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

Abstract

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.

Fig 1. Model and expectations under different imprinting hypotheses.

(A) Reconstructed, birth year-specific probabilities of imprinting (representative example specific to cases observed in 2015). Throughout the manuscript, group 1 HA subtypes are represented in blue and group 2 subtypes in red. (B) Expected imprinting protection against H1N1 or H3N2 under the three tested models. (C) Cartoon of expected age distribution of any influenza case, before controlling for subtype-specific imprinting. The shape of this curve is purely hypothetical, but each of our tested models combined demographic age distribution with a fitted, age-specific risk step function to generate similar, data-driven curves. (D-F) Fraction of each birth year unprotected by their childhood imprinting (from A) determines the shape of birth year-specific risk. (G-I) A linear combination of demography plus age-specific risk (as in C), and birth year-specific risk (as in D-F) give the expected age distribution of H1N1 or H3N2 cases under each model.

Fig 2. Observed age distributions, Arizona.

Points show fraction of confirmed H1N1 or H3N2 cases observed in each single year of age. Lines show a smoothing spline fit to observed distributions. (A) All confirmed cases in the data (aggregate across all seasons). (B-F) Age distributions from individual seasons in which both H1N1 and H3N2 circulated (seasons with ≥ 50 confirmed cases of each subtype are shown here. See S1 Fig. for all seasons).

Fig 3. Model fits and model selection.

(A) Fitted effects of age, after controlling for demographic age distribution and (B) imprinting effects from the NA subtype-level imprinting model, which provided the best fit to data. (C-D) Model fits to observed age distributions of H1N1 (C) and H3N2 (D) case. All models included demographic age distribution and age-specific risk.

Fig 4. Effect of antigenic advance on age distribution.

(A) Relationship between annual antigenic advance and the fraction of cases observed in children (0–10), or in adult age groups. Each data point represents a single influenza season in which at least 100 confirmed cases of a given subtype were observed. Blue label shows Spearman correlation between the fraction of H3N2 cases observed in each age group and annual antigenic advance. Blue dashes show linear trend fitted using lm() in R. (B) Season-specific age distributions of cases, colored by antigenic advance since the previous season.