisms within these two candidate genes and immune responses to MenC vaccine. MenC-specific IgG concentrations and serum bactericidal assay (SBA) titres were measured one month after a primary course of MenC vaccination in 318 human infants. Tagging SNPs (TagSNPs) within TLR3 and CD44 were genotyped and regional imputations carried out to screen these genes for variations associated with immunological responses to MenC vaccine. This study reports an association between an exonic variant (rs3775290, P=0.025) in TLR3 and MenC IgG concentrations, as well as an association between three SNPs in CD44 (rs3794109, P=0.021; rs3794110, P=0.022; rs112762, P=0.049) and MenC SBA titres. These data support our previous findings of an association between SNPs in TLR3 and CD44, and present novel findings implicating exonic variants in these genes with MenC vaccine responses.

McQuaid F, Snape MD, John TM, Kelly S, Robinson H, Houlden J, Voysey M, Toneatto D, Kitte C, Dull PM, Pollard AJ. 2014. Persistence of bactericidal antibodies to 5 years of age after immunization with serogroup B meningococcal vaccines at 6, 8, 12 and 40 months of age. Pediatr Infect Dis J, 33 (7), pp. 760-766. | Show Abstract | Read more

BACKGROUND: A serogroup B meningococcal vaccine (4CMenB) has been licensed by the European commission for use in various infant schedules. However, data are limited on persistence of serum bactericidal antibodies (SBA), which is necessary to inform cost-effectiveness analysis. METHODS: Sera were obtained from 3 groups of 5-year-old children previously immunized at 6, 8, 12 and 40 months with either 4CMenB or rMenB (which lacks the outer membrane vesicle of 4CMenB) or at 40 and 42 months with 4CMenB only. Forty-nine control children were also recruited and blood obtained before and after 2 doses of 4CMenB at 60 and 62 months of age. Sera were tested for SBA to meningococcal B reference strains. RESULTS: At 5 years of age, 67% of those receiving 4CMenB in infancy had SBA titers ≥1:4 for strain 44/76, 100% for 5/99, 17% for NZ98/254 and 45% for M10713. Results for rMenB recipients varied from 0 (NZ98/254) to 100% (5/99). Of those immunized with 4CMenB at 40 and 42 months, 38% had SBA titers ≥1:4 at age 5 for 44/76, 100% for 5/99, 0% (NZ98/254) and 83% (M10713). Among controls, SBA titers were ≥1:4 in 4% (H44/76, 5/99), 0% (NZ98/254) and 67% (M10713) at baseline, increasing to 100% (H44/76 and 5/99), 89% (NZ98/254) and 97% (M10713) postimmunization. CONCLUSION: The variable rates of waning of antibody to the 4 components of 4CMenB complicates estimates of duration of protection and should be taken into account in cost-effectiveness analyses. A 2-dose schedule of 4CMenB in 5-year-old children was immunogenic.

Pollard AJ, Riordan A, Ramsay M. 2014. Group B meningococcal vaccine: recommendations for UK use. Lancet, 383 (9923), pp. 1103-1104. | Read more

Andrews SM, Pollard AJ. 2014. A vaccine against serogroup B Neisseria meningitidis: dealing with uncertainty. Lancet Infect Dis, 14 (5), pp. 426-434. | Show Abstract | Read more

Neisseria meningitidis is an important cause of invasive bacterial infection in children worldwide. Although serogroup C meningococcal disease has all but disappeared in the past decade as a direct result of immunisation programmes in Europe, Canada, and Australia, meningitis and septicaemia caused by serogroup B meningococci remain uncontrolled. A vaccine (4CMenB) has now been licensed for use in the European Union, comprising three immunogenic antigens (identified with use of reverse vaccinology) combined with bacterial outer-membrane vesicles. The vaccine has the potential to reduce mortality and morbidity associated with serogroup B meningococci infections, but uncertainty remains about the breadth of protection the vaccine might induce against the diverse serogroup B meningococci strains that cause disease. We discuss drawbacks in the techniques used to estimate coverage and potential efficacy of the vaccine, and their effects on estimates of cost-effectiveness, both with and without herd immunity. For parents, and clinicians treating individual patients, the predicted benefits of vaccination outweigh existing uncertainties if any cases can be prevented, but future use of the vaccine must be followed by rigorous post-implementation surveillance to reassess its value to health systems with directly recorded epidemiological data.

Mitchell R, Kelly DF, Pollard AJ, Trück J. 2014. Polysaccharide-specific B cell responses to vaccination in humans. Hum Vaccin Immunother, 10 (6), pp. 1661-1668. | Show Abstract | Read more

The introduction of vaccines containing the capsular polysaccharides of N. meningitidis, S. pneumonia, and H. influenzae type b has driven a significant reduction in cases of disease caused by these bacteria. The polysaccharide-specific antibody responses following vaccination are well characterized, however less is known about the B cells underlying this response. Here, we summarize the plasma cell (PC) and memory B cell (BMEM) responses following plain polysaccharide and protein-polysaccharide conjugate vaccination, drawing together studies covering a range of vaccines and age groups. These studies show that infant primary PC and BMEM responses to polysaccharide-conjugate vaccines are low in relation to older age groups but are significantly higher following booster doses. PC kinetics have generally been found to follow a similar pattern irrespective of vaccine type or age group, whereas divergent BMEM responses have been reported following plain polysaccharide and conjugate vaccination. A degree of correlation between early BMEM responses and maintenance of protective antibody levels has been identified in some studies, but the relationship between the 2 remains unclear. Identification of the B cell subsets involved and the mechanisms by which they are induced may provide a better understanding of the role of B cells in maintaining protective immunity through vaccination.

Martin NG, Sadarangani M, Pollard AJ, Goldacre MJ. 2014. Hospital admission rates for meningitis and septicaemia caused by Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae in children in England over five decades: a population-based observational study. Lancet Infect Dis, 14 (5), pp. 397-405. | Show Abstract | Read more

BACKGROUND: Infection with Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae causes substantial mortality and long-term morbidity in children. We know of no study to assess the long-term trends in hospital admission rates for meningitis and septicaemia caused by these pathogens in children in England. We aimed to do such a study using routinely reported data in England. METHODS: In this population-based observational study, we used datasets that include routinely collected administrative statistics for hospital care: the Hospital In-Patient Enquiry (data for England from 1968 to 1985), the Hospital Episode Statistics dataset (data for England from 1989 onwards), and the Oxford record linkage study (data for Oxfordshire and surrounding areas from 1963 to 2011). We analysed annual age-specific and age-standardised admission rates in children younger than 15 years with H influenzae, meningococcal and pneumococcal meningitis, and septicaemia. FINDINGS: We saw a reduction in hospital admission rates for childhood invasive bacterial disease after the introduction of conjugate vaccines against H influenzae, N meningitidis, and S pneumoniae in England. Annual incidence of H influenzae meningitis per 100,000 children decreased from 6·72 admissions (95% CI 6·18-7·26) in 1992 to 0·39 admissions (0·26-0·52) in 1994, after the introduction of routine H influenzae type b vaccination. We saw a small rise in admissions in the early 2000s, peaking at 1·24 admissions per 100,000 children (0·99-1·48) in 2003, which decreased to 0·28 per 100,000 children (0·17-0·39) by 2008 after the introduction of catch-up (2003) and routine (2006) booster programmes for young children. Meningococcal disease increased during the 1990s, reaching a peak in 1999, with 34·54 admissions (33·30-35·78) per 100,000 children. Hospital admissions decreased after the meningococcal serogroup C vaccine was introduced in 1999 and was 12·40 admissions (11·68-13·12) per 100,000 in 2011. Admissions for invasive pneumococcal disease increased from the 1990s reaching a peak in 2006 at 4·45 admissions for meningitis (95% CI 4·0-4·9) per 100,000 children and 2·81 admissions for septicaemia (2·45-3·17) per 100,000 children. A reduction in admissions occurred after the introduction of the pneumococcal conjugate vaccine in 2006: hospital admission rates in 2011 were 2·03 per 100,000 children for meningitis and 1·12 per 100,000 children for septicaemia. INTERPRETATION: Vaccine-preventable invasive bacterial disease in children has decreased substantially in England in the past five decades, most notably with the advent of effective conjugate vaccines since the 1990s. Ongoing disease surveillance and continued development and implementation of vaccines against additional pneumococcal serotypes and serogroup B meningococcal disease are important. FUNDING: None.

Waddington CS, Darton TC, Jones C, Haworth K, Peters A, John T, Thompson BAV, Kerridge SA, Kingsley RA, Zhou L et al. 2014. An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clin Infect Dis, 58 (9), pp. 1230-1240. | Show Abstract | Read more

BACKGROUND: Typhoid fever is a major global health problem, the control of which is hindered by lack of a suitable animal model in which to study Salmonella Typhi infection. Until 1974, a human challenge model advanced understanding of typhoid and was used in vaccine development. We set out to establish a new human challenge model and ascertain the S. Typhi (Quailes strain) inoculum required for an attack rate of 60%-75% in typhoid-naive volunteers when ingested with sodium bicarbonate solution. METHODS: Groups of healthy consenting adults ingested escalating dose levels of S. Typhi and were closely monitored in an outpatient setting for 2 weeks. Antibiotic treatment was initiated if typhoid diagnosis occurred (temperature ≥38°C sustained ≥12 hours or bacteremia) or at day 14 in those remaining untreated. RESULTS: Two dose levels (10(3) or 10(4) colony-forming units) were required to achieve the primary objective, resulting in attack rates of 55% (11/20) or 65% (13/20), respectively. Challenge was well tolerated; 4 of 40 participants fulfilled prespecified criteria for severe infection. Most diagnoses (87.5%) were confirmed by blood culture, and asymptomatic bacteremia and stool shedding of S. Typhi was also observed. Participants who developed typhoid infection demonstrated serological responses to flagellin and lipopolysaccharide antigens by day 14; however, no anti-Vi antibody responses were detected. CONCLUSIONS: Human challenge with a small inoculum of virulent S. Typhi administered in bicarbonate solution can be performed safely using an ambulant-model design to advance understanding of host-pathogen interactions and immunity. This model should expedite development of diagnostics, vaccines, and therapeutics for typhoid control.

Waddington CS, Darton TC, Woodward WE, Angus B, Levine MM, Pollard AJ. 2014. Advancing the management and control of typhoid fever: a review of the historical role of human challenge studies. J Infect, 68 (5), pp. 405-418. | Show Abstract | Read more

Typhoid infection causes considerable morbidity and mortality worldwide, particularly in settings where lack of clean water and inadequate sanitation facilitate disease spread through faecal-oral transmission. Improved understanding of the pathogenesis, immune control and microbiology of Salmonella Typhi infection can help accelerate the development of improved vaccines and diagnostic tests necessary for disease control. S. Typhi is a human-restricted pathogen; therefore animal models are limited in their relevance to human infection. During the latter half of the 20th century, induced human infection ("challenge") studies with S. Typhi were used effectively to assess quantitatively the human host response to challenge and to measure directly the efficacy of typhoid vaccines in preventing clinical illness. Here, the findings of these historic challenge studies are reviewed, highlighting the pivotal role that challenge studies have had in improving our understanding of the host-pathogen interaction, and illustrating issues relevant to modern typhoid challenge model design.

Marshall ASJ, Barker CIS, Pulickal AS, Kibwana E, Gautam SC, Clutterbuck EA, Thorson SM, Shrestha S, Adhikari N, Pollard AJ, Kelly DF. 2014. The seroepidemiology of Haemophilus influenzae type b prior to introduction of an immunization programme in Kathmandu, Nepal. PLoS One, 9 (1), pp. e85055. | Show Abstract | Read more

Haemophilus influenzae type b (Hib) is now recognized as an important pathogen in Asia. To evaluate disease susceptibility, and as a marker of Hib transmission before routine immunization was introduced in Kathmandu, 71 participants aged 7 months-77 years were recruited and 15 cord blood samples were collected for analysis of anti-polyribosylribitol phosphate antibody levels by enzyme-linked immunosorbent assay. Only 20% of children under 5 years old had levels considered protective (>0.15 µg/ml), rising to 83% of 15-54 year-olds. Prior to introduction of Hib vaccine in Kathmandu, the majority of young children were susceptible to disease.

Perrett KP, John TM, Jin C, Kibwana E, Yu L-M, Curtis N, Pollard AJ. 2014. Long-term persistence of immunity and B-cell memory following Haemophilus influenzae type B conjugate vaccination in early childhood and response to booster. Clin Infect Dis, 58 (7), pp. 949-959. | Show Abstract | Read more

BACKGROUND: Protection against Haemophilus influenzae type b (Hib), a rapidly invading encapsulated bacteria, is dependent on maintenance of an adequate level of serum antibody through early childhood. In many countries, Hib vaccine booster doses have been implemented after infant immunization to sustain immunity. We investigated the long-term persistence of antibody and immunological memory in primary-school children following infant (with or without booster) Hib vaccination. METHODS: Anti-polyribosylribitol phosphate (PRP) immunoglobulin G (IgG) concentration and the frequency of circulating Hib-specific memory B cells were measured before a booster of a Hib-serogroup C meningococcal (MenC) conjugate vaccine and again 1 week, 1 month, and 1 year after the booster in 250 healthy children aged 6-12 years in an open-label phase 4 clinical study. RESULTS: Six to 12 years following infant priming with 3 doses of Hib conjugate vaccine, anti-PRP IgG geometric mean concentrations were 3.11 µg/mL and 0.71 µg/mL and proportions with anti-PRP IgG ≥1.0 µg/mL were 79% and 43% in children who had or had not, respectively, received a fourth Hib conjugate vaccine dose (mean age, 3.9 years). Higher baseline and post-Hib-MenC booster responses (anti-PRP IgG and memory B cells) were found in younger children and in those who had received a fourth Hib dose. CONCLUSIONS: Sustained Hib conjugate vaccine-induced immunity in children is dependent on time since infant priming and receipt of a booster. Understanding the relationship between humoral and cellular immunity following immunization with conjugate vaccines may direct vaccine design and boosting strategies to sustain individual and population immunity against encapsulated bacteria in early childhood. Clinical Trials Registration ISRCTN728588998.

Jones C, Darton TC, Pollard AJ. 2014. Why the development of effective typhoid control measures requires the use of human challenge studies. Front Microbiol, 5 (DEC), pp. 707. | Read more

Mehta OH, Norheim G, Hoe JC, Rollier CS, Nagaputra JC, Makepeace K, Saleem M, Chan H, Ferguson DJP, Jones C et al. 2014. Adjuvant effects elicited by novel oligosaccharide variants of detoxified meningococcal lipopolysaccharides on Neisseria meningitidis recombinant PorA protein: a comparison in mice. PLoS One, 9 (12), pp. e115713. | Show Abstract | Read more

Neisseria meningitidis lipopolysaccharide (LPS) has adjuvant properties that can be exploited to assist vaccine immunogenicity. The modified penta-acylated LPS retains the adjuvant properties of hexa-acylated LPS but has a reduced toxicity profile. In this study we investigated whether two modified glycoform structures (LgtE and IcsB) of detoxified penta-acylated LPS exhibited differential adjuvant properties when formulated as native outer membrane vesicles (nOMVs) as compared to the previously described LgtB variant. Detoxified penta-acylated LPS was obtained by disruption of the lpxL1 gene (LpxL1 LPS), and three different glycoforms were obtained by disruption of the lgtB, lgtE or icsB genes respectively. Mice (mus musculus) were immunized with a recombinant PorA P1.7-2,4 (rPorA) protein co-administered with different nOMVs (containing a different PorA serosubtype P1.7,16), each of which expressed one of the three penta-acylated LPS glycoforms. All nOMVs induced IgG responses against the rPorA, but the nOMVs containing the penta-acylated LgtB-LpxL1 LPS glycoform induced significantly greater bactericidal activity compared to the other nOMVs or when the adjuvant was Alhydrogel. Compared to LgtE or IcsB LPS glycoforms, these data support the use of nOMVs containing detoxified, modified LgtB-LpxL1 LPS as a potential adjuvant for future meningococcal protein vaccines.

Curtis N, Pollard AJ, Finn A. 2014. Hot topics in infection and immunity in children Journal of Infection, | Read more

Curtis N, Pollard AJ, Finn A. 2014. Hot topics in infection and immunity in children--Papers from the 10th annual IIC meeting, Oxford, UK, 2012. Preface. The Journal of infection, 68 Suppl 1

Read RC, Baxter D, Chadwick DR, Faust SN, Finn A, Gordon SB, Heath PT, Lewis DJM, Pollard AJ, Turner DPJ et al. 2014. Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial. Lancet, 384 (9960), pp. 2123-2131. | Show Abstract | Read more

BACKGROUND: Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS: In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS: Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION: Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING: Novartis Vaccines.

Hanieh S, Hamaluba M, Kelly DF, Metz JA, Wyres KL, Fisher R, Pradhan R, Shakya D, Shrestha L, Shrestha A et al. 2014. Streptococcus pneumoniae carriage prevalence in Nepal: evaluation of a method for delayed transport of samples from remote regions and implications for vaccine implementation. PLoS One, 9 (6), pp. e98739. | Show Abstract | Read more

BACKGROUND: Pneumococcal disease is a significant cause of morbidity and mortality in young children in Nepal, and currently available pneumococcal conjugate vaccines offer moderate coverage of invasive disease isolates. METHODS: A prevalence study of children aged 1.5 to 24 months in urban and rural Nepal was conducted. In the urban group, nasopharyngeal swabs (NPS) were transported using silica desiccant packages (SDP) with delayed processing (2 weeks), or skim-milk-tryptone-glucose-glycerin (STGG) with immediate processing (within 8 hours). Pneumococcal nasopharyngeal carriage prevalence, serogroup/type distribution and isolate genotypes (as defined by multilocus sequence typing) were determined. RESULTS: 1101 children were enrolled into the study: 574 in the urban group and 527 in the rural group. Overall carriage prevalence based on culture from specimens transported and stored in STGG was 58.7% (337/574), compared to 40.9% (235/574) in SDP. There was concordance of detection of pneumococcus in 67% of samples. Using the SDP method, pneumococcal carriage prevalence was higher in the rural population (69.2%; 364/526) compared to the urban population (40.9%; 235/574). Serogroup/type distribution varied with geographical location. Over half of the genotypes identified in both the urban and rural pneumococcal populations were novel. CONCLUSION: The combination of delayed culture and transport using SDP underestimates the prevalence of pneumococcal carriage; however, in remote areas, this method could still provide a useful estimate of carriage prevalence and serogroup/type distribution. Vaccine impact is unpredictable in a setting with novel genotypes and limited serotype coverage as described here. Consequently, continued surveillance of pneumococcal isolates from carriage and disease in Nepali children following the planned introduction of pneumococcal conjugate vaccines introduction will be essential.

Pollard AJ, Riordan A, Ramsay M. 2014. No conspiracy regarding recommendation for a group B meningococcus vaccine. BMJ, 348 (may08 2), pp. g2859. | Read more

Lang S, Ford KJ, John T, Pollard AJ, McCarthy ND. 2014. Immunisation errors reported to a vaccine advice service: intelligence to improve practice. Qual Prim Care, 22 (3), pp. 139-146. | Show Abstract

BACKGROUND: The success of immunisation programmes depends on the quality with which they are administered. The Vaccine Advice for CliniCians Service (VACCSline) is an advice service to support immunisers and promote excellence in immunisation practice, through specialist guidance and local education, covering a catchment population of two million people. All enquiries are recorded onto a database and categorised. Vaccine error is selected when a vaccine has not been prepared or administered according to national recommendations or relevant expert guidance. METHOD: All enquiries from 2009 to 2011, categorised on the VACCSline database as 'vaccine error' were analysed and subjected to a detailed free-text review. RESULTS: Of 4301 enquiries, 158 (3.7%) concerned vaccine errors. The greatest frequency of errors, 145 (92.9%) concerned immunisations delivered in primary care services; 92% of all errors occurred during either vaccine selection and preparation or history checking and scheduling. Administration of the wrong vaccine was the most frequent error recorded in 33.3% of reports. A shared first letter of the vaccine name was noted to occur in 13 error reports in which the incorrect vaccine was inadvertently administered. Consultations involving pairs of siblings were associated with various errors in seven enquiries. Failure to revaccinate after spillage (seven reports) showed a widespread knowledge gap in this area. CONCLUSION: Advice line enquiries provide intelligence to alert immunisers to the errors that are commonly reported and may serve to highlight processes that predispose to errors, thus informing immuniser training and updating.

Pollard AJ, Riordan A, Ramsay M. 2014. Group B meningococcal vaccine: Recommendations for UK use The Lancet, 383 (9923), pp. 1103-1104. | Read more

Trück J, Snape MD, Tatangeli F, Voysey M, Yu L-M, Faust SN, Heath PT, Finn A, Pollard AJ. 2014. Pneumococcal serotype-specific antibodies persist through early childhood after infant immunization: follow-up from a randomized controlled trial. PLoS One, 9 (3), pp. e91413. | Show Abstract | Read more

BACKGROUND: In a previous UK multi-center randomized study 278 children received three doses of 7-valent (PCV-7) or 13-valent (PCV-13) pneumococcal conjugate vaccine at 2, 4 and 12 months of age. At 13 months of age, most of these children had pneumococcal serotype-specific IgG concentrations ≥ 0.35 µg/ml and opsonophagocytic assay (OPA) titers ≥ 8. METHODS: Children who had participated in the original study were enrolled again at 3.5 years of age. Persistence of immunity following infant immunization with either PCV-7 or PCV-13 and the immune response to a PCV-13 booster at pre-school age were investigated. RESULTS: In total, 108 children were followed-up to the age of 3.5 years and received a PCV-13 booster at this age. At least 76% of children who received PCV-7 or PCV-13 in infancy retained serotype-specific IgG concentrations ≥ 0.35 µg/ml against each of 5/7 shared serotypes. For serotypes 4 and 18C, persistence was lower at 22-42%. At least 71% of PCV-13 group participants had IgG concentrations ≥ 0.35 µg/ml against each of 4/6 of the additional PCV-13 serotypes; for serotypes 1 and 3 this proportion was 45% and 52%. In the PCV-7 group these percentages were significantly lower for serotypes 1, 5 and 7F. A pre-school PCV-13 booster was highly immunogenic and resulted in low rates of local and systemic adverse effects. CONCLUSION: Despite some decline in antibody from 13 months of age, these data suggest that a majority of pre-school children maintain protective serotype-specific antibody concentrations following conjugate vaccination at 2, 4 and 12 months of age. TRIAL REGISTRATION: ClinicalTrials.gov NCT01095471.

Norheim G, Sadarangani M, Omar O, Yu LM, Mølbak K, Howitz M, Olcén P, Haglund M, Van Der Ende A, Pollard AJ. 2014. Association between population prevalence of smoking and incidence of meningococcal disease in Norway, Sweden, Denmark and the Netherlands between 1975 and 2009: A population-based time series analysis BMJ Open, 4 (2), | Show Abstract | Read more

Objective: To investigate the relationship between the prevalence of smoking in the population and incidence of invasive meningococcal disease (IMD) among children under 5 years of age. Design: Retrospective, longitudinal, observational study. Poisson regression controlled for confounding factors. Setting: Norway, Sweden, Denmark and the Netherlands between 1975 and 2009. Population: Total population of approximately 35 million people in these four countries. Data sources: Data were collected from the Ministries of Health, National Statistics Bureaus and other relevant national institutes. Results: In Norway, there was a significant positive relationship between the annual prevalence of daily smokers among individuals aged 25-49 years and the incidence of IMD in children under 5 years of age, unadjusted (RR=1.04-1.06, 95% CI 1.02 to 1.07, p < 0.001) and after adjustment for time of year (quarter), incidence of influenza-like illness and household crowding (RR=1.05-1.07, 95% CI 1.03 to 1.09, p < 0.001). Depending on age group, the risk of IMD increased by 5.2-6.9% per 1% increase in smoking prevalence among individuals aged 25-49 years in adjusted analyses. Using limited datasets from the three other countries, unadjusted analysis showed positive associations between IMD in children related to older smokers in Sweden and the Netherlands and negative associations related to younger smokers in Sweden. However, there were no demonstrable associations between incidence of IMD and prevalence of smoking, after adjustment for the same confounding variables. Conclusions: The reduced incidence of IMD in Norway between 1975 and 2009 may partly be explained by the reduced prevalence of smoking during this period. High-quality surveillance data are required to confirm this in other countries. Strong efforts to reduce smoking in the whole population including targeted campaigns to reduce smoking among adults may have a role to play in the prevention of IMD in children.

Norheim G, Sadarangani M, Omar O, Yu L-M, Mølbak K, Howitz M, Olcén P, Haglund M, van der Ende A, Pollard AJ. 2014. Association between population prevalence of smoking and incidence of meningococcal disease in Norway, Sweden, Denmark and the Netherlands between 1975 and 2009: a population-based time series analysis. BMJ Open, 4 (2), pp. e003312. | Show Abstract | Read more

OBJECTIVE: To investigate the relationship between the prevalence of smoking in the population and incidence of invasive meningococcal disease (IMD) among children under 5 years of age. DESIGN: Retrospective, longitudinal, observational study. Poisson regression controlled for confounding factors. SETTING: Norway, Sweden, Denmark and the Netherlands between 1975 and 2009. POPULATION: Total population of approximately 35 million people in these four countries. DATA SOURCES: Data were collected from the Ministries of Health, National Statistics Bureaus and other relevant national institutes. RESULTS: In Norway, there was a significant positive relationship between the annual prevalence of daily smokers among individuals aged 25-49 years and the incidence of IMD in children under 5 years of age, unadjusted (RR=1.04-1.06, 95% CI 1.02 to 1.07, p<0.001) and after adjustment for time of year (quarter), incidence of influenza-like illness and household crowding (RR=1.05-1.07, 95% CI 1.03 to 1.09, p<0.001). Depending on age group, the risk of IMD increased by 5.2-6.9% per 1% increase in smoking prevalence among individuals aged 25-49 years in adjusted analyses. Using limited datasets from the three other countries, unadjusted analysis showed positive associations between IMD in children related to older smokers in Sweden and the Netherlands and negative associations related to younger smokers in Sweden. However, there were no demonstrable associations between incidence of IMD and prevalence of smoking, after adjustment for the same confounding variables. CONCLUSIONS: The reduced incidence of IMD in Norway between 1975 and 2009 may partly be explained by the reduced prevalence of smoking during this period. High-quality surveillance data are required to confirm this in other countries. Strong efforts to reduce smoking in the whole population including targeted campaigns to reduce smoking among adults may have a role to play in the prevention of IMD in children.

Darton TC, Blohmke CJ, Pollard AJ. 2014. Typhoid epidemiology, diagnostics and the human challenge model. Curr Opin Gastroenterol, 30 (1), pp. 7-17. | Show Abstract | Read more

PURPOSE OF REVIEW: Infection caused by ingestion of human-restricted Salmonella enterica serovars Typhi and Paratyphi predominantly affects the most impoverished sections of society. In this review, we describe recent advances made in estimating the burden of illness and the important role improved diagnostic tests may have in controlling infection and report the development of a new human challenge model of typhoid infection. RECENT FINDINGS: Typhoid continues to be a major cause of morbidity, particularly in children and young adults in south east Asia, although accurate assessments are still hindered by the lack of reliable surveillance data. Recent reports of high rates of infection in Africa and the dominance of paratyphoid in several geographic areas are of particular concern. Diagnosis of enteric fever remains frustrated by the nonspecific clinical presentation of cases and the lack of test sensitivity. Methods to improve diagnostic accuracy are hindered by the incomplete understanding of immunobiological mechanisms of infection and lack of a suitable animal infection model. SUMMARY: Enteric fever is a major global problem, the burden of which has only partially been recognized. Control strategies utilizing cheap accurate diagnostics and effective vaccines are urgently required, and their development should be accelerated by the use of a human challenge model.

Waddington CS, Darton TC, Pollard AJ. 2014. The challenge of enteric fever Journal of Infection, 68 (SUPPL1), | Show Abstract | Read more

Enteric fever, a non-specific, systemic infection caused by S. Typhi or Paratyphi A, B or C, is common in resource-limited regions of the world, where poor sanitation infrastructure facilitates faeco-oral transmission. Prompt treatment with appropriate antibiotics minimises illness severity, but presentation to health care facilities is often delayed because of the non-specific nature of the symptoms and the lack of reliable diagnostic tests. Disease prevention requires significant investment in provision of clean water and sanitation in the long term; vaccination offers a more realistic strategy for medium term control. However, implementation of existing vaccines and development of more efficacious vaccines has been hindered by the lack of an established correlate of protection and under appreciation of the true disease burden. Human microbial infection studies could provide a vehicle for the rapid evaluation of novel vaccines and investigation of the immunobiology of enteric infection. © 2013 The British Infection Association.

Curtis N, Pollard AJ, Finn A. 2014. Preface Journal of Infection, 68 (SUPPL1), | Read more

Nagaputra JC, Rollier CS, Sadarangani M, Hoe JC, Mehta OH, Norheim G, Saleem M, Chan H, Derrick JP, Feavers I et al. 2014. Neisseria meningitidis native outer membrane vesicles containing different lipopolysaccharide glycoforms as adjuvants for meningococcal and nonmeningococcal antigens. Clin Vaccine Immunol, 21 (2), pp. 234-242. | Show Abstract | Read more

We evaluated the adjuvant effect of a modified glycoform of lipopolysaccharide (LPS) (LgtB-LpxL1) compared to that of the nonmodified glycoform Lpxl1 serogroup B meningococcal H44/76 native outer membrane vesicles (nOMVs) on immune responses to vaccination with the recombinant meningococcal protein, rPorA, tetanus toxoid, or meningococcal serogroup C capsular polysaccharide. We used LgtB-LpxL1 LPS because the disruption of the lgtB gene, which results in the exposure of N-acetylglucosamine-galactose-glucose residues in the LPS outer core, has been shown to enhance the activation of human dendritic cells in vitro. The responses were compared to those of a monophosphoryl lipid A (MPL)-based adjuvant and to an aluminum hydroxide suspension. The nOMVs induced blood serum IgG responses against each of the three antigens comparable to those obtained with MPL or aluminum salt. However, nOMVs elicited (i) a lower IgG1/IgG2a ratio against rPorA and (ii) serum bactericidal antibody titers superior to those achieved with aluminum salt, reaching similar titers to those obtained with MPL. Similarly, bactericidal antibody titers induced by immunization with meningococcal serogroup C polysaccharide and nOMVs were similar to those obtained using MPL but were better than those with aluminum salt. Immunization with tetanus toxoid and nOMVs resulted in tetanus toxoid-specific IgG responses similar to those obtained when adjuvanted with aluminum salt. These results highlight the potential utility of meningococcal LpxL1 LPS-containing nOMVs as an adjuvant for recombinant meningococcal protein vaccines and suggest their possible use with a variety of other antigens.

O'Connor D, Trück J, Lazarus R, Clutterbuck EA, Voysey M, Jeffery K, Pollard AJ. 2014. The effect of chronic cytomegalovirus infection on pneumococcal vaccine responses. J Infect Dis, 209 (10), pp. 1635-1641. | Show Abstract | Read more

BACKGROUND: Immune function declines with age and has been associated with reduced vaccine responsiveness. Chronic infection with cytomegalovirus (CMV) has been proposed as a contributor to poorer responses in older adults. A pneumococcal vaccine has been recommended in the United Kingdom for those aged >65 years since 2003 to prevent pneumococcal disease. METHODS: We evaluated the effect of age and CMV status on pneumococcal vaccine responses in 348 individuals aged 50-70 years. RESULTS: We found participant age to be associated with serotype-specific and functional antibody titers after pneumococcal vaccination, with a mean 6.2% (95% confidence interval, 2.9%-9.5%) reduction in postvaccination functional antibody titers per year. CMV status was not associated with serotype-specific immunoglobulin G concentrations or functional antibody titers after pneumococcal vaccination. However, CMV seropositivity was associated with higher levels of prevaccination functional antibody for 4 of 7 pneumococcal serotypes assessed. CONCLUSIONS: These data imply that CMV infection is not directly responsible for the decline in pneumococcal vaccine responses seen with age but suggest that CMV-seropositive individuals differ in their natural exposure to pneumococci or have altered mucosal immune responses after colonization with this organism.

McCann LJ, Ford KJ, Pollard AJ, Kulkarni R, Amirthalingam G, Smith A, McCarthy ND. 2013. Self-reported adverse events in adolescents aged 13–18 years after mass vaccination with pertussis-containing vaccine, following a school outbreak Public Health, 127 (12), pp. 1133-1136. | Read more

McCann LJ, Ford KJ, Pollard AJ, Kulkarni R, Amirthalingam G, Smith A, McCarthy ND. 2013. Self-reported adverse events in adolescents aged 13-18 years after mass vaccination with pertussis-containing vaccine, following a school outbreak. Public Health, 127 (12), pp. 1133-1136. | Read more

Micoli F, Romano MR, Tontini M, Cappelletti E, Gavini M, Proietti D, Rondini S, Swennen E, Santini L, Filippini S et al. 2013. Development of a glycoconjugate vaccine to prevent meningitis in Africa caused by meningococcal serogroup X. Proc Natl Acad Sci U S A, 110 (47), pp. 19077-19082. | Show Abstract | Read more

Neisseria meningitidis is a major cause of bacterial meningitis worldwide, especially in the African meningitis belt, and has a high associated mortality. The meningococcal serogroups A, W, and X have been responsible for epidemics and almost all cases of meningococcal meningitis in the meningitis belt over the past 12 y. Currently no vaccine is available against meningococcal X (MenX). Because the development of a new vaccine through to licensure takes many years, this leaves Africa vulnerable to new epidemics of MenX meningitis at a time when the epidemiology of meningococcal meningitis on the continent is changing rapidly, following the recent introduction of a glycoconjugate vaccine against serogroup A. Here, we report the development of candidate glycoconjugate vaccines against MenX and preclinical data from their use in animal studies. Following optimization of growth conditions of our seed MenX strain for polysaccharide (PS) production, a scalable purification process was developed yielding high amounts of pure MenX PS. Different glycoconjugates were synthesized by coupling MenX oligosaccharides of varying chain length to CRM197 as carrier protein. Analytical methods were developed for in-process control and determination of purity and consistency of the vaccines. All conjugates induced high anti-MenX PS IgG titers in mice. Antibodies were strongly bactericidal against African MenX isolates. These findings support the further development of glycoconjugate vaccines against MenX and their assessment in clinical trials to produce a vaccine against the one cause of epidemic meningococcal meningitis that currently cannot be prevented by available vaccines.

Hoschler K, Andrews NJ, Faust SN, Finn A, Pollard AJ, Snape MD, Walker WT, Zambon M, Miller E. 2014. Administration of AS03B-adjuvanted A(H1N1)pdm09 vaccine in children aged <3 years enhances antibody response to H3 and B viruses following a single dose of trivalent vaccine one year later. Clin Infect Dis, 58 (2), pp. 181-187. | Show Abstract | Read more

BACKGROUND: We report on a follow-up clinical and serological investigation of 274 children who received seasonal influenza vaccine (trivalent inactivated vaccine [TIV]) 1 year after receipt of either AS03(B)-adjuvanted subunit or whole virus monovalent A(H1N1)pdm09 vaccine and describe the antibody responses to the H3N2 A/Perth/16/2009 and B/Brisbane/60/2008 components of TIV. METHODS: Vaccine responses were analyzed using hemagglutination inhibition (HAI) assays. In children aged <3 years, previous receipt of adjuvanted vaccine resulted in higher HAI antibody responses to H3N2 and B strains compared with nonadjuvanted vaccine (fold change 16.8 vs 4.3 for H3N2 and 7.0 vs 1.6 for B). In children aged >3 years, responses to the H3 and B components of TIV were similar between vaccine groups. Sera taken before and after the pandemic vaccine were also analyzed by HAI using A/Perth/16/2009 virus. This analysis showed that 11.1% of children receiving the AS03(B)-adjuvanted vaccine but only 1.4% in the nonadjuvanted group had a 4-fold rise to A/Perth/16/2009. CONCLUSION: AS03B-adjuvanted A(H1N1)pdm09 influenza vaccine generates a cross-reactive antibody response to H3N2 in children and enhances responses to heterologous subtypes in children aged <3 years 1 year later.

