title: Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus.
abstract: Vaccines against influenza viruses with pandemic potential, including H5N1, are under development. Because of a lack of preexisting immunity to these viruses, adjuvants (immune potentiators or enhancers) are needed to improve immune responses, to conserve scarce vaccine, and for cross-protection against strains that have drifted evolutionarily from the original. Aluminum-based adjuvants do not improve vaccine immunogenicity for influenza subunit vaccines, whereas oil-in-water adjuvants are effective, especially with H5N1-inactivated vaccines. We used whole-genome-fragment phage display libraries followed by surface plasmon resonance (SPR) technologies to elucidate the effect of different adjuvants on the antibody repertoire against H5N1 vaccine in humans. The oil-in-water adjuvant MF59 induced epitope spreading from HA2 to HA1 in hemagglutinin (HA) and neuraminidase relative to unadjuvanted or aluminum-adjuvanted vaccines. Moreover, we observed an increase by a factor of 20 in the frequency of HA1-to-HA2-specific phage clones in sera after MF59-adjuvanted vaccine administration and a factor of 2 to 3 increase in the avidity of antibodies binding to properly folded HA1(28-319), as measured by SPR. The adjuvant-dependent increase in binding to conformational HA1 epitopes correlated with broadening of cross-clade neutralization and predicted improved in vivo protection. Thus, MF59 adjuvant improves the immune response to a H5N1 vaccine by inducing qualitative and quantitative expansion of the antibody repertoires with protective potential.
authors.affiliation: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Surender
authors.initials: S
authors.lastname: Khurana
authors.forename: Wanida
authors.initials: W
authors.lastname: Chearwae
authors.forename: Flora
authors.initials: F
authors.lastname: Castellino
authors.forename: Jody
authors.initials: J
authors.lastname: Manischewitz
authors.forename: Lisa R
authors.initials: LR
authors.lastname: King
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Honorkiewicz
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rock
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Edwards
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Del Giudice
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Hana
authors.initials: H
authors.lastname: Golding
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000327:Adsorption / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D000917:Antibody Formation / Q000187:drug effects; D001717:Birds / Q000276:immunology / Q000821:virology; D004196:Disease Outbreaks / Q000517:prevention & control*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D005585:Influenza in Birds / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D007251:Influenza, Human / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D007700:Kinetics; D008958:Models, Molecular; D019151:Peptide Library; D011136:Polysorbates / Q000494:pharmacology*; D017510:Protein Folding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013185:Squalene / Q000276:immunology / Q000494:pharmacology*; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D007252:Influenza Vaccines; C089950:MF59 oil emulsion; D019151:Peptide Library; D011136:Polysorbates; D013185:Squalene