Development of a durable and efficacious pre-erythrocytic malaria vaccine

Project Overview

Despite global efforts, malaria continues to cause significant morbidity and mortality worldwide, particularly in developing countries with greater than 70% of childhood related deaths occurring in Sub-Saharian Africa due to malaria. A malaria infection in humans starts with the bite of an infected mosquito which injects P. falciparum sporozoites into the skin as it takes a blood meal. Sporozoites then migrate to the liver where they infect hepatocytes and undergo asexual replication, subsequently leading to the formation and release of merozoites into the blood stream approximately 6-7 days later, which infect and re-infect red blood cells (RBCs).

Protection from the pre-erythrocytic stage of malaria can be achieved by either antibodies that block sporozoite invasion of hepatocytes or effector CD8+ T cells which locate and kill the infected hepatocytes. However due to the short time sporozoites are present in the blood (2 minutes) or hepatocytes (5 to 7 days in humans), both high titre antibodies and high numbers of effector CD8+ T cells are required.

Significant clinical advances have been made with two pre-erythrocytic stage recombinant vaccines strategies. RTS,S in AS01 (Mosquirix), is virus like particle (VLP) based vaccine which has been shown to induce high titre anti-sporozoite antibodies. Although it was approved for use by European regulators in 2015, efficacy in children wains significantly over 6 months, therefore the WHO have only recommended a pilot implementation program to ensure efficacy in the context of the normal vaccinations can be achieved in young children. The alternative approach is heterologous viral vector vaccination with simian Adenovirus serotype 63 (ChAd63) followed by modified vaccinia Ankara (MVA), both expressing a multiple epitope (ME) string fused to thrombospondin related anonymous protein (TRAP) and this primarily induces effector CD8+ T cells against TRAP to kill infected hepatocytes (O'Hara et al., 2012). While both vaccines have shown some degree of efficacy in African clinical trials (Ogwang et al., 2015; Rts, 2015), which was marginally enhanced (75% to 82.4% sterile efficacy) when vaccines were combined in malaria naïve individuals (Rampling et al., 2016), further vaccine development and regimen optimisation will be required to achieve long-term efficacy in the vaccine target population.

This project aims to combine the VLP and viral vectored vaccine platforms to develop a highly efficacious and long-lasting pre-erythrocytic malaria vaccine. By assessing combination approaches for both traditional and newly identified pre-erythrocytic malaria antigens, together with molecular adjuvant currently in development, we hope to develop a vaccine which dramatically improves both the level and duration of antibody and T cells responses, with the ultimate goal of translating this vaccines to the clinic.

This DPhil project combines the major steps for the development of a new generation of malaria vaccines; antigen identification, vaccine design and pre-clinical validation and will make use of transgenic P.berghei technology, thus provide training in molecular biology, immunology, parasitology. 

Training Opportunities

Both subject specific and generic training in research skills will be provided. Specific training will be available a large variety of immunoassays, cell biology, immuno-histochemistry, flow cytometry, vector construction, molecular biology, immunization techniques, parasitology, statistical analysis of data and experimental design. The research group is large and includes students, post-docs, clinical fellows, research nurses, clinical triallists, project managers, field researchers, and biomanufacturing experts, spanning activities in vaccinology and human genetics, thereby providing exposure to a broad range of research and development activities in the biomedical sciences. The Jenner Institute has performed more than 20 clinical trials and has accumulated unparalleled depth and breadth of experience in vaccinology, combining all the technologies required for the effective development of new vaccines, from vaccine design and production to pre-clinical studies and clinical trials.

