Influenza vaccines – Broad protection through vaccination

Project Overview

Influenza vaccines – Broad protection through vaccination

Compared with the 1918 influenza pandemic, which claimed an estimated 15-50 million lives worldwide, mortality associated with the recent H1N1 pandemic was fortunately low. However, the 2009 pandemic was unusual in that children and young adults were more susceptible to infection. Cross-reactive antibodies induced pre-1950 were found to be protective in the elderly [Skountzou et al., 2010]. However, the predominant humoral immune response following vaccination or seasonal influenza exposure is directed toward the head of hemagglutinin and these antibodies show little cross-reactivity between influenza isolates.

Importantly, the antigenic sites for cross-reactive hemagglutinin-specific antibodies have been characterised [Doms, 2010; Corti et al., 2011; Ekiert et al., 2009 & 2011] and we are combining this knowledge with our current clinical approach, to boost heterosubypic cellular immunity, to develop a candidate ‘universal’ influenza A vaccine.

In addition it has been commonly perceived that influenza A represents a more deadly infection compared with influenza B mediated disease; however, the overall mortality rates associated with influenza B remain higher than those seen with influenza A/H1N1 infection [Thompson 2003]. Indeed, the burden of disease due to influenza B viral infection falls largely on children and young adults, and causes a disproportionate number of paediatric deaths. We aim to use our previous experience with influenza A and also develop a universal influenza B vaccine to induce high titre antibodies and heterosubtypic T cells. A combination of both vaccines would potentially offer protective efficacy in the face of both seasonal and pandemic outbreaks of influenza.

Training Opportunities

Training opportunities will include both basic research and applied skills, including ELIspot, ELISA, pseudotyped lentivirus neutralisation assays, flow cytometric assays, tetramer staining, cell sorting, transient transfer of transgenic cells, data analysis and presentation and attendance of local and international conferences. This pre-clinical project will provide a unique insight into translational research and will allow the graduate student to interact with both basic researchers and clinicians.


Immunology & Infectious Disease


Project reference number: 404

Funding and admissions information


Name Department Institution Country Email
Professor Sarah C Gilbert Jenner Institute Oxford University, Old Road Campus Research Building GBR
Dr Teresa Lambe Jenner Institute Oxford University, Old Road Campus Research Building GBR

Impagliazzo A, Milder F, Kuipers H, Wagner MV, Zhu X, Hoffman RM, van Meersbergen R, Huizingh J, Wanningen P, Verspuij J, de Man M, Ding Z, Apetri A, Kükrer B, Sneekes-Vriese E, Tomkiewicz D, Laursen NS, Lee PS, Zakrzewska A, Dekking L, Tolboom J, Tettero L, van Meerten S, Yu W, Koudstaal W, Goudsmit J, Ward AB, Meijberg W, Wilson IA, Radošević K. 2015. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science, 349 (6254), pp. 1301-6. Read abstract | Read more

The identification of human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem revitalized hopes of developing a universal influenza vaccine. Using a rational design and library approach, we engineered stable HA stem antigens ("mini-HAs") based on an H1 subtype sequence. Our most advanced candidate exhibits structural and bnAb binding properties comparable to those of full-length HA, completely protects mice in lethal heterologous and heterosubtypic challenge models, and reduces fever after sublethal challenge in cynomolgus monkeys. Antibodies elicited by this mini-HA in mice and nonhuman primates bound a wide range of HAs, competed with human bnAbs for HA stem binding, neutralized H5N1 viruses, and mediated antibody-dependent effector activity. These results represent a proof of concept for the design of HA stem mimics that elicit bnAbs against influenza A group 1 viruses. Hide abstract

Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. 2003. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA, 289 (2), pp. 179-86. Read abstract | Read more

