Safety, Reactogenicity, and Immunogenicity of Inactivated Monovalent Influenza A(H5N1) Virus Vaccine Administered With or Without AS03 Adjuvant

Wilbur H Chen, Lisa A Jackson, Kathryn M Edwards, Wendy A Keitel, Heather Hill, Diana L Noah, C Buddy Creech, Shital M Patel, Brian Mangal, Karen L Kotloff, Wilbur H Chen, Lisa A Jackson, Kathryn M Edwards, Wendy A Keitel, Heather Hill, Diana L Noah, C Buddy Creech, Shital M Patel, Brian Mangal, Karen L Kotloff

Abstract

Background: The national stockpile for influenza pandemic preparedness includes vaccines against an array of strains and adjuvants that could be utilized to induce immunologic priming as a pandemic wave emerges. We assessed the feasibility of a strategy that allows the flexibility of postmanufacture mixture of vaccine and adjuvant at the point of care.

Methods: We conducted a randomized, double-blind, multicenter trial among healthy adults aged 18-49 years who received 2 doses of inactivated influenza A/Indonesia/05/2005 (H5N1 clade 2.2.3) virus vaccine containing either 3.75, 7.5, or 15 µg of hemagglutinin (HA) with or without AS03 adjuvant, administered 21 days apart. Subjects were observed for local (injection site) and systemic reactogenicity and adverse events. Sera were tested for hemagglutination inhibition (HAI) and microneutralization (MN) antibody levels against the homologous strain and 4 heterologous avian strains.

Results: Vaccine containing ASO3 adjuvant was associated with significantly more local reactions compared with nonadjuvanted vaccine, but these were short-lived and resolved spontaneously. Although the immune response to nonadjuvanted vaccine was poor, 2 doses of AS03-adjuvanted vaccine containing as little as 3.75 µg of HA elicited robust immune responses resulting in seroprotective titers (≥1:40) to the homologous strain in ≥86% of subjects by HAI and in 95% of subjects by MN. Cross-clade antibody responses were also observed with AS03-adjuvanted vaccine, but not nonadjuvanted vaccine.

Conclusions: AS03 adjuvant formulated with inactivated vaccine at the administration site significantly enhanced the immune responses to H5N1 vaccine and has the potential to markedly improve vaccine responses and accelerate delivery during an influenza pandemic.

Clinical trials registration: NCT01317758.

Keywords: adjuvants; avian influenza; pandemic influenza vaccine.

Figures

Figure 1.
Figure 1.
The percentage of subjects who experienced solicited adverse events, by maximum reactogenicity, during the 7 days after receipt of the first dose (A and C) or the second dose (B and D), according to vaccine dosage (3.75, 7.5, and 15 µg) and whether nonadjuvanted (A and B) or AS03-adjuvanted (C and D). aThe widest diameter was measured and graded as follows: small (mild) <20 mm, medium (moderate) 20–50 mm, and large (severe) >50 mm.
Figure 2.
Figure 2.
Geometric mean hemagglutination inhibition (HAI) and microneutralization (MN) titers to homologous (A/Indonesia/05/2005) virus strain, by dosage group.
Figure 3.
Figure 3.
Geometric mean hemagglutination inhibition (HAI) and microneutralization (MN) titers to heterologous virus strains (A/turkey/Turkey/01/2005, clade 2.2.1; A/Vietnam/1203/2004, clade 1; A/Anhui/1/2005, clade 2.3.4; and A/Hubei/1/2010, clade 2.3.2.1), by dosage group.

