title: Anti-HA Glycoforms Drive B Cell Affinity Selection and Determine Influenza Vaccine Efficacy.
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.
authors.affiliation: The Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Taia T
authors.initials: TT
authors.lastname: Wang
authors.affiliation: The Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Jad
authors.initials: J
authors.lastname: Maamary
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Gene S
authors.initials: GS
authors.lastname: Tan
authors.affiliation: The Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Bournazos
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Carl W
authors.initials: CW
authors.lastname: Davis
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Krammer
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Schlesinger
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: The Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: ravetch@rockefeller.edu.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000737:chemistry; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology*; D010950:Plasma Cells / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry / Q000276:immunology*; D011961:Receptors, Fc / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; D012794:Sialic Acids