CONTEXT: Influenza and respiratory syncytial virus (RSV) cause substantial morbidity and mortality. Statistical methods used to estimate deaths in the United States attributable to influenza have not accounted for RSV circulation. OBJECTIVE: To develop a statistical model using national mortality and viral surveillance data to estimate annual influenza- and RSV-associated deaths in the United States, by age group, virus, and influenza type and subtype. DESIGN, SETTING, AND POPULATION: Age-specific Poisson regression models using national viral surveillance data for the 1976-1977 through 1998-1999 seasons were used to estimate influenza-associated deaths. Influenza- and RSV-associated deaths were simultaneously estimated for the 1990-1991 through 1998-1999 seasons. MAIN OUTCOME MEASURES: Attributable deaths for 3 categories: underlying pneumonia and influenza, underlying respiratory and circulatory, and all causes. RESULTS: Annual estimates of influenza-associated deaths increased significantly between the 1976-1977 and 1998-1999 seasons for all 3 death categories (P<.001 for each category). For the 1990-1991 through 1998-1999 seasons, the greatest mean numbers of deaths were associated with influenza A(H3N2) viruses, followed by RSV, influenza B, and influenza A(H1N1). Influenza viruses and RSV, respectively, were associated with annual means (SD) of 8097 (3084) and 2707 (196) underlying pneumonia and influenza deaths, 36 155 (11 055) and 11 321 (668) underlying respiratory and circulatory deaths, and 51 203 (15 081) and 17 358 (1086) all-cause deaths. For underlying respiratory and circulatory deaths, 90% of influenza- and 78% of RSV-associated deaths occurred among persons aged 65 years or older. Influenza was associated with more deaths than RSV in all age groups except for children younger than 1 year. On average, influenza was associated with 3 times as many deaths as RSV. CONCLUSIONS: Mortality associated with both influenza and RSV circulation disproportionately affects elderly persons. Influenza deaths have increased substantially in the last 2 decades, in part because of aging of the population, underscoring the need for better prevention measures, including more effective vaccines and vaccination programs for elderly persons. Hide abstract

Skountzou I, Koutsonanos DG, Kim JH, Powers R, Satyabhama L, Masseoud F, Weldon WC, Martin Mdel P, Mittler RS, Compans R, Jacob J. 2010. Immunity to pre-1950 H1N1 influenza viruses confers cross-protection against the pandemic swine-origin 2009 A (H1N1) influenza virus. J. Immunol., 185 (3), pp. 1642-9. Read abstract | Read more

The 2009 H1N1 influenza virus outbreak is the first pandemic of the twenty-first century. Epidemiological data reveal that of all the people afflicted with H1N1 virus, <5% are over 51 y of age. Interestingly, in the uninfected population, 33% of those >60 y old have pre-existing neutralizing Abs against the 2009 H1N1 virus. This finding suggests that influenza strains that circulated 50-60 y ago might provide cross-protection against the swine-origin 2009 H1N1 influenza virus. To test this, we determined the ability of representative H1N1 influenza viruses that circulated in the human population from 1930 to 2000, to induce cross-reactivity to and cross-protection against the pandemic swine-origin H1N1 virus, A/California/04/09. We show that exposure of mice to the 1947 virus, A/FM/1/47, or the 1934 virus, A/PR/8/34, induced robust cross-protective immune responses and these mice were protected against a lethal challenge with mouse-adapted A/California/04/09 H1N1 virus. Conversely, we observed that mice exposed to the 2009 H1N1 virus were protected against a lethal challenge with mouse-adapted 1947 or 1934 H1N1 viruses. In addition, exposure to the 2009 H1N1 virus induced broad cross-reactivity against H1N1 as well as H3N2 influenza viruses. Finally, we show that vaccination with the older H1N1 viruses, particularly A/FM/1/47, confers protective immunity against the 2009 pandemic H1N1 virus. Taken together, our data provide an explanation for the decreased susceptibility of the elderly to the 2009 H1N1 outbreak and demonstrate that vaccination with the pre-1950 influenza strains can cross-protect against the pandemic swine-origin 2009 H1N1 influenza virus. Hide abstract

McCullers JA, Van De Velde LA, Allison KJ, Branum KC, Webby RJ, Flynn PM. 2010. Recipients of vaccine against the 1976 "swine flu" have enhanced neutralization responses to the 2009 novel H1N1 influenza virus. Clin. Infect. Dis., 50 (11), pp. 1487-92. Read abstract | Read more

