title: H5N1 Vaccine-Elicited Memory B Cells Are Genetically Constrained by the IGHV Locus in the Recognition of a Neutralizing Epitope in the Hemagglutinin Stem.
abstract: Because of significant viral diversity, vaccines that elicit durable and broad protection against influenza have been elusive. Recent research has focused on the potential of highly conserved regions of the viral hemagglutinin (HA) as targets for broadly neutralizing Ab responses. Abs that bind the highly conserved stem or stalk of HA can be elicited by vaccination in humans and animal models and neutralize diverse influenza strains. However, the frequency and phenotype of HA stem-specific B cells in vivo remain unclear. In this article, we characterize HA stem-specific B cell responses following H5N1 vaccination and describe the re-expansion of a pre-existing population of memory B cells specific for stem epitopes. This population uses primarily, but not exclusively, IGHV1-69-based Igs for HA recognition. However, within some subjects, allelic polymorphism at the ighv1-69 locus can limit IGHV1-69 immunodominance and may reduce circulating frequencies of stem-reactive B cells in vivo. The accurate definition of allelic selection, recombination requirements, and ontogeny of neutralizing Ab responses to influenza will aid rational influenza vaccine design.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Adam K
authors.identifier: http://orcid.org/0000-0002-5593-9387
authors.initials: AK
authors.lastname: Wheatley
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: James R R
authors.initials: JR
authors.lastname: Whittle
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, MA 02139; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lingwood
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Masaru
authors.initials: M
authors.lastname: Kanekiyo
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Hadi M
authors.initials: HM
authors.lastname: Yassine
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Steven S
authors.initials: SS
authors.lastname: Ma
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Sandeep R
authors.initials: SR
authors.lastname: Narpala
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Prabhakaran
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Matus-Nicodemos
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Sanofi, Cambridge, MA 02139.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Julie E
authors.initials: JE
authors.lastname: Ledgerwood
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; adrian.mcdermott@nih.gov.
authors.forename: Adrian B
authors.initials: AB
authors.lastname: McDermott
mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000097:blood; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood*; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D056426:Genetic Loci / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D007251:Influenza, Human / Q000097:blood / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA; D015164:Vaccines, Inactivated
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; D019444:Vaccines, DNA; D015164:Vaccines, Inactivated