Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting

Abstract

Two zoonotic influenza A viruses (IAV) of global concern, H5N1 and H7N9, exhibit unexplained differences in age distribution of human cases. Using data from all known human cases of these viruses, we show that an individual's first IAV infection confers lifelong protection against severe disease from novel hemagglutinin (HA) subtypes in the same phylogenetic group. Statistical modeling shows that protective HA imprinting is the crucial explanatory factor, and it provides 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 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.

Fig. 1

HA groups and reconstruction of 20^th century HA imprinting. (A) HA groups 1 and 2, and pairwise amino acid similarities in the HA stem region. Darker colored cells indicate higher similarity (see Fig. S1). Each within-group subtype pair is more similar (83.2%–97.8%) than any between-group pair (75.9%–81.7%). (B) History of seasonal IAV circulation, and (C) estimated fraction of each birth cohort in China with initial exposure to each subtype. Estimated patterns in other countries (not shown) are identical up to 1977, and very similar thereafter. Pandemic years are marked on the horizontal axis. Blue represents group 1 HA viruses, red represents group 2, and grey represents naïve children who have not yet experienced an IAV infection.

Fig. 2

H7N9 and H5N1 observed cases and deaths by birth year (bars). Black lines show a priori prediction based on demographic age distribution and reconstructed patterns of HA imprinting. (A) 680 H7N9 cases, from China, 2013–2015. (B) 835 H5N1 cases, from Cambodia, China, Egypt, Indonesia, Thailand and Vietnam, 1997–2015. (C, D) Case data normalized to demographic age distribution from appropriate countries and case observation years.

Fig. 3

Projected effects of HA imprinting on future pandemics. (A) Attack rate of severe cases, by age group, for hypothetical H5 (blue) and H7 (red) IAV pandemics in 2015 (R₀=2.5, relative infectiousness of imprinting-protected individuals (α)=0.5), assuming UK demography and age-structured mixing (Supplementary Text). Lines show the average of 100 simulated outcomes, and shaded regions show the central 95%. Three vaccination scenarios explored: vaccination of IAV-naïve children could cause dual imprinting to both HA groups (dashed lines), prevent imprinting to both groups (dotted lines), or have no effect on imprinting (solid lines). (B) Projected change in R_eff, for hypothetical H5 (blue) or H7 (red) IAV with R₀=1.2 and α=0.5, if group 1 IAVs make up 100% or 75% of seasonal circulation after 2015.