#18,718
While its fearsome and oft quote 50% case fatality rate (CFR) is probably overstated - inflated due to detection bias, where severe and/or hospitalized patients are more likely to be tested and identified - even a 5% fatal outcome from H5N1 would make it the worst pandemic on record.
H5N1 also has a reputation for hitting younger adults and children the hardest (see Nature Comms: Immune history shapes human antibody responses to H5N1 influenza viruses).
We can see a similar impact in the 1918 pandemic's infamous `W shaped Epi curve’ (below) which indicates that those in their teens, 20s, and 30s were particularly hard hit by that H1N1 virus.
It's not a new idea. In 2007's Seasonal Vaccine May Provide Small Protection Against Bird Flu we looked at two reports suggesting some (small) amount of cross-protection might be afforded by the seasonal flu shot.
Last summer, however, in CDC A(H5N1) Update: Population Immunity to A(H5N1) clade 2.3.3.4b Viruses, the CDC reported finding extremely low to no population immunity, even among those who recently received a seasonal flu vaccine.
Throughout the fall and winter we continued to see preprints and studies - albeit using different methods and materials (see below) - keeping the idea alive.
Preprint: Pre-existing H1N1 Immunity Reduces Severe Disease with Cattle H5N1 Influenza Virus
Preprint: Targets of influenza Human T cell Response are Mostly Conserved in H5N1
Two EID Journal Articles On Prior Immunity From A(H1N1)pdm09 Infection Against H5N1 (in Ferrets)
While today's study may not be the last word on the subject, researchers in the UK found:
- While QIVs significantly boosted neutralizing antibodies against seasonal A(H1N1), they detected little to no neutralizing antibody response against the two H5N1 strains
- Most participants (all age < 59) had no detectable neutralizing titers against the Texas H5N1 strain, and only a few had low-level titers for the Cambodia strain.
- No evidence that QIV vaccination provided a boost in cross-reactive immunity to H5N1
Dispatch
Phoebe Stevenson-Leggett1, Lorin Adams1, David Greenwood1, Abi Lofts, Vincenzo Libri, Bryan Williams, Sonia Gandhi, Charles Swanton, Steve Gamblin, Edward J. Carr1, Ruth Harvey1, Nicola S. Lewis1, Mary Y. Wu, Emma C. Wall
Abstract
We tested cross-neutralization against highly pathogenic avian influenza A(H5N1) virus in adults vaccinated with 2021–2023 seasonal quadrivalent influenza vaccine in the United Kingdom. Seasonal quadrivalent influenza vaccines are unlikely to protect vulnerable persons against severe H5N1 disease during widespread transmission. Enhanced measures are needed to protect vulnerable people from H5N1 virus infection.
(SNIP)
The Study
We compared humoral neutralization of 2 H5N1 viruses, A/dairy_cattle/Texas/24-008749-002/2024 (2.3.4.4b) and A/Cambodia/NPH230776/2023 (2.3.2.1c), in serum samples alongside a seasonal influenza A(H1N1) virus isolate, A/Wisconsin/67/2022, before and after QIV in participants from the University College London Hospitals–Francis Crick Institute Legacy study cohort (https://clinicaltrials.gov/study/NCT04750356External Link) (Appendix Figure).
The study included 61 adults (median age 49 [range 38–58] years); 44 (72%) were women, and 17 (28%) were men. Thirty (49%) adults were vaccinated in only the 2021–22 season, but all 61 were vaccinated in >1 study season (2021–22, 2022–23, and 2023–24). Median sampling duration after vaccine dose for 2021–22 was 81 (interquartile range [IQR] 61–81) days, for 2022–23 was 67 (IQR 38–68) days, and for 2023–24 was 77 (IQR 44–77) days. Twenty-seven (44%) participants reported a single underlying condition (Table).
In line with their effectiveness against seasonal influenza, each QIV generated a statistically significant boost in serum neutralization of A/Wisconsin/67/2022 in each season tested (p = 0.003–0.007 by χ2 test) (Figure). In contrast, HPAI H5 virus neutralization in our cohort of healthy adults was blunted or absent.
In prevaccine serum samples, we detected neutralization above background against A/Cambodia/NPH230776/2023 in a few samples but did not detect any neutralization against A/dairy_cattle/Texas/24-008749-002/2024 isolate (Figure). No seasonal QIV resulted in a cross-neutralization boost against either HPAI H5 virus (Figure).
