H5N1 Vaccine-Elicited Memory B Cells Are Genetically Constrained by the IGHV Locus in the Recognition of a Neutralizing Epitope in the Hemagglutinin Stem

Adam K Wheatley; James R R Whittle; Daniel Lingwood; Masaru Kanekiyo; Hadi M Yassine; Steven S Ma; Sandeep R Narpala; Madhu S Prabhakaran; Rodrigo A Matus-Nicodemos; Robert T Bailer; Gary J Nabel; Barney S Graham; Julie E Ledgerwood; Richard A Koup; Adrian B McDermott

doi:10.4049/jimmunol.1402835

H5N1 Vaccine-Elicited Memory B Cells Are Genetically Constrained by the IGHV Locus in the Recognition of a Neutralizing Epitope in the Hemagglutinin Stem

J Immunol. 2015 Jul 15;195(2):602-10. doi: 10.4049/jimmunol.1402835. Epub 2015 Jun 15.

Authors

Affiliations

¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
² Ragon Institute of MGH, MIT and Harvard, Boston, MA 02139; and.
³ Sanofi, Cambridge, MA 02139.
⁴ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; adrian.mcdermott@nih.gov.

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.

Publication types

Clinical Trial, Phase I
Research Support, N.I.H., Intramural

MeSH terms

Amino Acid Sequence
Antibodies, Neutralizing / biosynthesis
Antibodies, Neutralizing / blood
Antibodies, Viral / biosynthesis
Antibodies, Viral / blood*
Antigens, Viral / chemistry
Antigens, Viral / genetics
Antigens, Viral / immunology
B-Lymphocytes / cytology
B-Lymphocytes / immunology*
B-Lymphocytes / virology
Epitopes / chemistry
Epitopes / genetics
Epitopes / immunology
Genetic Loci / immunology
Hemagglutinin Glycoproteins, Influenza Virus / chemistry
Hemagglutinin Glycoproteins, Influenza Virus / genetics
Hemagglutinin Glycoproteins, Influenza Virus / immunology
Humans
Immunologic Memory*
Influenza A Virus, H5N1 Subtype / chemistry
Influenza A Virus, H5N1 Subtype / immunology*
Influenza Vaccines / administration & dosage
Influenza Vaccines / genetics
Influenza Vaccines / immunology
Influenza, Human / blood
Influenza, Human / immunology
Influenza, Human / prevention & control*
Influenza, Human / virology
Molecular Sequence Data
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / immunology
Single-Chain Antibodies / chemistry
Single-Chain Antibodies / genetics
Single-Chain Antibodies / immunology*
Vaccination
Vaccines, DNA
Vaccines, Inactivated

Substances

Antibodies, Neutralizing
Antibodies, Viral
Antigens, Viral
Epitopes
Hemagglutinin Glycoproteins, Influenza Virus
Influenza Vaccines
Recombinant Proteins
Single-Chain Antibodies
Vaccines, DNA
Vaccines, Inactivated

Grants and funding

Z99 AI999999/Intramural NIH HHS/United States