Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-07, Vol.112 (30), p.9346-9351
• Main Authors: Winarski, Katie L, Natalie J. Thornburg, Yingchun Yu, Gopal Sapparapu, James. E. Crowe, Benjamin W. Spiller
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; aerosols; affinity maturation; Amino Acid Sequence; antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Viral - chemistry; antigen recognition; Binding Sites; Biological Sciences; birds; Cells; Crystallography, X-Ray; ferrets; Genetic Variation; Glycoproteins; Hemagglutinin Glycoproteins, Influenza Virus - chemistry; hemagglutinins; human diseases; Humans; immune response; Immune system; immunity; Immunoglobulin Fragments - chemistry; Influenza; Influenza A virus; Influenza A Virus, H5N1 Subtype - immunology; Influenza Vaccines - immunology; Influenza, Human - immunology; Molecular Conformation; Molecular Sequence Data; Mustela; Mutation; N-Acetylneuraminic Acid - chemistry; Neutralization; Pandemics; Protein Binding; Protein Structure, Tertiary; Sequence Homology, Amino Acid; structural biology; Vaccines
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1502762112

Antigenic drift of circulating seasonal influenza viruses necessitates an international vaccine effort to reduce the impact on human health. A critical feature of the seasonal vaccine is that it stimulates an already primed immune system to diversify memory B cells to recognize closely related, but antigenically distinct, influenza glycoproteins (hemagglutinins). Influenza pandemics arise when hemagglutinins to which no preexisting adaptive immunity exists acquire the capacity to infect humans. Hemagglutinin 5 is one subtype to which little preexisting immunity exists and is only a few acquired mutations away from the ability to transmit efficiently between ferrets, and possibly humans. Here, we describe the structure and molecular mechanism of neutralization by H5.3, a vaccine-elicited antibody that neutralizes hemagglutinin 5 viruses and variants with expanded host range. H5.3 binds in the receptor-binding site, forming contacts that recapitulate many of the sialic acid interactions, as well as multiple peripheral interactions, yet is not sensitive to mutations that alter sialic acid binding. H5.3 is highly specific for a subset of H5 strains, and this specificity arises from interactions to the periphery of the receptor-binding site. H5.3 is also extremely potent, despite retaining germ line-like conformational flexibility. A small number of mutations to the viral hemagglutinin are sufficient to permit aerosol transmission, in a ferret model of human infection, of highly pathogenic avian H5N1 influenza A viruses. Here, we show how an antibody (H5.3) against hemagglutinin 5 (H5) recognizes both WT and variant H5 proteins. H5.3 retains germ-line characteristics, most remarkably a conformationally flexible combining site, consistent with an antibody that has not been through multiple cycles of affinity maturation. Many antibodies against H5 are lightly mutated and may arise from naive B cells, explaining the low antigenicity of H5N1 vaccines relative to seasonal influenza vaccines and supporting the idea that multiple exposures are necessary to develop a strong immune response to H5N1 strains.