Divergent antibody-mediated population immunity to H5, H7 and H9 subtype potential pandemic influenza viruses
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Influenza continues to cause significant mortality globally and has substantial pandemic potential. Assessing pandemic risk requires a clear understanding of existing population immunity. Leveraging a unique large-scale cohort of human sera, we evaluated total and neutralising antibody-mediated immunity to multiple haemagglutinin (HA) proteins, including those from subtypes with high pandemic potential. Our analysis reveals that population immunity is heterogeneous, with distinct age-dependent differences in responses to H5, H7, and H9 subtypes. These shifts align with historical circulation patterns of seasonal H1N1 and H3N2 viruses. Notably, H7 viruses were primarily neutralised through head domain epitopes, while H5 viruses were targeted mainly via stem epitopes - although in both instances some neutralisation occurred via receptor binding site-adjacent epitopes. Furthermore, H7 responses were dominated by IgG2 antibodies that remained after glycan removal, whereas H5 responses were primarily IgG1-mediated. These findings highlight varying levels of susceptibility across the population, supporting exposure history-informed vaccination approaches.
