If the world finds itself grappling with a flu pandemic soon, it won’t come as a surprise. The H5N1 avian influenza virus has been steadily spreading across the globe since 2021. It has evolved to become capable of infecting a diversity of avian species, marine mammals, cattle, and even, occasionally, humans.
The situation in California cows is dire. Since the first identification of three infected herds in the state in August, California authorities have found the virus in 659 of the state’s 984 dairies, leading Gov. Gavin Newsom to declare an emergency in December.
Although no sustained human-to-human transmission has been documented, at least 61 human H5N1 cases have been diagnosed in the United States, and recent scientific findings reveal that the virus might be closer to achieving pandemic potential than previously thought. That would be extremely dangerous, given that infections of humans by previous variants have caused up to 30 percent mortality.
H5N1 first raised alarms in 1997 when it infected 18 people in Hong Kong, killing six. The virus has appeared on pandemic watchlists ever since, as researchers uncovered the mutations it would likely need to spread efficiently among humans. These mutations involve changes in two viral components: the RNA polymerase, an enzyme that replicates, or copies, the virus’s genome, and hemagglutinin, the protein that enables the virus to latch onto host cells. (During my laboratory days, I was the co-discoverer of the polymerase of the human flu virus.)
Recent studies have amplified scientists’ concerns. A recent research article found that a single mutation in hemagglutinin — called 226L — was sufficient to allow the virus to bind more effectively to receptors in human airways. Scientists had previously thought two such mutations were necessary, but the discovery of this “shortcut” was alarming because it indicates that adaptation to humans is more advanced than previously predicted.
The case of a Canadian teenager hospitalized with H5N1 in November offers new clues. The virus samples from the patient showed signs of a mutation in hemagglutinin — though not the feared 226L. This suggests that the H5N1 virus may already be “experimenting” with mutations that could eventually lead to human-to-human transmissibility.
The teenager’s virus came from a bird strain that had undergone genetic mixing, or reassortment, of the eight RNA segments that comprise the flu virus’ genome. In this way, the viruses acquired a new neuraminidase protein (the “N” in H5N1), which could make the strain more adaptable.
The CDC reported this on December 26: “CDC has sequenced the influenza viruses in specimens collected from the patient in Louisiana who was infected with, and became severely ill from HPAI A(H5N1) virus. … The analysis identified low-frequency mutations in the hemagglutinin gene of a sample sequenced from the patient, which was not found in virus sequences from poultry samples collected on the patient’s property, suggesting the changes emerged in the patient after infection.”
The Louisiana Department of Health announced on January 6 that the patient had died.
This is why it is important to “flatten the curve” of infections in humans and animals, to reduce the number of opportunities for the virus to mutate.
The H5N1 strain involved in the Canadian and Louisiana severe cases — called D1.1 — is normally found among birds and differs from the strain circulating in cows (B3.13).
The occurrence of mutations or advantageous reassortments is all a matter of probability, and the more infections that occur, the more virus replication there is, and the more opportunities for new, worrisome variants to appear that will be winners in Darwinian evolution’s game of survival of the fittest.
Where are we now? As Dr. Jeremy Faust put it, “Our current circumstance is akin to a game of Russian roulette — and there have never been more bullets in the chamber.”
The case of H5N1 underscores a broader reality about pandemics: They are rare but not impossible. Each mutation can bring the virus one step closer to the brink, but predicting whether a virus will cross that threshold remains an uncertain science. That is why surveillance to track genetic changes of the virus and testing for infection in animals and humans is crucial.
As history has shown, the cost of underestimating a pandemic threat can be devastating. H5N1 may now be contained primarily within animals, but the steady march of new mutations is a reminder that nature can surprise us. Staying one step ahead of the virus — with surveillance, testing and research — could mean the difference between a close call and a global catastrophe.