Waddington CS, Darton TC, Pollard AJ. 2014. The challenge of enteric fever. J Infect, 68 Suppl 1 pp. S38-S50. | Show Abstract | Read more

Enteric fever, a non-specific, systemic infection caused by S. Typhi or Paratyphi A, B or C, is common in resource-limited regions of the world, where poor sanitation infrastructure facilitates faeco-oral transmission. Prompt treatment with appropriate antibiotics minimises illness severity, but presentation to health care facilities is often delayed because of the non-specific nature of the symptoms and the lack of reliable diagnostic tests. Disease prevention requires significant investment in provision of clean water and sanitation in the long term; vaccination offers a more realistic strategy for medium term control. However, implementation of existing vaccines and development of more efficacious vaccines has been hindered by the lack of an established correlate of protection and under appreciation of the true disease burden. Human microbial infection studies could provide a vehicle for the rapid evaluation of novel vaccines and investigation of the immunobiology of enteric infection.

Snape MD, Saroey P, John TM, Robinson H, Kelly S, Gossger N, Yu L-M, Wang H, Toneatto D, Dull PM, Pollard AJ. 2013. Persistence of bactericidal antibodies following early infant vaccination with a serogroup B meningococcal vaccine and immunogenicity of a preschool booster dose. CMAJ, 185 (15), pp. E715-E724. | Show Abstract | Read more

BACKGROUND: The multicomponent serogroup B meningococcal (4CMenB) vaccine was recently licensed for use in Europe. There are currently no data on the persistence of bactericidal antibodies induced by use of this vaccine in infants. Our objective was to evaluate serogroup B-specific bactericidal antibodies in children aged 40-44 months previously vaccinated at 2, 4, 6 and 12 months of age. METHODS: Participants given 4 doses of 4CMenB as infants received a fifth dose of the vaccine at 40-44 months of age. Age-matched participants who were MenB vaccine-naive received 4CMenB and formed the control group. We evaluated human complement serum bactericidal activity (hSBA) titres at baseline and 1 month after each dose of 4CMenB. RESULTS: Before a booster dose at enrolment, 41%-76% of 17 participants previously vaccinated with 4CMenB in infancy had hSBA titres of 4 or greater against 4 reference strains. Before vaccination in the control group (n = 40) these proportions were similar for strains 44/76-SL (63%) and M10713 (68%) but low for strains NZ98/254 (0%) and 5/99 (3%). A booster dose in the 4CMenB-primed participants generated greater increases in hSBA titres than in controls. INTERPRETATION: As has been observed with other meningococcal vaccines, bactericidal antibodies waned after vaccination with 4CMenB administered according to an approved infant vaccination schedule of 2, 4, 6 and 12 months of age, but there was an anamnestic response to a booster dose at 40-44 months of age. If 4CMenB were introduced into routine vaccination schedules, assessment of the need for a booster dose would require data on the impact of these declining titres on vaccine effectiveness. ClinicalTrials.gov, no. NCT01027351.

Bambery B, Selgelid M, Maslen H, Pollard AJ, Savulescu J. 2013. The case for mandatory flu vaccination of children. Am J Bioeth, 13 (9), pp. 38-40. | Read more

Rodgers GL, Esposito S, Principi N, Gutierrez-Brito M, Diez-Domingo J, Pollard AJ, Snape MD, Martinón-Torres F, Gruber WC, Patterson S et al. 2013. Immune response to 13-valent pneumococcal conjugate vaccine with a reduced dosing schedule. Vaccine, 31 (42), pp. 4765-4774. | Show Abstract | Read more

BACKGROUND: The 7-valent pneumococcal conjugate vaccine (PCV7) has demonstrated effectiveness against pneumococcal illnesses when administered as 3 infant doses plus a toddler dose (3+1 schedule) or as an abbreviated schedule of 2 infant doses plus a toddler dose (2+1 schedule). The 13-valent pneumococcal conjugate vaccine (PCV13) is approved and World Health Organization-prequalified for administration in a 2+1 schedule when used as part of routine immunization programs. OBJECTIVE: To summarize immunologic responses elicited by PCV13 administered in a 2+1 schedule and following 2 doses in a 3+1 schedule. METHODS: Studies were double-blind, randomized, active-controlled, multicenter studies except the Mexico study (open-label, single-arm). In 2+1 studies, PCV13 was administered at 2, 4, and 12 (UK) or 3, 5, and 11 (Italy) months. In 3+1 studies (Spain and Mexico), assessment was made postdose 2 of the primary series (2, 4, and 6 months). The primary immunogenicity endpoint was the proportion of participants achieving serotype-specific antipolysaccharide immunoglobulin (Ig)G concentrations ≥ 0.35μg/mL (i.e., responders) 1 month postdose 2. Pneumococcal IgG geometric mean concentrations (GMCs), opsonophagocytic activity (OPA), and concomitant vaccine responses were assessed. RESULTS: PCV13 and PCV7 elicited comparable immune responses for the 7 common serotypes after 2 infant doses. The proportion of PCV13 responders postdose 2 was >85% for most of the 7 common and 6 additional serotypes, except common serotypes 6B (27.9-81.4%) and 23F (55.8-77.5%) and additional serotypes 3 (73.8-96.9%) and 6A (79.2-94.4%). Serotypes 6B and 23F elicited lower IgG GMCs postdose 2 compared with other serotypes; all serotypes demonstrated boosting posttoddler dose. All serotypes demonstrated functional activity; >95% of participants achieved OPA levels ≥ 1:8 postdose 2. Concomitant vaccine responses were similar between PCV13 and PCV7 groups. CONCLUSION: Immune responses elicited by PCV13 following 2 infant doses support transition from PCV7 to PCV13 in countries using a 2+1 schedule.

Snape MD, Philip J, John TM, Robinson H, Kelly S, Gossger N, Yu L-M, Kittel C, Toneatto D, Dull PM, Pollard AJ. 2013. Bactericidal antibody persistence 2 years after immunization with 2 investigational serogroup B meningococcal vaccines at 6, 8 and 12 months and immunogenicity of preschool booster doses: a follow-on study to a randomized clinical trial. Pediatr Infect Dis J, 32 (10), pp. 1116-1121. | Show Abstract | Read more

BACKGROUND: In a previous study, 60 infants receiving an investigational serogroup B meningococcal vaccine containing recombinant meningococcal proteins alone (rMenB) or combined with an outer membrane vesicle from Neisseria meningitidis (4CMenB) at 6, 8 and 12 months of age produced serum bactericidal antibodies (SBAs) against meningococcal strains expressing vaccine antigens. We studied persistence of this response and the response to a booster dose of vaccine. METHODS: In this extension study, SBA titers were evaluated before and after a booster dose of rMenB or 4CMenB at 40 months of age. MenB vaccine naïve age-matched children served as a control group. RESULTS: Before the booster doses, the proportions of 4CMenB recipients with SBA titers ≥1:4 were 36% (n = 14, 95% confidence interval: 13-65%) for strain 44/76-SL, 100% (77-100%) for 5/99, 14% (2-43%) for NZ98/254 and 79% (49-95%) for M10713. These percentages were 14% to 29% for rMenB recipients (n = 14), except for 5/99 (93%, 66-100%). For controls (n = 40), these proportions were ≤3% for all strains except M10713 (53%, 36-68%). One month after the boosters, ≥93% of 4CMenB recipients had SBA titers ≥1:4 for all 4 strains. For controls receiving their first dose of 4CMenB, 23% (11-39%) had SBA titers ≥1:4 for NZ98/254, compared with 62% to 87% for the remaining strains. CONCLUSIONS: Bactericidal antibodies wane after infant immunization with rMenB or 4CMenB, but there is an anamnestic response to a booster dose. Booster doses of 4CMenB may be required to maintain immune protection through childhood and adolescence.

Mitchell R, Trück J, Pollard AJ. 2013. Use of the 13-valent pneumococcal conjugate vaccine in children and adolescents aged 6 - 17 years. Expert Opin Biol Ther, 13 (10), pp. 1451-1465. | Show Abstract | Read more

INTRODUCTION: The introduction of pneumococcal conjugate vaccines into infant immunization schedules has successfully reduced the incidence of pneumococcal disease caused by vaccine serotypes. Disease incidence is low in healthy 6 - 17-year-old children and young people; however, there are a number of clinical conditions that put individuals in this age group at increased risk. Expansion of the license of a 13-valent pneumococcal conjugate vaccine , PCV-13, to include the 6 - 17 age group has recently been approved by European and American regulatory bodies. AREAS COVERED: Studies assessing the safety, immunogenicity, and efficacy of pneumococcal conjugate vaccines in both healthy and high-risk 6 - 17-year-old children and adolescents are covered and the potential impact of PCV-13 in these populations is discussed. The use of the 23-valent pneumococcal polysaccharide vaccine, PPV-23, in high-risk children and adolescents is also considered. EXPERT OPINION: Expanding the use of PCV-13 to include high-risk children and adolescents aged 6 - 17 has the potential to prevent additional cases of disease; however, vaccination of this population may no longer be necessary when herd immunity to PCV-13 serotypes becomes fully established. Despite the broader serotype coverage of PPV-23, the benefits of this vaccine in high-risk populations are uncertain.

de Whalley PCS, Snape MD, Plested E, Thompson B, Nuthall E, Omar O, Borrow R, Pollard AJ. 2013. Long-term seroprotection after an adolescent booster meningococcal serogroup C vaccination. Arch Dis Child, 98 (9), pp. 686-691. | Show Abstract | Read more

OBJECTIVES: To determine long-term seroprotection after serogroup C meningococcal (MenC) vaccination at the age of 9-12 years, with or without booster vaccination at the age of 13-15 years. DESIGN: Observational cohort study; follow-on from randomised study. SETTING: Participants were recruited from English secondary schools (in Oxfordshire and Buckinghamshire). PARTICIPANTS AND INTERVENTIONS: Participants were primed with MenC CRM-glycoconjugate vaccine at the age of 9-12 years in the UK routine immunisation campaign. In previous studies they were randomised at 13 to 15 years of age to receive a booster dose of MenC-CRM glycoconjugate vaccine (CRM-group) or bivalent meningococcal serogroup A/C polysaccharide vaccine (PS-group), or they received no additional doses of MenC vaccine (control group). In this follow-on study, a blood sample was obtained 11 years after primary immunisation. Of 531 individuals eligible to participate, 134 were enrolled, and 124 were included in the analysis. MAIN OUTCOME MEASURES: MenC serum bactericidal antibody (SBA) geometric mean titre; proportion of participants with SBA titre ≥8 (putative protective threshold). RESULTS: Median ages at priming, boosting and blood sampling were 10.61, 14.42 and 22.11 years, respectively. Geometric mean titres for MenC SBA were: CRM group 1373 (95% CI 954 to 1977); PS group 1024 (687 to 1526); and controls 284 (167 to 483). SBA titres ≥8 were present in 50/54 (92.6%) controls and 70/70 (100%) boosted individuals. CONCLUSIONS: The planned introduction in the UK of an adolescent booster of MenC conjugate vaccine in 2013 is likely to provide sustained protection against MenC disease. TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT01459432).

Blanchard-Rohner G, Snape MD, Kelly DF, O'Connor D, John T, Kibwana E, Parks H, Ford K, Dull PM, Pollard AJ. 2013. Seroprevalence and placental transmission of maternal antibodies specific for Neisseria meningitidis serogroups A, C, y and W135 and influence of maternal antibodies on the immune response to a primary course of MenACWY-CRM vaccine in the United Kingdom Pediatric Infectious Disease Journal, 32 (7), pp. 768-776. | Show Abstract | Read more

Background: Maternal antibodies give neonates some protection against bacterial infection. We measured antibodies against Neisseria meningitidis serogroups A, C, Y and W135 in mothers and their 2-month-old infants at study enrollment. We also assessed the impact of maternal antibody present at 2 months of age on the immune response to a primary course of quadrivalent meningococcal conjugate vaccine (MenACWY-CRM197) given at 2 and 4 months of age. Methods: This was a single-center, open-label, randomized study undertaken in Oxford, United Kingdom. Two hundred sixteen healthy infants were enrolled in the study and vaccinated with MenACWY-CRM197 at 2 and 4 months of age. Blood was obtained from all mothers, in a subset of infants at 2 months and all infants at 5 months. Antibody and memory B-cell responses at 5 months were correlated with maternal antibodies. Results: Mothers had low IgG antibodies against serogroups C, W135 and Y polysaccharides, but high serogroup A antibody, whereas 61-78% had protective human complement serum bactericidal activity (hSBA) (≥1:4) for serogroups C, W135 and Y but only 31% for serogroup A. Only 9%, 32%, 45% and 19% of 2-month-old infants had hSBA ≥1:4 for serogroups A, C, W135 and Y, respectively. Maternal antibody had little association on responses to MenACWY-CRM197, except a moderate negative association between MenC-specific bactericidal antibody at 2 and 5 months (r =-0.5, P = 0.006, n = 28) and between carrier-specific IgG antibody at 2 months and MenC-specific hSBA/IgG antibody at 5 months (r =-0.4, P = 0.02 and 0.04, n = 32 and 23). Nonetheless, 90% of infants achieved protective MenC-hSBA titers after vaccination at 2 and 4 months of age. Conclusions: The levels of serogroup-specific meningococcal antibodies were low in mothers and 2-month-old infants. Immunizing mothers before or during pregnancy with meningococcal conjugate vaccines might increase antibody levels in early infancy and provide protection against infection due to N. meningitidis. Copyright © 2013 Lippincott Williams & Wilkins.

Xie O, Pollard AJ, Mueller JE, Norheim G. 2013. Emergence of serogroup X meningococcal disease in Africa: need for a vaccine. Vaccine, 31 (27), pp. 2852-2861. | Show Abstract | Read more

Neisseria meningitidis is responsible for the seasonal burden and recurrent epidemics of meningitis in an area of sub-Saharan Africa known as the meningitis belt. Historically, the majority of the cases in the meningitis belt are caused by serogroup A meningococci. Serogroup C meningococci were responsible for outbreaks in the meningitis belt in the 1980s, while serogroup W (formerly W-135) has emerged as a cause of epidemic meningitis since 2000. Serogroup X meningococci have previously been considered a rare cause of sporadic meningitis, but during 2006-2010, outbreaks of serogroup X meningitis occurred in Niger, Uganda, Kenya,Togo and Burkina Faso, the latter with at least 1300 cases of serogroup X meningitis among the 6732 reported annual cases. While serogroup X has not yet caused an epidemic wave of the scale of serogroup A in 1996-1997 or serogroup W in Burkina Faso during 2002, the existing reports suggest a similar seasonal hyperendemicity and capacity for localised epidemics. Serogroup X incidence appears to follow a pattern of highly localised clonal waves, and in affected districts, other meningococcal serogroups are usually absent from disease. Currently, no licensed vaccine is available against serogroup X meningococci. Following the introduction of a monovalent serogroup A conjugate vaccine (MenAfriVac(®)) in the meningitis belt and the upcoming introduction of pneumococcal conjugate vaccines, vaccine-based prevention of serogroup X may become a public health need. The serogroup X polysaccharide capsule is the most likely target for vaccine development, but recent data also indicate a potential role for protein-based vaccines. A multivalent vaccine, preferably formulated as a conjugate vaccine and covering at least serogroups A, W, and X is needed, and the efforts for vaccine development should be intensified.

Trück J, O'Connor D, Darton TC, John TM, Snape MD, Pollard AJ. 2013. Genetic material should be routinely collected in clinical vaccine trials--high consent rates can be achieved across all age groups. Vaccine, 31 (25), pp. 2744-2748. | Show Abstract | Read more

BACKGROUND: Genomic and transcriptomic studies underpin much investigation in biology and should be included routinely in clinical trials such as vaccine studies to provide new insight into the development of immunity and the genetic basis for adverse reactions. Interest in collecting and storing genetic material for subsequent high-throughput meta-analyses has increased substantially in recent years. Participants in clinical trials represent an important and invaluable source of clinical material and data. METHODS: Here, the experience of a single center in obtaining informed consent for the collection and long-term storage of genetic material from children, adolescents and adults, involved in clinical vaccine trials is presented and discussed. RESULTS: In 11 completed vaccine studies involving almost 3000 individuals, high rates of consent (in excess of 96%) for biobanking and future genetic testing were obtained. Rates were high for participants from all age groups; however, there was a significant increase toward greater uptake by older study participants. CONCLUSIONS: These high acceptance rates demonstrate that participants (and parents of young children) in vaccine studies are willing to consent and engage in genetic research, which provides support for routinely collecting genetic material in research involving healthy participants such as clinical vaccine trials.

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McGregor AC, Waddington CS, Pollard AJ. 2013. Prospects for prevention of Salmonella infection in children through vaccination Current Opinion in Infectious Diseases, 26 (3), pp. 254-262. | Show Abstract | Read more

Purpose of Review: Strains of Salmonella enterica subsp. enterica are amongst the most commonly identified invasive bacterial pathogens in resource-poor settings, and cause significant mortality, particularly in children. In this study we review recent progress in the development of vaccines against S. Typhi, S. Paratyphi and nontyphoidal Salmonella for children. RECENT FINDINGS: Typhoid remains common and S. Paratyphi A is increasingly recognized as a cause of enteric fever in Asia. In rural Africa, nontyphoidal salmonellae are among the most common invasive bacterial infections, although S. Typhi predominates in some urban centres. Licensed vaccines against typhoid have moderate but useful efficacy but neither of the two available vaccines can be used in infants. Although Ty21a may afford some cross-protection against S. Paratyphi B, there are no vaccines that specifically target paratyphoid or any nontyphoidal Salmonella. Several live attenuated vaccines are under development and may offer some advantages over Ty21a. Vi-conjugate vaccines should offer children excellent protection from typhoid once licensed. SUMMARY: There are few effective vaccines against Salmonella sp. and those that do exist target only one serovar, S. Typhi. Research is urgently needed to combat emerging agents of enteric fever such as S. Paratyphi A as well as nontyphoidal serovars, which commonly cause invasive disease in Africa. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Weissmueller NT, Schiffter HA, Pollard AJ. 2013. Intradermal powder immunization with protein-containing vaccines. Expert Rev Vaccines, 12 (6), pp. 687-702. | Show Abstract | Read more

The central importance for global public health policy of delivering life-saving vaccines for all children makes the development of efficacious and safe needle-free alternatives to hypodermic needles, preferably in a thermostable form, a matter of pressing urgency. This paper comprehensively reviews past in vivo studies on intradermal powder immunization with vaccine formulations that do not require refrigeration. Particular emphasis is given to the immune response in relation to antigen adjuvantation. While needle-free intradermal delivery of vaccines induces a predominantly Th2-type immune response, adjuvants powerfully enhance and modulate the magnitude and nature of the elicited immune response at various effector sites.

McGregor AC, Waddington CS, Pollard AJ. 2013. Prospects for prevention of Salmonella infection in children through vaccination. Curr Opin Infect Dis, 26 (3), pp. 254-262. | Show Abstract | Read more

PURPOSE OF REVIEW: Strains of Salmonella enterica subsp. enterica are amongst the most commonly identified invasive bacterial pathogens in resource-poor settings, and cause significant mortality, particularly in children. In this study we review recent progress in the development of vaccines against S. Typhi, S. Paratyphi and nontyphoidal Salmonella for children. RECENT FINDINGS: Typhoid remains common and S. Paratyphi A is increasingly recognized as a cause of enteric fever in Asia. In rural Africa, nontyphoidal salmonellae are among the most common invasive bacterial infections, although S. Typhi predominates in some urban centres. Licensed vaccines against typhoid have moderate but useful efficacy but neither of the two available vaccines can be used in infants. Although Ty21a may afford some cross-protection against S. Paratyphi B, there are no vaccines that specifically target paratyphoid or any nontyphoidal Salmonella. Several live attenuated vaccines are under development and may offer some advantages over Ty21a. Vi-conjugate vaccines should offer children excellent protection from typhoid once licensed. SUMMARY: There are few effective vaccines against Salmonella sp. and those that do exist target only one serovar, S. Typhi. Research is urgently needed to combat emerging agents of enteric fever such as S. Paratyphi A as well as nontyphoidal serovars, which commonly cause invasive disease in Africa.

O'Connor D, Pollard AJ. 2013. Characterizing vaccine responses using host genomic and transcriptomic analysis. Clin Infect Dis, 57 (6), pp. 860-869. | Show Abstract | Read more

Vaccines have had a profound influence on human health with no other health intervention rivaling their impact on the morbidity and mortality associated with infectious disease. However, the magnitude and persistence of vaccine immunity varies considerably between individuals, a phenomenon that is not well understood. Recent studies have used contemporary technologies to correlate variation in the genome and transcriptome to immunological measures of vaccine responsiveness. These approaches have provided fresh insight into the intrinsic factors determining the potency and duration of vaccine-induced immunity. The fundamental challenge will be to translate these findings into innovative and pragmatic strategies to develop new and more effective vaccines.

Pulickal AS, Callaghan MJ, Kelly DF, Maskey M, Mahat S, Hamaluba M, Dongol S, Adhikari N, Thorson S, Basynat B et al. 2013. Prevalence and genetic analysis of phenotypically Vi- negative Salmonella typhi isolates in children from Kathmandu, Nepal. J Trop Pediatr, 59 (4), pp. 317-320. | Show Abstract | Read more

The Vi capsular polysaccharide (ViPS) protects Salmonella enterica subspecies enterica serotype Typhi (S.Typhi) in vivo by multiple mechanisms. Recent microbiological reports from typhoid endemic countries suggest that acapsulate S.Typhi may occur in nature and contribute to clinical typhoid fever that is indistinguishable from disease caused by capsulate strains. The prevalence and genetic basis of ViPS-negative S.Typhi isolates in children from Kathmandu, Nepal, were tested in 68 isolates. Although 5.9% of isolates tested negative for capsular expression by slide agglutination tests, a novel multiplex PCR assay and individual PCR analyses demonstrated the presence of all 14 genes responsible for the synthesis, transportation and regulation of the ViPS. These data suggest that phenotypically acapsulate S.Typhi may not have a genetic basis for the same.

Bolze A, Mahlaoui N, Byun M, Turner B, Trede N, Ellis SR, Abhyankar A, Itan Y, Patin E, Brebner S et al. 2013. Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia. Science, 340 (6135), pp. 976-978. | Show Abstract | Read more

Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial infections. The unbiased analysis of exomes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients-a nonsense mutation, a frameshift duplication, and five different missense mutations-cause autosomal dominant ICA by haploinsufficiency. RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.

Blanchard-Rohner G, Snape MD, Kelly DF, O'Connor D, John T, Clutterbuck EA, Ohene-Kena B, Klinger CL, Odrljin T, Pollard AJ. 2013. The B-cell response to a primary and booster course of MenACWY-CRM₁₉₇ vaccine administered at 2, 4 and 12 months of age. Vaccine, 31 (20), pp. 2441-2448. | Show Abstract | Read more

A quadrivalent meningococcal vaccine conjugated to CRM197 (MenACWY-CRM197) is immunogenic in young infants. We assessed the memory B-cell and antibody responses after a primary and booster course of MenACWY-CRM197 in children. At 5 months of age, following primary immunisation, serogroup-specific memory B-cells were detectable in fewer than 25% of children, although protective antibody titres (hSBA ≥ 4) were detectable in 69% of children against serogroup A and more than 95% against the other serogroups. At 12 months, before booster immunisation the percentages with hSBA ≥ 4 were 5% for serogroup A, and between 44 and 70% for the other serogroups. One month after booster immunisation with MenACWY-CRM197 over 50% of children had detectable memory B-cells, and 91% had hSBA ≥ 4 against serogroup A and more than 99% against the other serogroups. These data show that few antigen-specific anticapsular memory B-cells can be detected after two-doses priming with MenACWY-CRM197. For MenC and CRM197, the antigens with the highest number of B-cells at 5 months, there was a definite (p ≤0 .02) but weak correlation with antibody persistence at 12 months. Although previous studies suggest that measuring memory B-cell responses after priming immunisations in infancy can be used to predict antibody persistence and memory responses, this may not be suitable for all antigens in young children.

Pollard AJ, Green C, Sadarangani M, Snape MD. 2013. Adolescents need a booster of serogroup C meningococcal vaccine to protect them and maintain population control of the disease. Arch Dis Child, 98 (4), pp. 248-251. | Read more

Blanchard-Rohner G, Snape MD, Kelly DF, O'Connor D, John T, Kibwana E, Parks H, Ford K, Dull PM, Pollard AJ. 2013. Seroprevalence and placental transmission of maternal antibodies specific for Neisseria meningitidis Serogroups A, C, Y and W135 and influence of maternal antibodies on the immune response to a primary course of MenACWY-CRM vaccine in the United Kingdom. Pediatr Infect Dis J, 32 (7), pp. 768-776. | Show Abstract | Read more

BACKGROUND: Maternal antibodies give neonates some protection against bacterial infection. We measured antibodies against Neisseria meningitidis serogroups A, C, Y and W135 in mothers and their 2-month-old infants at study enrollment. We also assessed the impact of maternal antibody present at 2 months of age on the immune response to a primary course of quadrivalent meningococcal conjugate vaccine (MenACWY-CRM197) given at 2 and 4 months of age. METHODS: This was a single-center, open-label, randomized study undertaken in Oxford, United Kingdom. Two hundred sixteen healthy infants were enrolled in the study and vaccinated with MenACWY-CRM197 at 2 and 4 months of age. Blood was obtained from all mothers, in a subset of infants at 2 months and all infants at 5 months. Antibody and memory B-cell responses at 5 months were correlated with maternal antibodies. RESULTS: Mothers had low IgG antibodies against serogroups C, W135 and Y polysaccharides, but high serogroup A antibody, whereas 61-78% had protective human complement serum bactericidal activity (hSBA) (≥1:4) for serogroups C, W135 and Y but only 31% for serogroup A. Only 9%, 32%, 45% and 19% of 2-month-old infants had hSBA ≥1:4 for serogroups A, C, W135 and Y, respectively. Maternal antibody had little association on responses to MenACWY-CRM197, except a moderate negative association between MenC-specific bactericidal antibody at 2 and 5 months (r = -0.5, P = 0.006, n = 28) and between carrier-specific IgG antibody at 2 months and MenC-specific hSBA/IgG antibody at 5 months (r = -0.4, P = 0.02 and 0.04, n = 32 and 23). Nonetheless, 90% of infants achieved protective MenC-hSBA titers after vaccination at 2 and 4 months of age. CONCLUSIONS: The levels of serogroup-specific meningococcal antibodies were low in mothers and 2-month-old infants. Immunizing mothers before or during pregnancy with meningococcal conjugate vaccines might increase antibody levels in early infancy and provide protection against infection due to N. meningitidis.

Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, AlSum Z, Al-Jumaah S, Al-Hajjar S, Frayha H et al. 2013. Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. Medicine (Baltimore), 92 (2), pp. 109-122. | Show Abstract | Read more

Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

Khatami A, Snape MD, Ohene-Kena B, Young K, Oeser C, Michaelis LJ, Macleod E, Smee H, Van Der Meeren O, Leyssen M et al. 2013. Phase II study of a three-dose primary vaccination course of DTPa-IPV/Hib-MenC-TT followed by a 12-month Hib-MenC-TT booster in healthy infants. Pediatr Infect Dis J, 32 (6), pp. 675-681. | Show Abstract | Read more

AIM: To test for immunologic noninferiority of antibody responses to Hib and MenC using a 6-in-1 combination vaccine (DTPa-IPV/Hib-MenC-TT) compared with DTPa-IPV-Hib plus MenC-CRM197, before and after a 12-month Hib-MenC-TT booster. METHODS: Pragmatic open-label, randomized, multicenter, UK study. "6-in-1" group received DTPa-IPV/Hib-MenC-TT at 2, 3 and 4 months; control group received DTPa-IPV-Hib at 2, 3 and 4 months and MenC-CRM197 at 3 and 4 months. Both groups received Hib-MenC-TT at 12 months. Concomitant vaccines: pneumococcal conjugate vaccine at 2, 4 and 13 months, and measles, mumps and rubella vaccine at 13 months. RESULTS: One hundred forty-two children were randomized to each group. One hundred children in the "6-in-1" group and 112 control group children completed the study according-to-protocol. One month postprimary immunizations: 100% of "6-in-1" group and 93.3% of control children had anti-polyribosylribitol phosphate (PRP) IgG ≥0.15 µg/mL; 96.2% and 100%, respectively, had rSBA-MenC titers ≥1:8. One month after booster all children met these thresholds, with anti-PRP geometric mean concentrations of 66.7 (53.3; 83.5) in "6-in-1" recipients and 26.9 (20.9; 34.6) in control children (4.4 [3.5; 5.4] and 3.0 [2.2-4.2] postprimary immunizations, respectively,). rSBA-MenC geometric mean titers were 3062.9 (2421.2; 3874.6) and 954.0 (761.3; 1195.5), respectively, postbooster and 393.2 (292.5; 528.7) and 3110.5 (2612; 3704.2) postprimary. CONCLUSION: Noninferiority of DTPa-IPV/Hib-MenC-TT compared with DTPa-IPV/Hib plus MenC-CRM197 was demonstrated. In the "6-in-1" group, lower postprimary and greater postbooster rSBA-MenC geometric mean titers suggest memory B-cell priming may be favored by this vaccine over plasma cell induction. Furthermore, greater immunogenicity of TT conjugates used in both primary and booster vaccines in this group may be important.

Snape MD, Pollard AJ. 2013. The beginning of the end for serogroup B meningococcus? Lancet, 381 (9869), pp. 785-787. | Read more

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Snape MD, Philip J, John TM, Robinson H, Kelly S, Gossger N, Yu LM, Kittel C, Toneatto D, Dull PM, Pollard AJ. 2013. Bactericidal antibody persistence 2 years after immunization with 2 investigational serogroup B meningococcal vaccines at 6, 8 and 12 months and immunogenicity of preschool booster doses: A follow-on study to a randomized clinical trial Pediatric Infectious Disease Journal, 32 (10), pp. 1116-1121. | Show Abstract | Read more

Background: In a previous study, 60 infants receiving an investigational serogroup B meningococcal vaccine containing recombinant meningococcal proteins alone (rMenB) or combined with an outer membrane vesicle from Neisseria meningitidis (4CMenB) at 6, 8 and 12 months of age produced serum bactericidal antibodies (SBAs) against meningococcal strains expressing vaccine antigens. We studied persistence of this response and the response to a booster dose of vaccine. Methods: In this extension study, SBA titers were evaluated before and after a booster dose of rMenB or 4CMenB at 40 months of age. MenB vaccine naïve age-matched children served as a control group. Results: Before the booster doses, the proportions of 4CMenB recipients with SBA titers ≥1:4 were 36% (n = 14, 95% confidence interval: 13-65%) for strain 44/76-SL, 100% (77-100%) for 5/99, 14% (2-43%) for NZ98/254 and 79% (49-95%) for M10713. These percentages were 14% to 29% for rMenB recipients (n = 14), except for 5/99 (93%, 66-100%). For controls (n = 40), these proportions were ≤3% for all strains except M10713 (53%, 36-68%). One month after the boosters, ≥93% of 4CMenB recipients had SBA titers ≥1:4 for all 4 strains. For controls receiving their first dose of 4CMenB, 23% (11-39%) had SBA titers ≥1:4 for NZ98/254, compared with 62% to 87% for the remaining strains. Conclusions: Bactericidal antibodies wane after infant immunization with rMenB or 4CMenB, but there is an anamnestic response to a booster dose. Booster doses of 4CMenB may be required to maintain immune protection through childhood and adolescence. Copyright © 2013 by Lippincott Williams & Wilkins.

Curtis N, Pollard AJ, Finn A. 2014. Preface Journal of Infection, 68 pp. S1-S1. | Read more

Yates TA, Paranthaman K, Yu L-M, Davis E, Lang S, Hackett SJ, Welch SB, Pollard AJ, Snape MD. 2013. UK vaccination schedule: persistence of immunity to hepatitis B in children vaccinated after perinatal exposure. Arch Dis Child, 98 (6), pp. 429-433. | Show Abstract | Read more

OBJECTIVE: To assess persistence of immunity to hepatitis B (HBV) in primary school children vaccinated following perinatal exposure. DESIGN: Serological survey. SETTING: Five UK sites (Berkshire East, Birmingham, Buckinghamshire, Milton Keynes and Oxfordshire). PARTICIPANTS: Children from 3 years 4 months to 10 years of age (mean age 6.2 years), vaccinated against HBV from birth following perinatal exposure. INTERVENTIONS: A single booster dose of the paediatric formulation of a recombinant HBV vaccine. MAIN OUTCOME MEASURES: Titres of antibody against hepatitis B Surface Antigen (anti-HBs) measured immediately before and 21-35 days after the HBV vaccine booster. RESULTS: Prebooster anti-HBs titres were >10 mIU/ml in 84.6% of children (n=26; 95% CI 65.1 to 95.6%). All children (n=25, 95% CI 86.3 to 100%) had titres >100 mIU/ml after the booster. CONCLUSIONS: This study of antibody persistence among UK children born to hepatitis B infected women, immunised with a 3-dose infant schedule with a toddler booster suggests sustained immunity through early childhood. These data should prompt further studies to address the need for a preschool booster. TRIAL REGISTRATION: Eudract Number 2008-004785-98.

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Bolze A, Mahlaoui N, Byun M, Turner B, Trede N, Ellis SR, Abhyankar A, Itan Y, Patin E, Brebner S et al. 2013. Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia Science, 340 (6135), pp. 976-978. | Show Abstract | Read more

Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial infections. The unbiased analysis of exomes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients - a nonsense mutation, a frameshift duplication, and five different missense mutations - cause autosomal dominant ICA by haploinsufficiency. RPSA encode s ribosomal protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.

De Whalley PCS, Pollard AJ. 2013. Pandemic influenza A (H1N1) 2009 vaccination in children: A UK perspective Journal of Paediatrics and Child Health, 49 (3), | Show Abstract | Read more

Pandemic H1N1 influenza infection was common in the UK in 2009 and children were particularly vulnerable. Most cases were mild or subclinical, but there was significant mortality, predominantly in those with pre-existing disease. Despite the rapid development of monovalent pandemic vaccines, and the fast-tracked approval process, these products were not available for large-scale use until the end of the second wave of infection. Vaccine uptake was relatively low, both among children and health-care workers. The monovalent pandemic vaccines and the 2010/2011 trivalent seasonal influenza vaccines were immunogenic and effective, and they probably reduced the impact of the third wave of infection. Vaccines containing novel adjuvants enabled antigen sparing, but safety concerns could limit the future use of these adjuvanted influenza vaccines in children. Public perceptions that the threat of the pandemic was exaggerated by the authorities, and concerns about vaccine safety, might prompt an inadequate response to the next influenza pandemic, potentially compromising public health. © 2012 The Authors. Journal of Paediatrics and Child Health © 2012 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

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Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, Alsum Z, Al-Jumaah S, Al-Hajjar S, Frayha H et al. 2013. Inherited IL-12p40 deficiency: Genetic, immunologic, and clinical features of 49 patients from 30 kindreds Medicine (United States), 92 (2), pp. 109-122. | Show Abstract | Read more

Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency.In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular. Copyright © 2013 by Lippincott Williams & Wilkins.