Ongoing adaptation of HPAI H5N1 clade 2.3.4.4b virus in cows and other mammal hosts found on dairy farms, including rodents and cats, substantially increases the risk for a major HPAI H5N1 virus epidemic or pandemic in humans (2,4). The paucity of human serologic memory against either H5N1 virus strain raises the potential for widespread vulnerability to infection within the adult population. We observed a predictable boost to neutralizing titers against the contemporary seasonal influenza A(H1N1) virus (A/Wisconsin/67/2022) that was absent for the 2 clinically relevant H5N1 viruses tested in our high-throughput neutralization assay (Appendix). Neutralizing antibody titers have long been used as a correlate of protection against seasonal influenza (12); thus, our observations suggest seasonal QIVs are unlikely to offer adequate serologic protection against H5N1 virus.
Immunity against influenza evolves throughout the lifespan, and early infection exposures influence subsequent antibody responses after infection and vaccination (13). Few participants in our study had detectable neutralizing titers above background to the 2.3.2.1c A/Cambodia/NPH230776/2023 virus and none to the 2.3.4.4b A/dairy_cattle/Texas/24-008749-002/2024 virus. Together with our observed lack of QIV boosting, our results suggest that strategies reliant on existing population-level or QIV-based immunity against H5N1 virus infection must be approached with caution.
One limitation of this study is the lack of in vivo challenge to test for cross-protection. Some studies have reported transient protection against H5N1 challenge after transferring QIV-vaccinated human serum to mice, which was not accurately predicted by in vitro assays, including virus neutralization assays (14,15). Cross-neutralization might also occur in the absence of nAbs, but without in vivo testing, we cannot conclusively determine the extent to which the QIV might provide protection against H5N1 virus. A second limitation is that our cohort, predominately working age, healthy adults receiving occupational QIV, do not represent a population at high risk for severe influenza disease and death.
However, they represent an immunocompetent population and would be expected to have the most robust detectable immunity. Third, although we tested 2 H5N1 viruses associated with recent human disease, despite extensive efforts, we could not eliminate background signal in our assay. Thus, we were unable to fully quantify neutralization at lower titers and opted to describe the range within which we detected background signal.
As of 2025, no neutralization titers were available from postinfection serum samples in dairy farm workers to further refine that cutoff (6). Further investigation is required to address the issue of background signal. However, other studies suggest nonspecific inhibition by human serum as a possible explanation for low-level readouts for protection (15).
Finally, our use of whole virus to assess nAb titers did not allow determination of the extent to which hemagglutinin- or neuraminidase-specific antibodies might have contributed to overall neutralization. However, the high-throughput live-virus neutralization we describe (Appendix) is a highly valuable tool for pandemic preparedness, offering a method for near real-time analysis of serum-based immunity to emerging viruses in large cohorts.
Conclusions
The effectiveness of QIV against influenza A(H5N1) virus remains uncertain, and clarification on the extent of cross-protection in humans is urgently needed. Considering that uncertainty, timely and effective deployment of targeted vaccines would be crucial during widespread influenza A(H5N1) outbreaks. To reduce risks for severe illness and death requires enhanced measures that mitigate the spread of HPAI H5N1 viruses to humans, accelerated pipelines for H5-directed influenza vaccines, and systems that rapidly and equitably reach clinically vulnerable persons worldwide (2).
Dr. Stevenson-Leggett is a specialist COVID Unit postdoctoral researcher at the Francis Crick Institute. Her research interests include high-throughput, live virus neutralization. Mr. Adams is a PhD student within the World Health Organization’s Worldwide Influenza Centre. His research interests include in vitro pathogenicity assessment of influenza viruses, including H5N1 strains.
While this advantage is thought to be small, and is likely offset by increasing comorbidities among this older cohort, it might be enough to skew the results.
There are still good reasons to get the seasonal flu vaccine, prior to - and even during - an H5Nx pandemic.
- It still may provide some small boost to your immune response. Neutralizing antibodies aren't the only immune defense against infection.
- It could help prevent a co-infection with H5N1 and seasonal flu, which has the potential for being more severe - or worse - generating a reassorted virus (see Preprint: Intelligent Prediction & Biological Validation of the High Reassortment Potential of Avian H5N1 and Human H3N2 Influenza Viruses).
Things like face masks, hand washing, ventilation, staying home while sick, and avoiding crowds.
Which is why I'm recommending that people consider now (see A Personal Pre-Pandemic Plan) what they will do when the next global health crises emerges.
