title: Heterologous prime-boost vaccination with MF59-adjuvanted H5 vaccines promotes antibody affinity maturation towards the hemagglutinin HA1 domain and broad H5N1 cross-clade neutralization.
abstract: In an open label clinical study (2007), MF59-adjuvanted hemagglutinin (HA) vaccine from H5N1-A/Vietnam/1194/2004 (clade 1) was administered to subjects previously vaccinated (primed) with clade 0 H5N3 (A/duck/Singapore/97) vaccine at least 6 years earlier (in 1999 or 2001). The primed individuals responded rapidly and generated high neutralizing antibody titers against the H5N1-Vietnam strain within 7 days of a single booster vaccination. Furthermore, significant cross-neutralization titers were measured against H5N1 clade 0, 1, and 2 viruses. In the current study, the impact of MF59 adjuvant during heterologous priming on the quality of humoral polyclonal immune response in different vaccine arms were further evaluated using real time kinetics assay by surface plasmon resonance (SPR). Total anti-H5N1 HA1 polyclonal sera antibody binding from the heterologous prime-boost groups after a single MF59-H5N1 boost was significantly higher compared with sera from unprimed individuals that received two MF59-H5N1 vaccinations. The antigen-antibody complex dissociation rates (surrogate for antibody affinity) of the polyclonal sera against HA1 of H5N1-A/Vietnam/1194/2004 from the MF59-H5N3 primed groups were significantly higher compared to sera from unadjuvanted primed groups or unprimed individuals that received two MF59-H5N1 vaccines. Furthermore, strong inverse correlations were observed between the antibody dissociation off-rates of the immune sera against HA1 (but not HA2) and the virus neutralization titers against H5 vaccine strains and heterologous H5N1 strains. These findings supports the use of oil-in-water-adjuvanted pandemic influenza vaccines to elicit long term memory B cells with high affinity BCR capable of responding to potential variant pandemic viruses likely to emerge and adapt to human transmissions.
authors.affiliation: Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland, United States of America.
authors.forename: Surender
authors.initials: S
authors.lastname: Khurana
authors.affiliation: Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland, United States of America.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Coyle
authors.affiliation: Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland, United States of America.
authors.forename: Milena
authors.initials: M
authors.lastname: Dimitrova
authors.affiliation: Novartis Vaccines and Diagnostics Srl, Sienna, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Castellino
authors.affiliation: Department of Infection, Inflammation, and Immunity, Maurice Shock Medical Sciences Building, University of Leicester, Leicester, United Kingdom.
authors.forename: Karl
authors.initials: K
authors.lastname: Nicholson
authors.affiliation: Novartis Vaccines and Diagnostics Srl, Sienna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Del Giudice
authors.affiliation: Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland, United States of America.
authors.forename: Hana
authors.initials: H
authors.lastname: Golding
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000914:Antibodies, Viral / Q000097:blood; D000915:Antibody Affinity / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology; D006388:Hemagglutinins / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007117:Immunization, Secondary; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000821:virology; D009500:Neutralization Tests; D011136:Polysorbates / Q000008:administration & dosage*; D017434:Protein Structure, Tertiary; D013185:Squalene / Q000008:administration & dosage*; D014611:Vaccination; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D006388:Hemagglutinins; D007252:Influenza Vaccines; C089950:MF59 oil emulsion; D011136:Polysorbates; D022223:Vaccines, Subunit; D013185:Squalene
references.citation: J Virol. 1994 Sep;68(9):6083-6
references.pmid: 8057487
references.citation: PLoS Pathog. 2012 Sep;8(9):e1002920
references.pmid: 23028320
references.citation: N Engl J Med. 2008 Oct 9;359(15):1631-3
references.pmid: 18843132
references.citation: J Exp Med. 2011 Jan 17;208(1):181-93
references.pmid: 21220454
references.citation: Nat Med. 2014 Feb;20(2):143-51
references.pmid: 24412922
references.citation: Lancet. 2001 Jun 16;357(9272):1937-43
references.pmid: 11425416
references.citation: Sci Transl Med. 2010 Jan 20;2(15):15ra5
references.pmid: 20371470
references.citation: J Clin Immunol. 2011 Jun;31(3):443-54
references.pmid: 21174144
references.citation: J Virol. 2012 Nov;86(22):12283-93
references.pmid: 22951833
references.citation: Vaccine. 1987 Sep;5(3):244-8
references.pmid: 3499714
references.citation: Proc Natl Acad Sci U S A. 2009 May 12;106(19):7962-7
references.pmid: 19416838
references.citation: Vaccine. 2003 Apr 2;21(15):1687-93
references.pmid: 12639491
references.citation: Science. 2009 Apr 10;324(5924):246-51
references.pmid: 19251591
references.citation: PLoS One. 2009;4(2):e4384
references.pmid: 19197383
references.citation: J Exp Med. 2011 Dec 19;208(13):2599-606
references.pmid: 22162833
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14330-5
references.pmid: 23940329
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3877-82
references.pmid: 19237568
references.citation: Immunol Rev. 2011 Jan;239(1):167-77
references.pmid: 21198671
references.citation: PLoS Med. 2009 Apr 21;6(4):e1000049
references.pmid: 19381279
references.citation: J Infect Dis. 2012 Feb 15;205(4):610-20
references.pmid: 22207649
references.citation: J Infect Dis. 2013 Aug 1;208(3):413-7
references.pmid: 23633404
references.citation: Cell Immunol. 1987 Oct 1;109(1):53-64
references.pmid: 3498544
references.citation: Science. 2013 Sep 13;341(6151):1205-11
references.pmid: 24031013
references.citation: Sci Transl Med. 2011 Jun 1;3(85):85ra48
references.pmid: 21632986
references.citation: Expert Rev Vaccines. 2012 Mar;11(3):349-66
references.pmid: 22380826