References

    1. Jennings LC, Monto AS, Chan PK, et al. Stockpiling prepandemic influenza vaccines: a new cornerstone of pandemic preparedness plans. Lancet Infect Dis. 2008;8:650–58.
    1. Belshe RB, Frey SE, Graham I, et al. Safety and immunogenicity of influenza A H5 subunit vaccines: effect of vaccine schedule and antigenic variant. J Infect Dis. 2011;203:666–73.
    1. Treanor JJ, Campbell JD, Zangwill KM, et al. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med. 2006;354:1343–51.
    1. Treanor JJ, Wilkinson BE, Masseoud F, et al. Safety and immunogenicity of a recombinant hemagglutinin vaccine for H5 influenza in humans. Vaccine. 2001;19:1732–37.
    1. Noah DL, Hill H, Hines D, et al. Qualification of the hemagglutination inhibition assay in support of pandemic influenza vaccine licensure. Clin Vaccine Immunol. 2009;16:558–66.
    1. Chen WH, Winokur PL, Edwards KM, et al. Phase 2 assessment of the safety and immunogenicity of two inactivated pandemic monovalent H1N1 vaccines in adults as a component of the U.S. pandemic preparedness plan in 2009. Vaccine. 2012;30:4240–48.
    1. Atmar RL, Keitel WA. Adjuvants for pandemic influenza vaccines. Curr Top Microbiol Immunol. 2009;333:323–44.
    1. Bresson JL, Perronne C, Launay O, et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet. 2006;367:1657–64.
    1. Keitel WA, Campbell JD, Treanor JJ, et al. Safety and immunogenicity of an inactivated influenza A/H5N1 vaccine given with or without aluminum hydroxide to healthy adults: results of a phase I-II randomized clinical trial. J Infect Dis. 2008;198:1309–16.
    1. Leroux-Roels I, Borkowski A, Vanwolleghem T, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet. 2007;370:580–9.
    1. Langley JM, Frenette L, Ferguson L, et al. Safety and cross-reactive immunogenicity of candidate AS03-adjuvanted prepandemic H5N1 influenza vaccines: a randomized controlled phase 1/2 trial in adults. J Infect Dis. 2010;201:1644–53.
    1. Department of Health and Human Services. HHS funds the advanced development of vaccines against the H5N1 influenza strain. 2007. . Accessed January 23, 2014.
    1. Dekker CL, Gordon L, Klein J; for the NVAC Subcommittee on Vaccine Development and Supply. Dose optimization strategies for vaccines: the role of adjuvants and new technologies, 2008 . Accessed January 23, 2014.
    1. Ferguson NM, Cummings DA, Fraser C, et al. Strategies for mitigating an influenza pandemic. Nature. 2006;442:448–52.
    1. Food and Drug Administration, Center for Biologics Evaluation and Research . Guidance for industry: clinical data needed to support the licensure of pandemic influenza vaccines. Rockville, MD: Department of Health and Human Services; 2007. . Accessed January 23, 2014.
    1. Schwarz TF, Horacek T, Knuf M, et al. Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine. 2009;27:6284–90.
    1. Gilca V, De Serres G, Hamelin ME, et al. Antibody persistence and response to 2010-2011 trivalent influenza vaccine one year after a single dose of 2009 AS03-adjuvanted pandemic H1N1 vaccine in children. Vaccine. 2011;30:35–41.
    1. Sridhar S, Begom S, Bermingham A, et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat Med. 2013;19:1305–12.
    1. WHO/OIE/FAO H5N1 Evolution Working Group. Continued evolution of highly pathogenic avian influenza A (H5N1): updated nomenclature. Influenza Other Respir Viruses. 2012;6:1–5.
    1. Langley JM, Risi G, Caldwell M, et al. Dose-sparing H5N1 A/Indonesia/05/2005 pre-pandemic influenza vaccine in adults and elderly adults: a phase III, placebo-controlled, randomized study. J Infect Dis. 2011;203:1729–38.
    1. Lasko B, Reich D, Madan A, et al. Rapid immunization against H5N1: a randomized trial evaluating homologous and cross-reactive immune responses to AS03(A)-adjuvanted vaccination in adults. J Infect Dis. 2011;204:574–81.
    1. Yang PC, Yu CJ, Chang SC, et al. Safety and immunogenicity of a split-virion AS03A-adjuvanted A/Indonesia/05/2005 (H5N1) vaccine in Taiwanese adults. J Formos Med Assoc. 2012;111:333–9.
    1. Rowe T, Abernathy RA, Hu-Primmer J, et al. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol. 1999;37:937–43.
    1. Baylor NW, Houn F. Considerations for licensure of influenza vaccines with pandemic and prepandemic indications. Curr Top Microbiol Immunol. 2009;333:453–70.
    1. De la Herran-Arita AK, Kornum BR, Mahlios J, et al. CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med. 2013;5:216ra176.

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