Immune history profoundly affects broadly protective B cell responses to influenza

• Type of Material: Article
• Authors: Sarah F. Andrews, University of Chicago; Yunping Huang, University of Chicago; Kaval Kaur, University of Chicago; Lyubov I. Popova, University of Chicago; Irvin Y. Ho, University of Chicago; Noel T. Pauli, University of Chicago; Carole J. Henry Dunand, University of Chicago; William M Taylor, University of Chicago; Samuel Lim, University of Chicago; Min Huang, University of Chicago; Xinyan Qu, University of Chicago; Jane-Hwei Lee, University of Chicago; Marlene Salgado-Ferrer, University of Chicago; Florian Krammer, Icahn School of Medicine at Mount Sinai; Peter Palese, Icahn School of Medicine at Mount Sinai; Jens Wrammert, Emory University; Rafi Ahmed, Emory University; Patrick C. Wilson, University of Chicago
• Language: English
• Date: 2015-12-02
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015, American Association for the Advancement of Science
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aad0522
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 7
• Issue: 316
• Start Page: 316ra192
• End Page: 316ra192
• Grant/Funding Information: Kaval Kaur was supported by a National Science Scholarship (PhD) from the Agency of Science, Technology and Research (A*STAR), Singapore.; This work was supported in parts by NIH grants 1U19AI08724 (PCW), 5U54AI057158 (PCW, RA), 5U19AI057266 (PCW, RA, JW), 1U19AI090023 (PCW, RA, JW), 1P01AI097092 (PCW, RA, PP), F32 AI93087 (SFA) and by funds provided by the Gwen Knapp Center for Lupus and Immunology Research.; Florian Krammer was supported by an Erwin Schrödinger fellowship (J3232) from the Austrian Science Fund (FWF).; This work was also partly supported by CRIP (Center for Research on Influenza Pathogenesis), an NIAID funded Center of Excellence for Influenza Research and Surveillance (CEIRS, contract # HHSN266200700010C) (PCW, PP and FK).
• Keywords: GENERATION; Science & Technology; Medicine, Research & Experimental; INFECTION; HUMAN MONOCLONAL-ANTIBODIES; HUMANS; Research & Experimental Medicine; ANTIGEN; VIRUS; STEM; H5N1 VACCINATION; Cell Biology; Life Sciences & Biomedicine; NEUTRALIZING ANTIBODIES; HEMAGGLUTININ STALK ANTIBODIES
• Research Categories: Health Sciences, Immunology; Health Sciences, Pharmacology; Health Sciences, General

Abstract

Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal antibodies generated from vaccineinduced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, hemagglutinin (HA) stalk-biased response. Higher preexisting serum antibody levels correlated with a strain-specific HA head-dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk-reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory B cells against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies.