Childhood immune imprinting shapes cohort and period influenza mortality.

Influenza viruses encountered in childhood can leave a lasting immunological imprint. To disentangle the mortality effects of age, the circulating seasonal strain, and immune history, we fit statistical mortality models to 54 years of influenza mortality data from the United States. We find strong signatures of subtype-level imprinting in H1N1-dominated seasons following the 2009 pandemic-cohorts imprinted with more similar H1N1 strains experience greater protection. Furthermore, we find large differences in age-specific mortality risk across cohorts based on their imprinted strain and the seasonal strains that were dominant throughout their lifetime. In contrast to older H1N1- and H2N2-imprinted cohorts, our results show that more recent cohorts imprinted with H3N2 have experienced substantially higher mortality through most of their lifetime. Our results highlight the long-term consequences of immune imprinting and its impact on period and cohort influenza mortality. Overall, our findings have important implications for vaccination efforts and future influenza mortality burden.