The immunological arms race between virus and vaccines may change in the future, at least for bird flu viruses. Scientists have developed a proof-of-concept vaccine against avian influenza viruses that offers protection against all the variants, including those that are yet to evolve (Nature 2025, DOI: 10.1038/s41586-025-09626-3).
Influenza A viruses are categorized into different subtypes according to a surface glycoprotein called hemagglutinin. The H5 subtype can evolve into highly pathogenic avian influenza viruses (HPAIVs) that devastate flocks of poultry and wild birds around the world. A lineage of bird flu has spread globally since it was first detected in Hong Kong in 1997. Variants of this virus have caused catastrophic outbreaks in marine mammals and US dairy cows; the continuous churning out of newer genetic and antigenic variants ensures that vaccines are always trying to catch up.
Mathilde Richard of Erasmus University Medical Center and her team decided to develop a master antigen that could immunize against all known H5 viruses. First, they used 14,896 nucleotide sequences collected from all known variants of H5 influenza to create an evolutionary tree of H5 the virus. They then used these sequences to create a high-resolution, 3D map showing the antigenic evolution of H5 influenza since 1959.
By focusing on 12 wild-type antigens at the map’s center, the researchers designed candidate vaccine antigens that could bind bird cells as well as human cells. They eventually settled on one called AC-Anhui.
To test its efficacy and breadth, the researchers vaccinated some ferrets with a vaccine prepared using AC-Anhui. Then they infected these ferrets with two variants, H5N1Giza and H5N6Sichuan, each selected from either end of the antigenic map to ensure the greatest evolutionary distance from AC-Anhui. Vaccinated ferrets infected with H5N1Giza did not develop any symptoms of disease, while those infected with H5N6Sichuan developed mild disease that did not spread outside the lungs. Moreover, the AC-Anhui vaccine performed as well as individual vaccines against H5N1Giza and H5N6Sichuan.
Adolfo Garcia-Sastre, a microbiologist at Mount Sinai’s medical school who wasn’t involved with the study, commends the work. It provides “a good vaccine to have ready in case of any outbreaks with this virus,” he tells C&EN in an email. However, he thinks this approach may fall short in tackling human influenza. “H5 changes in multiple directions, so a central antigen makes sense, while in the human flu or human SARS-CoV-2, the central antigen moves with time.”
Seema Lakdawala, a microbiologist at Emory University’s school of medicine who wasn’t involved with the study, was quite impressed by the vaccine’s ability in protecting ferrets from “a highly mismatched virus challenge (H5N6Sichuan).” She hopes that the researchers explore “duration of protection conferred by these vaccines” to see if similar protection can be conferred on poultry populations.
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