Background
There is an urgent need to understand the immune correlates of protection against avian influenza viruses (AIV), where pre-existing immunity may be limited.

Methods
Here, we characterized the antibody response in 12 severely ill A(H7N9) patients and examined its association with early-life imprinting and clinical outcome.

Results
We find that A(H7N9) patients imprinted with A(H2N2) during early life show minimal H7-IgM and a rapid IgG response across diverse hemagglutinin subtypes. They also have more high avidity H7-antibodies compared to older or younger patients. Early antibody titers against seasonal H1, H3, and conserved stalk domains trend negatively with clinical severity in A(H7N9) infection, while an inverse pattern is observed following severe A(H1N1) infection, potentially suggesting a different mechanism of immune regulation between seasonal and avian influenza virus infections.

Conclusions
These data provide direct serological evidence that birth imprinting profoundly shapes the humoral immune landscape during zoonotic influenza infection and may influence subsequent disease outcome.