Snape MD, Pollard AJ. 2013. The beginning of the end for serogroup B meningococcus? The Lancet, 381 (9869), pp. 785-787. | Read more

de Whalley PCS, Pollard AJ. 2013. Pandemic influenza A (H1N1) 2009 vaccination in children: a UK perspective. J Paediatr Child Health, 49 (3), pp. E183-E188. | Show Abstract | Read more

Pandemic H1N1 influenza infection was common in the UK in 2009 and children were particularly vulnerable. Most cases were mild or subclinical, but there was significant mortality, predominantly in those with pre-existing disease. Despite the rapid development of monovalent pandemic vaccines, and the fast-tracked approval process, these products were not available for large-scale use until the end of the second wave of infection. Vaccine uptake was relatively low, both among children and health-care workers. The monovalent pandemic vaccines and the 2010/2011 trivalent seasonal influenza vaccines were immunogenic and effective, and they probably reduced the impact of the third wave of infection. Vaccines containing novel adjuvants enabled antigen sparing, but safety concerns could limit the future use of these adjuvanted influenza vaccines in children. Public perceptions that the threat of the pandemic was exaggerated by the authorities, and concerns about vaccine safety, might prompt an inadequate response to the next influenza pandemic, potentially compromising public health.

Pollard AJ, Savulescu J, Oxford J, Hill AV, Levine MM, Lewis DJ, Read RC, Graham DY, Sun W, Openshaw P, Gordon SB. 2012. Human microbial challenge: the ultimate animal model. Lancet Infect Dis, 12 (12), pp. 903-905. | Read more

Grant CF, Lefevre EA, Carr BV, Prentice H, Gubbins S, Pollard AJ, Charreyre C, Charleston B. 2012. Assessment of T-dependent and T-independent immune responses in cattle using a B cell ELISPOT assay. Vet Res, 43 (1), pp. 68. | Show Abstract | Read more

Understanding the mechanisms that maintain protective antibody levels after immunisation is important for vaccine design. In this study, we have determined the kinetics of plasma and memory B cells detectable in the blood of cattle immunised with model T-dependent or T-independent antigens. Immunisation with the T-D antigen resulted in an expansion of TNP-specific plasma cells post-TNP primary and booster immunisations, which was associated with increased titres of TNP-specific IgG antibodies. Although no TNP-specific memory B cells were detected in the T-D group following the primary immunisation, we detected an increase in the number of TNP-specific memory B cells post-TNP boost. In contrast, no TNP-specific plasma or memory B cells were detected after primary or secondary immunisation with the T-I antigen. We then investigated if immunisation with a third party antigen (tetanus toxin fragment C, TTC) would result in a bystander stimulation and increase the number of TNP-specific plasma and memory B cells in the T-D and/or T-I group. TTC immunisation in the T-D group resulted in a small increase in the number of TNP-specific plasma cells post-TTC primary immunisation and boost, and in an increase in the number of TNP-specific memory B cells post-TTC boost. This bystander effect was not observed in the animals previously immunised with the T-I antigen. In conclusion, the present study characterised for the first time the B cell response in cattle to immunisation with T-D and T-I antigens and showed that bystander stimulation of an established T-D B cell memory response may occur in cattle.

Trück J, Lazarus R, Jonsdottir I, Klugman KP, Pollard AJ. 2012. Pneumococcal polysaccharide vaccine efficacy and routine use of conjugate vaccines in infants: there is no need for a vaccine program in older adults at present. Clin Infect Dis, 55 (11), pp. 1577-1579. | Read more

Perrett KP, Jin C, Clutterbuck E, John TM, Winter AP, Kibwana E, Yu L-M, Curtis N, Pollard AJ. 2012. B cell memory to a serogroup C meningococcal conjugate vaccine in childhood and response to booster: little association with serum IgG antibody. J Immunol, 189 (5), pp. 2673-2681. | Show Abstract | Read more

The maintenance of adequate serum Ab levels following immunization has been identified as the most important mechanism for individual long-term protection against rapidly invading encapsulated bacteria. The mechanisms for maintaining adequate serum Ab levels and the relationship between Ag-specific memory B cells and Ab at steady state are poorly understood. We measured the frequency of circulating serogroup C meningococcal (MenC)-specific memory B cells in 250 healthy 6- to 12-y-old children 6 y following MenC conjugate vaccine priming, before a booster of a combined Haemophilus influenzae type b-MenC conjugate vaccine and then 1 wk, 1 mo, and 1 y after the booster. We investigated the relationship between circulating MenC-specific memory B cell frequencies and Ab at baseline and following the booster vaccine. We found very low frequencies of circulating MenC-specific memory B cells at steady state in primary school-aged children and little association with MenC IgG Ab levels. Following vaccination, there were robust memory B cell booster responses that, unlike Ab levels, were not dependent on age at priming with MenC. Measurement of B cell memory in peripheral blood does not predict steady state Ab levels nor the capacity to respond to a booster dose of MenC Ag.

Zhou L, Pollard AJ. 2012. A novel method of selective removal of human DNA improves PCR sensitivity for detection of Salmonella Typhi in blood samples. BMC Infect Dis, 12 (1), pp. 164. | Show Abstract | Read more

BACKGROUND: Enteric fever is a major public health problem, causing an estimated 21million new cases and 216,000 or more deaths every year. Current diagnosis of the disease is inadequate. Blood culture only identifies 45 to 70% of the cases and is time-consuming. Serological tests have very low sensitivity and specificity. Clinical samples obtained for diagnosis of enteric fever in the field generally have <1 organism/ml of blood, so that even PCR-based methods, widely used for detection of other infectious diseases, are not a straightforward option in typhoid diagnosis. We developed a novel method to enrich target bacterial DNA by selective removal of human DNA from blood samples, enhancing the sensitivity of PCR tests. This method offers the possibility of improving PCR assays directly using clinical specimens for diagnosis of this globally important infectious disease. METHODS: Blood samples were mixed with ox bile for selective lysis of human blood cells and the released human DNA was then digested with addition of bile resistant micrococcal nuclease. The intact Salmonella Typhi bacteria were collected from the specimen by centrifugation and the DNA extracted with QIAamp DNA mini kit. The presence of Salmonella Typhi bacteria in blood samples was detected by PCR with the fliC-d gene of Salmonella Typhi as the target. RESULTS: Micrococcal nuclease retained activity against human blood DNA in the presence of up to 9% ox bile. Background human DNA was dramatically removed from blood samples through the use of ox bile lysis and micrococcal nuclease for removal of mammalian DNA. Consequently target Salmonella Typhi DNA was enriched in DNA preparations and the PCR sensitivity for detection of Salmonella Typhi in spiked blood samples was enhanced by 1,000 fold. CONCLUSIONS: Use of a combination of selective ox-bile blood cell lysis and removal of human DNA with micrococcal nuclease significantly improves PCR sensitivity and offers a better option for improved typhoid PCR assays directly using clinical specimens in diagnosis of this globally important infection disease which we believe could be of importance in improving clinical care and providing effective evaluation of novel vaccines.

Xie O, Bolgiano B, Gao F, Lockyer K, Swann C, Jones C, Delrieu I, Njanpop-Lafourcade B-M, Tamekloe TA, Pollard AJ, Norheim G. 2012. Characterization of size, structure and purity of serogroup X Neisseria meningitidis polysaccharide, and development of an assay for quantification of human antibodies. Vaccine, 30 (40), pp. 5812-5823. | Show Abstract | Read more

Serogroup X Neisseria meningitidis (MenX) has recently emerged as a cause of localized disease outbreaks in sub-Saharan Africa. In order to prepare for vaccine development, MenX polysaccharide (MenX PS) was purified by standard methods and analyzed for identity and structure by NMR spectroscopy. This study presents the first full assignment of the structure of the MenX PS using (13)C, (1)H and (31)P NMR spectroscopy and total correlation spectroscopy (TOCSY) and (1)H-(13)C heteronuclear single quantum coherence (HSQC). Molecular size distribution analysis using HPLC-SEC with multi-angle laser light scattering (MALLS) found the single peak of MenX PS to have a weight-average molar mass of 247,000g/mol, slightly higher than a reference preparation of purified serogroup C meningococcal polysaccharide. MenX PS tended to be more thermostable than serogroup A PS. A method for the quantification of MenX PS was developed by use of high performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD). A novel and specific ELISA assay for quantification of human anti-MenX PS IgG based on covalent linkage of the MenX PS to functionally modified microtitre plates was developed and found valid for the assessment of the specific antibody concentrations produced in response to MenX vaccination or natural infection. The current work thus provides the necessary background for the development of a MenX PS-based vaccine to prevent meningococcal infection caused by bacteria bearing this capsule.

Pollard AJ. 2012. Non-specific effects of vaccines: RCTs, not observational studies, are needed. Arch Dis Child, 97 (8), pp. 677-678. | Read more

Khatami A, Snape MD, Wysocki J, John TM, Westcar S, Mesaros N, Peddiraju K, Boutriau D, Yu L-M, Pollard AJ. 2012. Persistence of antibody response following a booster dose of Hib-MenC-TT glycoconjugate vaccine to five years: a follow-up study. Pediatr Infect Dis J, 31 (10), pp. 1069-1073. | Show Abstract | Read more

BACKGROUND: Antibodies against Haemophilus influenzae type b (Hib) and serogroup C Neisseria meningitidis (MenC) persist better to 3½ years of age after a 12-month booster dose of a combination Hib-MenC glycoconjugate vaccine (Hib-MenC-TT) in children primed in infancy with Hib-MenC-TT and diphtheria-tetanus-acellular-pertussis-inactivated poliovirus vaccine (DTaP-IPV) than in those who received a monovalent MenC-CRM197 and DTaP-IPV-Hib (also TT conjugated). Pertussis antibodies against filamentous hemagglutinin and pertactin are higher at 5 and 12 months in children who received DTaP-IPV compared with those immunized with DTaP-IPV-Hib. We evaluated whether these differences persisted to later childhood, following a preschool booster of DTaP-IPV at 3½ years of age. METHODS: Children in the United Kingdom and Poland previously enrolled in the aforementioned randomized-controlled trial had a blood sample taken at 5 years of age. Antipolyribosylribitol phosphate (Hib) IgG and MenC bactericidal antibody (baby rabbit complement) titers were compared between those immunized in infancy (at 2, 3 and 4 months) with DTaP-IPV/Hib-MenC-TT (Hib-MenC-TT group) and those who received DTaP-IPV-Hib with a monovalent MenC-CRM197 (control group). Antibody concentrations against filamentous hemagglutinin, pertactin and pertussis toxin were also measured at this visit. RESULTS: Two hundred sixty-eight participants aged 58-64 months were enrolled. MenC baby rabbit complement titers ≥1:8 were seen in 115 of 194 of the Hib-MenC-TT group (59.3% [52.0-66.3%]) and 26 of 58 (44.8% [31.7-58.5%]) of control group participants. MenC baby rabbit complement geometric mean titers were 30.4 and 11.3, respectively (ratio 2.70 [1.55- .73]). Antipolyribosylribitol phosphate (Hib) IgG concentrations ≥ 1.0 μg/mL were seen in 171 of 197 (86.8% [81.3-91.2%]) of the Hib-MenC-TT group and 36 of 58 (62.1% [48.4-74.5%]) of control group participants. Antipolyribosylribitol phosphate IgG geometric mean concentrations (GMCs) were 3.82 and 1.67, respectively (ratio 2.29 [1.59-3.28]). Sixty-eight UK participants aged 58-63 months had sera analyzed for the pertussis antigens (44 DTaP-IPV recipients, 14 DTaP-IPV-Hib recipients). Antipertussis toxin IgG GMCs were similar for participants immunized with DTaP-IPV and DTaP-IPV-Hib: 8.2 EL.U/mL (6.1 - 10.9) compared with 7.2 EL.U/mL (3.9 - 13.4). Antifilamentous hemagglutinin IgG GMCs were higher for DTaP-IPV recipients (164.7 EL.U/mL [119.4-227.1]) compared with DTaP-IPV-Hib recipients (66.8 EL.U/mL [43.8-101.7]), as were antipertactin IgG GMCs: 102.8 EL.U/mL (67.1-157.3) compared with 23.4 EL.U/mL (15.1-36.2). CONCLUSION: Vaccines used for infant immunization against Hib and MenC differ in their ability to prime responses to a booster dose of Hib-MenC-TT, and this difference persists to at least 5 years of age. Persistence of antipertussis antibody following a preschool booster of DTaP-IPV is also influenced by immunizations received at 2, 3 and 4 months of age, underlining the importance of infant immune priming in the maintenance of antibody levels through childhood.

Waddington C, Darton T, Jones C, Haworth K, Peters A, Kerridge S, Crook D, Lockhart S, Farrar J, Dougan G et al. 2012. Variations in attack rate in a single-blind, dose escalation challenge study of Salmonella Typhi in healthy adult volunteers INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E244-E244. | Read more

Jones C, Waddington C, Darton T, Bowman J, Farrar J, Dougan G, Levine M, Lockhart S, Sztein M, Crook D et al. 2012. Quantification of antibody secreting cell responses in a human challenge model of Salmonella Typhi infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E224-E224. | Read more

Darton T, Jones C, Waddington C, Dougan G, Sztein M, Levine M, Angus B, Farrar J, Lockhart S, Crook D et al. 2012. Demonstration of primary and asymptomatic DNAaemia in participants challenged with Salmonella Typhi (Quailes strain) during the development of a human model of typhoid infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E215-E215. | Read more

Pollard A. 2012. Typhoid vaccine landscape INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E30-E30. | Read more

Trück J, Lazarus R, Clutterbuck EA, Bowman J, Kibwana E, Bateman EAL, Pollard AJ. 2013. The zwitterionic type I Streptococcus pneumoniae polysaccharide does not induce memory B cell formation in humans. Immunobiology, 218 (3), pp. 368-372. | Show Abstract | Read more

In contrast to other pneumococcal serotypes, which are thought to be T-independent antigens, type 1 Streptococcus pneumoniae polysaccharide (Sp1) is a zwitterionic polysaccharide (ZPS). It has previously been shown to be processed and presented by antigen-presenting cells utilizing the MHC-II pathway, which leads to Sp1-induced T cell proliferation, a hallmark of thymus-dependent immune responses. We used peripheral blood mononuclear cells obtained from adults enrolled in a randomised clinical trial to investigate memory B cell responses following immunisation with the 23-valent pneumococcal plain polysaccharide vaccine. Administration of this serotype 1 containing vaccine resulted in the depletion of serotype 1 antigen-specific pre-existing memory B cells compared to baseline. This finding indicates that this ZPS is not processed by a classical TD mechanism within the MHC-II pathway.

Blanchard-Rohner G, Watt H, Kelly DF, Yu L-M, Snape MD, Pollard AJ. 2012. Baseline polysaccharide-specific antibodies may not consistently inhibit booster antibody responses in infants to a serogroup C meningococcal protein-polysaccharide conjugate vaccine. Vaccine, 30 (28), pp. 4153-4159. | Show Abstract | Read more

Negative correlations between baseline antibody concentrations and increases in antibody concentrations (after booster doses of vaccines) have been reported previously. Such correlation coefficients are widely reported by statisticians to be subject to mathematical coupling. Negative correlations may be attributable partly or wholly to the combination of mathematical coupling and measurement error (or other short term fluctuations in measurements) and therefore not clinically interpretable. In this study we re-analysed the serum antibody responses from five clinical trials of serogroup C meningococcal conjugate vaccine (MenCV) given to infants for priming followed by boosting with MenCV or a meningococcal A/C polysaccharide vaccine (MenA/C) at 12 months of age. Using Pearson's correlation method to assess the effect of pre-booster MenC-IgG concentration on the relative increase in MenC-IgG concentration post-booster, a significant negative correlation was observed for all the groups, indicating that high pre-booster antibody was associated with a smaller rise in antibody post-booster. We tested two additional statistical methods that account for mathematical coupling. Using Blomqvist method of adjustment to assess the plausible extent of bias, correlation coefficients were still negative providing error variance was low. The other method, a multilevel modelling specification of Oldham's method appeared not to be appropriate. In contrast, using Pearson's correlation method a consistent negative correlation between carrier protein-specific baseline antibody concentration and the increase in MenC-specific antibody concentration was only observed following booster immunisation with the protein-polysaccharide conjugate vaccine but not following the MenA/C plain polysaccharide vaccine. These findings suggest that analysis of the inhibitory effect of baseline antibody on the response to booster immunisation is challenging and should account for the possibility of mathematical coupling and measurement error. That an inhibitory effect of baseline antibody cannot be assumed a priori is supported by observations in animal models, which show that baseline antibody can both suppress or enhance the antibody response to a specific antigen.

Pace D, Pollard AJ. 2012. Meningococcal disease: clinical presentation and sequelae. Vaccine, 30 Suppl 2 (SUPPL. 2), pp. B3-B9. | Show Abstract | Read more

The clinical spectrum of invasive meningococcal disease is diverse with meningitis and/or septicaemia being the commonest modes of presentation. The severity of manifestations of meningococcal infection ranges from bacteraemia, associated with mild non-specific symptoms, to fulminant sepsis with multiorgan failure and death in approximately 10-15% of cases. Localised infections (such as conjunctivitis or septic arthritis) as well as chronic disease may be the sole clinical manifestations but can also lead to disseminated fulminant disease. Among survivors, disabling long-term sequelae can complicate meningococcal disease and result in potentially devastating effects on the quality of life of survivors, most of whom are infants, children and adolescents. The only rational approach to the prevention of meningococcal disease and the associated human suffering is through vaccination.

Lambe T, Spencer AJ, Mullarkey CE, Antrobus RD, Yu L-M, de Whalley P, Thompson BAV, Jones C, Chalk J, Kerridge S et al. 2012. T-cell responses in children to internal influenza antigens, 1 year after immunization with pandemic H1N1 influenza vaccine, and response to revaccination with seasonal trivalent-inactivated influenza vaccine. Pediatr Infect Dis J, 31 (6), pp. e86-e91. | Show Abstract | Read more

BACKGROUND: During seasonal influenza epidemics, 5-15% of the population are affected with an illness having a nontrivial mortality, morbidity and economic burden. Inactivated influenza vaccines are routinely used to prevent influenza infection, primarily by inducing humoral immunity. In addition, trivalent-inactivated influenza vaccines have previously been shown to boost influenza-specific T-cell responses in a small percentage of adults. We investigate here the influenza-specific T-cell response, in children, 1 year after pandemic H1N1 vaccination and the ability to boost the T-cell response with trivalent-inactivated influenza immunization. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from children previously vaccinated with pandemic H1N1 vaccine, pre- and postseasonal 2010-2011 trivalent influenza vaccine (TIV) vaccination. Samples were analyzed by interferon-gamma enzyme-linked immunosorbent spot for reactogenicity toward internal influenza antigens (nucleoprotein, matrix protein 1 and nonstructural protein 1). RESULTS: Basal ex vivo T-cell responses to nucleoprotein, matrix protein 1 and nonstructural protein 1 measured by interferon-gamma enzyme-linked immunosorbent spot assay were significantly higher in those children who had previously received an AS03B-adjuvanted split virion pandemic vaccine 12 months earlier rather than a nonadjuvanted whole virion vaccine. Boosting of these responses, 21 days after 2010/2011 seasonal TIV vaccination was observed regardless of age or prior pandemic vaccination regime, although boosting was greater in those groups with the lowest initial response. CONCLUSIONS: We show here that children previously vaccinated with the 2009 pandemic H1N1 vaccine have measurable T-cell responses 1 year after vaccination. The magnitudes of these responses are dependent on both age of vaccine and type of pandemic H1N1 vaccine used. After 2010/2011 seasonal TIV vaccination, these T-cell responses undergo a small but significant boost.

Clutterbuck EA, Lazarus R, Yu L-M, Bowman J, Bateman EAL, Diggle L, Angus B, Peto TE, Beverley PC, Mant D, Pollard AJ. 2012. Pneumococcal conjugate and plain polysaccharide vaccines have divergent effects on antigen-specific B cells. J Infect Dis, 205 (9), pp. 1408-1416. | Show Abstract | Read more

BACKGROUND: A 23-valent unconjugated pneumococcal polysaccharide vaccine (23vP), routinely administered at the age of 65, has limited effectiveness, and revaccination induces attenuated antibody responses. It is not known whether pneumococcal polysaccharide-protein conjugated vaccines (PCV), although highly effective in infants, offer any immunological advantages over 23vP in adults. METHODS: We immunized adults with schedules combining both PCV and 23vP and investigated B-cell responses to establish whether PCV7 (a 7-valent PCV) induced T-dependent responses in adults, to assess the role of memory B cells in 23vP-induced antibody hyporesponsiveness, and to identify the B-cell subtypes involved. RESULTS: A single dose of PCV7 induced significant increases in serotype-specific memory B-cell populations in peripheral blood indicating a T-dependent response. Conversely, immunization with 23vP resulted in a decrease in memory B-cell frequency. Furthermore, memory B-cell responses to subsequent immunization with PCV7, when given after 23vP, were attenuated. Notably, B1b cells, a subset important in protecting mice against pneumococci, were also depleted following immunization with 23vP in humans. CONCLUSIONS: This study indicates that PCV7 may have an immunological advantage over 23vP in adults and that 23vP-induced depletion of memory and B1b-cell subsets may provide a basis for antibody hyporesponsiveness and the limited effectiveness of 23vP. Clinical Trials Registration. ISRCTN: 78768849.

Scott CA, Atkinson SH, Sodha A, Tate C, Sadiq J, Lakhoo K, Pollard AJ. 2012. Management of lymphadenitis due to non-tuberculous mycobacterial infection in children. Pediatr Surg Int, 28 (5), pp. 461-466. | Show Abstract | Read more

PURPOSE: Non-tuberculous mycobacterial (NTM) infection is an important cause of cervico-facial lymph node enlargement in young children. The optimal treatment is thought to be early complete excision without chemotherapy. We compared management of patients referred to our centre to this "gold standard" and determined clinical outcomes by type of primary surgical intervention (complete excision vs. incomplete excision). METHODS: Retrospective study of management and clinical outcomes of all children (<12 years) with NTM lymphadenitis referred to a single UK centre between May 1998 and May 2008. RESULTS: We identified 43 children. Median time from onset of swelling to operation was 6 weeks. Management was: no operation (n = 1, 2 %), complete excision (n = 20, 47 %), incision and drainage (n = 17, 40 %) and fine needle aspirate (n = 5, 12 %). Children not treated by primary complete excision were more likely to have: re-operation (91 vs. 30 %; χ(2) = 16.48; p < 0.0001); persistent lymphadenitis (77 vs. 30 %; χ(2) = 9.45; p = 0.002); sinus formation (26 vs. 5 %; χ2 = 3.74; p = 0.05). CONCLUSION: Failure to undertake primary complete excision leads to further morbidity. A high index of suspicion is required for timely appropriate management to avoid unnecessary morbidity and further intervention.

Khatami A, Snape MD, Davis E, Layton H, John T, Yu L-M, Dull PM, Gill CJ, Odrjlin T, Dobson S et al. 2012. Persistence of the immune response at 5 years of age following infant immunisation with investigational quadrivalent MenACWY conjugate vaccine formulations. Vaccine, 30 (18), pp. 2831-2838. | Show Abstract | Read more

BACKGROUND AND AIMS: Serogroup A, C, W-135 and Y meningococcal (MenACWY) conjugate vaccines are recommended for routine adolescent immunisation in the United States and Canada. We evaluated the persistence of bactericidal antibodies through early childhood, following infant immunisation with varying schedules of MenACWY-CRM(197) vaccine. METHODS: UK and Canadian infants were immunised with 2-3 doses of MenACWY-CRM(197) or 2 doses of serogroup C meningococcal (MenC) conjugate vaccine, and either MenACWY-CRM(197), 1/5 dose of MenACWY polysaccharide vaccine or no booster at 12 months. Control groups recruited at 60 months had received country-specific infant doses of MenC conjugate vaccine. hSBA titres were measured in participants at 40 and 60 months of age. RESULTS: 382 children were enrolled in 12 groups (22-40 per group). By age 60 months, 3-11% of children primed and boosted with MenACWY-CRM(197) had hSBA titres≥1:8 against serogroup A, 14-45% against serogroup C, 57-85% against serogroup W-135 and 42-71% against serogroup Y. Children primed with MenC and boosted with MenACWY-CRM(197) had similar results, except for serogroup C (59%). In age-matched controls administered MenC vaccine at 2, 3, and 4 months (UK), 2 and 12 months or 12 months only (Canada), percentages with hSBA titres≥1:8 were 0-3%, 29-53%, 34-36% and 10-29% against serogroups A, C, W-135 and Y respectively. CONCLUSIONS: Serogroup-specific bactericidal antibody wane following infant immunisation with MenACWY-CRM(197), most markedly against serogroup A. Best persistence against serogroup C is observed with MenC conjugate vaccine priming and MenACWY-CRM(197) at 12 months, compared to schedules using only MenACWY-CRM(197), with the potential for providing broader protection compared to monovalent MenC vaccines alone.

Gossger N, Snape MD, Yu L-M, Finn A, Bona G, Esposito S, Principi N, Diez-Domingo J, Sokal E, Becker B et al. 2012. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA, 307 (6), pp. 573-582. | Show Abstract | Read more

CONTEXT: In the absence of an effective vaccine, serogroup B Neisseria meningitidis (MenB) remains a major cause of invasive disease in early childhood in developed countries. OBJECTIVE: To determine the immunogenicity and reactogenicity of a multicomponent MenB vaccine (4CMenB) and routine infant vaccines when given either concomitantly or separately. DESIGN, SETTING, AND PARTICIPANTS: Phase 2b, multicenter, open-label, parallel-group, randomized controlled study of 1885 infants enrolled at age 2 months from August 2008 to July 2010 in Europe. INTERVENTION: Participants were randomized 2:2:1:1 to receive (1) 4CMenB at 2, 4, and 6 months with routine vaccines (7-valent pneumococcal and combined diphtheria, tetanus, acellular pertussis, inactivated polio, hepatitis B, Haemophilus influenzae type b vaccines); (2) 4CMenB at 2, 4, and 6 months and routine vaccines at 3, 5, and 7 months; (3) 4CMenB with routine vaccines at 2, 3, and 4 months; or (4) routine vaccines alone at 2, 3, and 4 months. MAIN OUTCOME MEASURES: Percentage of participants with human complement serum bactericidal activity (hSBA) titer of 1:5 or greater against 3 MenB strains specific for vaccine antigens (NZ98/254, 44/76-SL, and 5/99). RESULTS: After three 4CMenB vaccinations, 99% or more of infants developed hSBA titers of 1:5 or greater against strains 44/76-SL and 5/99. For NZ98/254, this proportion was 79% (95% CI, 75.2%-82.4%) for vaccination at 2, 4, and 6 months with routine vaccines, 86.1% (95% CI, 82.9%-89.0%) for vaccination at 2, 4, and 6 months without routine vaccines, and 81.7% (95% CI, 76.6%-86.2%) for vaccination at 2, 3, and 4 months with routine vaccines. Responses to routine vaccines given with 4CMenB were noninferior to routine vaccines alone for all antigens, except for the responses to pertactin and serotype 6B pneumococcal polysaccharide. Fever was seen following 26% (158/602) to 41% (247/607) of 4CMenB doses when administered alone, compared with 23% (69/304) to 36% (109/306) after routine vaccines given alone and 51% (306/605) to 61% (380/624) after 4CMenB and routine vaccines administered together. CONCLUSION: A 4CMenB vaccine is immunogenic against reference strains when administered with routine vaccines at 2, 4, and 6 or at 2, 3, and 4 months of age, producing minimal interference with the response to routine infant vaccinations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00721396.

Walker WT, de Whalley P, Andrews N, Oeser C, Casey M, Michaelis L, Hoschler K, Harrill C, Moulsdale P, Thompson B et al. 2012. H1N1 antibody persistence 1 year after immunization with an adjuvanted or whole-virion pandemic vaccine and immunogenicity and reactogenicity of subsequent seasonal influenza vaccine: a multicenter follow-on study. Clin Infect Dis, 54 (5), pp. 661-669. | Show Abstract | Read more

BACKGROUND: We investigated antibody persistence in children 1 year after 2 doses of either an AS03(B)-adjuvanted split-virion or nonadjuvanted whole-virion monovalent pandemic influenza vaccine and assessed the immunogenicity and reactogenicity of a subsequent dose of trivalent influenza vaccine (TIV). METHODS: Children previously immunized at age 6 months to 12 years in the original study were invited to participate. After a blood sample was obtained to assess persistence of antibody against swine influenza A/H1N1(2009) pandemic influenza, children received 1 dose of 2010/2011 TIV, reactogenicity data were collected for 7 days, and another blood sample was obtained 21 days after vaccination. RESULTS: Of 323 children recruited, 302 received TIV. Antibody persistence (defined as microneutralization [MN] titer ≥1:40) 1 year after initial vaccination was significantly higher in the AS03(B)-adjuvanted compared with the whole-virion vaccine group, 100% (95% confidence interval [CI], 94.1%-100%) vs 32.4% (95% CI, 21.5%-44.8%) in children immunized <3 years old and 96.9% (95% CI, 91.3%-99.4%) vs 65.9% (95% CI, 55.3%-75.5%) in those 3-12 years old at immunization, respectively (P < .001 for both groups). All children receiving TIV had post-vaccination MN titers ≥1:40. Although TIV was well tolerated in all groups, reactogenicity in children <5 years old was slightly greater in those who originally received AS03(B)-adjuvanted vaccine. CONCLUSIONS: This study provides serological evidence that 2 doses of AS03(B)-adjuvanted pandemic influenza vaccine may be sufficient to maintain protection across 2 influenza seasons. Administration of TIV to children who previously received 2 doses of either pandemic influenza vaccine is safe and is immunogenic for the H1N1 strain.

Sadarangani M, Hoe JC, Callaghan MJ, Jones C, Chan H, Makepeace K, Daniels-Treffandier H, Deadman ME, Bayliss C, Feavers I et al. 2012. Construction of Opa-positive and Opa-negative strains of Neisseria meningitidis to evaluate a novel meningococcal vaccine. PLoS One, 7 (12), pp. e51045. | Show Abstract | Read more

Neisseria meningitidis is a major global pathogen causing invasive disease with a mortality of 5-10%. Most disease in developed countries is caused by serogroup B infection, against which there is no universal vaccine. Opacity-associated adhesin (Opa) proteins are major meningococcal outer membrane proteins, which have shown recent promise as a potential novel vaccine. Immunisation of mice with different Opa variants elicited high levels of meningococcal-specific bactericidal antibodies, demonstrating proof in principle for this approach. Opa proteins are critical in meningococcal pathogenesis, mediating bacterial adherence to host cells, and modulating human cellular immunity via interactions with T cells and neutrophils, although there are conflicting data regarding their effects on CD4(+) T cells. We constructed Opa-positive and Opa-negative meningococcal strains to allow further evaluation of Opa as a vaccine component. All four opa genes from N. meningitidis strain H44/76 were sequentially disrupted to construct all possible combinations of N. meningitidis strains deficient in one, two, three, or all four opa genes. The transformations demonstrated that homologous recombination of exogenous DNA into the meningococcal chromosome can occur with as little as 80 bp, and that minor sequence differences are permissible. Anti-Opa bactericidal antibody responses following immunisation of mice with recombinant Opa were specific to the Opa variant used in immunisation. No immunomodulatory effects were observed when Opa was contained within meningococcal outer membrane vesicles (OMVs), compared to Opa-negative OMVs. These observations support the incorporation of Opa in meningococcal vaccines.

Pradhan R, Shrestha U, Gautam SC, Thorson S, Shrestha K, Yadav BK, Kelly DF, Adhikari N, Pollard AJ, Murdoch DR. 2012. Bloodstream infection among children presenting to a general hospital outpatient clinic in urban Nepal. PLoS One, 7 (10), pp. e47531. | Show Abstract | Read more

BACKGROUND: There are limited data on the etiology and characteristics of bloodstream infections in children presenting in hospital outpatient settings in South Asia. Previous studies in Nepal have highlighted the importance of murine typhus as a cause of febrile illness in adults and enteric fever as a leading bacterial cause of fever among children admitted to hospital. METHODS: We prospectively studied a total of 1084 febrile children aged between 2 months and 14 years presenting to a general hospital outpatient department in Kathmandu Valley, Nepal, over two study periods (summer and winter). Blood from all patients was tested by conventional culture and by real-time PCR for Rickettsia typhi. RESULTS: Putative etiological agents for fever were identified in 164 (15%) patients. Salmonella enterica serovar Typhi (S. Typhi) was identified in 107 (10%), S. enterica serovar Paratyphi A (S. Paratyphi) in 30 (3%), Streptococcus pneumoniae in 6 (0.6%), S. enterica serovar Typhimurium in 2 (0.2%), Haemophilus influenzae type b in 1 (0.1%), and Escherichia coli in 1 (0.1%) patient. S. Typhi was the most common organism isolated from blood during both summer and winter. Twenty-two (2%) patients were PCR positive for R. typhi. No significant demographic, clinical and laboratory features distinguished culture positive enteric fever and murine typhus. CONCLUSIONS: Salmonella infections are the leading cause of bloodstream infection among pediatric outpatients with fever in Kathmandu Valley. Extension of immunization programs against invasive bacterial disease to include the agents of enteric fever and pneumococcus could improve the health of children in Nepal.

Pollard AJ. 2012. Non-specific effects of vaccines: RCTs, not observational studies, are needed Archives of Disease in Childhood, 97 (8), pp. 677-678. | Read more

Scott CA, Atkinson SH, Sodha A, Tate C, Sadiq J, Lakhoo K, Pollard AJ. 2012. Management of lymphadenitis due to non-tuberculous mycobacterial infection in children Pediatric Surgery International, 28 (5), pp. 461-466. | Show Abstract | Read more

Purpose: Non-tuberculous mycobacterial (NTM) infection is an important cause of cervico-facial lymph node enlargement in young children. The optimal treatment is thought to be early complete excision without chemotherapy. We compared management of patients referred to our centre to this "gold standard" and determined clinical outcomes by type of primary surgical intervention (complete excision vs. incomplete excision). Methods: Retrospective study of management and clinical outcomes of all children ( < 12 years) with NTM lymphadenitis referred to a single UK centre between May 1998 and May 2008. Results: We identified 43 children. Median time from onset of swelling to operation was 6 weeks. Management was: no operation (n = 1, 2 %), complete excision (n = 20, 47 %), incision and drainage (n = 17, 40 %) and fine needle aspirate (n = 5, 12 %). Children not treated by primary complete excision were more likely to have: reoperation (91 vs. 30 %; χ 2 = 16.48; p < 0.0001); persistent lymphadenitis (77 vs. 30 %; χ 2 = 9.45; p = 0.002); sinus formation (26 vs. 5 %; χ2 = 3.74; p = 0.05). Conclusion: Failure to undertake primary complete excision leads to further morbidity. A high index of suspicion is required for timely appropriate management to avoid unnecessary morbidity and further intervention. © Springer-Verlag 2012.

