Background
Highly pathogenic avian influenza A(H5) viruses pose a pandemic threat, with a history of mammalian adaptation and zoonotic spillovers into humans. We aimed to determine whether pre-existing cross-reactive immune responses to A(H5) clade 2.3.4.4b influenza viruses detected between 2020 and 2024 are present in the general population.
Methods
We conducted an observational, cross-sectional study within the prospective Surveillance of Respiratory Viruses in Healthcare and Animal Workers in the Netherlands (SENTINEL) cohort, in which we analysed a subset of health-care workers aged 18 years or older who provided blood samples at a periodic study visit in August or September, 2024. Blood samples were analysed for influenza A(H5)-specific antibody binding, haemagglutination inhibition, Fc-effector functions, neuraminidase (NA) inhibition, and T-cell responses.
Findings
We included 107 health-care workers. Participants’ median age was 50·0 years (IQR 40·0–58·0); 77 (72%) health-care workers were female, 29 (27%) were male, and one (1%) did not report their biological sex. Virus-specific antibodies were measured in 106 serum samples. Low-level binding antibodies directed against the A(H5) haemagglutinin (HA) head were detected in up to 28 individuals (depending on the antigen), but without haemagglutination inhibition activity. Nevertheless, we detected A(H5)-reactive antibodies with Fc-effector functions in all participants. Additionally, we observed high levels of antibodies with NA inhibition activity (geometric mean titre 208 [95% CI 153–284]) in up to 97% of the health-care workers against avian N1, and T-cell responses against HA and NA from A(H5) influenza viruses in 43–69% (46–74 of 107) health-care workers. A(H5)-specific responses correlated with immune responses targeting A(H1N1).
Interpretation
Together, our findings suggest that partial cross-reactive immunity to A(H5) influenza viruses exists in humans, likely induced by previous exposures to seasonal influenza viruses. This partial cross-reactive immunity might play an important role during future outbreaks, potentially by blunting disease severity. Characterising pre-existing baseline immunity is crucial for accurate pandemic risk assessment and preparedness planning.