10779/crick.11409672.v1 Joshua E Sealy Joshua E Sealy Tahir Yaqub Tahir Yaqub Thomas P Peacock Thomas P Peacock Pengxiang Chang Pengxiang Chang Burcu Ermetal Burcu Ermetal Anabel Clements Anabel Clements Jean-Remy Sadeyen Jean-Remy Sadeyen Arslan Mehboob Arslan Mehboob Holly Shelton Holly Shelton Juliet E Bryant Juliet E Bryant Rod S Daniels Rod S Daniels John W McCauley John W McCauley Munir Iqbal Munir Iqbal Association of increased receptor-binding avidity of influenza A(H9N2) viruses with escape from antibody-based immunity and enhanced zoonotic potential The Francis Crick Institute 2019 Pakistan antibody-based immunity enhanced zoonotic potential influenza influenza A(H9N2) virus receptor-binding avidity respiratory infections virus escape viruses zoonoses Animals Antibodies, Viral Antibody Affinity Antigenic Variation Binding Sites Erythrocytes Hemagglutinin Glycoproteins, Influenza Virus Humans Influenza A Virus, H9N2 Subtype Influenza in Birds Neuraminidase Phylogeny Poultry Poultry Diseases Receptors, Cell Surface Zoonoses McCauley FC001030 WIC 1108 Medical Microbiology 1117 Public Health and Health Services 1103 Clinical Sciences Microbiology 2019-12-19 18:07:47 Journal contribution https://crick.figshare.com/articles/journal_contribution/Association_of_increased_receptor-binding_avidity_of_influenza_A_H9N2_viruses_with_escape_from_antibody-based_immunity_and_enhanced_zoonotic_potential/11409672 We characterized 55 influenza A(H9N2) viruses isolated in Pakistan during 2014-2016 and found that the hemagglutinin gene is of the G1 lineage and that internal genes have differentiated into a variety of novel genotypes. Some isolates had up to 4-fold reduction in hemagglutination inhibition titers compared with older viruses. Viruses with hemagglutinin A180T/V substitutions conveyed this antigenic diversity and also caused up to 3,500-fold greater binding to avian-like and >20-fold greater binding to human-like sialic acid receptor analogs. This enhanced binding avidity led to reduced virus replication in primary and continuous cell culture. We confirmed that altered receptor-binding avidity of H9N2 viruses, including enhanced binding to human-like receptors, results in antigenic variation in avian influenza viruses. Consequently, current vaccine formulations might not induce adequate protective immunity in poultry, and emergence of isolates with marked avidity for human-like receptors increases the zoonotic risk.