Identification of low- and high-impact hemagglutinin amino acid substitutions that drive antigenic drift of influenza A(H1N1) viruses

Harvey, W. T., Benton, D. J., Gregory, V., Hall, J. P.J., Daniels, R. S., Bedford, T., Haydon, D. T. , Hay, A. J., McCauley, J. W. and Reeve, R. (2016) Identification of low- and high-impact hemagglutinin amino acid substitutions that drive antigenic drift of influenza A(H1N1) viruses. PLoS Pathogens, 12(4), e1005526. (doi:10.1371/journal.ppat.1005526) (PMID:27057693) (PMCID:PMC4825936)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Haydon, Professor Daniel and Reeve, Dr Richard and Harvey, Dr William
Authors: Harvey, W. T., Benton, D. J., Gregory, V., Hall, J. P.J., Daniels, R. S., Bedford, T., Haydon, D. T., Hay, A. J., McCauley, J. W., and Reeve, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Published Online:08 April 2016
Copyright Holders:Copyright © 2016 Harvey et al
First Published:First published in PLoS Pathogens 12(4): e1005526
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
580941MRC Doctoral Training Grant 2011-2015Mary Beth KneafseyMedical Research Council (MRC)MR/J50032X/1VICE PRINCIPAL RESEARCH & ENTERPRISE
473581Interactions and structures in antigenic variationJ BarryWellcome Trust (WELLCOME)083224/Z/07/ZIII - BACTERIOLOGY
507161Improving the quality of FMD (Foot-and-mouth disease) vaccines by understanding the correlation of vaccine-induced protection with humoral and cellular immune responsesRichard ReeveBiotechnology and Biological Sciences Research Council (BBSRC)BB/H009175/1RI BIODIVERSITY ANIMAL HEALTH & COMPMED