MF59 Adjuvant Enhances Diversity and Affinity of Antibody-Mediated Immune Response to Pandemic Influenza Vaccines

Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Science translational medicine (Impact Factor: 15.84). 06/2011; 3(85):85ra48. DOI: 10.1126/scitranslmed.3002336
Source: PubMed


Oil-in-water adjuvants have been shown to improve immune responses against pandemic influenza vaccines as well as reduce the effective vaccine dose, increasing the number of doses available to meet global vaccine demand. Here, we use genome fragment phage display libraries and surface plasmon resonance to elucidate the effects of MF59 on the quantity, diversity, specificity, and affinity maturation of human antibody responses to the swine-origin H1N1 vaccine in different age groups. In adults and children, MF59 selectively enhanced antibody responses to the hemagglutinin 1 (HA1) globular head relative to the more conserved HA2 domain in terms of increased antibody titers as well as a more diverse antibody epitope repertoire. Antibody affinity, as inferred by greatly diminished (≥10-fold) off-rate constants, was significantly increased in toddlers and children who received the MF59-adjuvanted vaccine. Moreover, MF59 also improved antibody affinity maturation after each sequential vaccination against avian H5N1 in adults. For both pandemic influenza vaccines, there was a close correlation between serum antibody affinity and virus-neutralizing capacity. Thus, MF59 quantitatively and qualitatively enhances functional antibody responses to HA-based vaccines by improving both epitope breadth and binding affinity, demonstrating the added value of such adjuvants for influenza vaccines.


Available from: Jonathan W Yewdell
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    • "MF59 acts locally by activating monocytes, macrophages and dendritic cells, which release a mixture of cytokines attracting phagocytic cells to the injection site, resulting in more efficient antigen-transport to the lymph nodes [18] [19]. MF59 has also been shown to enhance the immune response by increasing the binding strength of antibody to the influenza virus [16] [17] Influenza vaccines containing MF59 have also consistently demonstrated an established safety profile [20] [21] [22] [23]. The MF59-adjuvanted seasonal influenza vaccine, Fluad ® , is recommended in numerous countries for adults over the age of 65, but further research is particularly necessary to assess the effectiveness and safety of inclusion of MF59 adjuvant in seasonal vaccines for children. "
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    ABSTRACT: Background: Non-adjuvanted seasonal influenza vaccines show only modest efficacy in young children. This study compared the immunogenicity, reactogenicity and safety of the MF59-adjuvanted trivalent subunit vaccine (aTIV) with two non-adjuvanted trivalent vaccines, TIV-1, the non-adjuvanted version of aTIV, and TIV-2, a split virion vaccine. Methods: 6078 children received two doses of aTIV (n=3125), TIV-1 (n=1479), or TIV-2 (n=1474) four weeks apart (Days 1 and 29). Children aged 6 to <36 months and 36 to <72 months received 0.25 mL and 0.50 mL doses, respectively. Immunogenicity was assessed by hemagglutination inhibition (HI) assay (n=2435) on Days 1, 29, 50 and 209. Safety was assessed up to Day 394. Results: After the second vaccination (Day 50), the aTIV group showed significantly higher geometric mean HI titers and seroconversion rates than the TIV-1 or TIV-2 groups against all homologous and heterologous strains. The difference was enhanced at HI titers ≥110. aTIV elicited a faster, more persistent antibody response, with significantly higher titers in the aTIV group after one vaccination (Day 29) and after six months (Day 209) than in either TIV group. aTIV was more reactogenic than were TIV-1 and TIV-2 but rates of severe adverse events were very low for all three vaccines. Conclusion: In infants and young children, the MF59-adjuvanted vaccine induced substantially faster (after one dose), higher, persistent HI titers than the non-adjuvanted vaccines, with consistently higher seroprotection rates at increased threshold HI titers. This trial is registered at NCT01346592.
    Vaccine 09/2014; 32(46). DOI:10.1016/j.vaccine.2014.08.068 · 3.62 Impact Factor
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    • "This protective response is not boosted by subsequent immunization with the same vaccine and wanes within months. We conclude that strategies to increase the breadth and duration of the protective response elicited by conventional vaccines, such as adjuvants [34]–[36] or novel vaccination schedules involving DNA priming [37], [38], or altogether novel vaccine modalities are required to obtain ‘universal’ protection against influenza through vaccination. The human-to-mouse serum transfer and challenge model described here can assist the development of either of these strategies. "
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    ABSTRACT: Current influenza vaccines are believed to confer protection against a narrow range of virus strains. The identification of broadly influenza neutralizing antibodies (bnAbs) has triggered efforts to develop vaccines providing 'universal' protection against influenza. Several bnAbs were isolated from humans recently vaccinated with conventional influenza vaccines, suggesting that such vaccines could, in principle, be broadly protective. Assessing the breadth-of-protection conferred to humans by influenza vaccines is hampered by the lack of in vitro correlates for broad protection. We designed and employed a novel human-to-mouse serum transfer and challenge model to analyze protective responses in serum samples from clinical trial subjects. One dose of seasonal vaccine induces humoral protection not only against vaccine-homologous H1N1 challenge, but also against H5N1 challenge. This heterosubtypic protection is neither detected, nor accurately predicted by in vitro immunogenicity assays. Moreover, heterosubtypic protection is transient and not boosted by repeated inoculations. Strategies to increase the breadth and duration of the protective response against influenza are required to obtain 'universal' protection against influenza by vaccination. In the absence of known correlates of protection for broadly protective vaccines, the human-to-mouse serum transfer and challenge model described here may aid the development of such vaccines.
    PLoS ONE 07/2014; 9(7):e103550. DOI:10.1371/journal.pone.0103550 · 3.23 Impact Factor
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    • "Mechanistically, emulsions induce a chemokine-driven gradient at the site of injection that recruits leukocyte infiltration and antigen transport to local lymph nodes, and their induction of broadly reactive CD4 T cells predict the rise of neutralizing antibody titers after booster immunizations [20], [21]. The humoral responses induced by these adjuvants involve antibody epitope spreading from the HA2 portion of HA to large conformational domains in the globular HA1 region of HA, which correlate with broad cross-clade neutralization [22]. Despite their utility, vaccines containing emulsion-based adjuvants have not been approved in the United States, and ongoing large-scale epidemiological studies are evaluating their safety [23]–[26]. "
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    ABSTRACT: The ongoing threat from Influenza necessitates the development of new vaccine and adjuvant technologies that can maximize vaccine immunogenicity, shorten production cycles, and increase global vaccine supply. Currently, the most successful adjuvants for Influenza vaccines are squalene-based oil-in-water emulsions. These adjuvants enhance seroprotective antibody titers to homologous and heterologous strains of virus, and augment a significant dose sparing activity that could improve vaccine manufacturing capacity. As an alternative to an emulsion, we tested a simple lipid-based aqueous formulation containing a synthetic TLR4 ligand (GLA-AF) for its ability to enhance protection against H5N1 infection. GLA-AF was very effective in adjuvanting recombinant H5 hemagglutinin antigen (rH5) in mice and was as potent as the stable emulsion, SE. Both adjuvants induced similar antibody titers using a sub-microgram dose of rH5, and both conferred complete protection against a highly pathogenic H5N1 challenge. However, GLA-AF was the superior adjuvant in ferrets. GLA-AF stimulated a broader antibody response than SE after both the prime and boost immunization with rH5, and ferrets were better protected against homologous and heterologous strains of H5N1 virus. Thus, GLA-AF is a potent emulsion-free adjuvant that warrants consideration for pandemic influenza vaccine development.
    PLoS ONE 02/2014; 9(2):e88979. DOI:10.1371/journal.pone.0088979 · 3.23 Impact Factor
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