Anti-HA Glycoforms Drive B Cell Affinity Selection and Determine Influenza Vaccine Efficacy

• Type of Material: Article
• Authors: Taia T. Wang, Rockefeller University; Jad Maamary, Rockefeller University; Gene S. Tan, Icahn School of Medicine at Mount Sinai; Stylianos Bournazos, Rockefeller University; Carl Davis, Emory University; Florian Krammer, Icahn School of Medicine at Mount Sinai; Sarah J. Schlesinger, Rockefeller University; Peter Palese, Icahn School of Medicine at Mount Sinai; Rafi Ahmed, Emory University; Jeffrey V. Ravetch, Rockefeller University
• Language: English
• Date: 2015-07-02
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2015.06.026
• Title of Journal or Parent Work: Cell
• ISSN: 0092-8674
• Volume: 162
• Issue: 1
• Start Page: 160
• End Page: 169
• Grant/Funding Information: TTW was supported as a Rockefeller University Clinical Scholar in part by the Iris and Junming Le Foundation, the Rockefeller University Center for Clinical and Translational Science grant # UL1 TR000043 from the National Center for Advancing Translational Sciences, National Institutes of Health and the Clinical and Translational Science Award program.; FK was supported in part by the Centers of Excellence for Influenza Research and Surveillance, contract # HHSN266200700010C.; Research reported in this publication was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number U19AI111825 (J. Ravetch) and U19AI109946 (P. Palese).
• Keywords: RHEUMATOID-ARTHRITIS; GLOBULAR HEAD; FC-GAMMA-RIII; Life Sciences & Biomedicine; MECHANISM; SIALYLATION; Cell Biology; EFFECTOR FUNCTIONS; ANTIBODIES; Biochemistry & Molecular Biology; Science & Technology; VIRUS; IGG1; ANTIINFLAMMATORY ACTIVITY
• Research Categories: Biology, Microbiology; Biology, Cell; Health Sciences, Immunology

Abstract

Protective vaccines elicit high-affinity, neutralizing antibodies by selection of somatically hypermutated B cell antigen receptors (BCR) on immune complexes (ICs). This implicates Fc-Fc receptor (FcR) interactions in affinity maturation, which, in turn, are determined by IgG subclass and Fc glycan composition within ICs. Trivalent influenza virus vaccination elicited regulation of anti-hemagglutinin (HA) IgG subclass and Fc glycans, with abundance of sialylated Fc glycans (sFc) predicting quality of vaccine response. We show that sFcs drive BCR affinity selection by binding the Type-II FcR CD23, thus upregulating the inhibitory FcγRIIB on activated B cells. This elevates the threshold requirement for BCR signaling, resulting in B cell selection for higher affinity BCR. Immunization with sFc HA ICs elicited protective, high-affinity IgGs against the conserved stalk of the HA. These results reveal a novel, endogenous pathway for affinity maturation that can be exploited for eliciting high-affinity, broadly neutralizing antibodies through immunization with sialylated immune complexes.