Journal Article

Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination

Horton, Andrew P, Kwong, Peter D, Zhang, Baoshan, Krammer, Florian, Mascola, John R, Kong, Wing-Pui, Georgiou, George, Murrin, Ellen M, Zhang, Yi, Joyce, M Gordon, Carter, Chalise E, Lee, Chang-Han, Chrysostomou, Constantine, Vollmers, Christopher, Wilson, Patrick C, Ippolito, Gregory C, Hoi, Kam Hon, Druz, Aliaksandr, Ellington, Andrew D, Davis, Mark M, Lee, Jiwon, Park, Daechan, Wang, Lingshu, Quake, Stephen R, Chromikova, Veronika, Tsybovsky, Yaroslav, Dekker, Cornelia L, Boutz, Daniel R, Marcotte, Edward M, DeKosky, Brandon J, Thomas, Paul V, Lavinder, Jason J, Popova, Lyubov I, Leung, Kwanyee, Ross, Ted M

2016

Overview

Antibodies that bind to both H1 and H3 influenza strains exist in the pre-vaccination serum repertoire of healthy adults; most vaccine-elicited clonotypes bind either H1 or H3 strains. Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine. The serum repertoire comprised between 40 and 147 clonotypes that were specific to each of the three monovalent components of the trivalent influenza vaccine, with boosted pre-existing clonotypes accounting for ∼60% of the response. An unexpectedly high fraction of serum antibodies recognized both the H1 and H3 monovalent vaccines. Recombinant versions of these H1 + H3 cross-reactive antibodies showed broad binding to hemagglutinins (HAs) from previously circulating virus strains; several of these antibodies, which were prevalent in the serum of multiple donors, recognized the same conserved epitope in the HA head domain. Although the HA-head-specific H1 + H3 antibodies did not show neutralization activity in vitro , they protected mice against infection with the H1N1 and H3N2 virus strains when administered before or after challenge. Collectively, our data reveal unanticipated insights regarding the serological response to influenza vaccination and raise questions about the added benefits of using a quadrivalent vaccine instead of a trivalent vaccine.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/326/590 / 692/699/255/1578 / Adult / Adults / Analysis / Animals / Antibodies / Antibodies, Viral - immunology / Antibody response / B-cell receptor / B-Lymphocytes - immunology / Biomedicine / Cancer Research / Chromatography, Liquid / Cross Reactions / Dosage and administration / Epitopes / Female / Health aspects / Hemagglutinin Glycoproteins, Influenza Virus - immunology / Hemagglutinins / High-Throughput Nucleotide Sequencing / Humans / Immunogenicity, Vaccine / Immunoglobulin G - immunology / Immunoglobulins / Infectious Diseases / Influenza / Influenza A Virus, H1N1 Subtype - immunology / Influenza A Virus, H3N2 Subtype - immunology / Influenza vaccines / Influenza Vaccines - therapeutic use / Influenza, Human - prevention & control / Male / Metabolic Diseases / Mice / Molecular biology / Molecular Medicine / Neurosciences / Neutralization / Next-generation sequencing / Orthomyxoviridae - immunology / Physiological aspects / Polyclonal antibodies / Proteomics / Receptors, Antigen, B-Cell - genetics / RNA, Messenger - genetics / Sequence Analysis, RNA / Serology / Strains (organisms) / Tandem Mass Spectrometry / Vaccines / Viral antibodies / Young Adult / Young adults