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 puzzling differences in age distribution of human cases. Previous explanations cannot fully account for these patterns. We analyze data from all known human cases of H5N1 and H7N9 and show that an individual's first IAV infection confers lifelong protection against severe disease from novel hemagglutinin (HA) subtypes of the same phylogenetic group. Statistical modeling reveals protective HA imprinting to be the crucial explanatory factor, providing 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 to 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. Main TextThe spillover of novel influenza A virus (IAV) strains is a persistent threat to global public health. Current thinking assumes a central role for an immunologically naïve human population in the emergence of pandemic IAVs (1) . H5N1 and H7N9 are particularly concerning avian-origin IAVs, each having caused hundreds of severe or fatal human cases (2) . Despite commonalities in their reservoir hosts and epidemiology, these viruses show puzzling differences in age distribution of observed human cases (2,3). Explanations proposed to date, including possible protection against H5N1 from past exposure to the neuraminidase of H1N1 (4,5) and human behavioral factors (such as age bias in exposure to infected poultry) (6-8), cannot fully explain these opposing patterns of severe disease and mortality. Another idea is that severity of H5N1 and H7N9 differs by age class, leading to case ascertainment bias (2), but no explanatory mechanism has been proposed.The key determinants for IAV susceptibility are the virus's two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), where different numbered subtypes canonically indicate no cross-immunity. However, recent experiments have revealed that broadly crossprotective immune responses can provide immunity between different HA subtypes, typically within the same phylogenetic group (9-15). H5 belongs to HA group 1 (which also includes H1 and H2), while H7 is in group 2 (which includes H3). We hypothesized that the 1968 pandemic, which marked the transition from an era of group 1 HA circulation to . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/061598 doi: bioRxiv preprint first posted online Jul. 5, 2016; 2 an era dominated by a group 2 HA virus (1968-present) (Fig. 1A), caused a major shift in population susceptibility that explains why H5N1 cases are generally detected in younger people than H7N9 (3,(16)(17)(18). We found strong evidence that HA group-matched primary exposur...

Reply to Shanks and Brundage: Many plausible mechanisms of pandemic mortality disparities

“…Indeed, there is much evidence that immune responses, and hence risk of infection and disease severity, are heavily influenced by past influenza exposure (8,9). We agree with Shanks and Brundage (2) that exposure to a prior influenza strain is a plausible contributing factor in explaining age-specific mortality during the pandemic.…”

Identification and characterization of GLDC as host susceptibility gene to severe influenza

“…We sought to identify susceptibility gene(s) which may account for the inter‐individual variability to severe influenza from the GWAS previously conducted in the H7N9 cohort and the pandemic H1N1 cohort. Besides the genetic contribution, emerging evidence suggested that broadly protective immune responses due to the childhood infection can provide long‐term cross‐immunity among different HA subtypes, especially those in the same phylogenetic group (Gostic et al , ).…”

Meeting report and review: Immunological assays and correlates of protection for next‐generation influenza vaccines

“…For example, CD8+ T‐cell immunity toward epitopes against internal conserved viral proteins in both mice and ferrets is exaggerated as compared to humans and can provide very solid protection against challenge, something not observed to the same degree in humans. Another limitation of animal models is that humans have long and complex exposure histories to influenza viruses through vaccination and/or infection, including imprinting effects . These complex exposure histories influence the immune responses to subsequent infection and vaccination and cannot be effectively recapitulated in animal models (pre‐exposed ferret models can be used but are very simplified compared to humans) .…”