Lambe T, Spencer AJ, Mullarkey CE, Antrobus RD, Yu LM, de Whalley P, Thompson BAV, Jones C, Chalk J, Kerridge S et al. 2012. T-Cell Responses in Children to Internal Influenza Antigens, 1 Year After Immunization with Pandemic H1N1 Influenza Vaccine, and Response to Revaccination with Seasonal Trivalent-inactivated Influenza Vaccine Pediatric Infectious Disease Journal, 31 (6), pp. e86-e91. | Read more

Metz JA, Hanieh S, Pradhan R, Joshi A, Shakya D, Shrestha L, Shrestha A, Upadhyay B, Kelly SC, John TM et al. 2012. Evaluation of haemophilus influenzae type b vaccine for routine immunization in Nepali infants. Pediatr Infect Dis J, 31 (4), pp. e66-e72. | Show Abstract | Read more

BACKGROUND: Haemophilus influenzae type b (Hib) carriage and disease studies in Nepali children suggest a significant burden of infection. Hib conjugate vaccines (HibCV) do not have uniform immunogenicity between populations. We determined the immunogenicity of HibCV in Nepali infants, before its introduction into the routine immunization schedule. METHODS: Ninety infants recruited at Patan Hospital, Kathmandu, received 3 doses of the HibCV with routine immunizations (diphtheria, tetanus, whole cell pertussis-hepatitis B vaccine + oral polio vaccine) at 6, 10 and 14 weeks of age, and a HibCV booster at 52 weeks. Anti-polyribosylribitol phosphate (PRP) concentrations were measured at 18, 52 and 56 weeks, and the antibody persistence at 52 weeks was compared with antibody values in unimmunized controls (n = 30). RESULTS: After 3 doses of primary immunizations, at 18 weeks of age (n = 74), all infants had anti-PRP concentrations above the accepted thresholds for short- and long-term protection (0.15 and 1.0 µg/mL, respectively). At 1 year of age, before administration of the booster of HibCV, the anti-PRP geometric mean antibody concentration was 2.76 µg/mL (confidence interval: 1.88-4.07) in sera from the immunized children compared with 0.11 µg/mL (95% confidence interval: 0.08-0.17) in the nonimmunized control group (n = 30). Twenty-seven percent (20/74) of participants, however, had anti-PRP concentrations <1.0 µg/mL. Four weeks after the booster dose of HibCV, 98.5% of infants had anti-PRP concentrations above 1.0 µg/mL. CONCLUSION: Immunization with HibCV given as part of the Expanded Program on Immunization schedule in Nepal elicits robust antibody responses. Though the antibody wanes during the first year of life, most 1-year-old infants remain protected and respond robustly to a booster dose of the vaccine.

Khatami A, Snape MD, Davis E, Layton H, John T, Yu LM, Dull PM, Gill CJ, Odrjlin T, Dobson S et al. 2012. Persistence of the immune response at 5 years of age following infant immunisation with investigational quadrivalent MenACWY conjugate vaccine formulations Vaccine, 30 (18), pp. 2831-2838. | Show Abstract | Read more

Background and aims: Serogroup A, C, W-135 and Y meningococcal (MenACWY) conjugate vaccines are recommended for routine adolescent immunisation in the United States and Canada. We evaluated the persistence of bactericidal antibodies through early childhood, following infant immunisation with varying schedules of MenACWY-CRM 197 vaccine. Methods: UK and Canadian infants were immunised with 2-3 doses of MenACWY-CRM 197 or 2 doses of serogroup C meningococcal (MenC) conjugate vaccine, and either MenACWY-CRM 197 , 1/5 dose of MenACWY polysaccharide vaccine or no booster at 12 months. Control groups recruited at 60 months had received country-specific infant doses of MenC conjugate vaccine. hSBA titres were measured in participants at 40 and 60 months of age. Results: 382 children were enrolled in 12 groups (22-40 per group). By age 60 months, 3-11% of children primed and boosted with MenACWY-CRM 197 had hSBA titres≥1:8 against serogroup A, 14-45% against serogroup C, 57-85% against serogroup W-135 and 42-71% against serogroup Y. Children primed with MenC and boosted with MenACWY-CRM 197 had similar results, except for serogroup C (59%). In age-matched controls administered MenC vaccine at 2, 3, and 4 months (UK), 2 and 12 months or 12 months only (Canada), percentages with hSBA titres≥1:8 were 0-3%, 29-53%, 34-36% and 10-29% against serogroups A, C, W-135 and Y respectively. Conclusions: Serogroup-specific bactericidal antibody wane following infant immunisation with MenACWY-CRM 197 , most markedly against serogroup A. Best persistence against serogroup C is observed with MenC conjugate vaccine priming and MenACWY-CRM 197 at 12 months, compared to schedules using only MenACWY-CRM 197 , with the potential for providing broader protection compared to monovalent MenC vaccines alone. © 2012 Elsevier Ltd.

Cited:

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Scopus

Thompson C, Kneen R, Riordan A, Kelly D, Pollard AJ. 2012. Encephalitis in children Archives of Disease in Childhood, 97 (2), pp. 150-161. | Show Abstract | Read more

Encephalitis is an uncommon but potentially devastating neurological syndrome with different aetiologies including direct central nervous system infection with different agents (most commonly viral) and those mediated by the immune system. Whilst there have been several recent publications and guidelines on the management of bacterial central nervous system infections in adults and children, viral infections have been relatively neglected. Guidelines have been published for adults with encephalitis (www.liv.ac.uk/braininfections) but none exist for children. For these reasons, we have reviewed the literature on encephalitis and have formulated a suggested management strategy for children with suspected, clinically diagnosed and proven encephalitis. We have excluded neonates, as encephalitis in this age group has different clinical features and is beyond the scope of this review.

Sibley A, Sheehan M, Pollard AJ. 2012. Assent is not consent. J Med Ethics, 38 (1), pp. 3. | Show Abstract | Read more

A recent article from Archives of Disease in Childhood outlined problems with the act of gaining child assent for research participation. However the arguments used in the article are incomplete or misguided. Rather than being harmful, assent should be seen as an ethically-appropriate way in which we can engage with the child about his participation in research. While additional clarification of the concept of assent is needed, the child's family context can provide us with a valuable guide to the way we involve him in the decision-making process.

Moore CE, Hennig BJ, Perrett KP, Hoe JC, Lee SJ, Fletcher H, Brocklebank D, O'Connor D, Snape MD, Hall AJ et al. 2012. Single nucleotide polymorphisms in the Toll-like receptor 3 and CD44 genes are associated with persistence of vaccine-induced immunity to the serogroup C meningococcal conjugate vaccine. Clin Vaccine Immunol, 19 (3), pp. 295-303. | Show Abstract | Read more

The rate of decay of antibody concentration following serogroup C meningococcal (MenC) polysaccharide-protein conjugate vaccination varies between individuals. This depends partly on vaccination age but may be influenced by human genetics. We studied 721 single nucleotide polymorphisms (SNPs) across 131 candidate genes in a first cohort of 905 Caucasians (11 to 21 years old; mean time after vaccination, 4.9 years) and 30 SNPs across 17 genes in a replication study using 155 children, aged 6 to 12 years (mean time after vaccination, 6.7 years), and 196 infants (1 year old; mean time after vaccination, 8 months). Individuals were classified as responders or nonresponders for total MenC IgG concentration and MenC serum bactericidal antibody (SBA) measurements. Associated genes were examined further for quantitative outcome measures. Fifty-nine SNPs in 37 genes were associated with IgG persistence (adjusted for age at measurement), and 56 SNPs in 36 genes were associated with SBA persistence (adjusted for age at measurement and vaccine used). Three SNPs each within the Toll-like receptor 3 (TLR3) (rs3775291, rs3775292, and rs5743312) and CD44 (rs11033013, rs353644, and rs996076) genes were associated with IgG (adjusted for age at measurement) or SBA (adjusted for age at measurement and vaccine used) persistence in the initial genetic study (P, 0.02 to 0.04). Single SNPs within the TLR3 (rs7657186) (P = 0.004 [unadjusted]) and CD44 (rs12419062) (P = 0.01 [unadjusted]) genes were associated with IgG persistence in the replication study. These results suggest that genetic polymorphisms in the TLR3 and CD44 genes are associated with the persistence of the immune response to MenC vaccines 1 to 6 years after vaccination.

de Whalley P, Walker W, Snape MD, Oeser C, Casey M, Moulsdale P, Harrill C, Andrews N, Hoschler K, Thompson B et al. 2011. A 1-year follow-on study from a randomised, head-to-head, multicentre, open-label study of two pandemic influenza vaccines in children. Health Technol Assess, 15 (45), pp. v-128. | Show Abstract | Read more

INTRODUCTION: Pandemic influenza A H1N1 infections occurred worldwide from 2009. Children were particularly vulnerable. Novel vaccines were used during the pandemic. OBJECTIVE: To assess the persistence of antibody to H1N1 influenza 1 year after children aged 6 months to 12 years had been immunised with two doses of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B-adjuvanted split-virion H1N1 influenza vaccine; and also to assess the immunogenicity and reactogenicity in this population of a single dose of 2010-11 trivalent seasonal influenza vaccine. DESIGN: Multicentre, open-label, follow-on from randomised, head-to-head trial. SETTING: Five UK sites (Southampton, Oxford, Bristol, London and Exeter). PARTICIPANTS: Children who completed last year's head-to-head randomised study were invited to participate. Children who had subsequently received a further dose of H1N1 vaccine, or who had already received a dose of 2010-11 trivalent seasonal influenza vaccine, were excluded. INTERVENTIONS: In the previous study, children were randomised (in a 1 : 1 ratio) to receive two doses, 21 days apart, of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B-adjuvanted split-virion H1N1 influenza vaccine. In this follow-on study, a blood sample was taken to assess the persistence of antibody 1 year later, followed by administration of one 0.5 ml-dose of trivalent seasonal influenza vaccine. A second blood sample was taken 3 weeks later. MAIN OUTCOME MEASURES: Comparison between vaccines of the percentage of participants with a microneutralisation (MN) titre ≥ 1 : 40 and a haemagglutination titre ≥ 1 : 32, 1 year after vaccination. Immunogenicity of the trivalent seasonal influenza vaccine was assessed 3 weeks after vaccination by both the MN and the haemagglutination inhibition (HI) titres. Reactogenicity data were recorded for 7 days after vaccination. RESULTS: A total of 323 children were enrolled and 318 were included in the analysis of the persistence of antibody. One year after receipt of whole-virion vaccine, the MN titre was ≥ 1 : 40 in 32.4% of those vaccinated when < 3 years old and in 65.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1 : 32 in 63.2% and 79.1% of children in the respective age groups. One year after receipt of the adjuvanted vaccine, the MN titre was ≥ 1 : 40 in 100% of those vaccinated when < 3 years old and in 96.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1 : 32 in 98.4% and 96.9% of children in the respective age groups. Three hundred and two children were given trivalent seasonal influenza vaccination. Three weeks later, sera were obtained from 282 children; 100% had an MN titre ≥ 1 : 40 and HI titre ≥ 1 : 32. Trivalent seasonal influenza vaccine was well tolerated, although in children < 5 years old, fever ≥ 38 °C was reported in 13.6% of those who had previously received whole-virion vaccine, and in 18.3% of those who had received adjuvanted vaccine. CONCLUSIONS: Nearly all children who received two doses of AS03B-adjuvanted split-virion pandemic H1N1 influenza vaccine had titres of antibody deemed protective (HI titre ≥ 1 : 32, MN titre ≥ 1 : 40) 1 year later. Children who received two doses of whole-virion vaccine had lower titres, although many were above the putative protective thresholds. One year after either pandemic vaccine, the 2010-11 trivalent seasonal influenza vaccine produced a marked serological response to the H1N1 component of the vaccine and was well tolerated. We propose to investigate whether or not previous receipt of monovalent influenza vaccines affected serological response to the H3N2 and B components of the 2010-11 seasonal influenza vaccine, using stored sera. TRIAL REGISTRATION: ClinicalTrials.gov NCT01239537. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Pollard AJ, Constable L. 2011. Expert Review of Vaccines 10-year anniversary issue. Expert Rev Vaccines, 10 (11), pp. 1489-1491. | Read more

Khatami A, Peters A, Robinson H, Williams N, Thompson A, Findlow H, Pollard AJ, Snape MD. 2011. Maintenance of immune response throughout childhood following serogroup C meningococcal conjugate vaccination in early childhood. Clin Vaccine Immunol, 18 (12), pp. 2038-2042. | Show Abstract | Read more

The objectives of this study were to evaluate the kinetics of antibody decline through childhood in a longitudinal study of a single cohort following serogroup C meningococcal (MenC) vaccine immunization in early childhood and to calculate the proportion of 11 to 13 year olds with protective levels of bactericidal antibody 10 years after immunization. United Kingdom children aged 11 to 13 years in 2010 who had previously taken part in a longitudinal study at the Oxford Vaccine Group had blood samples drawn between 2001 and 2010. Sera from each time point were analyzed for the MenC serum bactericidal antibody titer using a baby rabbit complement (rSBA) assay. The median age at MenC immunization was 21 months (range, 1 year 3 months to 3 years 9 months). The MenC rSBA geometric mean titer (GMT) at age 3.5 to 5 years was 8.0 (95% confidence interval, 6.5 to 9.9; n = 287). By age 11.5 to 13.5 years, the rSBA GMT had declined to 3.3 (2.5 to 4.4; n = 98). The percentage of children with rSBA titers of ≥1:8 (the threshold for protection) also declined from 38% (35% to 41%) to 15% (12% to 19%). We concluded that MenC rSBA titers wane rapidly following vaccination in early childhood and continue to decline into the second decade of life. Since nasopharyngeal colonization in adolescents probably provides the major reservoir for MenC in the population, declining immunity in this cohort is of concern. Sustaining high levels of antibody through booster vaccination in this cohort is likely necessary to avoid a resurgence of disease in the decade ahead.

Pollard AJ, Thompson M, Stokes T. 2011. Response from NICE. Br J Gen Pract, 61 (591), pp. 606-607. | Read more

Pollard AJ. 2011. Infectious disease: childhood meningitis may be preventable if we can afford it. Nat Rev Neurol, 7 (10), pp. 539-540. | Show Abstract | Read more

Bacterial meningitis, one of the infections most feared by parents, and on the mind of every pediatrician who evaluates a febrile child, is an important cause of morbidity and mortality in childhood. New vaccines have the potential to prevent the majority of these cases and could transform child health. © 2011 Macmillan Publishers Limited. All rights reserved.

Andrews NJ, Walker WT, Finn A, Heath PT, Collinson AC, Pollard AJ, Snape MD, Faust SN, Waight PA, Hoschler K et al. 2011. Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and non-adjuvanted whole virion H1N1 (2009) pandemic influenza vaccines. Vaccine, 29 (45), pp. 7913-7919. | Show Abstract | Read more

In 2009, 943 children aged 6 months to 10 years were randomised to receive two doses of an oil-in water AS03B-adjuvanted split virion or a non-adjuvanted whole virion H1N1 (2009) vaccine. The large numbers allowed investigation of possible predictors of immune response and reactogenicity. We used regression analysis to examine the effect of variables including past receipt of seasonal vaccine, antipyretics post-vaccination, interval between doses and pre-existing antibodies to H1N1 (2009) on immunogenicity. We also examined the relationship between immunogenicity and reactogenicity and whether prior infection or underlying conditions affected reactogenicity. For both vaccines, haemagglutination-inhibition titres were 60% higher in children with fever ≥38 °C after vaccination and 29% lower in those previously given seasonal vaccine. Early use of antipyretics did not affect immunogenicity. Post-vaccination titres were higher with longer intervals between doses and in those with evidence of prior infection, but reactogenicity in the latter was unaffected. In the adjuvanted vaccine group, reactions were more common in children with atopy. Both vaccines were safe and immunogenic in those with prior infection. Reduction in the interval between doses for earlier protection would be at the cost of reduced immunogenicity. The effect of seasonal vaccine on immunogenicity merits further investigation.

Pollard AJ, Hill AVS. 2011. Antibody repertoire: embracing diversity. Sci Transl Med, 3 (93), pp. 93ps32. | Show Abstract | Read more

In this Perspective, we discuss two papers that show that the breadth of the antibody response to vaccines could be manipulated by the use of particular vaccine adjuvants that stimulate innate immune mechanisms. The ability to increase the repertoire of antibodies induced by a vaccine may help to control variable pathogens that alter their exposed antigens to evade the immune system.

Thompson C, Kneen R, Riordan A, Kelly D, Pollard AJ. 2012. Encephalitis in children. Arch Dis Child, 97 (2), pp. 150-161. | Show Abstract | Read more

Encephalitis is an uncommon but potentially devastating neurological syndrome with different aetiologies including direct central nervous system infection with different agents (most commonly viral) and those mediated by the immune system. Whilst there have been several recent publications and guidelines on the management of bacterial central nervous system infections in adults and children, viral infections have been relatively neglected. Guidelines have been published for adults with encephalitis (www.liv.ac.uk/braininfections) but none exist for children. For these reasons, we have reviewed the literature on encephalitis and have formulated a suggested management strategy for children with suspected, clinically diagnosed and proven encephalitis. We have excluded neonates, as encephalitis in this age group has different clinical features and is beyond the scope of this review.

de Whalley PCS, Snape MD, Kelly DF, Banner C, Lewis S, Diggle L, John TM, Yu L-M, Omar O, Borkowski A, Pollard AJ. 2011. Persistence of serum bactericidal antibody one year after a booster dose of either a glycoconjugate or a plain polysaccharide vaccine against serogroup C Neisseria meningitidis given to adolescents previously immunized with a glycoconjugate vaccine. Pediatr Infect Dis J, 30 (11), pp. e203-e208. | Show Abstract | Read more

BACKGROUND: Bactericidal antibody induced by immunization of infants with serogroup C Neisseria meningitidis (MenC) vaccines wanes rapidly during childhood. Adolescents are at particular risk from meningococcal disease, therefore they might benefit from a booster dose of vaccine. The duration of serologic response to such a booster in adolescents is unknown. METHODS: In a previous study, English schoolchildren, aged 9 to 12 years, who had received a monovalent MenC glycoconjugate vaccine in 1999-2000, were given either a plain polysaccharide vaccine (MenC-PS group, n = 150) or a glycoconjugate vaccine (MenC-CRM group, n = 95) at 13 to 15 years of age. In this follow-up study, serum bactericidal antibody titers and specific immunoglobulin G concentrations were assessed 1 year later. Results were compared with unboosted controls of similar age (control group, n = 298). RESULTS: Compliance with study protocol was achieved for 146 of the MenC-PS group, 92 of the MenC-CRM group, and 293 of the control group. Compared with the control group, both the MenC-PS and MenC-CRM groups had a significantly higher (P < 0.0001) geometric mean serum bactericidal antibody titers 1 year after the booster dose (geometric mean titers for MenC-PS group 3388 [95% confidence interval {CI}: 2460-4665]; MenC-CRM group 4417 [95% CI: 2951-6609]; control group 316 [95% CI: 252-396]). Specific immunoglobulin G concentration also rose and remained elevated 1 year after the booster. CONCLUSIONS: A booster dose of MenC vaccine given to adolescents produced a marked rise in bactericidal antibody, which remained elevated 1 year later. Introduction of an adolescent booster of MenC vaccine might provide enhanced long-term population control of the disease.

Rohner BG, Snape MD, Kelly DF, John T, Morant A, Yu L, Borkowski A, Ceddia F, Borrow R, Siegrist C-A, Pollard AJ. 2011. The magnitude of the antibody and memory B cell responses during priming with a protein-polysaccharide conjugate vaccine in human infants is associated with the persistence of antibody and the intensity of booster response (vol 180, pg 2165, 2008) JOURNAL OF IMMUNOLOGY, 186 (10), pp. 6064-6064. | Read more

Barnes E, Pollard AJ. 2011. Vaccines in clinical trials: infectious disease. Expert Rev Vaccines, 10 (5), pp. 555-557. | Read more

Blanchard-Rohner G, Pollard AJ. 2011. Long-term protection after immunization with protein-polysaccharide conjugate vaccines in infancy. Expert Rev Vaccines, 10 (5), pp. 673-684. | Show Abstract | Read more

The polysaccharide-encapsulated bacteria, Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae are important causes of invasive bacterial infection in childhood, accounting for most of the cases of bacterial pneumonia and meningitis worldwide. Protein-polysaccharide conjugate vaccines have been developed over the last 20 years and have proven very effective in controlling these infections. Although studies have consistently shown that herd immunity is critical for population protection, long-term individual protection against polysaccharide-encapsulated bacteria appears to depend on persisting antibody and, perhaps to a lesser extent, immunological memory. However, some studies have reported that the concentration of serum antibody and vaccine effectiveness are not sustained after infant immunization, despite persistence of immunological memory. In this article, we detail the mechanisms of protection against invasion by encapsulated bacteria, describe the age-dependent B-cell and antibody responses to protein-polysaccharide conjugate vaccines and propose strategies to guarantee protection during periods of increased disease burden.

Callaghan MJ, Lewis S, Sadarangani M, Bailey SES, Chan H, Ferguson DJP, Derrick JP, Feavers I, Maiden MC, Pollard AJ. 2011. Potential of recombinant opa proteins as vaccine candidates against hyperinvasive meningococci. Infect Immun, 79 (7), pp. 2810-2818. | Show Abstract | Read more

Neisseria meningitidis causes half a million cases of septicemia and meningitis globally each year. The opacity (Opa) integral outer membrane proteins from N. meningitidis are polymorphic and highly immunogenic. Particular combinations of Opa proteins are associated with the hyperinvasive meningococcal lineages that have caused the majority of serogroup B and C meningococcal disease in industrialized countries over the last 60 years. For the first time, this genetic structuring of a diverse outer membrane protein family has been used to select a novel combination of representative antigens for immunogenicity testing. Fourteen recombinant Opa variants were produced and used in murine immunizations inducing an increase in specific antimeningococcal total IgG levels. All 14 Opa proteins elicited bactericidal antibodies against at least one hyperinvasive meningococcal isolate, and most isolates from each hyperinvasive lineage were killed by at least one Opa antiserum at a titer of 1:16 or greater. Cross-reactive bactericidal antibody responses were observed among clonal complexes. A theoretical coverage of 90% can be achieved by using a particular combination of 6 Opa proteins against an isolate collection of 227 recent United Kingdom disease cases. This study indicates the potential of Opa proteins to provide broad coverage against multiple meningococcal hyperinvasive lineages.

Kelly DF, Snape MD, Perrett KP, Clutterbuck EA, Lewis S, Rohner GB, Jones M, Yu L-M, Pollard AJ. 2011. Plasma and memory B-cell kinetics in infants following a primary schedule of CRM197-conjugated serogroup C meningococcal polysaccharide vaccine (vol 127, pg 134, 2009) IMMUNOLOGY, 132 (4), pp. 589-589. | Read more

Lazarus R, Clutterbuck E, Yu L-M, Bowman J, Bateman EA, Diggle L, Angus B, Peto TE, Beverley PC, Mant D, Pollard AJ. 2011. A randomized study comparing combined pneumococcal conjugate and polysaccharide vaccination schedules in adults. Clin Infect Dis, 52 (6), pp. 736-742. | Show Abstract | Read more

BACKGROUND: The widely used 23-valent plain polysaccharide vaccine (23vP) has limited effectiveness, produces short-lived immune responses, and induces attenuated antibody production after subsequent challenge with pneumococcal vaccines. Our goal was to examine whether priming with the 7-valent pneumococcal conjugate vaccine (PCV7) could enhance the immunogenicity of 23vP for the PCV7 serotypes and to investigate whether 23vP induced hyporesponsiveness could be overcome using PCV7. METHODS: We conducted an open-label randomized study that compared 3 vaccine schedules, each of which consisted of 2 doses of PCV7 and 1 dose of 23vP (23vP-PCV7-PCV7, PCV7-23vP-PCV7, PCV7-PCV7-23vP) administered over a 1-year period in a cohort of 348 adults 50-70 years of age. All vaccines were administered intramuscularly and were given 6 months apart. Blood samples were obtained prior to and 1 month after each vaccination. RESULTS: 23vP administered after priming with 2 doses of PCV7 produced significantly higher antibody concentrations for 3 of the 7 PCV7 serotypes, compared with vaccination with a single dose of 23vP; however, the same immunogenicity could be achieved with a single dose of PCV7. Prior vaccination with 23vP attenuated the antibody response to subsequent PCV7, which was not restored by additional doses of PCV7. CONCLUSION: In adults, vaccination schedules combining PCV7 and 23vP do not provide improved immunogenicity over the use of a single dose of 23vP for most of the serotypes contained in PCV7.

Khatami A, Snape MD, John T, Westcar S, Klinger C, Rollinson L, Boutriau D, Mesaros N, Wysocki J, Galaj A et al. 2011. Persistence of immunity following a booster dose of Haemophilus influenzae type B-Meningococcal serogroup C glycoconjugate vaccine: follow-up of a randomized controlled trial. Pediatr Infect Dis J, 30 (3), pp. 197-202. | Show Abstract | Read more

BACKGROUND: Antibodies against Haemophilus influenzae type b (Hib) and serogroup C Neisseria meningitidis (MenC) wane after early infant immunization. METHODS: Children previously immunized in a randomized controlled trial at ages 2, 3, and 4 months with DTPa-IPV-Hib and MenC-CRM197 (MenC-CRM group) or DTPa-IPV and Hib-MenC-TT (Hib-MenC-TT group) had blood samples drawn at 1 and 2 years following a booster dose of Hib-MenC-TT at 12 to 15 months of age. A blood sample was also drawn at the year 2 follow-up from a separately recruited age-matched control group who had not received a booster. RESULTS: In 271 children at year 1, mean 14.6 months (range: 12-18 months) following the Hib-MenC-TT booster, MenC bactericidal titers above the protective threshold (rSBA ≥ 1:8) was demonstrated in 89.0% of the Hib-MenC-TT group and 69.5% of MenC-CRM participants. Antipolyribosylribitol phosphate Ig ≥ 1.0 μg/mL (Hib correlate for long-term protection) was seen in 94.9% and 82.5%, respectively.In 379 participants (including 72 control children) at year 2 (age: 39-43 months, 25-31 months post Hib-MenC-TT) persistence of MenC antibodies was demonstrated in 67.1% of the Hib-MenC-TT group and 40.5% of the MenC-CRM group, compared with 44.1% of control group participants. Antipolyribosylribitol phosphate Ig ≥ 1.0 μg/mL was seen in 89.0%, 74.7%, and 38.9%, respectively. CONCLUSIONS: A toddler Hib-MenC-TT booster helps sustain immunity against Hib to 3½ years of age. Persistence of MenC antibody is similar in children primed with MenC-CRM197 in infancy who receive a booster Hib-MenC-TT, to those who receive no booster. Persistence of MenC antibody is better when primed and boosted with Hib-MenC-TT.

Khatami A, Pollard AJ. 2011. The epidemiology of meningococcal disease and the impact of vaccines (vol 9, pg 285, 2010) EXPERT REVIEW OF VACCINES, 10 (3), pp. 398-398.

Williams EJ, Lewis J, John T, Hoe JC, Yu L, Dongol S, Kelly DF, Griffiths DT, Shah A, Limbu B et al. 2011. Haemophilus influenzae type b carriage and novel bacterial population structure among children in urban Kathmandu, Nepal. J Clin Microbiol, 49 (4), pp. 1323-1330. | Show Abstract | Read more

Haemophilus influenzae type b (Hib) is a major cause of invasive bacterial infection in children that can be prevented by a vaccine, but there is still uncertainty about its relative importance in Asia. This study investigated the age-specific prevalence of Hib carriage and its molecular epidemiology in carriage and disease in Nepal. Oropharyngeal swabs were collected from children in Kathmandu, Nepal, from 3 different settings: a hospital outpatient department (OPD), schools, and children's homes. Hib was isolated using Hib antiserum agar plates, and serotyping was performed with latex agglutination. Hib isolates from children with invasive disease were obtained during active microbiological surveillance at Patan Hospital, Kathmandu, Nepal. Genotyping of disease and carriage isolates was undertaken using multilocus sequence typing (MLST). Swabs were taken from 2,195 children, including 1,311 children at an OPD, 647 children attending schools, and 237 children in homes. Overall, Hib was identified in 5.0% (110/2,195; 95% confidence interval [95% CI], 3.9% to 6.4%). MLST was performed on 108 Hib isolates from children carrying Hib isolates and 15 isolates from children with invasive disease. Thirty-one sequence types (STs) were identified, and 20 of these were novel STs. The most common ST isolates were sequence type 6 (ST6) and the novel ST722. There was marked heterogeneity among the STs from children with disease and children carrying Hib. STs identified from invasive infections were those commonly identified in carriage. This study provides evidence of Hib carriage among children in urban Nepal with genetically diverse strains prior to introduction of universal vaccination. The Hib carriage rate in Nepal was similar to the rates observed in other populations with documented high disease rates prior to vaccination, supporting implementation of Hib vaccine in Nepal in 2009.

Andrews NJ, Walker WT, Finn A, Heath PT, Collinson AC, Pollard AJ, Snape MD, Faust SN, Waight PA, Hoschler K et al. 2011. Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and non-adjuvanted whole virion H1N1 (2009) pandemic influenza vaccines Vaccine,

Kelly DF, Thorson S, Maskey M, Mahat S, Shrestha U, Hamaluba M, Williams E, Dongol S, Werno AM, Portess H et al. 2011. The burden of vaccine-preventable invasive bacterial infections and pneumonia in children admitted to hospital in urban Nepal. Int J Infect Dis, 15 (1), pp. e17-e23. | Show Abstract | Read more

BACKGROUND: Protein-polysaccharide vaccines have made a significant impact on the burden of disease caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and have the potential to do so for Salmonella Typhi. Nepal is one of many resource-poor nations with limited information on the epidemiology of childhood infections caused by these pathogens. METHODS: Over a 21-month period, we studied children aged ≤12 years admitted to an urban hospital in Nepal with suspected bacteremia, meningitis, or pneumonia. Patan Hospital is a non-profit hospital with the second largest pediatric unit in the Kathmandu Valley. RESULTS: Of 2039 children enrolled in the study, 142 (7.5%) included in the analysis had positive blood cultures. The agents of enteric fever, Salmonella Typhi and Salmonella Paratyphi, accounted for 59/142 (42%) of all bacteremias and were the most frequently cultured pathogens in children ≥1 year of age. S. pneumoniae was isolated in 16% of positive blood cultures and was the most common cause of bacteremia in children <1 year of age. Pneumonia accounted for 51% of admissions in children ≥2 months, with 44% of these children having radiographically defined primary endpoint pneumonia. S. pneumoniae was the most commonly identified pathogen in cases of pneumonia and meningitis. The S. pneumoniae serotype distribution indicated that the 10-valent and 13-valent pneumococcal conjugate vaccines would cover 44% and 47%, respectively, of all S. pneumoniae cultured from blood or cerebrospinal fluid (CSF) isolates and 62% and 67%, respectively, of isolates associated with pneumonia. H. influenzae type b was isolated infrequently from blood or CSF cultures, but is likely to be more important as a cause of pneumonia. CONCLUSIONS: The data on the burden of invasive bacterial infections and pneumonia from this study suggest that vaccines in development against Salmonella Typhi and the pneumococcus have the potential to significantly improve the health of children in Nepal.

Chhetri UD, Shrestha S, Pradhan R, Shrestha A, Adhikari N, Thorson S, Pollard AJ, Murdoch DR, Kelly DF. 2011. Clinical profile of invasive pneumococcal diseases in Patan Hospital, Nepal. Kathmandu Univ Med J (KUMJ), 9 (33), pp. 45-49. | Show Abstract

BACKGROUND: Pneumococcal infection is one of the leading causes of pneumonia, meningitis and septicemia in developing countries. It accounts for one million deaths each year in children. OBJECTIVES: The objective of this study is to see the clinical profile of invasive pneumococcal disease, antibiotics sensitivity pattern and prevalent serotypes in children admitted at Patan Hospital. METHODS: This is a retrospective analytical study conducted in the department of Paediatrics, Patan hospital. The lab data of those children who grew pneumococci in their blood, cerebrospinal fluid or body fluids over a period of 3 years (January 2007 to Dec 2009) were collected and the case files were then studied. RESULTS: Out of 42 cases of invasive pneumococcal diseases studied admitted diagnoses included pneumonia, febrile seizure, bacteremia or septicemia, meningitis, acute gastroenteritis and glomerulonephritis. Twenty seven of them were children under five. The male to female ratio was 1.7:1. On investigation 64%, 52% and 5% of the patients had leucocytosis, anaemia, and leucopenia respectively. Twenty six of them had radiological changes suggestive of pneumonia. Streptococcus pneumoniae grew in 38 blood samples, 5 cerebrospinal fluid and 3 pleural fluids. Almost all of these isolates were sensitive to penicillin, cefotaxime, amoxycillin, choloramphenicol, erythromycin and ofloxacin and resistant to cotrimoxazole and gentamicin. Pneumococcal serotypes found in our study were 1, 14, 5, 23B, 6B, 8, 9A, 9V, 10A, 15 and 23F (11 serotypes). CONCLUSIONS: Penicillin is still the most effective antibiotic for streptococcal infection in our study. Of the pneumococcal serotypes identified; 36% were covered by the 7-valent pneumococcal conjugate vaccine, 54% each by PCV-10 and PCV-13, and 72% by the e 23 valent vaccines.

de Whalley P, Walker W, Snape MD, Oeser C, Casey M, Moulsdale P, Harrill C, Andrews N, Hoschler K, Thompson B et al. 2011. A 1-year follow-on study from a randomised, head-to-head, multicentre, open-label study of two pandemic influenza vaccines in children Health Technology Assessment, 15 (45), | Show Abstract | Read more

Introduction: Pandemic influenza A H1N1 infections occurred worldwide from 2009. Children were particularly vulnerable. Novel vaccines were used during the pandemic. Objective: To assess the persistence of antibody to H1N1 influenza 1 year after children aged 6 months to 12 years had been immunised with two doses of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03 B -adjuvanted split-virion H1N1 influenza vaccine; and also to assess the immunogenicity and reactogenicity in this population of a single dose of 2010-11 trivalent seasonal influenza vaccine. Design: Multicentre, open-label, follow-on from randomised, head-to-head trial. Setting: Five UK sites (Southampton, Oxford, Bristol, London and Exeter). Participants: Children who completed last year's head-to-head randomised study were invited to participate. Children who had subsequently received a further dose of H1N1 vaccine, or who had already received a dose of 2010-11 trivalent seasonal influenza vaccine, were excluded. Interventions: In the previous study, children were randomised (in a 1: 1 ratio) to receive two doses, 21 days apart, of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03 B -adjuvanted split-virion H1N1 influenza vaccine. In this follow-on study, a blood sample was taken to assess the persistence of antibody 1 year later, followed by administration of one 0.5 ml-dose of trivalent seasonal influenza vaccine. A second blood sample was taken 3 weeks later. Main outcome measures: Comparison between vaccines of the percentage of participants with a microneutralisation (MN) titre ≥ 1: 40 and a haemagglutination titre ≥ 1: 32, 1 year after vaccination. Immunogenicity of the trivalent seasonal influenza vaccine was assessed 3 weeks after vaccination by both the MN and the haemagglutination inhibition (HI) titres. Reactogenicity data were recorded for 7 days after vaccination. Results: A total of 323 children were enrolled and 318 were included in the analysis of the persistence of antibody. One year after receipt of whole-virion vaccine, the MN titre was ≥ 1: 40 in 32.4% of those vaccinated when < 3 years old and in 65.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1: 32 in 63.2% and 79.1% of children in the respective age groups. One year after receipt of the adjuvanted vaccine, the MN titre was ≥ 1: 40 in 100% of those vaccinated when < 3 years old and in 96.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1: 32 in 98.4% and 96.9% of children in the respective age groups. Three hundred and two children were given trivalent seasonal influenza vaccination. Three weeks later, sera were obtained from 282 children; 100% had an MN titre ≥ 1: 40 and HI titre ≥ 1: 32. Trivalent seasonal influenza vaccine was well tolerated, although in children < 5 years old, fever ≥ 38 °C was reported in 13.6% of those who had previously received whole-virion vaccine, and in 18.3% of those who had received adjuvanted vaccine. Conclusions: Nearly all children who received two doses of AS03 B -adjuvanted split-virion pandemic H1N1 influenza vaccine had titres of antibody deemed protective (HI titre ≥ 1: 32, MN titre ≥ 1: 40) 1 year later. Children who received two doses of whole-virion vaccine had lower titres, although many were above the putative protective thresholds. One year after either pandemic vaccine, the 2010-11 trivalent seasonal influenza vaccine produced a marked serological response to the H1N1 component of the vaccine and was well tolerated. We propose to investigate whether or not previous receipt of monovalent influenza vaccines affected serological response to the H3N2 and B components of the 2010-11 seasonal influenza vaccine, using stored sera. Trial registration: ClinicalTrials.gov NCT01239537. Funding: The National Institute for Health Research Health Technology Assessment programme. © Queen's Printer and Controller of HMSO 2011.

