A new global review reveals how rapidly evolving H5 bird flu viruses are reaching new species, including dairy cattle, and stresses the urgent need for coordinated action to prevent the next pandemic.
Three influenza A (H5N1/bird flu) virus particles (rod-shaped). Note: Layout incorporates two CDC transmission electron micrographs that have been inverted, repositioned, and colorized by NIAID. Scale has been modified. Image Credit: CDC and NIAID
Since its discovery in 1996, the Gs/Gd lineage of highly pathogenic avian influenza viruses with H5 haemagglutinin, including H5N1 and other H5Nx subtypes, has caused widespread infections and mortality among numerous animal species and sporadic infections among humans, with outbreaks now reaching every continent, even Antarctica.
In a recent review published in the journal Nature Reviews Microbiology, researchers at the Department of Viroscience, Erasmus MC, the Netherlands, reviewed the current knowledge on the evolution, global spread, and growing risks posed by this persistent and adaptable virus.
Influenza viruses
Influenza A viruses have caused four human pandemics and countless outbreaks among animal populations in the past century. Among them, highly pathogenic avian influenza viruses (HPAIVs) pose a major threat due to their ability to evolve rapidly. While most avian influenza viruses circulate harmlessly among wild waterbirds, some have mutated into more deadly forms, particularly the H5 and H7 subtypes. When these viruses spill over to poultry, they can evolve into highly pathogenic forms that cause severe disease and death.
The Gs/Gd lineage of H5 viruses, which includes the well-known H5N1 subtype (first identified in humans in Hong Kong in 1997) and other H5Nx variants, emerged from a complex mix of avian viruses and has since diversified into numerous lineages. This lineage has become a dominant global threat, spreading across continents and infecting a wide range of birds and mammals. Furthermore, despite ongoing surveillance and control efforts, gaps remain in understanding how this virus spreads, evolves, and adapts to new hosts, including humans.
The current study
The researchers conducted a comprehensive review of scientific literature, surveillance reports, and genetic analyses to understand the evolution and spread of highly pathogenic H5 avian influenza viruses of the Gs/Gd lineage. They traced the virus's origins back to a 1996 outbreak in domestic geese in Guangdong, China, and followed its genetic diversification through global outbreaks over the past 25 years.
The team examined how the virus has changed through a process known as reassortment, where gene segments from different influenza viruses mix in co-infected hosts, creating new virus variants. They focused on outbreaks in wild birds, poultry, and mammals, including tigers, sea lions, mink, and dairy cattle.
The study also analyzed how the virus crosses species barriers. This included reviewing molecular data on mutations in viral proteins, including hemagglutinin, neuraminidase, and polymerase components, that help the virus adapt to mammalian cells. Structural features of hemagglutinin that affect binding to host receptors, as well as changes in viral ribonucleic acid (RNA) polymerase that enhance replication in mammals, were examined. Additionally, the study investigated the immune responses in different species and how the virus evades these defenses.
To assess the impact on human health, the authors also reviewed data on confirmed human infections, exposure risks, and clinical symptoms, considered the role of environmental and agricultural practices in facilitating the spread of the virus, and examined current control measures like culling, vaccination, and surveillance.
Key findings
The study reported that the H5 viruses from the Gs/Gd lineage have undergone significant genetic evolution, enabling them to infect a wider range of species and persist globally. The virus, which originally circulated in poultry, has now spread to wild birds and mammals, including rare spillovers into humans.
Most alarmingly, it has recently reached dairy cattle in the United States, where it has spread primarily due to the movement of infected animals between farms. Contaminated milking equipment facilitates transmission within farms and causes widespread infections. The virus has now been detected on every continent, including Antarctica, marking an unprecedented expansion.
Its ability to reassort with other influenza viruses has also generated multiple variants, including those with new gene combinations that enhance adaptation to mammals. This genetic mixing has also improved the virus's ability to bind to human-like receptors and resist mammals' innate immune defenses.
Since 1997, there have been over 1,000 laboratory-confirmed cases of Gs/Gd lineage infections in humans, with more than 500 reported deaths; however, the true case fatality rate is uncertain due to likely underreporting of mild and subclinical infections and variability in severity between outbreaks. Most infections occurred after direct contact with infected poultry, but recent cases in the U.S. involving dairy farm workers suggested new transmission routes. Though sustained human-to-human transmission has not occurred, the increase in mild or undetected human infections raises concerns about pandemic potential.
The virus has also had devastating impacts on wildlife, with high mortality among sea lions, seals, and birds being documented across the Americas and Europe. Mammal-to-mammal transmission, especially in farmed mink and sea lion colonies, also indicates that the virus may be evolving toward more efficient spread among mammals.
The review highlights that available options for managing outbreaks in wildlife are limited and may include carcass removal and targeted vaccination of endangered species.
Conclusions
The ongoing spread and evolution of the Gs/Gd H5 lineage viruses, including H5N1 and other H5Nx subtypes, emphasize the serious threat these influenza viruses pose to animals, ecosystems, and human health. With increasing evidence of cross-species transmission and global distribution, this virus remains a looming concern.
The review highlights the critical need for a unified “One Health” approach that integrates animal, human, and environmental health strategies at a global level. The review indicated that strengthening surveillance, advancing vaccine strategies, expanding the use of newer vaccine technologies, coordinating international vaccine stockpiling and deployment, and integrating efforts across animal and human health sectors are crucial steps towards preventing future outbreaks and reducing the risk of a potential pandemic.
Journal reference:
- Bellido-Martín, B., Rijnink, W.F., Iervolino, M. et al. (2025). Evolution, spread and impact of highly pathogenic H5 avian influenza A viruses. Nature Reviews Microbiology, DOI: 10.1038/s41579-025-01189-4, https://www.nature.com/articles/s41579-025-01189-4