Neuraminidase imprinting and the age-related risk of zoonotic influenza

Highly pathogenic avian influenza of the H5N1 subtype has shown recent unprecedented expansion in its geographic and host range, increasing the pandemic threat. The younger age of H5N1 versus H7N9 avian influenza in humans has previously been attributed to imprinted pre-immunity to hemagglutinin stalk (HA2) epitopes shared with group 1 (H1N1, H2N2) versus group 2 (H3N2) influenza A subtypes predominating in the human population before versus after 1968, respectively. Here we review the complex immuno-epidemiological interactions underpinning influenza risk assessment and extend the imprinting hypothesis to include a potential role for cross-protective neuraminidase (NA) imprinting. We compare H5N1 distributions and case fatality ratios by age and birth cohort (as proxy for HA2 and/or NA imprinting epoch) not only to H7N9 but also H5N6 and H9N2 avian influenza, representing more varied conditions of zoonotic influenza relatedness to human subtypes of the past century. We show homosubtypic NA imprinting likely further modulates the age-related risk of zoonotic H5N1 and H9N2, with implications for pandemic risk assessment and response.