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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
1Influenza 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
1Influenza 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
1Influenza Group, The Pirbright Institute, Pirbright, Woking, UK
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Abstract

Avian influenza A(H9N2) viruses are a threat to global poultry production as well as human health through zoonotic infection and are therefore considered viruses with pandemic potential. Vaccination of poultry is a key element of disease control in endemic countries and human vaccination would be a major component of the response in a pandemic situation. Vaccine effectiveness is however persistently challenged by the emergence of antigenically variant H9N2 viruses. Here we employed a combination of techniques to provide an enhanced understanding of the genetic basis of H9N2 antigenic variability and evaluate the role of different molecular mechanisms of immune escape. We collated every published H9N2 monoclonal antibody escape mutant and systematically tested their influence on polyclonal chicken antiserum binding, determining that many have no significant effect in this vital context. Amino acid substitutions introducing additional glycosylation sites were a notable exception; however, these are relatively rare among circulating viruses. To identify substitutions responsible for antigenic variation among circulating viruses, we performed an integrated meta-analysis of all published H9 haemagglutinin sequences and antigenic data from serological assays. We validated this statistical analysis experimentally using reverse genetics and allocated several new residues to H9N2 antigenic sites using a panel of previously characterised monoclonal antibodies. These results provide new molecular markers of antigenic change for H9N2 viruses that will help explain vaccine breakdown in the field. Conventionally, changes to epitope structure determine antigenicity. We find evidence for the importance of other mechanisms of immune escape, 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 May 02, 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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