title: Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses.
abstract: Determining phenotype from genetic data is a fundamental challenge. Identification of emerging antigenic variants among circulating influenza viruses is critical to the vaccine virus selection process, with vaccine effectiveness maximized when constituents are antigenically similar to circulating viruses. Hemagglutination inhibition (HI) assay data are commonly used to assess influenza antigenicity. Here, sequence and 3-D structural information of hemagglutinin (HA) glycoproteins were analyzed together with corresponding HI assay data for former seasonal influenza A(H1N1) virus isolates (1997-2009) and reference viruses. The models developed identify and quantify the impact of eighteen amino acid substitutions on the antigenicity of HA, two of which were responsible for major transitions in antigenic phenotype. We used reverse genetics to demonstrate the causal effect on antigenicity for a subset of these substitutions. Information on the impact of substitutions allowed us to predict antigenic phenotypes of emerging viruses directly from HA gene sequence data and accuracy was doubled by including all substitutions causing antigenic changes over a model incorporating only the substitutions with the largest impact. The ability to quantify the phenotypic impact of specific amino acid substitutions should help refine emerging techniques that predict the evolution of virus populations from one year to the next, leading to stronger theoretical foundations for selection of candidate vaccine viruses. These techniques have great potential to be extended to other antigenically variable pathogens.
authors.affiliation: Boyd Orr Centre for Population and Ecosystem Health and Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: William T
authors.initials: WT
authors.lastname: Harvey
authors.affiliation: The Crick Worldwide Influenza Centre, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, United Kingdom (formerly WHO Collaborating Centre for Reference and Research on Influenza, Division of Virology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom).
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Benton
authors.affiliation: The Crick Worldwide Influenza Centre, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, United Kingdom (formerly WHO Collaborating Centre for Reference and Research on Influenza, Division of Virology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom).
authors.forename: Victoria
authors.initials: V
authors.lastname: Gregory
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: James P J
authors.initials: JP
authors.lastname: Hall
authors.affiliation: The Crick Worldwide Influenza Centre, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, United Kingdom (formerly WHO Collaborating Centre for Reference and Research on Influenza, Division of Virology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom).
authors.forename: Rodney S
authors.initials: RS
authors.lastname: Daniels
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Trevor
authors.initials: T
authors.lastname: Bedford
authors.affiliation: Boyd Orr Centre for Population and Ecosystem Health and Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Haydon
authors.affiliation: The Crick Worldwide Influenza Centre, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, United Kingdom (formerly WHO Collaborating Centre for Reference and Research on Influenza, Division of Virology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom).
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Hay
authors.affiliation: The Crick Worldwide Influenza Centre, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, United Kingdom (formerly WHO Collaborating Centre for Reference and Research on Influenza, Division of Virology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom).
authors.forename: John W
authors.initials: JW
authors.lastname: McCauley
authors.affiliation: Boyd Orr Centre for Population and Ecosystem Health and Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Reeve
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000940:Antigenic Variation / Q000235:genetics / Q000276:immunology; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology; D007251:Influenza, Human / Q000821:virology*; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D010802:Phylogeny
chemical_list: D000956:Antigens, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines