#19,118
Until relatively recently it was assumed that most of the world's population had little to no immunity against HPAI H5 viruses. In June of 2024 (see CDC A(H5N1) Bird Flu Response Update: Population Immunity to A(H5N1) clade 2.3.3.4b Viruses) the CDC reported:
Data from this study suggest that there is extremely low to no population immunity to clade 2.3.4.4b A(H5N1) viruses in the United States. Antibody levels remained low regardless of whether or not the participants had gotten a seasonal flu vaccination, meaning that seasonal flu vaccination did not produce antibodies to A(H5N1) viruses.
This means that there is little to no pre-existing immunity to this virus and most of the population would be susceptible to infection from this virus if it were to start infecting people easily and spreading from person-to-person. This finding is not unexpected because A(H5N1) viruses have not spread widely in people and are very different from current and recently circulating human seasonal influenza A viruses.
Since then, however, we've seen a number of studies which have reported serological evidence of limited immunity - particularly in older cohorts - against some strains of H5N1.
Probably not enough to prevent infection, but perhaps enough to reduce the severity of infection.
A few recent examples include:
mBio: Low levels of influenza H5N1 HA and NA antibodies in the human population are boosted by seasonal H1N1 infection but not by H3N2 infection or influenza vaccination
Preprint: Cross-Reactive Human Antibody Responses to H5N1 Influenza Virus Neuraminidase are Shaped by Immune History
How much `real-world' protection any of this might offer is anyone's guess. But with a pandemic specific vaccine unlikely in the opening months of an outbreak, and growing concerns over our antiviral armamentarium, any immunological edge - no matter how small - would be welcome.
While most of the studies we've seen to date have focused on the American Bovine B3.13 strain, today we've a study from the Netherlands which uses two European clade 2.3.4.4b H5N1 viruses along with an older Chinese (2005) clade 2.3.4 virus.
The research summary reads:
Evidence before this studyWe searched PubMed from Jan 1, 1997, to July 1, 2025 in English using combinations of “influenza”, “heterosubtypic”, “immunity”, “cross-immunity”, “baseline”, “population”, “humans”, “H5N1”, “avian influenza”, “clade 2.3.4.4b”, “humoral”, “antibodies”, “hemagglutinin”, “neuraminidase”, “cellular”, and “T-cells”. Previous reports on immunity to A(H5) influenza viruses on a population level are fragmented, because most examined binding or functional antibodies exclusively, and few examined T-cell responses.Added value of this studyWe profiled immune responses targeting A(H5) influenza viruses in a presumed unexposed cross-sectional cohort of health-care workers (n=107) by combining the measurement of antibody binding, haemagglutinin inhibition, antibody-dependent cellular cytotoxicity (ADCC), neuraminidase (NA) inhibition, and T-cell responses. A(H5) antibodies binding the haemagglutinin stalk, and NA inhibition-mediating and ADCC-mediating antibodies were common. Cross-reactive T cells targeting the haemagglutinin and NA of A(H5) influenza viruses were detected. Our rational selection of antigens from both seasonal and avian influenza viruses enabled a direct comparison of multiple effector mechanisms, establishing the first integrated baseline map of humoral and cellular responses against A(H5) influenza viruses.
Implications of all the available evidence
Our findings, in combination with existing research, show that partial immunity to A(H5) influenza viruses is widespread. Repeated exposure to seasonal influenza viruses likely led to the development of a cross-reactive antibody and T-cell repertoire recognising A(H5) influenza viruses. Although the protective value of cross-reactive immune responses remains speculative, evidence from animal model systems suggests that these responses might confer partial protection.
The full study, while fairly technical, is well worth reading. I've posted the abstract below. I'll have a bit more after the break.
Mark A Power, MSca,∗ ∙ Willemijn F Rijnink, MSca,∗ ∙ Widia Soochit, PhDa ∙ Lennert Gommers, BSca ∙ Anne van der Linden, BSca ∙ Felicity Chandler, BSca ∙ Femke Volker, BSca ∙ Theo M Bestebroer, BSca ∙ Babs E Verstrepen, PhDa ∙ Alba Grifoni, PhDb ∙ Ngoc H Tan, MPharma ∙ Susanne Bogers, MSca ∙ Gijsbert P van Nierop, PhDa ∙ Prof Alessandro Sette, PhDb,c ∙ Prof Marion P G Koopmans, PhDa ∙ Corine H Geurts van Kessel, PhDa,† ∙ Reina S Sikkema, PhDa,† ∙ Mathilde Richard, PhDa,‡ ∙ Rory D de Vries, PhDa,‡ r.d.devries@erasmusmc.nl Show lessPublished April 13, 2026DOI: 10.1016/j.lanmic.2026.101367 External LinkDownload PDFSummaryBackgroundHighly 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.MethodsWe 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.FindingsWe 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).InterpretationTogether, 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.
While some of the headlines overnight in the European press (see Likely no deadly bird flu pandemic: Immunity against regular flu also works on H5N1) overstate these findings, any degree of immunity to H5N1 beats no immunity at all.
Since this study utilized a convenience sample of healthcare workers, it did not include children or adolescents (< 20), or the elderly (> 70).
But they did report: In an age-stratified analysis, antibody levels against A(H5) influenza virus HA0 antigens appeared higher in health-care workers older than 60 years.
This increased immunity is likely the consequence of a lifetime of exposure to influenza viruses, but the majority (61%) of the test cohort also reported receipt of the seasonal flu vaccine over the past 4 years
Since we've seen other studies showing some limited protection against H5N1 (in ferrets) from the seasonal flu vaccine, it is possible that prior flu vaccination contributed to - or amplified - some of the preexisting immunity reported in this study.
While I find plenty of good reasons to get the flu shot each year, perhaps for some, that will provide an added incentive to get one this fall.
At least, one can hope.