Sadarangani M, Pollard AJ. 2011. Bacterial meningitis in childhood. Adv Exp Med Biol, 719 pp. 185-199. | Show Abstract | Read more

A wide variety of pathogens cause childhood meningitis and clinical features and-outcomes vary according to the organism. Bacterial meningitis caused by Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) is of particular importance as it has a high mortality and morbidity, has been relatively common and is treatable with antibiotics. In the last two decades widespread introduction of highly effective conjugate vaccines against these pathogens in many industrialised countries has led to a significant reduction in the incidence of bacterial meningitis, although there is still a substantial global burden of disease, predominantly occurring in resource-poor countries, where case-fatality rates are higher and long-term sequelae are more common. © 2011 Springer Science+Business Media, LLC.

De Whalley PCS, Snape MD, Kelly DF, Banner C, Lewis S, Diggle L, John TM, Yu LM, Omar O, Borkowski A, Pollard AJ. 2011. Persistence of serum bactericidal antibody one year after a booster dose of either a glycoconjugate or a plain polysaccharide vaccine against serogroup C neisseria meningitidis given to adolescents previously immunized with a glycoconjugate vaccine Pediatric Infectious Disease Journal, 30 (11), | Show Abstract | Read more

Background: Bactericidal antibody induced by immunization of infants with serogroup C Neisseria meningitidis (MenC) vaccines wanes rapidly during childhood. Adolescents are at particular risk from meningococcal disease, therefore they might benefit from a booster dose of vaccine. The duration of serologic response to such a booster in adolescents is unknown. Methods: In a previous study, English schoolchildren, aged 9 to 12 years, who had received a monovalent MenC glycoconjugate vaccine in 1999-2000, were given either a plain polysaccharide vaccine (MenC-PS group, n = 150) or a glycoconjugate vaccine (MenC-CRM group, n = 95) at 13 to 15 years of age. In this follow-up study, serum bactericidal antibody titers and specific immunoglobulin G concentrations were assessed 1 year later. Results were compared with unboosted controls of similar age (control group, n = 298). Results: Compliance with study protocol was achieved for 146 of the MenC-PS group, 92 of the MenC-CRM group, and 293 of the control group. Compared with the control group, both the MenC-PS and MenC-CRM groups had a significantly higher (P < 0.0001) geometric mean serum bactericidal antibody titers 1 year after the booster dose (geometric mean titers for MenC-PS group 3388 [95% confidence interval {CI}: 2460-4665] ; MenC-CRM group 4417 [95% CI: 2951-6609]; control group 316 [95% CI: 252-396] ). Specific immunoglobulin G concentration also rose and remained elevated 1 year after the booster. Conclusions: A booster dose of MenC vaccine given to adolescents produced a marked rise in bactericidal antibody, which remained elevated 1 year later. Introduction of an adolescent booster of MenC vaccine might provide enhanced long-term population control of the disease. © 2011 by Lippincott Williams & Wilkins.

Pollard AJ. 2011. Infectious disease: Childhood meningitis may be preventable if we can afford it Nature Reviews Neurology,

Shrestha S, Upadhyay B, Limbu B, Pradhan R, Nakagomi T, Thorson S, Pollard AJ, Adhikari N. 2011. Rotavirus and its Genotype Distribution among Children Less than Three Years Presenting with Acute Watery Diarrhoea to a General Hospital in Urban Nepal Journal of Nepal Paediatric Society, 31 (2), pp. 110-115. | Show Abstract | Read more

Introduction: Viruses are the most common cause for diarrhoea in infants and small children. Rotavirus is the most frequent viral etiology, causing 125 million episodes of infantile diarrhoea and over 600,000 deaths per year. Materials and methods: A cross sectional study between January and March 2008 was conducted at Patan Hospital, Kathmandu to find out the prevalence of rotavirus among children < 3 years with watery diarrhoea and to identify common strains of rotavirus in the study population. Testing for rotavirus was undertaken by using Rota/Adeno screen Dipstick M583CE. Rotavirus strain identification was done at Nagasaki University Japan. Data was analyzed using SPSS® for Windows V 15.0 software. Results: 119 children with acute watery diarrhoea were enrolled. Rotavirus antigen was found in 63 cases (53%). The highest percentage of rotavirus infection was found in the second six months of life. Among the children with positive rotavirus antigen, the median age was 10 months (IRQ 8.00). The most predominant strain of rotavirus identified was G12 followed by G9 and G1. Most predominant G and P combination was G9 P[8] followed by G12P[6] . Conclusion: The study has shown the prevalence of unusual serotypes of rotavirus. Though rotavirus vaccine has been studied, used widely and found to be very effective, none of the vaccine efficacy studies have included common serotypes identified in Nepal. Level of protection conferred by infant immunization with the current rotavirus vaccines against the strains circulating in Nepal is unknown and careful surveillance through vaccine implementation is needed.

Khatami A, Pollard AJ. 2011. Corrigendum Expert Review of Vaccines, 10 (3), pp. 398-398. | Read more

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Sadarangani M, Pollard AJ, Gray-Owen SD. 2011. Opa proteins and CEACAMs: Pathways of immune engagement for pathogenic Neisseria FEMS Microbiology Reviews, 35 (3), pp. 498-514. | Show Abstract | Read more

Neisseria meningitidis and Neisseria gonorrhoeae are globally important pathogens, which in part owe their success to their ability to successfully evade human immune responses over long periods. The phase-variable opacity-associated (Opa) adhesin proteins are a major surface component of these organisms, and are responsible for bacterial adherence and entry into host cells and interactions with the immune system. Most immune interactions are mediated via binding to members of the carcinoembryonic antigen cell adhesion molecule (CEACAM) family. These Opa variants are able to bind to different receptors of the CEACAM family on epithelial cells, neutrophils, and T and B lymphocytes, influencing the innate and adaptive immune responses. Increased epithelial cell adhesion creates the potential for prolonged infection, invasion and dissemination. Furthermore, Opa proteins may inhibit T-lymphocyte activation and proliferation, B-cell antibody production, and innate inflammatory responses by infected epithelia, in addition to conferring increased resistance to antibody-dependent, complement-mediated killing. While vaccines containing Opa proteins could induce adhesion-blocking and bactericidal antibodies, the consequence of CEACAM binding by a candidate Opa-containing vaccine requires further investigation. This review summarizes current knowledge of the immunological consequences of the interaction between meningococcal and gonococcal Opa proteins and human CEACAMs, considering the implications for pathogenesis and vaccine development. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd.

Hennig BJ, Fielding K, Broxholme J, Diatta M, Mendy M, Moore C, Pollard AJ, Rayco-Solon P, Sirugo G, van der Sande MA et al. 2011. Correction: host genetic factors and vaccine-induced immunity to hepatitis B virus infection. PLoS One, 6 (2), | Show Abstract | Read more

[This corrects the article on p. e1898 in vol. 3.].

Sadarangani M, Pollard AJ, Gray-Owen SD. 2011. Opa proteins and CEACAMs: pathways of immune engagement for pathogenic Neisseria. FEMS Microbiol Rev, 35 (3), pp. 498-514. | Show Abstract | Read more

Neisseria meningitidis and Neisseria gonorrhoeae are globally important pathogens, which in part owe their success to their ability to successfully evade human immune responses over long periods. The phase-variable opacity-associated (Opa) adhesin proteins are a major surface component of these organisms, and are responsible for bacterial adherence and entry into host cells and interactions with the immune system. Most immune interactions are mediated via binding to members of the carcinoembryonic antigen cell adhesion molecule (CEACAM) family. These Opa variants are able to bind to different receptors of the CEACAM family on epithelial cells, neutrophils, and T and B lymphocytes, influencing the innate and adaptive immune responses. Increased epithelial cell adhesion creates the potential for prolonged infection, invasion and dissemination. Furthermore, Opa proteins may inhibit T-lymphocyte activation and proliferation, B-cell antibody production, and innate inflammatory responses by infected epithelia, in addition to conferring increased resistance to antibody-dependent, complement-mediated killing. While vaccines containing Opa proteins could induce adhesion-blocking and bactericidal antibodies, the consequence of CEACAM binding by a candidate Opa-containing vaccine requires further investigation. This review summarizes current knowledge of the immunological consequences of the interaction between meningococcal and gonococcal Opa proteins and human CEACAMs, considering the implications for pathogenesis and vaccine development.

Maheshi R, Elizabeth C, Jaclyn B, Snape MD, Mushiya M, Kathryn H, Pollard AJ. 2010. MEMORY B CELL RESPONSES FOLLOWING IMMUNISATION WITH POLYSACCHARIDE AND CONJUGATE QUADRIVALENT MENINGOCOCCAL ACYW135 VACCINES IN HEALTHY ADULT VOLUNTEERS JOURNAL OF INFECTION, 61 (6), pp. 517-517.

Findlow J, Borrow R, Snape MD, Dawson T, Holland A, John TM, Evans A, Telford KL, Ypma E, Toneatto D et al. 2010. Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy. Clin Infect Dis, 51 (10), pp. 1127-1137. | Show Abstract | Read more

BACKGROUND: In the absence of an efficacious broadly protective vaccine, serogroup B Neisseria meningitidis (MenB) is the leading cause of bacterial meningitis and septicemia in many industrialized countries. An investigational recombinant vaccine that contains 3 central proteins; Neisserial adhesin A (NadA), factor H binding protein (fHBP) and Neisserial heparin binding antigen (NHBA) has been developed. These antigens have been formulated with and without outer membrane vesicles (rMenB+OMV and rMenB, respectively) from the New Zealand epidemic strain (B:4:P1.7-2,4). In this trial, we assessed the immunogenicity of these formulations in infants, who are at greatest risk of contracting MenB disease. METHODS: A total of 147 infants from the United Kingdom were enrolled and randomly assigned to receive rMenB or rMenB+OMV at 2, 4, 6, and 12 months of age or a single dose at 12 months of age. Serum samples taken before and after vaccination were assayed in a standardized serum bactericidal antibody assay against 7 MenB strains. Local and systemic reactogenicity were recorded for 7 days after each vaccination. Analysis was according to protocol. RESULTS: After 3 doses, both vaccines were immunogenic against strains expressing homologous or related NadA and fHBP. rMenB+OMV demonstrated greater immunogenicity than did rMenB and was immunogenic against strains expressing homologous PorA. Both vaccines elicited anamnestic responses after the fourth dose. For both vaccines, responses were lower against strains expressing heterologous fHBP variants and after a single dose at 12 months. CONCLUSIONS: The rMenB+OMV vaccine has the potential to protect infants from MenB disease, although the breadth of protection afforded to heterologous antigens requires additional investigation.

Snape MD, Dawson T, Oster P, Evans A, John TM, Ohene-Kena B, Findlow J, Yu L-M, Borrow R, Ypma E et al. 2010. Immunogenicity of two investigational serogroup B meningococcal vaccines in the first year of life: a randomized comparative trial. Pediatr Infect Dis J, 29 (11), pp. e71-e79. | Show Abstract | Read more

BACKGROUND: An investigational vaccine against serogroup B meningococcal (MenB) disease containing 3 main recombinant proteins (factor H-binding protein, Neisserial adhesion A, and Neisserial heparin-binding antigen) has been developed. We evaluated the immunogenicity and reactogenicity of a 3-dose course of this vaccine administered alone (recombinant MenB [rMenB]) or combined with the outer membrane vesicle (OMV) component of the vaccine used in New Zealand (rMenB+OMV). METHODS: A randomized, single-blind, comparative study of 60 healthy infants enrolled at 6 to 8 months of age and immunized with rMenB or rMenB+OMV at day 0, day 60, and at age 12 months. Blood samples obtained at baseline and 1 month following the second and third doses of vaccine were analyzed for serum bactericidal antibody (SBA) using human complement (hSBA) against 7 MenB strains. The putative correlate of protection was an hSBA titer of ≥4. RESULTS: The per-protocol analysis included 24 of 30 participants randomized to each group. After 3 doses of rMenB+OMV, 90% or more of participants had an hSBA titer ≥4 for 5 MenB strains, with 70% of participants having an hSBA titer ≥4 for a sixth strain. rMenB alone was immunogenic for only 3 strains. Both vaccines were well tolerated. CONCLUSIONS: Three doses of rMenB+OMV in the second half of infancy induce bactericidal antibodies against strains expressing vaccine antigens, demonstrating the potential for broader vaccine prevention of MenB disease. This vaccine is now in phase III clinical trials.

Trück J, Pollard AJ. 2010. Challenges in immunisation against bacterial infection in children. Early Hum Dev, 86 (11), pp. 695-701. | Show Abstract | Read more

Polysaccharide-encapsulated organisms such as S. pneumoniae, H. influenzae type b and N. meningitidis are the leading causes of serious invasive bacterial diseases and pneumonia in children. The use of conjugate vaccines in developed countries has markedly decreased the burden of disease and mortality from these organisms through direct protection of the immunised and through herd immunity. Although conjugate vaccines are highly immunogenic, antibody levels after immunisation in early infancy wane, leading to the need for programmes which include booster doses. Understanding the generation of long-term immunity could lead to improvements in vaccine formulation and scheduling with the ultimate goal of providing more sustained protection. Prematurity is a risk factor for disease caused by polysaccharide-encapsulated bacteria and the available data indicate that preterm infants should be immunised according to their chronological age to provide early protection.

Ladhani SN, Davila S, Hibberd ML, Heath PT, Ramsay ME, Slack MPE, Pollard AJ, Booy R. 2010. Association between single-nucleotide polymorphisms in Mal/TIRAP and interleukin-10 genes and susceptibility to invasive haemophilus influenzae serotype b infection in immunized children. Clin Infect Dis, 51 (7), pp. 761-767. | Show Abstract | Read more

BACKGROUND: The development of invasive Haemophilus influenzae serotype b (Hib) disease after prior immunization with the Hib conjugate vaccine (ie, Hib vaccine failure) is extremely rare, suggesting that affected children may have an underlying genetic susceptibility in their immune response. The objective of this study was to investigate single-nucleotide polymorphisms (SNPs) known to affect function in biologically plausible genes in relation to the risk of Hib vaccine failure and its clinical manifestations. METHODS: The families of UK children with Hib vaccine failure diagnosed during the period October 1992 through December 2005 were identified through enhanced national surveillance and approached for the study at a median interval of 4 years after invasive disease. The Wellcome Trust Case Control Consortium data sets were used as controls. Nineteen functional SNPs in 14 immune response genes were investigated in 172 white children. RESULTS: The recessive homozygous genotype for a SNP in the TIRAP (also known as MAL) gene (rs1893352) that is in strong linkage disequilibrium (r2=0.93) with the known functional Ser180Leu polymorphism in white persons was strongly associated with nonmeningitis cases of Hib vaccine failure (odds ratio, 5.6; 95% confidence interval, 2.7-11.5; P=1.2 x 10(-7)). In addition, the recessive homozygous genotype for another SNP (rs1554286) in strong linkage disequilibrium with both the C-819T (r2=0.87) and C-592A (r2=0.75) promoter polymorphisms in the interleukin-10 gene was associated with epiglottitis only (odds ratio, 5.8; 95% confidence interval, 2.4-14.2; P=1.1 x 10(-5)). CONCLUSIONS: Our findings strongly suggest that the development of invasive Hib disease after prior immunization is in part genetically determined and may direct the immune response to specific clinical manifestations.

Waddington C, Andrews N, Hoschler K, Walker W, Oeser C, Reiner A, John T, Wilkins S, Casey M, Eccleston P et al. 2010. Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6 months to 12 years of age. Health Technol Assess, 14 (46), pp. 1-130. | Show Abstract | Read more

OBJECTIVE: To evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children aged 6 months to 12 years. DESIGN: Multicentre, randomised, head-to-head, open-label trial. SETTING: Five UK sites (Oxford, Bristol, Southampton, Exeter and London). PARTICIPANTS: Children aged 6 months to < 13 years, for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures, were eligible for inclusion. INTERVENTIONS: A tocopherol/oil-in-water emulsion-adjuvanted (AS03(B)) egg culture-derived split-virion H1N1 vaccine and a non-adjuvanted cell culture-derived whole-virion vaccine, given as a two-dose schedule, 21 days apart, were compared. Participants were grouped into those aged 6 months to < 3 years (younger group) and 3 years to < 13 years of age (older group) and were randomised by study investigators (1 : 1 ratio) to receive one of the two vaccines. Vaccines were administered by intramuscular injection (deltoid or anterior-lateral thigh, depending on age and muscle bulk). Local reactions and systemic symptoms were collected for 1 week post immunisation, and serum was collected at baseline and after the second dose. To assess safety and tolerability, parents or guardians recorded the following information in diary cards from days 0-7 post vaccination: axillary temperature, injection site reactions, solicited and unsolicited systemic symptoms, and medications. MAIN OUTCOME MEASURE: Comparison between vaccines of the percentage of participants demonstrating seroconversion by microneutralisation assay. RESULTS: Among 937 children receiving vaccine, per-protocol seroconversion rates were higher after the AS03(B)-adjuvanted vaccine than after the whole-virion vaccine (98.2% vs 80.1% in children < 3 years, 99.1% vs 95.9% among those aged 3-12 years), as were severe local reactions (3.6% vs 0.0% in those under 5 years, 7.8% vs 1.1% in those aged 5-12 years), irritability in children < 5 years (46.7% vs 32.0%), and muscle pain in older children (28.9% vs 13.2%). The second dose of the adjuvanted vaccine was more reactogenic than the first, especially for fever > 38.0°C in those under 5 years of age (8.9% vs 22.4%). CONCLUSION: The adjuvanted vaccine, although reactogenic, was more immunogenic, especially in younger children, indicating the potential for improved immunogenicity of influenza vaccines in this age group. TRIAL REGISTRATION NUMBER: ISRCTN89141709.

Blanchard-Rohner G, Galli G, Clutterbuck EA, Pollard AJ. 2010. Comparison of a limiting dilution assay and ELISpot for detection of memory B-cells before and after immunisation with a protein-polysaccharide conjugate vaccine in children. J Immunol Methods, 358 (1-2), pp. 46-55. | Show Abstract | Read more

In the present study, the limiting dilution assay (LDA) and the ELISpot are compared in their ability to detect serogroup C meningococcal (MenC)-specific memory B-cells in peripheral blood of 12month old children, after 3-dose priming with serogroup C meningococcal conjugate vaccine (MenCV) in infancy. At 12 months of age, MenC-memory B-cells were detected by ELISpot in 61% of children and in 5% by LDA. In contrast, carrier-specific memory B-cells were measurable in 36% of children by LDA and 78% by ELISpot. One month after a booster dose of MenCV given at 12 months of age, MenC-specific memory B-cells were detected in 89% of children by ELISpot and 65% of children by LDA, while diphtheria toxoid-specific memory B-cells were detected in 88% of children by ELISpot and in 74% of children by LDA. Two statistical methods were applied to enumerate memory B-cells with the LDA assay; the Poisson method allowed determination of very low frequencies that could not be determined by the Reed and Muench method. These data are examples of alternative methods to assess long-term protection after protein-polysaccharide conjugate vaccines, through direct measurement of memory B-cells in peripheral blood shortly after immunisation.

Perrett KP, Winter AP, Kibwana E, Jin C, John TM, Yu LM, Borrow R, Curtis N, Pollard AJ. 2010. Antibody persistence after serogroup C meningococcal conjugate immunization of United Kingdom primary-school children in 1999-2000 and response to a booster: a phase 4 clinical trial. Clin Infect Dis, 50 (12), pp. 1601-1610. | Show Abstract | Read more

BACKGROUND: After immunization with serogroup C meningococcal (MenC) conjugate vaccine, antibody responses and vaccine effectiveness are sustained in adolescents, in contrast to rapid waning in young children. We investigated the persistence of serum bactericidal antibody (SBA) titers in children 6 years after immunization with MenC vaccine (primed between 2 months and 6 years of age). The response to a Haemophilus influenzae type b-MenC conjugate (Hib-MenC) booster was also measured. METHODS: A phase 4 clinical trial was conducted among 250 healthy 6-12-year-old children. SBA titers were measured before, 1 month after, and 1 year after Hib-MenC administration. The correlate of protection was an SBA titer of 8. RESULTS: An SBA titer of 8 was observed in 61 (25% [95% confidence interval {CI}, 20%-30%]) of 244 participants (mean age, 9.1 years; mean interval since MenC immunization, 6.75 years). The proportion with an SBA titer of 8 and the SBA geometric mean titer increased with age, from 12% (95% CI, 4%-23%) to 48% (95% CI, 29%-67%) and from 2.90 (95% CI, 2.11-3.99) to 17.20 (95% CI, 6.80-43.5), respectively, from a mean age of 7.0 to 12.1 years. One month after the Hib-MenC booster, all participants had an SBA titer of 8, which was sustained in 99.6% at 1 year. CONCLUSIONS: As a result of waning antibody, the majority of 6-12-year-old children in the United Kingdom have inadequate serological protection against MenC. The persistence of MenC immunity and the response to a Hib-MenC booster is dependent on age at priming. A booster was highly effective in this cohort and could sustain population immunity against MenC disease. Trial registration. Current Controlled Trials ( http://www.controlled-trials.com ) identifier: ISRCTN72858898 .

Holt KE, Baker S, Dongol S, Basnyat B, Adhikari N, Thorson S, Pulickal AS, Song Y, Parkhill J, Farrar JJ et al. 2010. High-throughput bacterial SNP typing identifies distinct clusters of Salmonella Typhi causing typhoid in Nepalese children. BMC Infect Dis, 10 (1), pp. 144. | Show Abstract | Read more

BACKGROUND: Salmonella Typhi (S. Typhi) causes typhoid fever, which remains an important public health issue in many developing countries. Kathmandu, the capital of Nepal, is an area of high incidence and the pediatric population appears to be at high risk of exposure and infection. METHODS: We recently defined the population structure of S. Typhi, using new sequencing technologies to identify nearly 2,000 single nucleotide polymorphisms (SNPs) that can be used as unequivocal phylogenetic markers. Here we have used the GoldenGate (Illumina) platform to simultaneously type 1,500 of these SNPs in 62 S. Typhi isolates causing severe typhoid in children admitted to Patan Hospital in Kathmandu. RESULTS: Eight distinct S. Typhi haplotypes were identified during the 20-month study period, with 68% of isolates belonging to a subclone of the previously defined H58 S. Typhi. This subclone was closely associated with resistance to nalidixic acid, with all isolates from this group demonstrating a resistant phenotype and harbouring the same resistance-associated SNP in GyrA (Phe83). A secondary clone, comprising 19% of isolates, was observed only during the second half of the study. CONCLUSIONS: Our data demonstrate the utility of SNP typing for monitoring bacterial populations over a defined period in a single endemic setting. We provide evidence for genotype introduction and define a nalidixic acid resistant subclone of S. Typhi, which appears to be the dominant cause of severe pediatric typhoid in Kathmandu during the study period.

McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DRW, Willcocks LC, Koukoulaki M, Brazma A, Jovanovic V, Kemeny DM et al. 2010. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med, 16 (5), pp. 586-591. | Show Abstract | Read more

Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of potentially toxic immunosuppressive therapy. Gene expression-based biomarkers facilitating such tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice. We show that transcriptional profiling of purified CD8(+) T cells, which avoids the confounding influences of unseparated cells, identifies two distinct subject subgroups predicting long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium-sized and small blood vessels, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction. We show that the subset of genes defining the poor prognostic group is enriched for genes involved in the interleukin-7 receptor (IL-7R) pathway and T cell receptor (TCR) signaling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8(+) T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest new potential therapeutic targets in autoimmunity.

Ladhani S, Heath PT, Aibara RJ, Ramsay ME, Slack MPE, Hibberd ML, Pollard AJ, Moxon ER, Booy R. 2010. Long-term complications and risk of other serious infections following invasive Haemophilus influenzae serotype b disease in vaccinated children. Vaccine, 28 (10), pp. 2195-2200. | Show Abstract | Read more

This study describes the long-term complications in children with Haemophilus influenzae serotype b (Hib) vaccine failure and to determine their risk of other serious infections. The families of 323 children with invasive Hib disease after appropriate vaccination (i.e. vaccine failure) were contacted to complete a questionnaire relating to their health and 260 (80.5%) completed the questionnaire. Of the 124 children with meningitis, 18.5% reported serious long-term sequelae and a further 12.1% of parents attributed other problems to Hib meningitis. Overall, 14% (32/231 cases) of otherwise healthy children and 59% (17/29 cases) of children with an underlying condition developed at least one other serious infection requiring hospital admission. In a Poisson regression model, the risk of another serious infection was independently associated with the presence of an underlying medical condition (incidence risk ratio (IRR) 7.6, 95% CI 4.8-12.1; p<0.0001), both parents having had a serious infection (IRR 4.1, 95% CI 1.6-10.3; p=0.003), requirement of more than two antibiotic courses per year (IRR 2.3, 95% CI 1.4-3.6; p=0.001) and the presence of a long-term complication after Hib infection (IRR 1.8, 95% CI 1.1-3.1; p=0.03). Thus, rates of long-term sequelae in children with vaccine failure who developed Hib meningitis are similar to those in unvaccinated children in the pre-vaccine era. One in seven otherwise healthy children (14%) with Hib vaccine failure will go on to suffer another serious infection requiring hospital admission in childhood, which is higher than would be expected for the UK paediatric population.

Ahmed SA, Zengeya S, Kini U, Pollard AJ. 2010. Familial isolated congenital asplenia: case report and literature review. Eur J Pediatr, 169 (3), pp. 315-318. | Show Abstract | Read more

Congenital asplenia is a rare life-threatening condition, often presenting with pneumococcal sepsis. It may arise as part of situs abnormalities or result from an unrelated specific defect of spleen development. The mode of inheritance is usually autosomal dominant, though sporadic cases are also reported. In affected individuals, the use of appropriate antibiotic prophylaxis and immunisations could save lives. In our report, we describe a family of three siblings with isolated congenital asplenia and unaffected parents, suggestive of recessive inheritance. The diagnosis in the proband was made post mortem following overwhelming pneumococcal sepsis. We also review the literature and compare the eight families previously reported with congenital isolated asplenia.

Khatami A, Pollard AJ. 2010. The epidemiology of meningococcal disease and the impact of vaccines. Expert Rev Vaccines, 9 (3), pp. 285-298. | Show Abstract | Read more

Neisseria meningitidis causes endemic meningococcal disease worldwide. Serogroups B and C are responsible for the majority of cases of meningococcal disease in Europe, serogroups B, C and Y cause most disease in the Americas, and serogroups A, C and W135 predominate in Asia and Africa. Polysaccharide vaccines against meningococcal serogroups A, C, Y and W135 have been available for several decades, but have been little used due to poor immunogenicity in young children and minimal effects on nasopharyngeal carriage. Conversely, the introduction of the conjugate serogroup C meningococcal vaccine has dramatically changed the epidemiology of the disease in industrialized nations, showing potential for broader control with A, C, Y and W135 conjugates, and leaving serogroup B as the predominant cause of disease. Development of vaccines for prevention of serogroup B disease in industrialized nations and serogroup A conjugate vaccines for Africa could lead to global control of meningococcal disease.

Sadarangani M, Pollard AJ. 2010. Serogroup B meningococcal vaccines-an unfinished story. Lancet Infect Dis, 10 (2), pp. 112-124. | Show Abstract | Read more

Most invasive meningococcal disease in developed countries is caused by Neisseria meningitidis with a serogroup B capsule. However, despite availability of vaccines for other serogroups since the 1960s, no serogroup B vaccine exists. In this Review we look at the development of serogroup B vaccines over the past 40 years. Outer membrane vesicle vaccines have been successfully used to control geographically isolated epidemics, but most have not been highly immunogenic in young children or provided broad cross-protection from infections with other strains. Vaccines based on subcapsular antigens have recently produced promising results in early clinical trials, and the disease burden might be substantially reduced over the next few years.

Visintin C, Mugglestone MA, Fields EJ, Jacklin P, Murphy MS, Pollard AJ, Guideline Development Group, National Institute for Health and Clinical Excellence. 2010. Management of bacterial meningitis and meningococcal septicaemia in children and young people: summary of NICE guidance. BMJ, 340 pp. c3209. | Read more

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Waddington CS, Walker WT, Oeser C, Reiner A, John T, Wilkins S, Casey M, Eccleston PE, Allen RJ, Okike I et al. 2010. Safety and immunogenicity of AS03<inf>B</inf>adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: Open label, randomised, parallel group, multicentre study BMJ (Online), 340 (7759), pp. 1292. | Show Abstract | Read more

Objectives: To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom. Design: Open label, randomised, parallel group, phase II study. Setting: Five UK centres (Oxford, Southampton, Bristol, Exeter, and London). Participants: Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months- < 3 years (younger group) and 3- < 13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis. Interventions: Participants were randomised 1:1 to receive AS03 B (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both we re given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose. Main outcome measures: Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of ≥1:40 from before vaccination to three weeks after the second dose). Results: Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%,95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P < 0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P < 0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P < 0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P < 0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever ≥38°C in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P < 0.001). Conclusions: In this first direct comparison of an AS03 B adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group. Trial registration: Clinical trials.gov NCT00980850; ISRCTN89141709.

Visintin C, Mugglestone MA, Fields EJ, Jacklin P, Murphy MS, Pollard AJ. 2010. Management of bacterial meningitis and meningococcal septicaemia in children and young people: Summary of NICE guidance BMJ (Online), 341 (7763), pp. 92-94. | Read more

Waddington CS, Walker WT, Oeser C, Reiner A, John T, Wilkins S, Casey M, Eccleston PE, Allen RJ, Okike I et al. 2010. Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study. BMJ, 340 (may27 1), pp. c2649. | Show Abstract | Read more

OBJECTIVES: To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom. DESIGN: Open label, randomised, parallel group, phase II study. SETTING: Five UK centres (Oxford, Southampton, Bristol, Exeter, and London). PARTICIPANTS: Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-<3 years (younger group) and 3-<13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis. INTERVENTIONS: Participants were randomised 1:1 to receive AS03(B) (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both were given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose. MAIN OUTCOME MEASURES: Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of >or=1:40 from before vaccination to three weeks after the second dose). RESULTS: Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P<0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P<0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P<0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P<0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever >or=38 masculineC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P<0.001). CONCLUSIONS: In this first direct comparison of an AS03(B) adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group. TRIAL REGISTRATION: Clinical trials.gov NCT00980850; ISRCTN89141709.

Zhou L, Pollard AJ. 2010. A fast and highly sensitive blood culture PCR method for clinical detection of Salmonella enterica serovar Typhi. Ann Clin Microbiol Antimicrob, 9 (1), pp. 14. | Show Abstract | Read more

BACKGROUND: Salmonella Typhi causes an estimated 21 million new cases of typhoid fever and 216,000 deaths every year. Blood culture is currently the gold standard for diagnosis of typhoid fever, but it is time-consuming and takes several days for isolation and identification of causative organisms. It is then too late to initiate proper antibiotic therapy. Serological tests have very low sensitivity and specificity, and no practical value in endemic areas. As early diagnosis of the disease and prompt treatment are essential for optimal management, especially in children, a rapid sensitive detection method for typhoid fever is urgently needed. Although PCR is sensitive and rapid, initial research indicated similar sensitivity to blood culture and lower specificity. We developed a fast and highly sensitive blood culture PCR method for detection of Salmonella Typhi, allowing same-day initiation of treatment after accurate diagnosis of typhoid. METHODS: An ox bile tryptone soy broth was optimized for blood culture, which allows the complete lysis of blood cells to release intracellular bacteria without inhibiting the growth of Salmonella Typhi. Using the optimised broth Salmonella Typhi bacteria in artificial blood samples were enriched in blood culture and then detected by a PCR targeting the fliC-d gene of Salmonella Typhi. RESULTS: Tests demonstrated that 2.4% ox bile in blood culture not only lyzes blood cells completely within 1.5 hours so that the intracellular bacteria could be released, but also has no inhibiting effect on the growth of Salmonella Typhi. Three hour enrichment of Salmonella Typhi in tryptone soya broth containing 2.4% ox bile could increase the bacterial number from 0.75 CFU per millilitre of blood which is similar to clinical typhoid samples to the level which regular PCR can detect. The whole blood culture PCR assay takes less than 8 hours to complete rather than several days for conventional blood culture. CONCLUSIONS: This novel blood culture PCR method is superior in speed and sensitivity to both conventional blood culture and PCR assays. Its use in clinical diagnosis may allow early detection of the causative organism and facilitate initiation of prompt treatment among patients with typhoid fever.

Burton MJ, Pollard AJ, Ramsden JD. 2010. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev, 9 (9), pp. CD008669. | Show Abstract | Read more

BACKGROUND: PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome) is a rare clinical syndrome of unknown cause usually identified in children. OBJECTIVES: To assess the efficacy of tonsillectomy (with or without adenoidectomy) in children with PFAPA. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010 Issue 1); MEDLINE (PubMed); EMBASE; CINAHL; mRCT (metaRegister of clinical trials, including ClinicalTrials.gov); NRR (National Research Register); LILACS; KoreaMed; IndMed; PakMediNet; China Knowledge Network; CAB Abstracts; Web of Science; BIOSIS Previews; ICTRP (International Clinical Trials Registry Platform) and Google. The date of the last search was 21 January 2010. SELECTION CRITERIA: Randomised studies comparing adeno-/tonsillectomy with non-surgical treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: Two trials involving 67 children were included. One high quality study demonstrated a dramatic benefit of adenotonsillectomy in children with PFAPA diagnosed according to rigid, standard criteria with a relative 'risk' (RR) of symptom resolution after 18 months of 12.63 (95% CI 1.81 to 87.98) and a lower rate of episodes per patient-month (rate ratio 0.07; 95% CI 0.04 to 0.13). A less methodologically rigorous study enrolled some children with PFAPA, but probably included others with alternative types of recurrent pharyngitis, and performed tonsillectomy alone. This also demonstrated a significant benefit for surgery at six months: RR 1.93 (95% CI 1.11 to 3.36); rate ratio episodes per patient-month 0.10 (95% CI 0.04 to 0.28). The pooled relative risk of symptom resolution was 3.25 (95% CI 1.78 to 5.92) and the resulting number needed to treat (NNT) 2 (95% CI 1 to 3). AUTHORS' CONCLUSIONS: The trials included in this review reported follow up at 18 and six months respectively but it is well-established that children with PFAPA recover spontaneously and treatment can be administered to try and reduce the severity of individual episodes. Therefore, the parents and carers of children with PFAPA must weigh the risks and consequences of surgery (hospitalisation, a predictable period of time postoperatively away from school/nursery, the risks of surgery) against the alternative of a finite period of recurrent episodes of disease at predictable intervals, potentially requiring time off school and the regular use of medication. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.

