title: Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells.
abstract: We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority (25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection.
authors.affiliation: Emory Vaccine Center, Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Gui-Mei
authors.initials: GM
authors.lastname: Li
authors.forename: Christopher
authors.initials: C
authors.lastname: Chiu
authors.forename: Jens
authors.initials: J
authors.lastname: Wrammert
authors.forename: Megan
authors.initials: M
authors.lastname: McCausland
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Andrews
authors.forename: Nai-Ying
authors.initials: NY
authors.lastname: Zheng
authors.forename: Jane-Hwei
authors.initials: JH
authors.lastname: Lee
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Xinyan
authors.initials: X
authors.lastname: Qu
authors.forename: Srilatha
authors.initials: S
authors.lastname: Edupuganti
authors.forename: Mark
authors.initials: M
authors.lastname: Mulligan
authors.forename: Suman R
authors.initials: SR
authors.lastname: Das
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yewdell
authors.forename: Aneesh K
authors.initials: AK
authors.lastname: Mehta
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007156:Immunologic Memory / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010802:Phylogeny; D017422:Sequence Analysis, DNA
chemical_list: D000911:Antibodies, Monoclonal; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D007252:Influenza Vaccines