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The molecular basis of antigenic variation among A(H9N2) avian influenza viruses

View ORCID ProfileThomas P. Peacock, View ORCID ProfileWilliam T. Harvey, Jean-Remy Sadeyen, View ORCID ProfileRichard Reeve, Munir Iqbal
doi: https://doi.org/10.1101/312967
Thomas P. Peacock
1Avian Influenza Group, The Pirbright Institute, Pirbright, Woking, UK
2Department of Virology, Imperial College London, UK
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William T. Harvey
3Boyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
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Jean-Remy Sadeyen
1Avian Influenza Group, The Pirbright Institute, Pirbright, Woking, UK
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Richard Reeve
3Boyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
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  • For correspondence: richard.reeve@glasgow.ac.uk
Munir Iqbal
1Avian Influenza Group, The Pirbright Institute, Pirbright, Woking, UK
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Abstract

Avian influenza A(H9N2) viruses are an increasing threat to global poultry production and, through zoonotic infection, to human health where they are considered viruses with pandemic potential. Vaccination of poultry is a key element of disease control in endemic countries, but vaccine effectiveness is persistently challenged by the emergence of antigenic variants. Here we employed a combination of techniques to investigate the genetic basis of H9N2 antigenic variability and evaluate the role of different molecular mechanisms of immune escape. We systematically tested the influence of published H9N2 monoclonal antibody escape mutants on chicken antisera binding, determining that many have no significant effect. Substitutions introducing additional glycosylation sites were a notable exception, though these are relatively rare among circulating viruses. To identify substitutions responsible for antigenic variation in circulating viruses, we performed an integrated meta-analysis of all published H9 haemagglutinin sequences and antigenic data. We validated this statistical analysis experimentally and allocated several new residues to H9N2 antigenic sites providing molecular markers that will help explain vaccine breakdown in the field and inform vaccine selection decisions. We find evidence for the importance of alternative mechanisms of immune escape, beyond simple modulation of epitope structure, with substitutions increasing glycosylation or receptor-binding avidity exhibiting the largest impacts on chicken antisera binding. Of these, meta-analysis indicates avidity regulation to be more relevant to the evolution of circulating viruses, suggesting that a specific focus on avidity regulation is required to fully understand the molecular basis of immune escape by influenza, and potentially other viruses.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 26, 2018.
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The molecular basis of antigenic variation among A(H9N2) avian influenza viruses
Thomas P. Peacock, William T. Harvey, Jean-Remy Sadeyen, Richard Reeve, Munir Iqbal
bioRxiv 312967; doi: https://doi.org/10.1101/312967
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The molecular basis of antigenic variation among A(H9N2) avian influenza viruses
Thomas P. Peacock, William T. Harvey, Jean-Remy Sadeyen, Richard Reeve, Munir Iqbal
bioRxiv 312967; doi: https://doi.org/10.1101/312967

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