title: Immune history profoundly affects broadly protective B cell responses to influenza.
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 vaccine-induced 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.
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Andrews
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA. Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Kaval
authors.initials: K
authors.lastname: Kaur
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Lyubov I
authors.initials: LI
authors.lastname: Popova
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Irvin Y
authors.initials: IY
authors.lastname: Ho
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA. Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Noel T
authors.initials: NT
authors.lastname: Pauli
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Carole J
authors.initials: CJ
authors.lastname: Henry Dunand
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Taylor
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Lim
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Qu
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jane-Hwei
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Marlene
authors.initials: M
authors.lastname: Salgado-Ferrer
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: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 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: Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Wrammert
authors.affiliation: Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA. Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA. wilsonp@uchicago.edu.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D001402:B-Lymphocytes / Q000821:virology*; D002469:Cell Separation; D004285:Dogs; D000939:Epitopes / Q000276:immunology; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000821:virology*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D020349:Surface Plasmon Resonance
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines