title: Immunogenic Stimulus for Germline Precursors of Antibodies that Engage the Influenza Hemagglutinin Receptor-Binding Site.
abstract: Influenza-virus antigenicity evolves to escape host immune protection. Antibody lineages within individuals evolve in turn to increase affinity and hence potency. Strategies for a "universal" influenza vaccine to elicit lineages that escape this evolutionary arms race and protect against seasonal variation and novel, pandemic viruses will require directing B cell ontogeny to focus the humoral response on conserved epitopes on the viral hemagglutinin (HA). The unmutated common ancestors (UCAs) of six distinct, broadly neutralizing antibody lineages from one individual bind the HA of a virus circulating at the time the participant was born. HAs of viruses circulating more than 5 years later no longer bind the UCAs, but mature antibodies in the lineages bind strains from the entire 18-year lifetime of the participant. The analysis shows how immunological memory shaped the response to subsequent influenza exposures and suggests that early imprinting by a suitable influenza antigen may enhance likelihood of later breadth.
authors.affiliation: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Schmidt
authors.affiliation: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Khoi T
authors.initials: KT
authors.lastname: Do
authors.affiliation: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: McCarthy
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710, USA; Department of Medicine, Duke University Medical School, Durham, NC 27710, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical School, Durham, NC 27710, USA; Department of Immunology, Duke University Medical School, Durham, NC 27710, USA.
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710, USA; Department of Medicine, Duke University Medical School, Durham, NC 27710, USA; Department of Immunology, Duke University Medical School, Durham, NC 27710, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA. Electronic address: harrison@crystal.harvard.edu.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
mesh_terms: D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology*; D000917:Antibody Formation; D001665:Binding Sites; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology; D011485:Protein Binding
chemical_list: D057134:Antibodies, Neutralizing; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines