www.thelancet.com/microbe | 2026
14 April 2026
Highly pathogenic avian influenza A(H5) viruses, particularly those belonging to clade 2.3.4.4b, represent a persistent and evolving pandemic threat as they continue to spread globally among birds and spill over into mammalian populations. A critical question for pandemic preparedness is whether human populations possess any degree of pre-existing immunity to these viruses. A new observational study conducted in the Netherlands and published in The Lancet Microbe provides a comprehensive map of baseline immunity, suggesting that previous exposure to seasonal influenza has equipped many humans with a significant, albeit partial, immune defense against these avian strains.
The research team analyzed blood samples from 107 healthcare workers in the SENTINEL cohort to profile various arms of the immune system, including antibody binding, neutralization capacity, Fc-effector functions, and T-cell responses. While the study found that neutralizing antibodies, specifically those measured by hemagglutination inhibition assays, were entirely absent across the cohort, nearly all participants possessed other functional defenses. Specifically, every participant exhibited antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC) against H5 antigens, a mechanism that helps the body clear infected cells.
These cross-reactive responses appear to be driven by "molecular mimicry" or shared structural features between avian H5 viruses and the seasonal A(H1N1) viruses that regularly circulate in humans. The study found a strong positive correlation between immune responses targeting seasonal H1N1 and those targeting H5N1, particularly regarding neuraminidase (NA) inhibition and antibodies directed at the conserved "stalk" region of the hemagglutinin (HA) protein. Notably, high levels of antibodies with NA inhibition activity against avian N1 were detected in up to 97% of the healthcare workers.
Beyond antibodies, the researchers identified robust cellular immunity, with 43% to 69% of participants demonstrating T-cell responses against the HA and NA proteins of H5 viruses. These T cells, which recognize conserved internal epitopes, are thought to play a vital role in limiting the severity of the disease even when infection cannot be prevented. While this pre-existing immunity is unlikely to provide "sterilizing immunity" that prevents infection altogether, the authors suggest it could significantly blunt the severity of illness during a potential H5 pandemic. Characterizing this baseline landscape is considered a crucial step for accurate risk assessment and the development of future vaccination strategies.