Snape MD, Klinger CL, Daniels ED, John TM, Layton H, Rollinson L, Pestridge S, Dymond S, Galiza E, Tansey S et al. 2010. Immunogenicity and reactogenicity of a 13-valent-pneumococcal conjugate vaccine administered at 2, 4, and 12 months of age: a double-blind randomized active-controlled trial. Pediatr Infect Dis J, 29 (12), pp. e80-e90. | Show Abstract | Read more

BACKGROUND: A 2-, 4-, and 12-month schedule of a novel 13-valent-pneumococcal conjugate vaccine (PCV13), containing serotype 1, 3, 4, 5, 6A, 6B 7F, 9V, 14, 18C, 19A, 19F, and 23F polysaccharides individually conjugated to CRM197 was evaluated in a randomized, double-blind, controlled infant study. METHODS: Two hundred eighty-six healthy infants received PCV13 or the 7-valent-pneumococcal conjugate vaccine (PCV7) at 2, 4, and 12 months of age, alongside a serogroup C meningococcal (MenC) vaccine (2 and 4 months of age), DTaP-IPV-Hib (2, 3, and 4 months), and a Hib-MenC vaccine (12 months). Specific antibody responses were assessed at age 5, 12, and 13 months. RESULTS: At 13 months of age, >97% of PCV13 recipients had pneumococcal serotype-specific serum IgG concentrations ≥0.35 µg/mL for each vaccine serotype except serotype 3 (88.2%), and at least 93% of PCV13 recipients had OPA titers ≥1:8 for each serotype. At 5 months, 110/114 (96.5%) of PCV13 recipients and 100/102 (98.0%) of PCV7 recipients had serum anti-PRP (Hib) IgG concentration ≥0.15 µg/mL (difference, 1.5%; CI, -7.1%–3.7%), while 119/120 (99.2%) and 117/118 (99.2%), respectively, had MenC serum bactericidal assay titers of ≥1:8. All PCV13 recipients and 110/113 (97.3%) of PCV7 recipients had IgG concentrations against fimbrial agglutinogens of ≥2.2 EU/mL; IgG concentrations for the remaining pertussis antigens were ≥5 EU/mL for all participants. Local reactions and systemic events were similar in the PCV13 and PCV7 groups. CONCLUSIONS: A 2-, 4-, and 12-month course of PCV13 was immunogenic for all 13 vaccine serotypes and was well tolerated.

Finn A, Curtis N, Pollard AJ. 2010. Advances in Experimental Medicine and Biology: Preface Advances in Experimental Medicine and Biology, 659

Blanchard-Rohner G, Pulickal AS, Jol-van der Zijde CM, Snape MD, Pollard AJ. 2009. Appearance of peripheral blood plasma cells and memory B cells in a primary and secondary immune response in humans. Blood, 114 (24), pp. 4998-5002. | Show Abstract | Read more

In humans, the kinetics of the appearance of memory B cells and plasma cells during primary immunization are not well defined. In this study, we assessed the primary B-cell response of rabies-antigen naive volunteers during a 3-dose course of rabies vaccine compared with the B-cell response to a booster dose of rabies vaccine given to previously immunized volunteers. After a single dose of vaccine, in the naive group plasma and memory B cells appeared later (peak at day 10) than in the primed group (peak at day 7) and were at lower frequency. The most rapid responses (day 4) were detected after a third immunization in the naive group. This is the first study to document the detailed kinetics of the plasma cell and memory B-cell responses to immunization in adult humans and to demonstrate differences in the responses that relate to the preexisting immune status of the persons.

Leroux-Roels I, Van der Wielen M, Kafeja F, Vandermeulen C, Lazarus R, Snape MD, John T, Carre C, Nougarede N, Pepin S et al. 2009. Humoral and cellular immune responses to split-virion H5N1 influenza vaccine in young and elderly adults. Vaccine, 27 (49), pp. 6918-6925. | Show Abstract | Read more

We evaluated the humoral and cellular immunogenicity of adjuvanted and non-adjuvanted H5N1 influenza vaccine in two groups of 300 adults: aged 18-60 and >60 years in a randomized, open-label, uncontrolled phase 2 trial. Participants received two injections (D0, D21) of 7.5 microg hemagglutinin without adjuvant or 30 microg with aluminum hydroxide adjuvant. Antibody responses and cytokine secretion were assessed before and after vaccination. Excluding the 6/300 non-elderly and 47/300 elderly participants with pre-existing antibodies, geometric mean titers (dil(-1)) on D42 were higher with 30 microg+Ad and were comparable between age groups. Participants with pre-existing antibodies responded strongly to the first vaccination (GMTs in the range 147-228 on D21). Vaccination increased both Th1 and Th2 T-cell responses. The predominantly Th1 profile observed before vaccination was unaffected by vaccination. H5N1 influenza vaccine is no less immunogenic in elderly adults than in younger adults and, due to a higher proportion non-naïve elderly, immunogenicity was higher in this latter group.

Pollard AJ, Reiner A, John T, Sheasby E, Snape M, Faust S, Collinson A, Finn A, Heath PT, Miller E. 2009. Future of flu vaccines. Expediting clinical trials in a pandemic. BMJ, 339 (nov10 1), pp. b4652. | Read more

Ladhani S, Heath PT, Ramsay ME, Slack MPE, Kibwana E, Pollard AJ, Booy R. 2009. Long-term immunological follow-up of children with haemophilus influenzae serotype b vaccine failure in the United Kingdom. Clin Infect Dis, 49 (3), pp. 372-380. | Show Abstract | Read more

BACKGROUND: It is not known how long children with Haemophilus influenzae serotype b (Hib) vaccine failure retain protective Hib antibody concentrations after infection. The objective of this study was to determine Hib antibody concentrations in children several years after infection and to identify risk factors for low antibody concentrations. METHODS: The families of children from the United Kingdom who developed invasive Hib disease after prior immunization with Hib conjugate vaccine (i.e., Hib vaccine failure) from October 1992 through December 2005 were asked to complete a questionnaire. A blood sample was also obtained from each child. RESULTS: Of 323 families approached, 260 (80.5%) returned a completed questionnaire, and 175 (54.2%) children provided a blood sample. The median age at follow-up was 8.4 years (interquartile range [IQR], 6.2-15.4 years), and the median duration of follow-up was 4.1 years (IQR, 3.5-9.7 years). Twenty-seven children (16.1%) had been born prematurely and/or had an underlying medical condition, and 18 (10.8%) had immunoglobulin deficiency. The median Hib antibody concentration was 0.70 microg/mL (IQR, 0.22-5.8 microg/mL). Overall, 95 children (56.9%) had antibody concentrations <1.0 microg/mL, and 27 (16.2%) had antibody concentrations <0.15 microg/mL. All 3 children with Down syndrome and 10 (42%) of 24 children aged <5 years at follow-up had Hib antibody concentrations <0.15 microg/mL. An antibody concentration <0.15 microg/mL was independently associated with underlying conditions, young age at onset of Hib disease, and shorter time from Hib disease to follow-up. CONCLUSIONS: More than one-half of the children with Hib vaccine failure had antibody concentrations below those considered to confer long-term protection, which suggests that these children might be at further risk of invasive Hib disease and would benefit from another dose of Hib vaccine.

Pace D, Pollard AJ, Messonier NE. 2009. Quadrivalent meningococcal conjugate vaccines. Vaccine, 27 Suppl 2 (SUPPL. 2), pp. B30-B41. | Show Abstract | Read more

Neisseria meningitidis is an important cause of bacterial meningitis and septicaemia with most disease caused by meningococci bearing serogroups A, B, C, Y and W-135 polysaccharides. Monovalent serogroup C conjugate vaccines have become established in the immunisation programmes in many countries and the first quadrivalent meningococcal vaccine, containing the polysaccharides from 4 of the serogroups A, C, Y and W-135 meningococci conjugated to a protein carrier was licensed in the US in 2005. This vaccine and others in development offer the potential to broaden population protection against meningococcal disease.

Lewis S, Sadarangani M, Hoe JC, Pollard AJ. 2009. Challenges and progress in the development of a serogroup B meningococcal vaccine. Expert Rev Vaccines, 8 (6), pp. 729-745. | Show Abstract | Read more

Serogroup B meningococci cause the majority of the meningococcal disease burden in developed countries. Production of an effective and safe vaccine for serogroup B organisms has been hampered by the poor immunogenicity of the capsular polysaccharide that defines this group of bacteria. Previous efforts have focused on outer membrane vesicle vaccines, which have been implemented successfully during clonal outbreaks. However, the search for a universal vaccine against endemic polyclonal serogroup B meningococcal disease continues. In this review, we have highlighted recent development of outer membrane vesicle vaccines and progress in the evaluation of recombinant outer membrane protein vaccines.

Kelly DF, Snape MD, Perrett KP, Clutterbuck EA, Lewis S, Blanchard Rohner G, Jones M, Yu L-M, Pollard AJ. 2009. Plasma and memory B-cell kinetics in infants following a primary schedule of CRM 197-conjugated serogroup C meningococcal polysaccharide vaccine. Immunology, 127 (1), pp. 134-143. | Show Abstract | Read more

The induction of persistent protective levels of pathogen-specific antibody is an important goal of immunization against childhood infections. However, antibody persistence is poor after immunization in infancy versus later in life. Serogroup C meningococci (MenC) are an important cause of bacteraemia and meningitis in children. The use of protein-polysaccharide conjugate vaccines against MenC has been associated with a significant decline in the incidence of invasive disease. However, vaccine effectiveness is negligible by more than 1 year after a three-dose priming series in infancy and corresponds to a rapid decline in antibody following an initial immune response. The cellular mechanisms underlying the generation of persistent antibody in this age group are unclear. An essential prelude to larger studies of peripheral blood B cells is an understanding of B-cell kinetics following immunization. We measured MenC- and diphtheria-specific plasma and memory B-cell kinetics in infants receiving a CRM(197) (cross-reactive material; mutant diphtheria toxoid)-conjugated MenC vaccine at 2, 3 and 4 months of age. Plasma cell responses were more delayed after the first dose when compared with the rapid appearance of plasma cells after the third dose. Memory B cells were detectable at all time-points following the third dose as opposed to the low frequency seen following a first dose. This study provides data on B-cell kinetics following a primary schedule of immunization in young infants upon which to base further studies of the underlying cellular mechanism of humoral immunity.

Williams EJ, Thorson S, Maskey M, Mahat S, Hamaluba M, Dongol S, Werno AM, Yadav BK, Shah AS, Kelly DF et al. 2009. Hospital-based surveillance of invasive pneumococcal disease among young children in urban Nepal. Clin Infect Dis, 48 Suppl 2 (s2), pp. S114-S122. | Show Abstract | Read more

BACKGROUND: Streptococcus pneumoniae is a leading cause of pneumonia and meningitis in young children. Before implementation of the pneumococcal conjugate vaccine in developing countries, there is an urgent need to provide regional epidemiological data on pneumococcal disease. The aims of this study were to determine the prevalence and serotype distribution of invasive pneumococcal disease among young children hospitalized in urban Nepal. METHODS: Children aged 2 months to 5 years who were admitted to Patan Hospital, Kathmandu, with fever and/or suspected pneumonia, meningitis, or bacteremia were recruited. Blood culture specimens were collected from all participants. In cases of suspected meningitis, cerebrospinal fluid specimens were cultured and were tested for S. pneumoniae antigen. RESULTS: A total of 885 children were recruited during the 21-month study period. Of these, 76 (9%) had meningitis and 498 (56%) had pneumonia, on the basis of clinical criteria. Radiographically confirmed pneumonia occurred in 354 (40%), and probable or definite meningitis occurred in 47 (5%). S. pneumoniae was isolated in specimens from 17 (2%) of the children. Serotypes 1 and 12A were isolated most frequently, and only 1 of 17 isolates had a serotype contained in the currently available 7-valent pneumococcal conjugate vaccine. CONCLUSIONS: More than 60% of children aged <5 years who were admitted with fever and/or suspected invasive bacterial disease in urban Nepal had the clinical syndromes of meningitis and/or pneumonia. A new generation of pneumococcal vaccines that prevent infection with a broader range of serotypes may be necessary to most effectively control pneumococcal disease in young children in Kathmandu.

Perrett KP, Snape MD, Ford KJ, John TM, Yu L-MM, Langley JM, McNeil S, Dull PM, Ceddia F, Anemona A et al. 2009. Immunogenicity and immune memory of a nonadjuvanted quadrivalent meningococcal glycoconjugate vaccine in infants. Pediatr Infect Dis J, 28 (3), pp. 186-193. | Show Abstract | Read more

BACKGROUND: The highest rate of invasive meningococcal disease is among children under 2 years of age. There is currently no licensed quadrivalent (serogroups A, C, W-135, and Y) meningococcal glycoconjugate vaccine approved for infants. We evaluated the immunogenicity and reactogenicity of a novel quadrivalent nonadjuvanted meningococcal glycoconjugate vaccine (MenACWY-CRM) in healthy infants. METHODS: One hundred eighty infants (90 in Canada and 90 in the United Kingdom) received 2 doses of MenACWY-CRM at 2 and 4 months of age administered concomitantly with routine infant vaccines. At 12 months of age, the Canadian infants received either MenACWY-CRM or a reduced dose of a licensed meningococcal polysaccharide vaccine. In the United Kingdom, all infants received a further dose of MenACWY-CRM. The serological marker of protection was a titer of > or =1:4 using a serum bactericidal assay with human complement (hSBA). RESULTS: Two doses of MenACWY-CRM induced hSBA titers > or =1:4 in 57% (95% confidence interval [CI]: 45-67) and 50% (95% CI: 38-62) of infants against serogroup A in Canada and the United Kingdom, respectively, 93% (95% CI: 85-97) and 86% (95% CI: 46-93) against serogroup C, 95% (95% CI: 87-99) and 82% (95% CI: 71-90) against serogroup W-135, and 91% (95% CI: 82-96) and 74% (95% CI: 63-83) against serogroup Y. After a booster dose of MenACWY-CRM at 12 months, at least 94% of participants achieved hSBA titers > or =1:4 against each of the serogroups C, W-135, and Y and more than 79% against serogroup A. The vaccine was well tolerated. CONCLUSIONS: The nonadjuvanted MenACWY-CRM is immunogenic and well tolerated in infancy and could provide broad protection against meningococcal disease in this vulnerable age group.

Pollard AJ, Perrett KP, Beverley PC. 2009. Maintaining protection against invasive bacteria with protein-polysaccharide conjugate vaccines. Nat Rev Immunol, 9 (3), pp. 213-220. | Show Abstract | Read more

Polysaccharide-encapsulated organisms are the leading cause of bacterial meningitis and pneumonia in children. The use of protein-polysaccharide conjugate vaccines in developed countries over the past two decades has markedly decreased the burden of disease and mortality from these organisms through direct protection of the immunized and through herd immunity. In the next decade, the widespread use of conjugate vaccines in the developing world should prevent millions of deaths. In this Science and Society article, we describe how vaccine-induced immunity wanes rapidly after vaccination in early childhood and argue that strategies that sustain protection in the population must be considered.

Kelly DF, Moxon ER, Yu L-M, Pollard AJ. 2009. Anti-polyribosylribitol phosphate antibody concentrations and avidities in children since the start of Haemophilus influenzae type b immunization of infants in the United Kingdom. Clin Vaccine Immunol, 16 (2), pp. 246-252. | Show Abstract | Read more

The introduction of routine infant immunization with Haemophilus influenzae type b (Hib) conjugate vaccines in the United Kingdom in 1992 led to a significant reduction in invasive disease due to this organism. Subsequently, between 1999 and 2003 there was an increase in the number of immunized children with Hib infection. We investigated whether the rise in cases was related to changes in anti-polyribosylribitol phosphate (PRP) antibody concentration or avidity. Using stored sera, we analyzed temporal changes in antibody levels among 3- to 5-year-old children immunized between 1991 and 2000. Anti-PRP antibody concentrations were higher in 3- to 5-year-olds who received infant immunization in 1991 than those in subsequent years. This difference may be related to changes in either the mode of administration of Hib conjugate vaccines or the rates of Hib nasopharyngeal carriage. This study emphasizes the factors affecting anti-PRP antibody concentration following immunization with conjugate vaccines and the importance of these in long-term protection from invasive disease.

Snape MD, Maclennan JM, Lockhart S, English M, Yu L-M, Moxon RE, Pollard AJ. 2009. Demonstration of immunologic memory using serogroup C meningococcal glycoconjugate vaccine. Pediatr Infect Dis J, 28 (2), pp. 92-97. | Show Abstract | Read more

BACKGROUND: Studies of glycoconjugate vaccines have traditionally used an immune challenge with a plain polysaccharide vaccine to demonstrate immunologic memory. Plain polysaccharide vaccines are poorly immunogenic in children and can induce subsequent immunologic hyporesponsiveness. We therefore assessed the use of glycoconjugate vaccines as an alternative method of demonstrating immunologic memory. METHODS: Children immunized with hepatitis B vaccine or serogroup C meningococcal glycoconjugate vaccine (MenCC) at age 2, 3, 4 months received a plain polysaccharide meningococcal serogroup A/C vaccine (MenACP) or MenCC at age 12 months. A post hoc analysis of serum bactericidal activity responses to MenCC assessed whether this differed in MenCC primed and MenCC naive infants. RESULTS: MenCC primed children displayed higher geometric mean serum bactericidal titers than MenCC naive children following MenACP (1518 compared with 30; P = 0.003). A similar difference was seen after a dose of MenCC to toddlers (MenCC primed: 8663, MenCC naive: 710; P < 0.001). The latter comparison became a borderline significance after adjusting for higher pretoddler immunization serum bactericidal geometric mean titers in the MenCC primed group (P = 0.068). CONCLUSIONS: Administration of glycoconjugate vaccines provides an important alternative method of demonstrating immunologic memory, avoiding the use of plain polysaccharide vaccines that are potentially deleterious in children. This has implications for the design of all future clinical trials of glycoconjugate vaccines.

Pulickal AS, Gautam S, Clutterbuck EA, Thorson S, Basynat B, Adhikari N, Makepeace K, Rijpkema S, Borrow R, Farrar JJ, Pollard AJ. 2009. Kinetics of the natural, humoral immune response to Salmonella enterica serovar Typhi in Kathmandu, Nepal. Clin Vaccine Immunol, 16 (10), pp. 1413-1419. | Show Abstract | Read more

Typhoid fever is a major public health problem in developing countries, conservatively estimated to occur in 17 million cases and be responsible for 200,000 deaths annually. We investigated the acquisition of natural immunity to Salmonella enterica serovar Typhi in a region where typhoid is endemic by testing sera from an age-stratified sample of 210 healthy participants in Kathmandu, Nepal, for bactericidal activity toward S. Typhi and for anti-Vi capsular polysaccharide antibodies. Bactericidal titers in children were significantly lower than those in newborns and adults (P < 0.0001). Anti-S. Typhi bactericidal geometric mean titers were age dependent, increasing 10-fold during childhood. Anti-Vi polysaccharide antibody geometric mean concentrations were also lower in children than in adults. Data presented here indicate the possibility of a relationship between low levels of bactericidal activity toward S. Typhi in serum and susceptibility to disease, as observed for other polysaccharide-encapsulated bacteria. Bactericidal antibody may be a marker of protective immunity against S. Typhi.

Finn A, Curtis N, Pollard AJ. 2009. Advances in Experimental Medicine and Biology: Preface Advances in Experimental Medicine and Biology, 634

Pollard AJ, Reiner A, John T, Sheasby E, Snape M, Faust S, Collinson A, Finn A, Heath PT, Miller E. 2009. Future of flu vaccines. Expediting clinical trials in a pandemic. BMJ (Clinical research ed.), 339

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Knoll MD, Moïsi JC, Muhib FB, Wonodi CB, Lee EH, Grant L, Gilani Z, Anude CJ, O'Brien KL, Cherian T et al. 2009. Standardizing surveillance of pneumococcal disease Clinical Infectious Diseases, 48 (SUPPL. 2), | Show Abstract | Read more

Background. Surveillance for invasive pneumococcal disease has been conducted using a variety of case ascertainment methods and diagnostic tools. Interstudy differences in observed rates of invasive pneumococcal disease could reflect variations in surveillance methods or true epidemiological differences in disease incidence. To facilitate comparisons of surveillance data among countries, investigators of Pneumococcal Vaccines Accelerated Development and Introduction Plan-sponsored projects have developed standard case definitions and data reporting methods. Methods. Investigators developed case definitions for meningitis, pneumonia, and very severe disease using existing World Health Organization guidelines and clinical definitions from Africa and Asia. Standardized case definitions were used to standardize reporting of aggregated results. Univariate analyses were conducted to compare results among countries and to identify factors contributing to detection of Streptococcus pneumoniae. Results. Surveillance sites varied with regard to the age groups targeted, disease syndromes monitored, specimens collected, and laboratory methods employed. The proportion of specimens positive for pneumococcus was greater for cerebrospinal fluid specimens (1.2%-19.4%) than for blood specimens (0.1%-1.4%) in all countries (range, 1.3-38-fold greater). The distribution of disease syndromes and pneumonia severity captured by surveillance differed among countries. The proportion of disease cases with pneumococcus detected varied by syndrome (meningitis, 1.4%-10.8%; pneumonia, 0.2%-1.3%; other, 0.2%-1.2%) and illness severity (nonsevere pneumonia, 0%-2.7%; severe pneumonia, 0.2%-1.2%), although these variations were not consistent for all sites. Antigen testing and polymerase chain reaction increased the proportion of cerebrospinal fluid specimens with pneumococcus identified by 1.3-5.5-fold, compared with culture alone. Conclusions. Standardized case definitions and data reporting enhanced our understanding of pneumococcal epidemiology and enabled us to assess the contributions of specimen type, disease syndrome, pneumonia severity, and diagnostic tools to rate of pneumococcal detection. Broader standardization and more-detailed data reporting would further improve interpretation of surveillance results. © 2009 by the Infectious Diseases Society of America. All rights reserved.

Pace D, Snape M, Westcar S, Oluwalana C, Yu L-M, Begg N, Wysocki J, Czajka H, Maechler G, Boutriau D, Pollard AJ. 2008. A novel combined Hib-MenC-TT glycoconjugate vaccine as a booster dose for toddlers: a phase 3 open randomised controlled trial. Arch Dis Child, 93 (11), pp. 963-970. | Show Abstract | Read more

OBJECTIVE: To study the immunogenicity and reactogenicity of a combined Haemophilus influenzae type b and Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine (Hib-MenC-TT) when administered as a booster dose in combination with a measles, mumps and rubella vaccine (MMR). DESIGN: A phase 3 open randomised controlled trial. SETTING: One centre in Oxford, UK and nine centres in Poland. SUBJECTS: 12-15-month-old healthy children. INTERVENTIONS: In the primary stage of the study 500 healthy 6-12-week-old infants were randomised in a 3:1 ratio to receive Hib-MenC-TT+DTPa-IPV or MenC-CRM197 vaccine+DTPa-IPV-Hib. In the booster stage, 476 participants (190 in the UK and 286 in Poland) were vaccinated with Hib-MenC-TT and MMR. MAIN OUTCOME MEASURES: The proportion of children with protective serum antibody levels against MenC and Hib 6 weeks following a Hib-MenC-TT booster dose. RESULTS: The co-primary objectives were met: the Hib-MenC-TT booster dose induced protective antibody titres in children vaccinated with Hib-MenC-TT+DTPa-IPV or MenC-CRM197+DTPa-IPV-Hib at 2, 3 and 4 months of age. 94.8% (lower limit of (LL) 95% CI 92.4) of participants had rSBA-MenC >or=1:128 and 100% (LL 95% CI 99.2) achieved anti-PRP concentrations >or=1.0 microg/ml. The percentage of toddlers with a post boost rSBA-MenC of 1:128 was significantly higher after priming with Hib-MenC-TT (97.7%) than after MenC-CRM197 (86%) (difference: 11.7%; 95% CI 6.2 to 19.4). CONCLUSION: The waning antibody titres against Hib and MenC following primary immunisation can be boosted to protective levels by administering the Hib-MenC-TT vaccine at 12-15 months of age, supporting the recent introduction of this vaccine in the UK immunisation schedule to sustain protection of children against Hib and MenC disease. TRIAL REGISTRATION NUMBER: NCT00258700. Study ID: 103974 (http://clinicaltrials.gov).

Callaghan MJ, Buckee C, McCarthy ND, Ibarz Pavón AB, Jolley KA, Faust S, Gray SJ, Kaczmarski EB, Levin M, Kroll JS et al. 2008. Opa protein repertoires of disease-causing and carried meningococci. J Clin Microbiol, 46 (9), pp. 3033-3041. | Show Abstract | Read more

The meningococcal Opa proteins play an important role in pathogenesis by mediating invasion of human cells. The aim of this investigation was to determine whether carried and disease-associated meningococci possess different Opa repertoires and whether the diversity of these proteins is associated with clinical severity of disease. Opa repertoires in 227 disease-associated meningococci, isolated in the United Kingdom over a period of 6 years, were compared to the repertoires in 190 asymptomatically carried meningococci isolated in the United Kingdom from a contemporary, nonepidemic period. Multidimensional scaling (MDS) was employed to investigate the association between Opa repertoires and multilocus sequence typing (MLST) genotypes. Associations with clinical severity were also analyzed statistically. High levels of diversity were observed in opa alleles, variable regions, and repertoires, and MDS revealed that MLST genotypes were strongly associated with particular Opa repertoires. Individual Opa proteins or repertoires were not associated with clinical severity, though there was a trend toward an association with the opaD locus. Meningococcal Opa repertoire is strongly linked to MLST genotype irrespective of epidemiological sampling and therefore correlates with invasiveness. It is not, however, strongly associated with severity of meningococcal disease.

Pulickal AS, Hambleton S, Callaghan MJ, Moore CE, Goulding J, Goodsall A, Baretto R, Lammas DA, Anderson ST, Levin M, Pollard AJ. 2008. Biliary cirrhosis in a child with inherited interleukin-12 deficiency. J Trop Pediatr, 54 (4), pp. 269-271. | Show Abstract | Read more

Interleukin-12 (IL-12) is a key cytokine in the defense against intracellular bacteria notably Mycobacteria and Salmonella species. We report a case of disseminated mycobacterial infection, following BCG vaccination, in a child who later developed tuberculosis. Functional tests and a novel diagnostic polymerase chain reaction (PCR) assay, revealed a loss-of-function deletion in the IL12 gene. Analysis of samples from the parents and siblings of the patient indicated an autosomal recessive inheritance pattern with varying degrees of phenotypic expression in identical genotypes. Interferon-gamma (IFN-gamma) therapy was associated with marked clinical improvement. Biliary cirrhosis, a hitherto unreported complication of IL-12 deficiency, developed later and required liver transplantation. A defect in the IL-12-IFN-gamma pathway should be suspected in patients presenting with multiple, repeated or persistent infection with intracellular bacteria. The diagnostic work-up and the immuno-genetic assay described here can aid in the quick and reliable diagnosis of IL-12 deficiency resulting from genetic defects and its subsequent management.

Blanchard-Rohner G, Pollard AJ. 2008. Sustaining immunity after immunization against encapsulated bacteria. Hum Vaccin, 4 (4), pp. 309-312. | Show Abstract | Read more

Infections by encapsulated bacteria are important causes of infant mortality worldwide. Over the last 20 years protein-polysaccharide conjugate vaccines have been developed to protect against the major invasive bacterial diseases of childhood, Streptococcus pneumoniae, Haemophilus influenzae type b (Hib) and Neisseria meningitidis. These vaccines are highly immunogenic and have resulted in a huge reduction in the diseases caused by these bacteria in the countries that have introduced them in their immunisation schedules. However, it has been reported that infant immunisation is associated with a relatively short duration of antibody levels and vaccine effectiveness, despite the demonstrable presence of booster responses to further vaccine dose. In contrast, at older ages, more sustained protection has been described with just a single dose of a conjugate vaccine. Understanding the generation of long-term immunity, by protein-polysaccharide conjugate vaccines, is essential to reduce infant mortality through the improvement of vaccine formulation and scheduling.

Snape MD, Kelly DF, Lewis S, Banner C, Kibwana L, Moore CE, Diggle L, John T, Yu LM, Borrow R et al. 2008. Seroprotection against serogroup C meningococcal disease in adolescents in the United Kingdom: observational study. BMJ, 336 (7659), pp. 1487-1491. | Show Abstract | Read more

OBJECTIVE: To determine the persistence of bactericidal antibody titres following immunisation with serogroup C meningococcal glycoconjugate vaccine at age 6-15 years in order to examine changes in persistence of antibodies with age. DESIGN: Observational study. SETTING: Secondary and tertiary educational institutions in the United Kingdom. PARTICIPANTS: Healthy adolescents aged 11-20 years previously immunised between 6 and 15 years of age with one of the three serogroup C meningococcal vaccines. INTERVENTION: Serum obtained by venepuncture. MAIN OUTCOME MEASURES: Percentage of participants with (rabbit complement) serum bactericidal antibody titres of at least 1:8; geometric mean titres of serogroup C meningococcal serum bactericidal antibody. RESULTS: Five years after immunisation, 84.1% (95% confidence interval 81.6% to 86.3%) of 987 participants had a bactericidal antibody titre of at least 1:8. Geometric mean titres of bactericidal antibody were significantly lower in 11-13 year olds (147, 95% confidence interval 115 to 188) than in 14-16 year olds (300, 237 to 380) and 17-20 year olds (360, 252 to 515) (P<0.0001 for both comparisons). Within these age bands, no significant difference in geometric mean titres of bactericidal antibody between recipients of the different serogroup C meningococcal vaccines was seen. More than 70% of participants had received a vaccine from one manufacturer; in this cohort, geometric mean titres were higher in those immunised at aged 10 years or above than in those immunised before the age of 10. CONCLUSIONS: Higher concentrations of bactericidal antibody are seen five years after immunisation with serogroup C meningococcal vaccine at age 10 years or above than in younger age groups, possibly owing to immunological maturation. This provides support for adolescent immunisation programmes to generate sustained protection against serogroup C meningococcal disease not only for the vaccine recipients but also, through the maintenance of herd immunity, for younger children.

Oh SY, Griffiths D, John T, Lee YC, Yu LM, McCarthy N, Heath PT, Crook D, Ramsay M, Moxon ER, Pollard AJ. 2008. School-aged children: a reservoir for continued circulation of Haemophilus influenzae type b in the United Kingdom. J Infect Dis, 197 (9), pp. 1275-1281. | Show Abstract | Read more

BACKGROUND: A resurgence of Haemophilus influenzae type b (Hib) disease occurred in the United Kingdom between 1999 and 2003 and was partially attributed to lower immunogenicity of combination vaccines. The reservoir for Hib that led to transmission in this period is unknown. METHODS: We estimated the point prevalence of Hib carriage in school-aged children and adults, using oropharyngeal swabbing and selective media. We characterized the Hib isolates by multilocus sequence typing (MLST) and measured Hib antibody concentrations in adults by enzyme-linked immunosorbent assay. RESULTS: Point prevalence for Hib carriage in 855 children aged 6-16 years was 4.2% (95% confidence interval [CI], 2.5%-5.9%). Five clonal groups of Hib were identified by MLST, 86% from the lineage of sequence type 6. No Hib was isolated in 385 adults (upper limit of 95% CI, 0.95%). The geometric mean concentration of serum antibody to polyribosylribitol phosphate was 0.47 microg/mL (95% CI, 0.37-0.59 mirog/mL) in adults. CONCLUSIONS: Hib carriage is common in school-aged children, who are a significant reservoir for ongoing transmission of Hib to susceptible individuals in the United Kingdom. Surveillance of transmission and immunity across all ages of the population is essential to monitor the evolution of Hib epidemiology.

John T, Hope T, Savulescu J, Stein A, Pollard AJ. 2008. Children's consent and paediatric research: is it appropriate for healthy children to be the decision-makers in clinical research? Arch Dis Child, 93 (5), pp. 379-383. | Show Abstract | Read more

AIM: To determine the appropriateness of asking healthy children to make a decision regarding participation in a research study. METHODS: Participants constituted a group of children taking part in a follow-up to a vaccine study which involved a blood test to look at the persistence of antibodies. Information about the study was given to each child and following venepuncture an oral questionnaire was completed to establish understanding of the vaccine study. Parental views concerning their child's ability to make a decision regarding research participation were also sought. RESULTS: 73 children participated overall. Following venepuncture 59% (n = 43) had grasped some aspect of the reasoning behind venepuncture with 33% (n = 24) unclear. The majority of parents (n = 55) and a substantial number of children (n = 28) believed that the parent should make the decision about study participation, although it is clear that a significant minority of parents thought it is right to involve the child in that process. CONCLUSION: New guidance about the requirements for informed consent involving children in research is needed, which can respect the autonomy of the child and the role of the parent, while recognising the limited capacity of some children to understand age-appropriate information.

Hennig BJ, Fielding K, Broxholme J, Diatta M, Mendy M, Moore C, Pollard AJ, Rayco-Solon P, Sirugo G, van der Sande MA et al. 2008. Host genetic factors and vaccine-induced immunity to hepatitis B virus infection. PLoS One, 3 (3), pp. e1898. | Show Abstract | Read more

BACKGROUND: Vaccination against hepatitis B virus infection (HBV) is safe and effective; however, vaccine-induced antibody level wanes over time. Peak vaccine-induced anti-HBs level is directly related to antibody decay, as well as risk of infection and persistent carriage despite vaccination. We investigated the role of host genetic factors in long-term immunity against HBV infection based on peak anti-HBs level and seroconversion to anti-HBc. METHODS: We analyzed 715 SNP across 133 candidate genes in 662 infant vaccinees from The Gambia, assessing peak vaccine-induced anti-HBs level and core antibody (anti-HBc) status, whilst adjusting for covariates. A replication study comprised 43 SNPs in a further 393 individuals. RESULTS: In our initial screen we found variation in IFNG, MAPK8, and IL10RA to affect peak anti-HBs level (GMTratio of < 0.6 or > 1.5 and P < or = 0.001) and lesser associations in other genes. Odds of core-conversion was associated with variation in CD163. A coding change in ITGAL (R719V) with likely functional relevance showed evidence of association with increased peak anti-HBs level in both screens (1st screen: s595_22 GMTratio 1.71, P = 0.013; 2nd screen: s595_22 GMTratio 2.15, P = 0.011). CONCLUSION: This is to our knowledge the largest study to date assessing genetic determinants of HBV vaccine-induced immunity. We report on associations with anti-HBs level, which is directly related to durability of antibody level and predictive of vaccine efficacy long-term. A coding change in ITGAL, which plays a central role in immune cell interaction, was shown to exert beneficial effects on induction of peak antibody level in response to HBV vaccination. Variation in this gene does not appear to have been studied in relation to immune responses to viral or vaccine challenges previously. Our findings suggest that genetic variation in loci other than the HLA region affect immunity induced by HBV vaccination.

