Background Highly pathogenic avian influenza A(H5) viruses pose a pandemic threat, with a history of zoonotic spillovers into humans that are presumed immunologically na?ve. Whether the general population is currently immunologically na?ve to circulating A(H5) influenza viruses is unknown.

Methods To evaluate the presence of cross-reactive immune responses to emerging A(H5) clade 2.3.4.4b influenza viruses in the general population, we conducted comprehensive immune profiling on cross-sectional samples from healthcare workers (n=107). Samples were collected in August and September 2024 in the scope of an ongoing prospective follow-up study: ‘Surveillance of rEspiratory viruses iN healThcare and anImal workers in the NethErLands’ (SENTINEL).

Findings Low-level antibody responses directed against the A(H5) hemagglutinin (HA) head were detected in a limited number of individuals, but without hemagglutination inhibition activity. Nevertheless, we detected in most participants A(H5)-reactive antibodies with Fc-effector functions, likely directed at the conserved HA stalk. Additionally, we observed abundant neuraminidase (NA) inhibiting antibodies against avian N1s and T-cell responses against HAs and NAs from A(H5) influenza viruses. These responses correlated strongly with immune responses targeting an A(H1N1) seasonal influenza virus, indicating they were likely induced by prior exposures.

Interpretation Together, our findings suggest that partial cross-reactive immunity to A(H5) influenza viruses exists in humans, which may play an important role during future outbreaks, potentially by blunting disease severity. Characterizing such baseline immunity is crucial for accurate pandemic risk assessment and preparedness planning.