title: Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin.
abstract: Seasonal antigenic drift of circulating influenza virus leads to a requirement for frequent changes in vaccine composition, because exposure or vaccination elicits human antibodies with limited cross-neutralization of drifted strains. We describe a human monoclonal antibody, CH65, obtained by isolating rearranged heavy- and light-chain genes from sorted single plasma cells, coming from a subject immunized with the 2007 trivalent influenza vaccine. The crystal structure of a complex of the hemagglutinin (HA) from H1N1 strain A/Solomon Islands/3/2006 with the Fab of CH65 shows that the tip of the CH65 heavy-chain complementarity determining region 3 (CDR3) inserts into the receptor binding pocket on HA1, mimicking in many respects the interaction of the physiological receptor, sialic acid. CH65 neutralizes infectivity of 30 out of 36 H1N1 strains tested. The resistant strains have a single-residue insertion near the rim of the sialic-acid pocket. We conclude that broad neutralization of influenza virus can be achieved by antibodies with contacts that mimic those of the receptor.
authors.affiliation: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: James R R
authors.initials: JR
authors.lastname: Whittle
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhang
authors.forename: Surender
authors.initials: S
authors.lastname: Khurana
authors.forename: Lisa R
authors.initials: LR
authors.lastname: King
authors.forename: Jody
authors.initials: J
authors.lastname: Manischewitz
authors.forename: Hana
authors.initials: H
authors.lastname: Golding
authors.forename: Philip R
authors.initials: PR
authors.lastname: Dormitzer
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Emmanuel B
authors.initials: EB
authors.lastname: Walter
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology; D000915:Antibody Affinity / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology*; D001665:Binding Sites; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000276:immunology; D006031:Glycosylation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D011991:Receptors, Virus / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022801:Complementarity Determining Regions; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus