Across decades of co-circulation in humans, influenza A subtypes H1N1 and H3N2 have caused seasonal epidemics characterized by different age distributions of infection and mortality. H3N2 causes the majority of cases in high-risk elderly cohorts, and the majority of overall deaths, whereas H1N1 causes incidence shifted towards young and middle-aged adults, and fewer deaths. These contrasting age profiles may result from differences in childhood exposure to H1N1 and H3N2 or from differences in evolutionary rate between subtypes. Here we analyze a large epidemiological surveillance dataset to test whether childhood immune imprinting shapes seasonal influenza epidemiology, and if so, whether it acts primarily via immune memory of a particular influenza subtype or via broader immune memory that protects across subtypes. We also test the impact of evolutionary differences between influenza subtypes on age distributions of infection. Likelihood-based model comparison shows that narrow, within-subtype imprinting is the strongest driver of seasonal influenza risk. The data do not support a strong effect of evolutionary rate, or of broadly protective imprinting that acts across subtypes. Our findings emphasize that childhood exposures can imprint a lifelong immunological bias toward particular influenza subtypes, and that these cohort-specific biases shape epidemic age distributions. As a result, newer and less "senior" antibody responses acquired later in life do not provide the same strength of protection as responses imprinted in childhood. Finally, we project that the relatively low mortality burden of H1N1 may increase in the coming decades, as cohorts that lack H1N1-specific imprinting eventually reach old age.

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