The H5N1 avian influenza virus, long considered a major pandemic threat, is once again under intense scientific scrutiny as evidence mounts of its expanding reach across species and its increasing ability to adapt to mammals. Although sustained human-to-human transmission has not yet been detected, researchers warn that the virus may be edging closer to that threshold.
Since its first detection in poultry in southern China in 1997, H5N1 has evolved continuously, spreading far beyond birds to infect a wide range of wild animals, marine mammals and, most recently, cattle. What began as a regional outbreak has now turned into a global panzootic, with scientists describing the virus’s spread among animals as largely uncontrollable.
According to the World Health Organization, between January 2003 and November 5, 2025, a total of 992 laboratory-confirmed human cases of H5N1 infection were reported across 25 countries. Of these, 476 cases proved fatal, giving the virus a strikingly high case fatality rate of nearly 48 per cent. While most human infections have occurred through direct contact with infected animals, experts caution that the virus’s continued evolution could alter this pattern.
The current wave of concern stems from the emergence and global spread of the H5N1 clade 2.3.4.4b, which is believed to have evolved between 2018 and 2020. By 2021–2023, this clade had spread widely across Asia, Europe, Africa, the Middle East and North America. In the United States alone, more than 285 million birds have been affected since February 2022, marking one of the largest avian influenza outbreaks in history.
Alarmingly, the virus has also crossed into cattle populations. In the US, at least 71 cases of animal-to-human transmission linked to poultry or cattle have been detected, resulting in two deaths. While these cases do not yet indicate sustained human transmission, scientists view them as warning signs of increasing viral adaptability.
Researchers stress that the virus does not need to undergo a dramatic transformation to become a pandemic threat. Several studies suggest H5N1 may be only a single mutation away from achieving efficient human-to-human transmission. Experimental evidence also indicates that newer strains have a greater capacity for airborne infection compared to earlier variants, raising concerns about how easily the virus could spread once adapted to humans.
A key mechanism driving pandemic risk is genome reassortment, a process in which influenza viruses exchange genetic material when multiple strains infect the same host. With H5N1 now circulating widely across species, the opportunities for such reassortment events have increased significantly, heightening the likelihood of a strain capable of spreading efficiently among humans.
Recent research from the University of Cambridge and the University of Glasgow has added another layer of concern. Scientists found that certain avian influenza viruses possess genetic traits that allow them to tolerate higher temperatures, similar to those of birds. A specific viral gene, PB1, enables the virus to remain stable even when exposed to fever-like conditions. This raises the possibility that one of the human body’s natural defence mechanisms against influenza elevated temperature may be less effective against avian-origin pandemic strains.
Despite these warnings, many scientists argue that global preparedness remains inadequate. In April 2025, the Global Virus Network, comprising virologists from more than 40 countries, urged governments to strengthen surveillance, improve farm biosecurity and prepare for the possibility of human-to-human transmission. They warned that delayed detection could leave authorities with little time to contain an outbreak.
This concern is echoed by recent modelling studies from India, which suggest that by the time even a small number of initial human cases—between two and ten—are detected, the virus may already have spread widely. Such a scenario would make containment extremely difficult, if not impossible.
Meanwhile, the virus continues to evolve. In December, the US Department of Agriculture confirmed a new spillover of H5N1 clade 2.3.4.4b genotype D1.1 from wildlife into dairy cattle, separate from earlier transmission events. Scientists view this as further evidence of the virus’s expanding host range.
Parallel to the H5N1 threat, health authorities are also monitoring the rise of a new Influenza A (H3N2) subclade, known as K. Although unrelated to bird flu and not considered a pandemic strain, this variant has shown an increased ability to evade pre-existing immunity. During the 2024 and 2025 influenza seasons, A(H3N2) and A(H1N1) viruses caused widespread illness across all age groups in the US, including children.
By mid-2025, the H3N2 subclade K had been detected in multiple regions, including the United Kingdom, Australia, Africa and Asia. Data from the Global Initiative on Sharing All Influenza Data indicates that the subclade accounted for 33 per cent of all global A(H3N2) cases between May and November 2025, with Europe reporting nearly half of these infections.
Scientists emphasise that while H3N2 subclade K does not currently pose a pandemic risk, its rapid spread and genetic drift underscore the importance of continuous surveillance and timely vaccine updates.
Taken together, the evolving threats from both avian and seasonal influenza viruses highlight a broader challenge: the world’s tendency to respond reactively rather than proactively. As H5N1 continues to mutate across species and geographies, experts warn that ignoring early signals could prove costly, especially when history shows that pandemics often emerge quietly before erupting at scale.