title: Oral priming with replicating adenovirus serotype 4 followed by subunit H5N1 vaccine boost promotes antibody affinity maturation and expands H5N1 cross-clade neutralization.
abstract: A Phase I trial conducted in 2009-2010 demonstrated that oral vaccination with a replication competent Ad4-H5 (A/Vietnam) vector with dosages ranging from 107-1011 viral particles was well tolerated. HA-specific T-cell responses were efficiently induced, but very limited hemagglutination-inhibiting (HI) humoral responses were measured. However, a single boost of Ad4-H5-Vtn vaccinated individuals with a unadjuvanted licensed H5N1 (A/Vietnam) subunit vaccine resulted in superior HI titers compared with unprimed subjects. In the current study, the impact of Ad4-H5 priming on the quality of the polyclonal humoral immune response was evaluated using a real-time kinetics assay by surface plasmon resonance (SPR). Total binding of serum polyclonal antibodies from the Ad4-H5-Vtn primed groups against both homologous H5N1-A/Vietnam/1194/2004 (clade 1) and heterologous A/Indonesia-5/2005 (clade 2.1) HA1 head domain was significantly higher compared with sera from individuals that received subunit H5N1 vaccination alone. SPR measurements also demonstrated that the antigen-antibody complex dissociation rates (a surrogate for antibody affinity) of serum antibodies against the HA1 of H5N1-A/Vietnam were significantly higher in the Ad4-H5 primed groups compared with those from the unprimed group. Furthermore, strong correlations were observed between the antibody affinities for HA1 (but not HA2) and the virus neutralization titers against the homologous strain and a panel of heterologous clade 2 H5N1 strains. These findings support the concept of oral prime-boost vaccine approaches against pandemic influenza to elicit long-term memory B cells with high affinity capable of rapid response to variant pandemic viruses likely to emerge and adapt to human transmissions.
authors: Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, Maryland, United States of America, 20903.
authors: Surender
authors: S
authors: Khurana
authors: Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, Maryland, United States of America, 20903.
authors: Elizabeth M
authors: EM
authors: Coyle
authors: Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, Maryland, United States of America, 20903.
authors: Jody
authors: J
authors: Manischewitz
authors: Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, Maryland, United States of America, 20903.
authors: Lisa R
authors: LR
authors: King
authors: PaxVax, San Diego, CA, United States of America, 92121.
authors: Glenn
authors: G
authors: Ishioka
authors: PaxVax, San Diego, CA, United States of America, 92121.
authors: Jeff
authors: J
authors: Alexander
authors: PaxVax, San Diego, CA, United States of America, 92121.
authors: Jon
authors: J
authors: Smith
authors: PaxVax, Redwood City, CA, United States of America, 94063.
authors: Marc
authors: M
authors: Gurwith
authors: Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, Maryland, United States of America, 20903.
authors: Hana
authors: H
authors: Golding
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D000915:Antibody Affinity / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D003429:Cross Reactions / Q000276:immunology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007117:Immunization, Secondary; D053124:Influenza A Virus, H5N1 Subtype / Q000145:classification / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007252:Influenza Vaccines; D022223:Vaccines, Subunit
references: J Virol. 2011 Feb;85(3):1246-56
references: 21084473
references: Immunol Rev. 2011 Jan;239(1):167-77
references: 21198671
references: Sci Transl Med. 2011 Jun 1;3(85):85ra48
references: 21632986
references: J Clin Immunol. 2011 Jun;31(3):443-54
references: 21174144
references: Lancet Infect Dis. 2011 Dec;11(12):916-24
references: 21975270
references: J Exp Med. 2011 Dec 19;208(13):2599-606
references: 22162833
references: J Infect Dis. 2012 Feb 15;205(4):610-20
references: 22207649
references: Expert Rev Vaccines. 2012 Mar;11(3):349-66
references: 22380826
references: PLoS Pathog. 2012 Sep;8(9):e1002920
references: 23028320
references: J Virol. 2012 Nov;86(22):12283-93
references: 22951833
references: Lancet Infect Dis. 2013 Mar;13(3):238-50
references: 23369412
references: J Infect Dis. 2013 Aug 1;208(3):413-7
references: 23633404
references: Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14330-5
references: 23940329
references: Science. 2013 Sep 13;341(6151):1205-11
references: 24031013
references: J Virol. 2014 Jan;88(1):314-24
references: 24155379
references: J Infect Dis. 2014 Jun 15;209(12):1860-9
references: 24604819
references: Cell Immunol. 1987 Oct 1;109(1):53-64
references: 3498544
references: Vaccine. 1987 Sep;5(3):244-8
references: 3499714
references: Proc Natl Acad Sci U S A. 1989 Sep;86(17):6763-7
references: 2570422
references: J Virol. 1994 Sep;68(9):6083-6
references: 8057487
references: Dev Biol Stand. 1994;82:71-7
references: 7958485
references: Dev Biol Stand. 1995;84:153-6
references: 7796948
references: Nat Med. 1997 Jun;3(6):651-8
references: 9176492
references: J Virol. 1998 Feb;72(2):1052-9
references: 9444999
references: J Clin Microbiol. 1999 Apr;37(4):937-43
references: 10074505
references: N Engl J Med. 2006 Mar 30;354(13):1343-51
references: 16571878
references: PLoS One. 2009;4(2):e4384
references: 19197383
references: Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3877-82
references: 19237568
references: Vaccine. 2010 Jan 8;28(3):664-72
references: 19895924
references: Sci Transl Med. 2010 Jan 20;2(15):15ra5
references: 20371470
references: PLoS One. 2010;5(7):e11548
references: 20634959
references: J Exp Med. 2011 Jan 17;208(1):181-93
references: 21220454