Panzootic H5 influenza viruses acquired resistance to human head interface antibodies

Antibodies to the influenza hemagglutinin protein (HA) confer the strongest protection against infection. Immunity elicited by endemic, seasonal, human viruses is correlated with diminished disease severity and death caused by antigenically novel viruses. Antibodies to the HA head interface are broadly protective and abundant in human serologic and memory repertoires. Notably, few head interface antibodies from H5 naive donors are reported to bind H5 HAs. We find head interface antibodies engage a wide range of H5 isolates but fail to engage most isolates from the goose Guangdong (GsGd) lineage. We identify a single substitution, P221S, largely dictates antibody binding. Phylogenetic analysis indicates that P221S arose in a Chinese avian reservoir by the year 2000. Descendants of these viruses have caused the current global panzootic and have achieved sustained mammal-mammal transmission in farmed and wild mammals. Our findings demonstrate that viral evolution in non-mammalian species can, by chance, produce viruses that resist broadly protective human antibody responses.