BACKGROUND. The world is facing a novel H1N1 influenza pandemic. A pandemic scare with a similar influenza virus in 1976 resulted in the vaccination of nearly 45 million persons. We hypothesized that prior receipt of the 1976 "swine flu" vaccine would enhance immune responses to the 2009 novel H1N1 influenza strain. METHODS. A prospective, volunteer sample of employees aged > or = 55 years at a children's cancer hospital in August 2009 was assessed for antibody responses to the 2009 pandemic H1N1 influenza virus and the 2008-2009 seasonal H1N1 influenza virus. RESULTS. Antibody responses by hemagglutination-inhibition assay were high against both the seasonal influenza virus (89.7% had a titer considered seroprotective) and pandemic H1N1 influenza virus (88.8% had a seroprotective titer). These antibodies were effective at neutralizing the seasonal H1N1 influenza virus in 68.1% of participants (titer > or = 40), but only 18.1% had detectable neutralizing titers against the pandemic H1N1 influenza virus. Of 116 participants, 46 (39.7%) received the 1976 "swine flu" vaccine. Receipt of this vaccine significantly enhanced neutralization responses; 8 (17.4%) of 46 vaccine recipients had titers > or = 160, compared with only 3 (4.3%) of 70 who did not receive the vaccine (P = .018 by chi(2) test). CONCLUSIONS. In this cohort, persons aged > or = 55 years had evidence of robust immunity to the 2008-2009 seasonal H1N1 influenza virus. These antibodies were cross-reactive but nonneutralizing against the 2009 pandemic H1N1 influenza strain. Receipt of a vaccine to a related virus significantly enhanced the neutralization capacity of these responses, suggesting homologous vaccination against the 2009 pandemic H1N1 influenza virus would have a similar effect. Hide abstract

Doms RW. 2010. Immunology. Prime, boost, and broaden. Science, 329 (5995), pp. 1021-2. | Read more

Corti D, Voss J, Gamblin SJ, Codoni G, Macagno A, Jarrossay D, Vachieri SG, Pinna D, Minola A, Vanzetta F, Silacci C, Fernandez-Rodriguez BM, Agatic G, Bianchi S, Giacchetto-Sasselli I, Calder L, Sallusto F, Collins P, Haire LF, Temperton N, Langedijk JP, Skehel JJ, Lanzavecchia A. 2011. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science, 333 (6044), pp. 850-6. Read abstract | Read more

The isolation of broadly neutralizing antibodies against influenza A viruses has been a long-sought goal for therapeutic approaches and vaccine design. Using a single-cell culture method for screening large numbers of human plasma cells, we isolated a neutralizing monoclonal antibody that recognized the hemagglutinin (HA) glycoprotein of all 16 subtypes and neutralized both group 1 and group 2 influenza A viruses. Passive transfer of this antibody conferred protection to mice and ferrets. Complexes with HAs from the group 1 H1 and the group 2 H3 subtypes analyzed by x-ray crystallography showed that the antibody bound to a conserved epitope in the F subdomain. This antibody may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency. Hide abstract

Ekiert DC, Friesen RH, Bhabha G, Kwaks T, Jongeneelen M, Yu W, Ophorst C, Cox F, Korse HJ, Brandenburg B, Vogels R, Brakenhoff JP, Kompier R, Koldijk MH, Cornelissen LA, Poon LL, Peiris M, Koudstaal W, Wilson IA, Goudsmit J. 2011. A highly conserved neutralizing epitope on group 2 influenza A viruses. Science, 333 (6044), pp. 843-50. Read abstract | Read more

Current flu vaccines provide only limited coverage against seasonal strains of influenza viruses. The identification of V(H)1-69 antibodies that broadly neutralize almost all influenza A group 1 viruses constituted a breakthrough in the influenza field. Here, we report the isolation and characterization of a human monoclonal antibody CR8020 with broad neutralizing activity against most group 2 viruses, including H3N2 and H7N7, which cause severe human infection. The crystal structure of Fab CR8020 with the 1968 pandemic H3 hemagglutinin (HA) reveals a highly conserved epitope in the HA stalk distinct from the epitope recognized by the V(H)1-69 group 1 antibodies. Thus, a cocktail of two antibodies may be sufficient to neutralize most influenza A subtypes and, hence, enable development of a universal flu vaccine and broad-spectrum antibody therapies. Hide abstract

Ekiert DC, Bhabha G, Elsliger MA, Friesen RH, Jongeneelen M, Throsby M, Goudsmit J, Wilson IA. 2009. Antibody recognition of a highly conserved influenza virus epitope. Science, 324 (5924), pp. 246-51. Read abstract | Read more