Blanchard Rohner G, Snape MD, Kelly DF, John T, Morant A, Yu L-M, Borkowski A, Ceddia F, Borrow R, Siegrist C-A, Pollard AJ. 2008. The magnitude of the antibody and memory B cell responses during priming with a protein-polysaccharide conjugate vaccine in human infants is associated with the persistence of antibody and the intensity of booster response. J Immunol, 180 (4), pp. 2165-2173. | Show Abstract | Read more

Rapid waning of anti-polysaccharide bactericidal Ab and vaccine effectiveness is observed following infant immunization with the serogroup C meningococcal (MenC) glycoconjugate vaccine. This is despite the demonstrable presence of immunological memory. Persistence of functional Ab, therefore, appears to be the key determinant of MenC conjugate vaccine effectiveness. Ab persistence is thought to depend in the short term on the survival of plasma cells generated during priming and in the longer term on the production of new Ab secreting cells from memory B cells. In this study, we found a strong association between the level of MenC-specific Ab and the frequency of memory B cells measured at 5 mo of age (1 mo after 3-dose primary immunization with MenC conjugate vaccine), and the persistence of functional Ab at one year of age. These findings suggest that these two parameters are good markers of B cell responses to priming and can be used as predictors of long term humoral immunity induced by glycoconjugate vaccines received in early infancy.

Faust SN, Pollard AJ, Nadel S, Ninis N, Levin M. 2008. Ceftriaxone drug alert: no longer for first line use in meningococcal sepsis. Arch Dis Child, 93 (2), pp. 184-185.

Clutterbuck EA, Oh S, Hamaluba M, Westcar S, Beverley PCL, Pollard AJ. 2008. Serotype-specific and age-dependent generation of pneumococcal polysaccharide-specific memory B-cell and antibody responses to immunization with a pneumococcal conjugate vaccine. Clin Vaccine Immunol, 15 (2), pp. 182-193. | Show Abstract | Read more

Glycoconjugate vaccines have dramatically reduced the incidence of encapsulated bacterial diseases in toddlers under 2 years of age, but vaccine-induced antibody levels in this age group wane rapidly. We immunized adults and 12-month-old toddlers with heptavalent pneumococcal conjugate vaccine to determine differences in B-cell and antibody responses. The adults and 12-month-old toddlers received a pneumococcal conjugate vaccine. The toddlers received a second dose at 14 months of age. The frequencies of diphtheria toxoid and serotype 4, 14, and 23F polysaccharide-specific plasma cells and memory B cells were determined by enzyme-linked immunospot assay. The toddlers had no preexisting polysaccharide-specific memory B cells or serum immunoglobulin G (IgG) antibody but had good diphtheria toxoid-specific memory responses. The frequencies of plasma cells and memory B cells increased by day 7 (P < 0.0001) in the adults and the toddlers following a single dose of conjugate, but the polysaccharide responses were significantly lower in the toddlers than in the adults (P = 0.009 to <0.001). IgM dominated the toddler antibody responses, and class switching to the IgG was serotype dependent. A second dose of vaccine enhanced the antibody and memory B-cell responses in the toddlers but not the ex vivo plasma cell responses. Two doses of pneumococcal conjugate vaccine are required in toddlers to generate memory B-cell frequencies and antibody class switching for each pneumococcal polysaccharide equivalent to that seen in adults.

Lee YC, Kelly DF, Yu L-M, Slack MPE, Booy R, Heath PT, Siegrist C-A, Moxon RE, Pollard AJ. 2008. Haemophilus influenzae type b vaccine failure in children is associated with inadequate production of high-quality antibody. Clin Infect Dis, 46 (2), pp. 186-192. | Show Abstract | Read more

BACKGROUND: Despite the excellent immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines, breakthrough cases of Hib disease still affect a small proportion of vaccinated children in the United Kingdom. We performed a retrospective study to compare the avidity of antibody directed against the Hib polysaccharide capsule (PRP) in children who experienced Hib vaccine failure in the United Kingdom among 3 historical cohorts and with age-matched healthy control subjects. METHODS: Serum samples from vaccinated children with invasive Hib disease were collected beginning in 1992 as part of enhanced surveillance for Hib disease following vaccine introduction. A total of 251 children who experienced Hib vaccine failure were identified from 3 historical cohorts (1992-1995, 1996-1999, and 2000-2003). The anti-PRP antibody concentration and avidity from healthy age-matched control subjects was obtained for the 3 contemporary time points (1995, 1999, and 2002). Serum anti-PRP antibody concentration was measured in each of the samples using a standard Hib ELISA, and antibody avidity was determined using thiocyanate elution. RESULTS: Within the first 60 days after disease onset, there was no change in the anti-PRP antibody avidity, and there was no statistically significant difference in the geometric mean Hib antibody avidity over the 3 study periods. However, the children who experienced Hib vaccine failure had significantly lower Hib antibody avidity than did healthy control subjects, despite a marked antibody response following infection. CONCLUSIONS: Children who experience Hib disease despite vaccination appear to have a defect in immunological priming, leading to a qualitative difference in Hib-specific memory B cells. Low anti-PRP antibody avidity decreases the functional activity of anti-PRP antibody in the sera of these children experiencing vaccine failure, leading to disease susceptibility.

Snape MD, Perrett KP, Ford KJ, John TM, Pace D, Yu L-M, Langley JM, McNeil S, Dull PM, Ceddia F et al. 2008. Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial. JAMA, 299 (2), pp. 173-184. | Show Abstract | Read more

CONTEXT: Immunization with a meningococcal tetravalent (serogroup ACWY) glycoconjugate vaccine is recommended for all US adolescents. However, the currently licensed vaccine is poorly immunogenic in infancy, when the highest rates of disease are observed. OBJECTIVE: To determine the immunogenicity of a novel tetravalent CRM(197)-conjugated meningococcal vaccine (MenACWY) in infants. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, controlled study of 225 UK and 196 Canadian 2-month-olds from August 2004 to September 2006. INTERVENTION: UK infants received a primary course of MenACWY (at 2, 3, and 4 months or 2 and 4 months) or Neisseria meningitidis serogroup C monovalent meningococcal glycoconjugate vaccine (MenC) (at 2 and 4 months). All received MenACWY at 12 months. Canadian infants received MenACWY at 2, 4, and 6 months or 2 and 4 months; at 12 months they received MenACWY, a plain tetravalent polysaccharide vaccine, or no vaccine. MAIN OUTCOME MEASURE: Percentage of infants with a human complement serum bactericidal activity (hSBA) titer >or=1:4 after a primary course of MenACWY and after a 12-month booster. Safety and reactogenicity of MenACWY were also assessed. RESULTS: According to the prespecified per-protocol analysis, the percentages (95% CIs) of MenACWY 2-, 3-, and 4-month recipients with hSBA titers >or=1:4 after primary immunization were serogroup A, 93% (84%-98%); C, 96% (89%-99%); W-135, 97% (90%-100%); and Y, 94% (86%-98%). With a post hoc intention-to-treat analysis with imputed values for missing data, these values were unchanged for serogroups C and Y; for serogroup A, values were 92% (84%-97%), and for W-135, 97% (91%-99%). For the per-protocol analysis of MenACWY 2-, 4-, and 6-month recipients, the percentages (95% CIs) of responders were A, 81% (71%-89%); C, 98% (92%-100%); W-135, 99% (93%-100%); and Y, 98% (92%-100%). With the imputed value analysis, these values were A, 83% (74%-89%); C, 98% (93%-99%); W-135, 99% (94%-100%); and Y, 98% (92%-99%). At least 84% of MenACWY 2- and 4-month recipients achieved hSBA titers >or=1:4 for serogroups C, W-135, and Y after primary immunization, as did at least 60% for serogroup A (per-protocol and imputation analysis). At least 95% of primary and booster MenACWY recipients achieved hSBA titers >or=1:4 for serogroups C, W-135, and Y at 13 months, as did at least 84% for serogroup A (per-protocol and imputation analysis). During the primary immunization course, postimmunization pain on leg movement was observed in 2% of UK MenACWY 2- and 4-month recipients and 4% of MenC 2- and 4-month recipients; a temperature of 38 degrees C or greater was observed in 4% and 2% in these groups, respectively. CONCLUSION: MenACWY is well tolerated and immunogenic in infancy. Trial Registration clinicaltrials.gov Identifier: NCT00262002.

Mytton OT, Simpson A, Thompson AAR, Oram RA, Darowski A, Yu L-M, Collier DJ, Pollard AJ. 2008. Manual assessment of the initial fall in blood pressure after orthostatic challenge at high altitude. Wilderness Environ Med, 19 (4), pp. 225-232. | Show Abstract | Read more

OBJECTIVE: Dizziness is a symptom of acute mountain sickness (AMS). This study tested whether immediate fall in systolic blood pressure (BP) on standing was more severe at altitude and whether this was associated with symptoms of dizziness. METHODS: Eighty-five lowlanders flew into La Paz, Bolivia (3650 m), and after 4 to 5 days of acclimatization ascended in 90 minutes to the Chacaltaya Laboratory (5200 m) by road. Blood pressure was measured on 5 occasions, 3 times at 5200 m and twice at sea level, before and after the expedition using a mercury sphygmomanometer. Both a supine and an erect (within 15 seconds of standing) BP measurement were recorded. Participants recorded whether they felt dizzy on standing. A mixed-effect model was used to test for a difference in the change in BP for time and altitude. RESULTS: The immediate fall in systolic BP observed on standing was significantly greater (P < .001) on all 3 altitude study days (18.2, 23.4, and 20.7 mm Hg) than at sea level (12.2 and 12.4 mm Hg). There was no significant difference in the change in diastolic BP or change in mean arterial BP between sea level and altitude. CONCLUSIONS: The immediate drop in systolic BP observed on standing was greater at altitude. However, mean arterial pressure was maintained, and we found no association between the degree of immediate fall in BP and dizziness or AMS.

Warrell MJ, Riddell A, Yu L-M, Phipps J, Diggle L, Bourhy H, Deeks JJ, Fooks AR, Audry L, Brookes SM et al. 2008. A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods. PLoS Negl Trop Dis, 2 (4), pp. e224. | Show Abstract | Read more

BACKGROUND: The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. METHODS: Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. FINDINGS: All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. CONCLUSIONS: This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN 30087513.

Callaghan MJ, Rockett K, Banner C, Haralambous E, Betts H, Faust S, Maiden MCJ, Kroll JS, Levin M, Kwiatkowski DP, Pollard AJ. 2008. Haplotypic diversity in human CEACAM genes: effects on susceptibility to meningococcal disease. Genes Immun, 9 (1), pp. 30-37. | Show Abstract | Read more

Adhesion between the opacity-associated adhesin (Opa) proteins of Neisseria meningitidis and human carcino-embryonic antigen cell adhesion molecule (CEACAM) proteins is an important stage in the pathogenesis of meningococcal disease, a globally important bacterial infection. Most disease is caused by a small number of meningococcal genotypes known as hyperinvasive lineages. As these are also carried asymptomatically, acquisition of them alone cannot explain why only some hosts develop meningococcal disease. Our aim was to determine whether genetic diversity in CEACAM is associated with susceptibility to meningococcal disease. Frequency distributions of alleles, genotypes and haplotypes were compared in four CEACAM genes in 384 case samples and 190 controls. Linkage disequilibrium among polymorphic sites, haplotype structures and relationships were also analysed. A number of polymorphisms were observed in CEACAM genes but the diversity of CEACAM1, to which most Opa proteins bind, was lower, and a small number of high-frequency haplotypes were detected. Dose-dependent associations of three CEACAM haplotypes with meningococcal disease were observed, with the effect of carrying these haplotypes amplified in homozygous individuals. Two haplotypes were protective while one haplotype in CEACAM6 was associated with a twofold increase in disease susceptibility. These data imply that human CEACAM may be one determinant of human susceptibility to meningococcal disease.

Finn A, Pollard AJ. 2008. Hot topics in infection and immunity in children IV: Preface Advances in Experimental Medicine and Biology, 609

Chantler T, Pace D, Wright A, Pollard AJ, Yu LM, Nguyen-Van-Tam JS, MacDonald N. 2007. Uptake and acceptability of influenza vaccination in day nursery children. Community Pract, 80 (12), pp. 32-36. | Show Abstract

Preschoolers play an important role in the transmission of influenza, and suffer significant morbidity. Paediatric vaccination could prevent serious outcomes and offer broader societal benefits. This study explored parental views on influenza and paediatric vaccination and determined the uptake of a nursery-based vaccination programme for infants aged 6-23 months. Children were offered two doses of inactivated vaccine in 2004/05, and a single dose at the start of the 2005/06 season. An uptake rate of 11% (60/535) was achieved with 83% (50/60) of participants completing the programme. Semi-structured interviews were conducted with 10 parents. Thematic analysis of the data informed the development of a questionnaire. This was distributed to 650 parents, with children aged 6-30 months attending one of the 18 supporting nurseries. A response rate of 13% (83/650) was achieved. The low uptake rate achieved in the programme and findings from the interviews/questionnaire suggest parents were not convinced about the seriousness of paediatric influenza. Indeed, over two-thirds (55/81) questioned the necessity for an annual vaccination. Parents found it difficult to differentiate influenza from other respiratory illnesses, and expressed concerns about the need for annual injections and vaccine safety. Paediatric vaccination to increase herd immunity was held in balance with the notion that children should only be vaccinated if they are the main beneficiaries. Parental education on the burden of childhood influenza, on the direct benefits of influenza vaccination, and on indirect benefits to society is a necessity for a successful paediatric vaccination programme.

Pollard AJ. 2007. Hepatitis B vaccination BRITISH MEDICAL JOURNAL, 335 (7627), pp. 950-950. | Read more

Pollard AJ. 2007. Hepatitis B vaccination. BMJ, 335 (7627), pp. 950. | Read more

Pace D, Snape M, Westcar S, Hamaluba M, Yu L-M, Begg N, Wysocki J, Czajka H, Maechler G, Boutriau D, Pollard AJ. 2007. A new combination haemophilus influenzae type B and Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine for primary immunization of infants. Pediatr Infect Dis J, 26 (11), pp. 1057-1059. | Show Abstract | Read more

We conducted a phase 3 randomized controlled trial looking at the immunogenicity and safety of a novel combined Haemophilus influenzae type b and Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine, Hib-MenC-TT in a 2-, 3-, and 4-month primary infant immunization schedule. SBA MenC titers > or =1:8 and anti-PRP concentrations > or =0.15 microg/mL were measured in 99.2% and 100%, respectively, of the infants receiving Hib-MenC-TT.

Curtis N, Pollard AJ. 2007. Physicians' perception of pandemic influenza. Arch Dis Child, 92 (10), pp. 938. | Read more

Pace D, Pollard AJ. 2007. Meningococcal A, C, Y and W-135 polysaccharide-protein conjugate vaccines. Arch Dis Child, 92 (10), pp. 909-915. | Show Abstract | Read more

Serogroup C meningococcal conjugate vaccines, first launched in the UK in 1999, have been used successfully in Australia, Canada and several other European countries. Combination conjugate vaccines, containing more than one meningococcal polysaccharide, have been developed to broaden protection against the disease. A tetravalent meningococcal A, C, Y and W-135 conjugate vaccine was licensed for use in 11-55 year old adolescents and adults in the US in January 2005, and subsequently also in 2-11 year old children in Canada in May 2006. This article discusses the different glycoconjugate meningococcal vaccines which have been developed and the potential for their use to control disease caused by serogroups A, C, Y and W-135 of Neisseria meningitidis.

Jay F, Chantler T, Lees A, Pollard AJ. 2007. Children's participation in vaccine research: parents' views. Paediatr Nurs, 19 (8), pp. 14-18. | Show Abstract | Read more

AIM: Vaccine studies that evaluate the persistence of protection following immunisation require subjects to continue participation in a research protocol over many years. As parents' attitudes and opinions may change over time, and with experience of research, it is important to consider the factors influencing parents' decision-making about their child's continued participation in such prolonged vaccine studies. METHOD: Parental views about participation of their child in a one-year follow-up vaccine study were explored by means of a self-administered questionnaire. Of the 254 eligible parents, 187 took part (74 per cent). RESULTS: Parents who provided consent were more likely to agree that having a home visit to take blood was very helpful (p=0.005) and that information obtained during the earlier part of the study influenced their decision to take part in a follow-up study (p<0.0001). Parents who did not consent to their child's participation were more likely to report the presence of personal reasons as a variable influencing their decision (p<0.0001). CONCLUSIONS: The relationship between study staff and parents is the cornerstone for success in performing studies involving vaccines and children. Provision of clear study information (oral and written) and offering the convenience of home visits are important in retaining participants in paediatric vaccine trials.

Granoff DM, Pollard AJ. 2007. Reconsideration of the use of meningococcal polysaccharide vaccine. Pediatr Infect Dis J, 26 (8), pp. 716-722. | Show Abstract | Read more

In 2005, a quadrivalent meningococcal conjugate vaccine was licensed in the United States for persons aged 11-55 years of age. For children aged 2-10 years with underlying diseases associated with increased risk of meningococcal disease, unconjugated meningococcal polysaccharide (MPS) vaccination is still recommended. This article reviews the increasing evidence that MPS vaccination impairs serum anticapsular antibody responses to subsequent injections of MPS or meningococcal conjugate vaccines (antibody hyporesponsiveness). Administering MPS as a probe to assess conjugate vaccine-induced immunologic memory also can extinguish subsequent memory anticapsular antibody responses, whereas conjugate vaccination regenerates memory B cells. Whether induction of antibody hyporesponsiveness or loss of immunologic memory increase the risk of acquiring meningococcal disease remains speculative. However, for children at increased risk of meningococcal disease, immunization with meningococcal quadrivalent conjugate vaccine off-label instead of MPS vaccine should be considered. Requirements for licensure of new glycoconjugate vaccines that include performing comparative clinical trials to demonstrate noninferiority with MPS vaccine, or use of a MPS challenge to assess conjugate-induced immunologic memory also should be modified because there are safer approaches for obtaining the same information.

Pulickal AS, Pollard AJ. 2007. Vi polysaccharide-protein conjugate vaccine for the prevention of typhoid fever in children: hope or hype? Expert Rev Vaccines, 6 (3), pp. 293-295. | Read more

Riddell A, Buttery JP, McVernon J, Chantler T, Lane L, Bowen-Morris J, Diggle L, Morris R, Lockhart S, Pollard AJ et al. 2007. A randomized study comparing the safety and immunogenicity of a conjugate vaccine combination containing meningococcal group C and pneumococcal capsular polysaccharide--CRM197 with a meningococcal group C conjugate vaccine in healthy infants: challenge phase. Vaccine, 25 (19), pp. 3906-3912. | Show Abstract | Read more

BACKGROUND: A combination nonavalent pneumococcal-group C meningococcal conjugate vaccine (Pnc9-MenC) was previously found to be safe and immunogenic when administered to infants at 2, 3 and 4 months. This study describes the persistence of immunity at 12 months of age and the immunologic response to a challenge dose of either meningococcal polysaccharide vaccine (Meningivac A+C; MnA+C), or MenC. METHODS: A phase II, randomized, controlled trial of healthy infants. Subjects were given Pnc9-MenC or MenC vaccine at 2, 3 and 4 months of age and then challenged with either MenC or MnA+C. Group C meningococcal immunogenicity was measured by serum bactericidal assay (SBA) and an enzyme-linked immunosorbent assay (ELISA) adapted to measure antibody avidity pre- and post-challenge. RESULTS: The MenC vaccine was more immunogenic than the Pnc9-MenC vaccine in persistence of serogroup C meningococcal polysaccharide antibodies at 12 months of age. Post-challenge at 13 months there were significant differences between the four groups in the induction of serogroup C meningococcal polysaccharide antibodies. The responses to MenC/MenC were significantly higher than in the other groups (p<0.001) and the responses to Pnc9-MenC/MnA+C were significantly lower than in the other groups (p<0.001). There was no difference between the four groups in the proportions with geometric mean concentrations (GMC) greater than 2 microg/ml (p=0.18) or with SBA titres greater than or equal to the protective level of 1:8 (p=0.89). The SBA geometric mean ratio (GMR) between pre- and post-challenge was higher in the groups challenged with MenC than those challenged with MnA+C. Antibody avidity increased over time. CONCLUSION: We have shown that Pnc9-MenC primes effectively for immunological memory. At 13 months of age the highest immune responses were seen in the subjects primed and challenged with MenC alone. However, all groups achieved the threshold levels required for protection.

Salt P, Banner C, Oh S, Yu L-M, Lewis S, Pan D, Griffiths D, Ferry B, Pollard A. 2007. Social mixing with other children during infancy enhances antibody response to a pneumococcal conjugate vaccine in early childhood. Clin Vaccine Immunol, 14 (5), pp. 593-599. | Show Abstract | Read more

Children who have siblings and/or who attend day care have higher rates of nasopharyngeal colonization with pneumococci than lone children do. Pneumococcal colonization is usually asymptomatic but is a prerequisite for invasive disease. We studied the effect of social mixing with other children on immunity to a pneumococcal vaccine. One hundred sixty children aged 1 year were immunized with a 7-valent conjugate pneumococcal vaccine. A blood sample was obtained before and 9 to 11 days after the vaccine. The concentration and avidity of antibody against vaccine pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) were studied in relation to pneumococcal carriage rate and measures of social mixing. Children with increased social mixing had higher antibody concentrations against serotypes 4, 9V, 14, and 23F than lone children did. The least-carried serotype, serotype 4, was the one of the most immunogenic. This contrasts with serotype 6B, the most common nasopharyngeal isolate but the least immunogenic. Social mixing in infancy enhances the immune response to a Streptococcus pneumoniae polysaccharide-protein conjugate vaccine at 1 year of age. Exposure to pneumococci in the first year of life may induce immunological priming. An alternative explanation is that differences in immunological experience, such as increased exposure to respiratory viral infections in early childhood, alters the response to vaccines perhaps by affecting the balance between Th1 and Th2 cytokines. The low immunogenicity of serotype 6B polysaccharide might make conditions more favorable for carriage of the 6B organism and explain why 6B pneumococci were more frequently isolated than other serotypes.

Pollard AJ. 2007. Childhood immunisation: what is the future? Arch Dis Child, 92 (5), pp. 426-433. | Show Abstract | Read more

Improved immunisation programmes and the development of new vaccines provide unprecedented opportunities to improve and sustain the health of our children. There are major challenges ahead in communicating the benefits of immunisation to all populations and in delivering vaccines to those in greatest need. In this review on immunisation, I have asked international opinion leaders to comment on the present and the future of immunisation to provide signposts for the narrative.

Pollard AJ, Nadel S, Ninis N, Faust SN, Levin M. 2007. Emergency management of meningococcal disease: eight years on. Arch Dis Child, 92 (4), pp. 283-286. | Read more

Chantler TEA, Lees A, Moxon ER, Mant D, Pollard AJ, Fiztpatrick R. 2007. The role familiarity with science and medicine plays in parents' decision making about enrolling a child in vaccine research. Qual Health Res, 17 (3), pp. 311-322. | Show Abstract | Read more

Parental consent to children's participation in vaccine research has resulted in the licensure of essential vaccines. Recruitment to this type of research is typically difficult, however, and many parents decline. In this study, the authors interviewed parents about their decision for or against enrolling their child in a vaccine study. The data analysis suggests that parents' ability to evaluate a vaccine study depends on how attuned they are with science and medicine, either professionally or as consumers of health services. Familiarity does not predispose parents to enrolling their child in research; rather, it is a predictor of parents' confidence in their decision making. Many parents were motivated by altruism and trust, which, if uninformed, can leave the parents prone to exploitation. It is vital to ensure that parents are confident in their judgment of a study and its potential benefit to their child and society.

Ruggeberg JU, Collins C, Clarke P, Johnson N, Sinha R, Everest N, Chang J, Stanford E, Balmer P, Borrow R et al. 2007. Immunogenicity and induction of immunological memory of the heptavalent pneumococcal conjugate vaccine in preterm UK infants. Vaccine, 25 (2), pp. 264-271. | Show Abstract | Read more

Data on the immunogenicity and memory induction of pneumococcal conjugate vaccines in very preterm infants is limited. We vaccinated 69 full term and 68 preterm infants (median gestational age (GA) 30 weeks) with a 7-valent pneumococcal conjugate vaccine (PCV7) at 2/3/4 months of age, followed by a plain polysaccharide booster at 12 months of age. IgG-GMC (ELISA) was significantly lower in preterm infants to six vaccine serotypes (ST) at 2 months and 5 months of age, to five ST at 12 months of age and to three ST at 13 months of age. A significantly lower proportion of preterm infants achieved IgG levels>or=0.35 microg/ml to ST 4, 6B and 9V at 5 months and to ST 4, 6B, 18C, 19F and 23F at 12 months of age. Fold rises following the polysaccharide booster were comparable to those of term infants. At least 93% of both cohorts achieved IgG>or=0.35 microg/ml to all STs following booster vaccination. Pneumococcal conjugate vaccine at an accelerated schedule of 2/3/4 months of age is likely to provide protection against pneumococcal disease for preterm infants. Antibody concentrations wane over the first year of life in both preterm and term infants and booster vaccination is therefore likely to be important.

Ford K, Yu LM, Pollard A, Diggle L. 2007. Paracetamol and infant immunisation Practice Nurse, 33 (8),

Ruggeberg JU, Collins C, Clarke P, Johnson N, Sinha R, Everest N, Chang J, Stanford E, Balmer P, Borrow R et al. 2007. Immunogenicity and induction of immunological memory of the heptavalent pneumococcal conjugate vaccine in preterm UK infants Vacunas, 8 (2), pp. 82-90. | Show Abstract

Data on the immunogenicity and memory induction of pneumococcal conjugate vaccines in very preterm infants is limited. We vaccinate 69 full term and 68 preterm infants (median gestational age (GA) 30 weeks) with a 7-valent pneumococcal conjugate vaccine (PCV7) at 2/3/4 months of age, followed by a plain polysaccharide booster at 12 months of age. IgG-GMC (ELISA) was significantly lower in preterm infants to six vaccine serotypes (ST) at 2 months and 5 months of age, to five ST at 12 months of age and to three ST at 13 months of age. A significantly lower proportion of preterm infants achieved IgG levels ≥ 0.35 μg/ml to ST 4, 6B and 9V at 5 months and to ST 4, 6B, 18C, 19F and 23F at 12 months of age. Fold rises following the polysaccharide booster were comparable to those of term infants. At least 93% of both cohorts achieved IgG ≥ 0.35 μg/ml to all STs following booster vaccination. Pneumococcal conjugate vaccine at an accelerated schedule of 2/3/4 months of age is likely to provide protection against pneumococcal disease for preterm infants. Antibody concentrations wane over the first year of life in both preterm and term infants and booster vaccination is therefore likely to be important.

Pollard AJ. 2007. New combination vaccines still need a boost. Arch Dis Child, 92 (1), pp. 1-2. | Read more

Snape MD, Kelly DF, Salt P, Green S, Snowden C, Diggle L, Borkowski A, Yu L-M, Moxon ER, Pollard AJ. 2006. Serogroup C meningococcal glycoconjugate vaccine in adolescents: persistence of bactericidal antibodies and kinetics of the immune response to a booster vaccine more than 3 years after immunization. Clin Infect Dis, 43 (11), pp. 1387-1394. | Show Abstract | Read more

BACKGROUND: The persistence of protection from meningococcal disease following immunization with serogroup C meningococcal (MenC) glycoconjugate vaccines in infancy is short-lived. The duration of protective immunity afforded by these vaccines in other at-risk age groups (i.e., adolescents and young adults) is not known. We evaluated the persistence of bactericidal antibodies following immunization with a MenC glycoconjugate vaccine (MenCV) in adolescents and the kinetics of immune response to a meningococcal AC plain polysaccharide vaccine (MenPS) challenge or a repeat dose of MenCV. METHODS: We conducted a randomized comparative trial of 274 healthy 13-15-year-olds from whom a total of 4 blood samples were obtained (prior to administration of a dose of MenPS or MenCV, again on 2 further occasions at varying times from days 2-7 after vaccination, and finally on day 28 after vaccination. The correlate of protection was a serum bactericidal assay titer > or = 8 (with a serum bactericidal assay using human complement). RESULTS: A serum bactericidal assay using human complement titer > or = 8 was observed in 75% of participants at baseline (mean age, 14.5 years; mean time since routine MenCV vaccination, 3.7 years). No increase in serum bactericidal assay geometric mean titers was detected until day 5 after administration of MenPS. Geometric mean titers following administration of MenCV were significantly higher than those observed following administration of MenPS, at days 5, 7, and 28. CONCLUSIONS: This study showed sustained levels of bactericidal antibodies for at least 3 years after immunization of adolescents with MenCV. After challenge of immunized adolescents with MenPS, there was no increase in serum bactericidal assay observed until day 5 after vaccination, indicating that immunological memory may be too slow to generate protection against this potentially rapidly invasive organism.

Snape MD, Pollard AJ. 2006. African tick bite fever. Lancet Infect Dis, 6 (11), pp. 750. | Read more

Clutterbuck EA, Salt P, Oh S, Marchant A, Beverley P, Pollard AJ. 2006. The kinetics and phenotype of the human B-cell response following immunization with a heptavalent pneumococcal-CRM conjugate vaccine. Immunology, 119 (3), pp. 328-337. | Show Abstract | Read more

Primary immunization of infants with protein-polysaccharide conjugate vaccines induces antipolysaccharide antibody and is highly effective in preventing invasive disease caused by encapsulated bacteria. However, recent experience from the UK indicates that this immunity is not sustained in the absence of booster doses of vaccine. This study aimed to establish the kinetics and phenotype of B-cell subpopulations responding to booster immunization with a heptavalent pneumococcal conjugate vaccine (Pnc7), which is to be introduced into the primary immunization schedule in the UK during 2006. Six adult volunteers received a booster dose of Pnc7 12-18 months after primary immunization. CD27hi CD38hi CD20(+/-) IgG antibody-forming cells were detected in peripheral blood with maximum frequency at days 6-7 after immunization. This was accompanied by a more prolonged rise in memory B cells that required in vitro stimulation with Staphylococcus aureus Cowan strain and interleukin-2 to induce antibody secretion. These data provide evidence for at least two subsets of antibody-forming cells involved in the secondary humoral response to a glycoconjugate vaccine in primed individuals. A briefly circulating subset of B cells that spontaneously secrete immunoglobulin G may be responsible for early defence against re-encountered encapsulated bacteria. However, the kinetics of the appearance of these cells may indicate that the humoral immune response is too slow in defence against an organism that invades within days of acquisition. The more sustained presence of a memory population may provide persistence of antipolysaccharide antibody after a booster dose of vaccine and may also include re-circulatory populations responsible for further anamnestic responses.

Kelly DF, Snape MD, Clutterbuck EA, Green S, Snowden C, Diggle L, Yu L-M, Borkowski A, Moxon ER, Pollard AJ. 2006. CRM197-conjugated serogroup C meningococcal capsular polysaccharide, but not the native polysaccharide, induces persistent antigen-specific memory B cells. Blood, 108 (8), pp. 2642-2647. | Show Abstract | Read more

Neisseria meningitidis is one of the leading causes of bacterial meningitis and septicemia in children. Vaccines containing the purified polysaccharide capsule from the organism, a T cell-independent antigen, have been available for decades but do not appear to provide protection in infancy or immunologic memory as measured by antibody responses. By contrast, T cell-dependent serogroup C protein-polysaccharide conjugate vaccines protect against serogroup C meningococcal disease from infancy onward and prime for immunologic memory. We compared the magnitude and kinetics of plasma cell and memory B-cell responses to a meningococcal plain polysaccharide vaccine and a serogroup C glycoconjugate vaccine in adolescents previously primed with the conjugate vaccine. Plasma cell kinetics were similar for both vaccines, though the magnitude of the response was greater for the glycoconjugate. In contrast to the glycoconjugate vaccine, the plain polysaccharide vaccine did not induce a persistent immunoglobulin G (IgG) memory B-cell response. This is the first study to directly show that serogroup C meningococcal glycoconjugate vaccines induce persistent production of memory B cells and that plain polysaccharide vaccines do not, supporting the use of the conjugate vaccine for sustained population protection. Detection of peripheral blood memory B-cell responses after vaccination may be a useful signature of successful induction of immunologic memory during novel vaccine evaluation.

Snape MD, Pollard AJ. 2006. No evidence for capsule replacement following mass immunisation with meningococcal serogroup C conjugate vaccines in England and Wales - Authors' reply LANCET INFECTIOUS DISEASES, 6 (10), pp. 617-618. | Read more

Diggle L, Deeks JJ, Pollard AJ. 2006. Effect of needle size on immunogenicity and reactogenicity of vaccines in infants: randomised controlled trial. BMJ, 333 (7568), pp. 571. | Show Abstract | Read more

OBJECTIVES: To assess the immunogenicity of vaccines for infants and to investigate whether the incidence of reactogenicity is reduced after each immunisation dose using needles of varying lengths and gauges. DESIGN: Randomised controlled trial. SETTING: 18 general practices within two UK primary care trusts. PARTICIPANTS: 696 healthy infants vaccinated at 2, 3, and 4 months of age, with follow-up to 5 months of age. INTERVENTIONS: Combined diphtheria, tetanus, whole cell pertussis, and Haemophilus influenzae type b vaccine and a serogroup C meningococcal glycoconjugate vaccine administered using either a wide, long needle (23 gauge/0.6 mm diameter, 25 mm), a narrow, short needle (25 gauge/0.5 mm diameter, 16 mm), or a narrow, long needle (25 gauge, 25 mm). MAIN OUTCOME MEASURES: Local and general reactions recorded by parents for three days after each dose; and diphtheria, tetanus, and H influenzae type b antibody concentrations and functional antibody against serogroup C Neisseria meningitidis 28-42 days after the third dose. RESULTS: Local reactions to diphtheria, tetanus, whole cell pertussis, H influenzae type b vaccinations decreased significantly with wide, long needles compared with narrow, short needles. At all three doses one less infant experienced local reactions at days 1, 2, or 3 for every six to eight vaccinated. Significantly fewer infants vaccinated with the long needle experienced severe local reactions. Non-inferiority of the immune response was shown using a wide, long needle rather than a narrow, short needle for serogroup C meningococcal glycoconjugate vaccine and for diphtheria but not for H influenzae type b or tetanus, although no evidence was found of a decrease. Little difference was found between needles of the same length but different gauges in local reaction or immune response. CONCLUSIONS: Long (25 mm) needles for infant immunisations can significantly reduce vaccine reactogenicity at each dose while achieving comparable immunogenicity to that of short (16 mm) needles. Trial registration Current Controlled Trials ISRCTN62032215 [controlled-trials.com].

Keyserling HL, Pollard AJ, DeTora LM, Gilmet GP. 2006. Experience with MCV-4, a meningococcal, diphtheria toxoid conjugate vaccine against serogroups A, C, Y and W-135. Expert Rev Vaccines, 5 (4), pp. 445-459. | Show Abstract | Read more

Invasive disease due to Neisseria meningitidis continues to cause debility and death worldwide in otherwise healthy individuals. Disease epidemiology varies globally, but most cases are due to serogroups A, B, C, W-135 or Y. MenactraTM (MCV-4), a quadrivalent, meningococcal diphtheria-conjugate vaccine against serogroups A, C, Y, and W-135, was licensed in the USA for individuals 11-55 years of age. Published results of clinical trials demonstrated robust immune responses that correlate with indicators of protection. MCV-4-induced antibody persist for up to 3 years after administration and anamnestic responses to revaccination. The vaccine was well tolerated; the most common reactions were transient, mild injection-site reactions and headache. MCV-4 should provide significant clinical benefits in the future.