Theme

Immunology & Infectious Disease and Tropical Medicine & Global Health

Admissions

Project reference number: 944

Funding and admissions information

Supervisors

Name Department Institution Country Email
Dr Alexandra J Spencer Jenner Institute Oxford University, Old Road Campus Research Building GBR alex.spencer@ndm.ox.ac.uk
Professor Adrian VS Hill Jenner Institute Oxford University, Old Road Campus Research Building GBR adrian.hill@ndm.ox.ac.uk

O'Hara GA, Duncan CJ, Ewer KJ, Collins KA, Elias SC, Halstead FD, Goodman AL, Edwards NJ, Reyes-Sandoval A, Bird P, Rowland R, Sheehy SH, Poulton ID, Hutchings C, Todryk S, Andrews L, Folgori A, Berrie E, Moyle S, Nicosia A, Colloca S, Cortese R, Siani L, Lawrie AM, Gilbert SC, Hill AV. 2012. Clinical assessment of a recombinant simian adenovirus ChAd63: a potent new vaccine vector. J. Infect. Dis., 205 (5), pp. 772-81. Read abstract | Read more

BACKGROUND: Vaccine development in human Plasmodium falciparum malaria has been hampered by the exceptionally high levels of CD8(+) T cells required for efficacy. Use of potently immunogenic human adenoviruses as vaccine vectors could overcome this problem, but these are limited by preexisting immunity to human adenoviruses. METHODS: From 2007 to 2010, we undertook a phase I dose and route finding study of a new malaria vaccine, a replication-incompetent chimpanzee adenovirus 63 (ChAd63) encoding the preerythrocytic insert multiple epitope thrombospondin-related adhesion protein (ME-TRAP; n = 54 vaccinees) administered alone (n = 28) or with a modified vaccinia virus Ankara (MVA) ME-TRAP booster immunization 8 weeks later (n = 26). We observed an excellent safety profile. High levels of TRAP antigen-specific CD8(+) and CD4(+) T cells, as detected by interferon γ enzyme-linked immunospot assay and flow cytometry, were induced by intramuscular ChAd63 ME-TRAP immunization at doses of 5 × 10(10) viral particles and above. Subsequent administration of MVA ME-TRAP boosted responses to exceptionally high levels, and responses were maintained for up to 30 months postvaccination. CONCLUSIONS: The ChAd63 chimpanzee adenovirus vector appears safe and highly immunogenic, providing a viable alternative to human adenoviruses as vaccine vectors for human use. CLINICAL TRIALS REGISTRATION: NCT00890019. Hide abstract

Ogwang C, Kimani D, Edwards NJ, Roberts R, Mwacharo J, Bowyer G, Bliss C, Hodgson SH, Njuguna P, Viebig NK, Nicosia A, Gitau E, Douglas S, Illingworth J, Marsh K, Lawrie A, Imoukhuede EB, Ewer K, Urban BC, Hill AVS, Bejon P, MVVC group. 2015. Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults. Sci Transl Med, 7 (286), pp. 286re5. Read abstract | Read more

Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum. On Cox regression, vaccination reduced the risk of infection by 67% [95% confidence interval (CI), 33 to 83%; P = 0.002] during 8 weeks of monitoring. T cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio, 0.24; 95% CI, 0.08 to 0.75; P = 0.016). Hide abstract

Rampling T, Ewer KJ, Bowyer G, Bliss CM, Edwards NJ, Wright D, Payne RO, Venkatraman N, de Barra E, Snudden CM, Poulton ID, de Graaf H, Sukhtankar P, Roberts R, Ivinson K, Weltzin R, Rajkumar BY, Wille-Reece U, Lee CK, Ockenhouse CF, Sinden RE, Gerry S, Lawrie AM, Vekemans J, Morelle D, Lievens M, Ballou RW, Cooke GS, Faust SN, Gilbert S, Hill AV. 2016. Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP. J. Infect. Dis., 214 (5), pp. 772-81. Read abstract | Read more

BACKGROUND: The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector. METHOD: Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara-vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls. RESULTS: No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected. CONCLUSIONS: The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types. CLINICAL TRIALS REGISTRATION: NCT01883609. Hide abstract

RTS,S Clinical Trials Partnership. 2015. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet, 386 (9988), pp. 31-45. Read abstract | Read more

BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. METHODS: From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. FINDINGS: 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. INTERPRETATION: RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative. Hide abstract