Two zoonotic influenza A viruses (IAV) of global concern, H5N1 and H7N9, exhibit puzzling differences in age distribution of human cases. Previous explanations cannot fully account for these patterns. We analyze data from all known human cases of H5N1 and H7N9 and show that an individual's first IAV infection confers lifelong protection against severe disease from novel hemagglutinin (HA) subtypes of the same phylogenetic group. Statistical modeling reveals protective HA imprinting to be the crucial explanatory factor, providing 75% protection against severe infection and 80% protection against death for both H5N1 and H7N9. Our results enable us to predict age distributions of severe disease for future pandemics and to demonstrate that a novel strain's pandemic potential increases yearly when a group-mismatched HA subtype dominates seasonal influenza circulation. These findings open new frontiers for rational pandemic risk assessment.
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