Childhood immune imprinting to influenza A shapes birth year-specific risk during seasonal H1N1 and H3N2 epidemics

Across decades of co-circulation in humans, influenza A subtypes H1N1 and H3N2 have caused seasonal epidemics characterized by different age distributions of cases and mortality. H3N2 causes the majority of severe, clinically attended cases in high-risk elderly cohorts, and the majority of overall deaths, whereas H1N1 causes fewer deaths overall, and cases shifted towards young and middle-aged adults. These contrasting age profiles may result from differences in childhood imprinting 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 homosubtypic immune memory or via broader, heterosubtypic memory. We also test the impact of evolutionary differences between influenza subtypes on age distributions of cases. Likelihood-based model comparison shows that narrow, within-subtype imprinting shapes seasonal influenza risk alongside age-specific risk factors. 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 consequence, 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. Author summary Influenza viruses of subtype H1N1 and H3N2 both cause seasonal epidemics in humans, but with different age-specific impacts. H3N2 causes a greater proportion of cases in older adults than H1N1, and more deaths overall. People tend to gain the strongest immune memory of influenza viruses encountered in childhood, and so differences in H1N1 and H3N2's age-specific impacts may reflect that individuals born in different eras of influenza circulation have been imprinted with different immunological risk profiles. Another idea is that H3N2 may be more able to infect immunologically experienced adults because it evolves slightly faster than H1N1 and can more quickly escape immune memory. We analyzed a large epidemiological data set and found that birth year-specific differences in childhood immune imprinting, not differences in evolutionary rate, explain differences in H1N1 and H3N2's age-specific impacts. These results can help epidemiologists understand how epidemic risk from specific influenza subtypes is distributed across the population and predict how population risk may shift as differently imprinted birth years grow older. Further, these results provide immunological clues to which facets of immune memory become biased in childhood, and then later play a strong role in protection during seasonal influenza epidemics.