Influenza virus presents an important and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Cocrystal structures were determined at 2.2 and 2.7 angstrom resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1 and HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza. Hide abstract

Berthoud TK, Hamill M, Lillie PJ, Hwenda L, Collins KA, Ewer KJ, Milicic A, Poyntz HC, Lambe T, Fletcher HA, Hill AV, Gilbert SC. 2011. Potent CD8+ T-cell immunogenicity in humans of a novel heterosubtypic influenza A vaccine, MVA-NP+M1. Clin. Infect. Dis., 52 (1), pp. 1-7. Read abstract | Read more

BACKGROUND: Influenza A viruses cause occasional pandemics and frequent epidemics. Licensed influenza vaccines that induce high antibody titers to the highly polymorphic viral surface antigen hemagglutinin must be re-formulated and readministered annually. A vaccine providing protective immunity to the highly conserved internal antigens could provide longer-lasting protection against multiple influenza subtypes. METHODS: We prepared a Modified Vaccinia virus Ankara (MVA) vector encoding nucleoprotein and matrix protein 1 (MVA-NP+M1) and conducted a phase I clinical trial in healthy adults. RESULTS: The vaccine was generally safe and well tolerated, with significantly fewer local side effects after intramuscular rather than intradermal administration. Systemic side effects increased at the higher dose in both frequency and severity, with 5 out of 8 volunteers experiencing severe nausea/vomiting, malaise, or rigors. Ex vivo T-cell responses to NP and M1 measured by IFN-γ ELISPOT assay were significantly increased after vaccination (prevaccination median of 123 spot-forming units/million peripheral blood mononuclear cells, postvaccination peak response median 339, 443, and 1443 in low-dose intradermal, low-dose intramuscular, and high-dose intramuscular groups, respectively), and the majority of the antigen-specific T cells were CD8(+). CONCLUSIONS: We conclude that the vaccine was both safe and remarkably immunogenic, leading to frequencies of responding T cells that appear to be much higher than those induced by any other influenza vaccination approach. Further studies will be required to find the optimum dose and to assess whether the increased T-cell response to conserved influenza proteins results in protection from influenza disease. Hide abstract

Lillie PJ, Berthoud TK, Powell TJ, Lambe T, Mullarkey C, Spencer AJ, Hamill M, Peng Y, Blais ME, Duncan CJ, Sheehy SH, Havelock T, Faust SN, Williams RL, Gilbert A, Oxford J, Dong T, Hill AV, Gilbert SC. 2012. Preliminary assessment of the efficacy of a T-cell-based influenza vaccine, MVA-NP+M1, in humans. Clin. Infect. Dis., 55 (1), pp. 19-25. Read abstract | Read more

BACKGROUND: The novel influenza vaccine MVA-NP+M1 is designed to boost cross-reactive T-cell responses to internal antigens of the influenza A virus that are conserved across all subtypes, providing protection against both influenza disease and virus shedding against all influenza A viruses. Following a phase 1 clinical study that demonstrated vaccine safety and immunogenicity, a phase 2a vaccination and influenza challenge study has been conducted in healthy adult volunteers. METHODS: Volunteers with no measurable serum antibodies to influenza A/Wisconsin/67/2005 received either a single vaccination with MVA-NP+M1 or no vaccination. T-cell responses to the vaccine antigens were measured at enrollment and again prior to virus challenge. All volunteers underwent intranasal administration of influenza A/Wisconsin/67/2005 while in a quarantine unit and were monitored for symptoms of influenza disease and virus shedding. RESULTS: Volunteers had a significantly increased T-cell response to the vaccine antigens following a single dose of the vaccine, with an increase in cytolytic effector molecules. Intranasal influenza challenge was undertaken without safety issues. Two of 11 vaccinees and 5 of 11 control subjects developed laboratory-confirmed influenza (symptoms plus virus shedding). Symptoms of influenza were less pronounced in the vaccinees and there was a significant reduction in the number of days of virus shedding in those vaccinees who developed influenza (mean, 1.09 days in controls, 0.45 days in vaccinees, P = .036). CONCLUSIONS: This study provides the first demonstration of clinical efficacy of a T-cell-based influenza vaccine and indicates that further clinical development should be undertaken. CLINICAL TRIALS REGISTRATION: NCT00993083. Hide abstract