Chantler T, Newton S, Lees A, Diggle L, Mayon-White R, Pollard AJ, Fitzpatrick R. 2006. Parental views on the introduction of an infant pneumococcal vaccine. Community Pract, 79 (7), pp. 213-216. | Show Abstract

Streptococcus pneumoniae is a major cause of early childhood morbidity and mortality. A heptavalent pneumococcal conjugate vaccine (PnC7) is licensed for use and could prevent the majority of infant invasive pneumococcal infections. A recent announcement confirmed its inclusion into the U.K. childhood immunisation programme. In anticipation of PnC7 being recommended for use, this study explored parental understanding of pneumococcal disease and their views on the possible introduction of this vaccine. Twenty three interviews and two focus groups were held with parents of children under two years of age. Four main themes emerged from the data analysis: 'Confidence and belief in immunisation'; 'Anxiety about immunisation'; 'Trust and understanding of immunisation information' and 'Response to a new immunisation'. Overall parental confidence in immunisation has been affected by the MMR controversy. With little knowledge of pneumococcal disease, parents want information about the safety and effectiveness of PnC7. Information needs to be conveyed in a way that restores parents' trust in immunisation.

Pollard AJ, Nadel S. 2006. Course of Disease and Clinical Management pp. 481-517. | Read more

Lee YC, Newport MJ, Goetghebuer T, Siegrist CA, Weiss HA, Pollard AJ, Marchant A, MRC Twin Study Group. 2006. Influence of genetic and environmental factors on the immunogenicity of Hib vaccine in Gambian twins. Vaccine, 24 (25), pp. 5335-5340. | Show Abstract | Read more

The differences in incidence rates of Haemophilus influenzae type b disease and the variation in Hib conjugate vaccine efficacy achieved among different ethnic groups suggest genetic influences on the immune response to Hib vaccine. The serum anti-PRP antibody concentration of 43 monozygotic (MZ) and 147 dizygotic (DZ) twin pairs in the Gambia was measured using a standardised Hib ELISA. Intrapair correlations for MZ and DZ twin pairs were compared and heritability in antibody responses to Hib conjugate vaccine was estimated to be 51% (95% CI: 32-66%), indicating a significant genetic contribution in the response. We conclude that genetic factors may be involved in the variation in immune response to Hib vaccine observed in different populations and may contribute to cases of vaccine failure.

Johnson NG, Ruggeberg JU, Balfour GF, Lee YC, Liddy H, Irving D, Sheldon J, Slack MPE, Pollard AJ, Heath PT. 2006. Haemophilus influenzae type b reemergence after combination immunization. Emerg Infect Dis, 12 (6), pp. 937-941. | Show Abstract | Read more

An increase in Haemophilus influenzae type b (Hib) in British children has been linked to the widespread use of a diphtheria/tetanus/acellular pertussis combination vaccine (DTaP-Hib). We measured anti-polyribosyl-ribitol phosphate antibody concentration and avidity before and after a Hib booster in 176 children 2-4 years of age who had received 3 doses of DTP-Hib (either DT whole cell pertussis-Hib or DTaP-Hib) combination vaccine in infancy. We also measured pharyngeal carriage of Hib. Antibody concentrations before and avidity indices after vaccination were low (geometric mean concentration 0.46 mug/mL, 95% confidence interval [CI] 0.36-0.58; geometric mean avidity index 0.16, 95% CI 0.14-0.18) and inversely related to the number of previous doses of DTaP-Hib (p = 0.02 and p<0.001, respectively). Hib was found in 2.1% (95% CI 0.7%-6.0%) of study participants. Our data support an association between DTaP-Hib vaccine combinations and clinical Hib disease through an effect on antibody concentration and avidity.

Doroshenko A, Sherrard J, Pollard AJ. 2006. Syphilis in pregnancy and the neonatal period. Int J STD AIDS, 17 (4), pp. 221-227. | Show Abstract | Read more

The recent increase in the number of cases of syphilis in the UK, including among women of reproductive age, has stimulated the need for a review of practices concerning assessment and management of syphilis in pregnancy and the neonatal period. This paper summarizes available evidence from published guidelines, primary and secondary research. Optimal management of syphilis in pregnancy and the neonatal period relies on the early diagnosis and staging of maternal disease, prompt treatment to prevent congenital syphilis, and timely assessment of newborns.

Segal S, Pollard AJ, Watts C, Wainwright A, Lalvani A, Connell J. 2006. Osteomyelitis of the humerus complicating BCG vaccination. Arch Dis Child, 91 (3), pp. 244. | Read more

Snape MD, Pollard AJ. 2006. No evidence for capsule replacement…and Wales – Authors' Reply The Lancet Infectious Diseases, 6 (10), pp. 617-618. | Read more

Pollard AJ, Finn A. 2006. Hot Topics in Infection and Immunity in Children III: Preface Advances in Experimental Medicine and Biology, 582

Zhang Q, Bernatoniene J, Bagrade L, Pollard AJ, Mitchell TJ, Paton JC, Finn A. 2006. Serum and mucosal antibody responses to pneumococcal protein antigens in children: relationships with carriage status. Eur J Immunol, 36 (1), pp. 46-57. | Show Abstract | Read more

Streptococcus pneumoniae causes significant morbidity and mortality especially in children. Some pneumococcal protein antigens can protect mice against infection. Little information is available concerning the nature of naturally acquired protective immunity to pneumococci in humans induced by these antigens. This study investigates the relationships between systemic and local antibody production and carriage in children. Children undergoing adenoidectomy (n=112, ages 2-12 years) were studied. Nasopharyngeal swabs were collected for pneumococcal culture. Serum and saliva were assayed for antibodies to several pneumococcal proteins: choline binding protein A (CbpA), pneumolysin (Ply), pneumococcal surface adhesin A (PsaA) and pneumococcal surface protein A (PspA). Adenoidal mononuclear cells (MNC) were cultured with pneumococcal culture supernatants or recombinant proteins. Cell culture supernatants were analyzed for antigen-specific antibodies. Carriage rates fell with age and serum levels of anti-CbpA, Ply and PspA rose. Anti-CbpA and -Ply serum and salivary IgG antibody levels were higher in children who were culture negative than those who were colonized. Antigen stimulation increased respective antigen-specific IgG production by adenoidal MNC and these responses were greater in those who were colonized than in culture-negative children. Antibodies to CbpA and Ply may protect children aged 2 years and older against pneumococcal colonization. Adenoids may be important local induction and effector sites for both mucosal and systemic antibody production to pneumococcal proteins in children.

Kelly DF, Pollard AJ, Moxon ER. 2005. Immunological memory: the role of B cells in long-term protection against invasive bacterial pathogens. JAMA, 294 (23), pp. 3019-3023. | Show Abstract | Read more

Protein-polysaccharide conjugate vaccines that protect against Haemophilus influenzae type b (Hib), serogroup C Neisseria meningitidis, and multiple capsular serotypes of Streptococcus pneumoniae have had a major impact on invasive bacterial disease in childhood when incorporated into routine infant immunization schedules. However, effectiveness data from the United Kingdom suggest that primary infant immunization alone may not be associated with long-term protection. Both immunological priming and antibody persistence are important aspects of long-term protection induced by these vaccines. An improved understanding of the immunobiology of the B-cell response to these vaccines may direct development of immunization strategies that provide sustained protection.

Perrett KP, Pollard AJ. 2005. Towards an improved serogroup B Neisseria meningitidis vaccine. Expert Opin Biol Ther, 5 (12), pp. 1611-1625. | Show Abstract | Read more

Meningococcal disease, presenting primarily as septicaemia and meningitis, continues to be a devastating problem around the world. Over the last century, vaccine development has been undertaken in earnest for the prevention of this disease. Polysaccharide vaccines have been available for almost 40 years, yet they are poorly immunogenic in young children who are at the highest risk. Since their introduction into some routine immunisation schedules in 1999, polysaccharide-protein conjugate vaccines for the prevention of serogroup C meningococcal infection have proven efficacious. A quadrivalent polysaccharide-protein conjugate vaccine against serogroups A, C, W135 and Y, which is being introduced in the US this year, is hoped to control disease caused by these serogroups. To date, however, the development of a universally safe, immunogenic and effective serogroup B Neisseria meningitidis vaccine has remained a challenge. This review details the many conventional vaccine strategies and the more recent genome-derived technological approaches being used in serogroup B vaccine development. The future prevention of serogroup B disease will rely on both outer membrane vesicle vaccines being used for serosubtype-specific outbreaks and new vaccines containing multiple other antigens. Investment by the pharmaceutical industry in preclinical research and development provides hope that an efficacious serogroup B meningococcal vaccine can be developed.

Collins CL, Ruggeberg JU, Balfour G, Tighe H, Archer M, Bowen-Morris J, Diggle L, Borrow R, Balmer P, Buttery JP et al. 2005. Immunogenicity and immunologic memory of meningococcal C conjugate vaccine in premature infants. Pediatr Infect Dis J, 24 (11), pp. 966-968. | Show Abstract | Read more

BACKGROUND: Protein-polysaccharide conjugate vaccines against Neisseria meningitidis serogroup C were introduced into the U.K. routine immunization schedule in 1999. This study is the first to describe both persistence of antibody and evidence for induction of immune memory using meningococcal C conjugate (MCC) vaccine in preterm infants. METHODS: Immunogenicity and induction of immunologic memory by as MCC vaccine was assessed in premature infants; 62 preterm and 60 term controls received MCC at the accelerated schedule (2, 3 and 4 months of age). A meningococcal C polysaccharide challenge was administered at 12 months of age. RESULTS: Both groups achieved similar protective titers after primary immunization that then waned significantly by 1 year of age. Postchallenge serum bactericidal activity was significantly lower in preterm infants (P = 0.03); 73% of preterm versus 88% of term controls achieved a 4-fold rise in serum bactericidal activity (P = 0.07). CONCLUSIONS: MCC vaccine is immunogenic and primes for immunologic memory in preterm infants. The decreased memory responses in these preterm infants in conjunction with waning clinical efficacy data for all U.K. infants suggest a role for a routine booster dose of vaccine in all infants receiving MCC, especially those born preterm.

Maitland K, Nadel S, Pollard AJ, Williams TN, Newton CRJC, Levin M. 2005. Management of severe malaria in children: proposed guidelines for the United Kingdom. BMJ, 331 (7512), pp. 337-343. | Show Abstract | Read more

Malaria is the most important imported mosquito borne infection in the United Kingdom As preventive measures are never 100% effective, malaria should be suspected in any patient with "flu-like symptoms" who has travelled to malarious areas within a year Most cases of severe malaria result from a failure to expedite prompt "same day" diagnosis and initiate appropriate treatment in patients with suspected malaria Oral quinine and chloroquine or pyrimethamine with sulfadoxine should never be prescribed to treat falciparum malaria in children In children, the development of one or more features of severe or complicated malaria constitutes a medical emergency The emergency assessment of a child with severe malaria should follow the structured approach advocated by the Advanced Paediatric Life Support guidelines If in doubt: admit, monitor closely, and seek specialist advice.

Snape MD, Pollard AJ. 2005. Meningococcal polysaccharide-protein conjugate vaccines (vol 5, pg 21, 2005) LANCET INFECTIOUS DISEASES, 5 (5), pp. 270-270.

Buttery JP, Riddell A, McVernon J, Chantler T, Lane L, Bowen-Morris J, Diggle L, Morris R, Harnden A, Lockhart S et al. 2005. Immunogenicity and safety of a combination pneumococcal-meningococcal vaccine in infants: a randomized controlled trial. JAMA, 293 (14), pp. 1751-1758. | Show Abstract | Read more

CONTEXT: The success of conjugate vaccines in decreasing invasive disease due to Streptococcus pneumoniae and group C Neisseria meningitidis has placed pressure on crowded infant immunization schedules, making development of combination vaccines a priority. OBJECTIVE: To determine the safety and immunogenicity of a combination 9-valent pneumococcal-group C meningococcal conjugate candidate vaccine (Pnc9-MenC) administered as part of the routine UK infant immunization schedule at ages 2, 3, and 4 months. DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized controlled trial conducted from August 2000 to January 2002 and enrolling 240 healthy infants aged 7 to 11 weeks from 2 UK centers, with home follow-up visits at ages 2, 3, 4, and 5 months. INTERVENTION: Pnc9-MenC (n = 120) or monovalent group C meningococcal conjugate vaccine (MenC) (n = 120) administered in addition to routine immunizations (diphtheria and tetanus toxoids and whole-cell pertussis [DTwP], Haemophilus influenzae type b [Hib] polyribosylribitol phosphate-tetanus toxoid protein conjugate, oral polio vaccine). MAIN OUTCOME MEASURES: Group C meningococcal immunogenicity measured by serum bactericidal titer (SBT) 1 month following the third dose; rates of postimmunization reactions. RESULTS: MenC component immunogenicity was reduced in the Pnc9-MenC vs the MenC group (geometric mean SBT, 179 [95% confidence interval {CI}, 133-243] vs 808 [95% CI, 630-1037], respectively; P<.001). The proportion with group C meningococcal SBT greater than 1:8 was lower in the Pnc9-MenC vs the MenC group (95% vs 100%, P = .05). The geometric mean concentration of antibodies to concomitantly administered Hib vaccine was reduced in the Pnc9-MenC vs the MenC group (2.11 [95% CI, 1.57-2.84] microg/mL vs 3.36 [95% CI, 2.57-4.39] microg/mL; P = .02), as were antibodies against diphtheria (0.74 [95% CI, 0.63-0.87] microg/mL vs 1.47 [95% CI, 1.28-1.69] microg/mL; P<.001). Pnc9-MenC was immunogenic for each of 9 contained pneumococcal serotypes, with responses greater than 0.35 microg/mL observed in more than 88% of infants. Increased irritability and decreased activity were observed after the third dose in the Pnc9-MenC group. CONCLUSIONS: Pnc9-MenC combination vaccine administered to infants at ages 2, 3, and 4 months demonstrated reduced group C meningococcal immunogenicity compared with MenC vaccine. The immunogenicity of concomitantly administered Hib and DTwP vaccines was also diminished. The Pnc9-MenC vaccine was safe and immunogenic for all contained pneumococcal serotypes. The reduced MenC immunogenicity may limit the development of the Pnc9-MenC vaccine.

Pollard AJ. 2005. Pulmonary tuberculosis and extreme prematurity - Commentary ARCHIVES OF DISEASE IN CHILDHOOD, 90 (2), pp. F180-F181. | Read more

Pollard AJ. 2005. Pulmonary tuberculosis and extreme prematurity - Commentary ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION, 90 (2), pp. 180-181.

Hoang LMN, Thomas E, Tyler S, Pollard AJ, Stephens G, Gustafson L, McNabb A, Pocock I, Tsang R, Tan R. 2005. Rapid and fatal meningococcal disease due to a strain of Neisseria meningitidis containing the capsule null locus. Clin Infect Dis, 40 (5), pp. e38-e42. | Show Abstract | Read more

BACKGROUND: Neisseria meningitidis continues to be an important cause of invasive bacterial disease among children and young adults worldwide. In Canada, N. meningitidis strains that bear serogroups B and C polysaccharide capsules predominate. We report the first documented case of invasive meningococcal disease in an immunocompetent host caused by an acapsular strain of N. meningitidis containing the capsule null locus (cnl). METHODS: Analysis of the isolate was performed with use of serological and molecular methods, including multilocus sequence typing and cnl gene identification. Analysis of 16S ribosomal RNA (rRNA) and porA genes was also performed to confirm the identity of the bacterium. RESULTS: The patient was a healthy, immunocompetent 13-year-old child, and N. meningitidis was recovered from a sample of her cerebrospinal fluid before death. The isolate was nontypeable by both conventional antisera and indirect whole-cell enzyme-linked immuosorbent assay methods using antibodies to serogroups B, C, Y, and W135. The isolate was further identified as a cnl strain, serotype 15 (ST-198). N. meningitidis-specific DNA was identified in the isolate and in the pre- and postmortem specimens by 16S rRNA and porA gene analysis. CONCLUSIONS: This is the first reported case of fatal meningococcal disease caused by an acapsular cnl strain of N. meningitidis that was isolated from an immunocompetent host. Routine molecular diagnostic methods targeted at the cnl locus failed to detect this organism, indicating a need to determine the incidence of infection with cnl strains among patients with culture-negative invasive disease.

Waterhouse T, Pollard AJ. 2005. Clinical trials: consent in children. Expert Rev Vaccines, 4 (1), pp. 1-3. | Read more

Snape MD, Kelly DF, Green B, Moxon ER, Borrow R, Pollard AJ. 2005. Lack of serum bactericidal activity in preschool children two years after a single dose of serogroup C meningococcal polysaccharide-protein conjugate vaccine. Pediatr Infect Dis J, 24 (2), pp. 128-131. | Show Abstract | Read more

BACKGROUND: There is an increased risk of invasive meningococcal disease during the teenage years. A cohort of children vaccinated with a single dose of meningococcal C protein-polysaccharide conjugate (MenC) vaccine in early childhood during the U.K. catch up campaign will enter this age group during the coming decade. The duration of protective immunity against invasive meningococcal C disease provided by this single dose regimen is uncertain.A serum bactericidal titer of <1/8 correlates with susceptibility to invasive meningococcal disease. We assessed this correlate of protection in a cohort of children approximately 2 years after a single dose of vaccine. METHODS: Serum bactericidal activity was assessed in 94 children (median age, 4.0 years) at a median time of 1.8 years after vaccination. RESULTS: Of the 94 children, 59 (63%) had a serum bactericidal titer <1/8. CONCLUSION: The data from this study add to previous evidence indicating that immunity wanes rapidly after vaccination with serogroup C meningococcal glycoconjugate vaccines in infancy and early childhood. Such observations suggest that booster doses of MenC vaccine may be needed to maintain the successful contribution this vaccine has made to child health in the United Kingdom.

Curtis N, Finn A, Pollard AJ. 2013. Hot Topics in Infection and Immunity in Children IX Preface HOT TOPICS IN INFECTION AND IMMUNITY IN CHILDREN IX, 764 pp. V-V.

Hurley P, Isaacs D, Pollard AJ, Elias-Jones AC, Larcher V. 2005. Pulmonary tuberculosis and extreme prematurity: Commentary Archives of Disease in Childhood: Fetal and Neonatal Edition, 90 (2),

Snape MD, Pollard AJ. 2005. Meningococcal polysaccharide-protein conjugate vaccines. Lancet Infect Dis, 5 (1), pp. 21-30. | Show Abstract | Read more

It is now 5 years since the UK became the first country to introduce the serogroup C meningococcal polysaccharide-protein conjugate vaccines (MenC) into its routine immunisation schedule. This article reviews the global use of MenC with particular reference to the range of immunisation strategies used internationally. To date, concerns that MenC may result in an increase in meningococcal disease due to non-C serogroups have not been realised. The vaccine has proved to be highly safe and effective; however, concerns have arisen regarding the duration of vaccine effectiveness. Although booster doses of MenC may potentially extend the duration of protection offered by the vaccine, there are, as yet, no studies assessing this option. Clinical trials are underway to assess new combination conjugate vaccines (containing A, C, Y, and W polysaccharides), and it is probable that these more broadly protective vaccines will become available in the near future.

Snape MD, Pollard AJ. 2005. Erratum The Lancet Infectious Diseases, 5 (5), pp. 270-270. | Read more

Pollard AJ. 2004. Global epidemiology of meningococcal disease and vaccine efficacy. Pediatr Infect Dis J, 23 (12 Suppl), pp. S274-S279. | Show Abstract | Read more

BACKGROUND: Control of meningococcal infection has a high priority in many industrialized nations, because of the high mortality rates associated with invasive infection, the public health effects of disease outbreaks, and the position of Neisseria meningitidis as a leading infectious cause of death in childhood. Throughout the past 200 years, epidemics of meningococcal infection have been noted in Europe, Africa, Asia, the United States, and New Zealand. The proportions of cases caused by the 5 predominant capsular types (A, B, C, Y, and W135) associated with the disease vary among different regions and within specific geographic areas with time. Comprehensive disease control can be achieved only with the use of vaccines that target all of these disease-causing serogroups. METHODS: Routine immunization with a new generation of conjugate vaccines against serogroup C meningococci in the United Kingdom since 1999 has had a major effect on serogroup C disease in the region. The success of the vaccine involves 2 mechanisms, ie, (1) direct protective effects for vaccinated individuals through induction of bactericidal antibodies and (2) reductions in nasopharyngeal carriage of the organism and consequent generation of herd immunity through reductions in transmission to unimmunized individuals. CONCLUSIONS: Ongoing development of tetravalent A, C, Y, and W135 conjugate vaccines raises the hope that disease caused by these serogroups can be controlled in the near future. However, development of effective strategies to control serogroup B meningococcal disease is still needed for comprehensive control of meningococcal disease.

Cited:

31

Scopus

Collins CL, Salt P, McCarthy N, Chantler T, Lane L, Hemme F, Diggle L, Buttery J, Kitchin NRE, Moxon ER, Pollard AJ. 2004. Immunogenicity and safety of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine as a pre-school booster in UK children VACCINE, 22 (31-32), pp. 4262-4269. | Show Abstract | Read more

This open, randomised controlled trial studied the immunogenicity and reactogenicity of two combined low-dose diphtheria, tetanus and acellular pertussis vaccines (Td5aP-IPV, REPEVAX™, Aventis Pasteur MSD; and Td5aP, COVAXIS™, Aventis Pasteur MSD + OPV, GlaxoSmithKline) in comparison with a standard dose diphtheria pre-school booster vaccine (DT2aP-IPV, TETRAVAC™, Aventis Pasteur MSD) in a population of 3.5-5-year-old children administered concomitantly with measles, mumps and rubella vaccine (M-M-R™II, Aventis Pasteur MSD). A linked sub-study aimed to evaluate the immunogenicity and reactogenicity of Td5aP-IPV in a population of younger children, aged 3-3.5 years. This study demonstrated non-inferiority of seroprotection rates for diphtheria and tetanus for the study vaccines and comparable immunogenicity for pertussis and polio components of the vaccines. Reactogenicity was similar for all three vaccines. The study vaccines containing low-dose diphtheria antigen (Td5aP-IPV and Td5aP + OPV) are immunogenic and have acceptable reactogenicity for use as a pre-school booster vaccine administered concomitantly with MMR. © 2004 Elsevier Ltd. All rights reserved.

Collins CL, Salt P, McCarthy N, Chantler T, Lane L, Hemme F, Diggle L, Buttery J, Kitchin NRE, Moxon ER, Pollard AJ. 2004. Immunogenicity and safety of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine as a pre-school booster in UK children. Vaccine, 22 (31-32), pp. 4262-4269. | Show Abstract | Read more

This open, randomised controlled trial studied the immunogenicity and reactogenicity of two combined low-dose diphtheria, tetanus and acellular pertussis vaccines (Td5aP-IPV, REPEVAX, Aventis Pasteur MSD; and Td5aP, COVAXIS, Aventis Pasteur MSD + OPV, GlaxoSmithKline) in comparison with a standard dose diphtheria pre-school booster vaccine (DT2aP-IPV, TETRAVAC, Aventis Pasteur MSD) in a population of 3.5-5-year-old children administered concomitantly with measles, mumps and rubella vaccine (M-M-R II, Aventis Pasteur MSD). A linked sub-study aimed to evaluate the immunogenicity and reactogenicity of Td5aP-IPV in a population of younger children, aged 3-3.5 years. This study demonstrated non-inferiority of seroprotection rates for diphtheria and tetanus for the study vaccines and comparable immunogenicity for pertussis and polio components of the vaccines. Reactogenicity was similar for all three vaccines. The study vaccines containing low-dose diphtheria antigen (Td5aP-IPV and Td5aP + OPV) are immunogenic and have acceptable reactogenicity for use as a pre-school booster vaccine administered concomitantly with MMR.

Kelly DF, Moxon ER, Pollard AJ. 2004. Haemophilus influenzae type b conjugate vaccines. Immunology, 113 (2), pp. 163-174. | Show Abstract | Read more

Haemophilus influenzae type b (Hib) is one of the leading causes of invasive bacterial infection in young children worldwide. During childhood, acquisition of antibody directed against the polysaccharide capsule of the organism, presumably as a result of asymptomatic carriage, confers protection and disease is much less common after the age of 4 years. Like other polysaccharides, the polyribosyl ribitol phosphate (PRP) of the Hib capsule is a T-independent antigen and not immunogenic when administered as a vaccine in infancy. Because the highest rates of disease occur in the first 2 years of life, efficacious Hib vaccines have been designed by covalently linking the PRP capsule to a carrier protein that recruits T-cell help for the polysaccharide immune response and induces anti-PRP antibody production even in the first 6 months of life. Introduction of Hib protein-polysaccharide conjugate vaccines into many industrialized countries over the past 15 years has resulted in the virtual elimination of invasive Hib disease. However, despite the success of the vaccine programme several factors may interfere with the effectiveness of the vaccine in the routine programme, as observed in the UK recently. Such factors may include interference with other concomitant vaccines, waning immunity in the absence of booster doses of vaccine, and reduced natural boosting as a result of decreased transmission of the organism. However, the burden of disease remains highest in resource-poor countries and urgent efforts are needed to provide the benefits of this vaccine for children living in regions where it cannot be used for economic and logistical reasons.

Pollard AJ, Ochnio J, Ho M, Callaghan M, Bigham M, Dobsong S. 2004. Disease susceptibility to ST11 complex meningococci bearing serogroup C or W135 polysaccharide capsules, North America. Emerg Infect Dis, 10 (10), pp. 1812-1815. | Show Abstract | Read more

Clusters of meningococcal disease caused by a hyperinvasive lineage of Neisseria meningitidis, the ST11 complex, bearing a serogroup C polysaccharide capsule, have been prominent in Europe and North America since the early 1990s. This situation has led to expensive public health measures for outbreak control and, finally, to the introduction of a serogroup C glyconjugate vaccine into the primary immunization schedule in the United Kingdom and elsewhere. ST11 complex meningococci may also express serogroup W135 polysaccharide capsules. We investigated the level of population immunity to this hyperinvasive clone in association with the appearance of outbreaks of meningococcal disease in southern British Columbia. We found that most adults and almost all children were apparently susceptible to infection with ST11 complex meningococci bearing both C and W135 polysaccharide capsules, which suggests that a vaccine program directed against only serogroup C meningococci may be insufficient to prevent hyperinvasive ST11 disease.

Pollard AJ, Savulescu J. 2004. Ethics in practice - Eligibility of overseas visitors and people of uncertain residential status for NHS treatment BRITISH MEDICAL JOURNAL, 329 (7461), pp. 346-349. | Read more

Pollard AJ, Savulescu J. 2004. Eligibility of overseas visitors and people of uncertain residential status for NHS treatment. BMJ, 329 (7461), pp. 346-349. | Read more

Pollard AJ, Currie A, Rosenberger CM, Heale J-P, Finlay BB, Speert DP. 2004. Differential post-transcriptional activation of human phagocytes by different Pseudomonas aeruginosa isolates. Cell Microbiol, 6 (7), pp. 639-650. | Show Abstract | Read more

Pseudomonas aeruginosa is a pulmonary pathogen in individuals with impaired mucociliary clearance such as cystic fibrosis or mechanical ventilation. Non-opsonic phagocytosis of P. aeruginosa can be mediated by either CR3 or CD14 and different strains appear to have a bias towards one or the other receptor. Strain Fc808 is ingested through CD14 whereas P1 (Fc194) uses CR3. In an in vitro culture system, the inflammatory response of macrophages to these two different strains of P. aeruginosa was divergent at the protein level, with higher IL-6 and tumour necrosis factor (TNF)-alpha production generated in response to strain P1 and higher IL-1 beta production in response to strain Fc808. Interaction of macrophages with these two bacterial strains induced distinct gene expression patterns as detected by gene array analysis, with prominence of genes encoding pro-inflammatory cytokines, surface receptors, transcription factors and proteins involved in phagocytosis. However, comparison of gene expression data and cytokine response data with the two bacterial strains indicated that production of IL-1 beta, IL-6 and TNF-alpha was under differential post-transcriptional control. Interestingly, this effect did not correlate with receptor bias but instead was related to the different LPSs of the two strains. The use of specific mitogen-activated protein kinase (MAPK) inhibitors suggested a role for extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in the differential cytokine production by strains P1 and Fc808. These results indicate that strains of the same species of bacteria may induce differential macrophage phagocytic and inflammatory responses with likely consequence for bacterial clearance and host injury.

Pollard AJ, Prendergast M. 2004. Depressive pseudodementia in a child with autism. Dev Med Child Neurol, 46 (7), pp. 485-489. | Show Abstract | Read more

Depression is rare in early childhood and unusual in autism in this age group. We describe a female child aged 6 years with autism who presented with regression of developmental skills previously gained. Her sleep and appetite were poor, her affect was sad, and she had morbid speech content. She responded to treatment with antidepressant medication. When this clinical picture occurs in adults it is called depressive pseudodementia; paediatric neurologists and neuropsychiatrists need to be aware of it in children.

Gunawardana SS, Earley AR, Pollard AJ, Bethell D. 2004. Twelfth nerve palsy due to a retropharyngeal tuberculous abscess. Arch Dis Child, 89 (6), pp. 579. | Read more

Bethell D, Hall G, Goodman TR, Klein N, Pollard AJ. 2004. Resolution of orbitocerebral aspergillosis during combination treatment with voriconazole and amphotericin plus adjunctive cytokine therapy. J Pediatr Hematol Oncol, 26 (5), pp. 304-307. | Show Abstract | Read more

Orbitocerebral aspergillosis has a very high fatality rate and cure is unusual. We describe the successful management of a child with cereberal aspergillosis who had a dramatic response to therapy with a combination of liposomal amphotericin and voriconazole with adjunctive cytokine therapy during immunosuppresive chemotherapy for acute lymphoblastic leukaemia.

Bentham JR, Pollard AJ, Milford CA, Anslow P, Pike MG. 2004. Cerebral infarct and meningitis secondary to Lemierre's syndrome. Pediatr Neurol, 30 (4), pp. 281-283. | Show Abstract | Read more

The case is reported of a young man with Fusobacterium necrophorum septicemia who developed cavernous sinus thrombosis, meningitis, carotid artery stenosis and stroke. This article presents the only reported case of arterial stroke in Lemierre's syndrome. Clinical presentation, diagnostic difficulty and treatment are discussed.

Swinson S, Hall G, Pollard AJ. 2004. Reactivation of the bacille Calmette-Guérin scar following immune reconstitution during treatment of infant acute lymphoblastic leukemia. J Pediatr Hematol Oncol, 26 (2), pp. 112-115. | Show Abstract | Read more

The authors describe an infant presenting at 2 weeks of age with congenital acute lymphoblastic leukemia who had previously received routine bacille Calmette-Guérin (BCG) vaccination at birth. The risk of BCG dissemination in immunocompromised infants is discussed and the use of antimycobacterial prophylaxis in such cases considered.

Rüggeberg JU, Pollard AJ. 2004. Meningococcal vaccines. Paediatr Drugs, 6 (4), pp. 251-266. | Show Abstract | Read more

Meningococcal disease is one of the most feared and serious infections in the young and its prevention by vaccination is an important goal. The high degree of antigenic variability of the organism makes the meningococcus a challenging target for vaccine prevention. Meningococcal polysaccharide vaccines against serogroup A and C are efficacious and have been widely used, often in combination with serogroup Y and W135 components. Their relative lack of immunogenicity in young children and infants can be overcome by conjugation to a protein carrier. The effectiveness of serogroup C glycoconjugate vaccines in children of all ages has been demonstrated and they have now been introduced into routine vaccination schedules. Conjugate vaccines against other serogroups, including A, Y, and W135 will soon be available and it is hoped they may emulate this success. Prevention of serogroup B disease has proven more elusive. Several serogroup B vaccines based on outer membrane vesicles have been shown to be immunogenic and reasonably effective in adults and older children, but the protection offered by them is chiefly strain-specific. Multivalent recombinant PorA vaccines have been developed to broaden the protective effect, but no efficacy data are available as yet. Intensive efforts have been directed at other outer membrane protein vaccine candidates and lipopolysaccharide, and some of these have been shown to offer protection in experimental animal models. Nonpathogenic Neisseriae spp. such as Neisseria lactamica are also possible vaccine candidates. Previously unknown proteins have been identified from in silico analysis of the meningococcal genome and their vaccine potential explored. However, none of these has yet been presented as the 'universal' protective antigen and work in this field continues to be held back by our limited knowledge concerning the mechanisms of natural protection against serogroup B meningococci.

Pollard AJ, Currie A, Rosenberger CM, Heale JP, Finlay BB, Speert DP. 2004. Differential post-transcriptional activation of human phagocytes by different Pseudomonas aeruginosa isolates Cellular Microbiology, 6 (7), pp. 639-650. | Show Abstract | Read more

Pseudomonas aeruginosa is a pulmonary pathogen in individuals with impaired mucocillary clearance such as cystic fibrosis or mechanical ventilation. Non-opsonic phagocytosis of P. aeruginosa can be mediated by either CR3 or CD14 and different strains appear to have a bias towards one or the other receptor. Strain Fc808 is ingested through CD14 whereas P1 (Fc194) uses CR3. In an in vitro culture system, the inflammatory response of macrophages to these two different strains of P. aeruginosa was divergent at the protein level, with higher IL-6 and tumour necrosis factor (TNF)-α production generated in response to strain P1 and higher IL-1β production in response to strain Fc808. Interaction of macrophages with these two bacterial strains induced distinct gene expression patterns as detected by gene array analysis, with prominence of genes encoding pro-inflammatory cytokines, surface receptors, transcription factors and proteins involved in phagocytosis. However, comparison of gene expression data and cytokine response data with the two bacterial strains indicated that production of IL-1β, IL-6 and TNF-α was under differential post-transcriptional control. Interestingly, this effect did not correlate with receptor bias but instead was related to the different LPSs of the two strains. The use of specific mitogen-activated protein kinase (MAPK) inhibitors suggested a role for extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in the differential cytokine production by strains P1 and Fc808. These results indicate that strains of the same species of bacteria may induce differential macrophage phagocytic and inflammatory responses with likely consequence for bacterial clearance and host injury. © 2004 Blackwell Publishing Ltd.

Curtis N, Pollard AJ, Finn A. 2014. Hot topics in infection and immunity in children. J Infect, 69 Suppl 1 pp. S1. | Read more

Segal S, Pollard AJ. 2004. The last of the meningococcus? Adv Exp Med Biol, 549 pp. 201-209.

Segal S, Pollard AJ. 2004. Vaccines against bacterial meningitis. Br Med Bull, 72 (1), pp. 65-81. | Show Abstract | Read more

Meningitis remains an important cause of morbidity and mortality among children >5 years of age and is especially prevalent in developing countries. Effective routine immunization against Hib, pneumococcus and serogroupC meningococcus has had a significant impact on both invasive disease and carriage caused by these encapsulated bacteria. The major challenge in prevention of meningitis remains the delivery of vaccines worldwide, especially to resource-poor regions with the greatest disease burden.

Cited:

42

Scopus

Bentham JR, Pollard AJ, Milford CA, Anslow P, Pike MG. 2004. Cerebral infarct and meningitis secondary to Lemierre's syndrome Pediatric Neurology, 30 (4), pp. 281-283. | Show Abstract | Read more

The case is reported of a young man with Fusobacterium necrophorum septicemia who developed cavernous sinus thrombosis, meningitis, carotid artery stenosis and stroke. This article presents the only reported case of arterial stroke in Lemierre's syndrome. Clinical presentation, diagnostic difficulty and treatment are discussed. © 2004 by Elsevier Inc. All rights reserved.

Ison CA, Anwar N, Cole MJ, Pollard AJ, Morley SL, Fidler K, Sandiford C, Banks J, Kroll SJ, Levin M. 2003. Age dependence of in vitro survival of meningococci in whole blood during childhood. Pediatr Infect Dis J, 22 (10), pp. 868-873. | Show Abstract | Read more

OBJECTIVES: To determine the association between the ability of a different strains