By Antonio Scalari
“For decades they had seen it approaching, like a dark dot on the horizon.” The science writer David Quammen describes it thus in his latest essay, Breathless, the arrival of the Covid-19 pandemic. The experts had seen it, it wasn’t a surprise. There was no telling how long it would take for that dot to arrive. But we knew that sooner or later he would do it.
Pandemics, we now know – be it influenza viruses, coronaviruses, or possible other pathogens – are a possibility. Sometimes they are catastrophic, like the “Spanish” flu of 1918. Others, milder, like the swine flu pandemic of 2009. But, in any case, we know that it is one of the risks for which we must prepare. Or why we should do it. One of these dark spots is avian influenza, specifically H5N1. Scientists and health authorities have been keeping an eye on this virus for years as a possible candidate for a next pandemic. Some recent developments are increasing this attention.
The global rise of a virus
The H5N1 virus, one of the highly pathogenic avian influenza viruses, was first identified in 1996 in a goose farm in southern China. The following year, after having entered a poultry farm in Hong Kong, it had already infected 18 humans, killing 6. Then, for a few years, the virus remained silent. It reappeared in 2003, again causing outbreaks on farms in China and other Asian countries.
Since then it has spread around the world, flying on the wings of wild birds, along migratory routes, sparking outbreaks among domestic birds in Africa, the Middle East and Europe. And causing sporadic infections among humans: 889 confirmed cases from 2003 to 2024, 463 deaths. This is one of the most disturbing aspects of H5N1. The mortality rate, 50-60 percent, appears enormous. The percentage indicates the ratio between deaths and diagnosed cases. But the one calculated on all infected people should be lower, because there may have been asymptomatic or minimally symptomatic cases.
In 2020, as the Covid-19 pandemic raged around the world, a lineage of H5N1 called 2.3.4.4b emerged and began circulating among domestic and wild birds at a rate never seen before. In 2021 it landed in Canada and over the following year it traveled across the rest of the American continent. In 2024 the virus was found in Antarctica in two dead birds, a species similar to seagulls. Bird flu has become a panzootic, the animal equivalent of a pandemic. And it’s not just about birds anymore.
In October 2022, H5N1 entered a mink farm in the community of Galicia, Spain, coinciding with a wave of infections that had occurred nearby among seabirds. These were not isolated cases, but a contagion. The animals that became ill were in neighboring enclosures, a detail that suggests the possibility of transmission, albeit limited, by air.
It could all have started from a mink that managed to capture an infected bird, falling ill and infecting its neighbors. A study later demonstrated that the virus that affected these animals was actually capable of transmitting through the air, although still very inefficiently. A mutation differentiates it from that of birds, one in particular, which gives the virus a greater ability to replicate.
The list of mammals in which H5N1 is found is growing. Foxes, cats, dogs, mice, alpacas, coyotes, elephant seals, dolphins and other species. In 2024 the virus reached one of particular importance for its relationships with humans: dairy cattle. In March, in the United States, health and veterinary authorities began investigating some cases of cows in Texas and Kansas, which showed symptoms such as loss of appetite, fever, lethargy, reduced milk production, and a viscous and yellowish appearance. Tests found that the animals were infected with the H5N1 virus. To date, according to the US Department of Agriculture, there are 93 cases, found in stables spread across twelve states.
After the discovery of the first sick cows, it wasn’t long before infections were recorded among humans too. Three men, all stable workers, contracted H5N1 infection. The first two presented symptoms limited to the eyes, redness and subconjunctival hemorrhages, the third developed a respiratory picture more typical of the flu.
Scientists are wondering what happened, how H5N1 arrived in cattle herds and how the virus is spreading. First, the drive chain. Analyzes of the viral genome indicate that H5N1 must have jumped from wild birds to cattle in one go spillover, the event that marks the passage of a pathogen from one species to another. The virus causes inflammation of the udder in cows. Analyzes have revealed that there are “astronomical” quantities of viral particles in the unpasteurized milk of sick cows.
They are propagated by milking operations, through workers, machinery and materials. Men and cows moving from one farm to another. Some cows also have mild respiratory symptoms, raising the question of whether even limited airborne transmission is taking place. The virus, therefore, passed from birds to cows. But it also went the opposite way, from cows to other domestic birds. And towards some mammals that live nearby, such as humans. The virus circulated for months before it was discovered and it is likely that more cows, and perhaps even people, contracted it than confirmed cases.
The possible road to a pandemic
The natural history of H5N1 in recent years, and its spread among American cows, makes one question increasingly pressing: how close are we to a pandemic? H5N1 is not the only avian influenza virus with pandemic potential, others are known such as H7N9, of which human cases have already occurred. The letters H and N indicate two proteins present on the surface of influenza viruses, called hemagglutinin and neuraminidase. The first allows the virus to attach to the host’s cells and penetrate them, the second to leave them to infect other cells. Different H and N are known, and their combinations identify numerous subtypes of influenza A viruses.
The function of hemagglutinin makes it a key protein in the pathway that can lead an avian influenza virus to adapt to new species, including humans. For now, H5N1 isn’t good enough at infecting cells in the respiratory tract of mammals. It could become one, if its hemagglutinin gene were to acquire some mutations that would modify the shape of the protein to the point of allowing it to attach more efficiently to the cells of new hosts.
Other changes would be necessary to make hemagglutinin stable enough to allow its transport by air, within respiratory droplets. A decisive step to initiate sustained transmission of the virus from one host to another. Then, there is the polymerase complex, the enzyme responsible for viral replication. Some mutations could make it better suited to work in mammalian cells.
At the moment H5N1 still appears to be behind on the path that could lead to it becoming an imminent threat to humanity. But scientists are concerned about its spread in American cattle herds, complaining about the slow collection and sharing of data by agencies, and inadequate testing and tracking of cases. The same happened during the Covid-19 pandemic.
The spread of H5N1 globally among an ever-increasing number of species, especially mammals, could make it increasingly less controllable. The emergence of a viral lineage with a lucky (for us, unlucky) combination of mutations could only be a matter of time. The window of opportunity is closing rapidly, says virologist Isabella Eckerle. As usual, the conflict is between the need to implement all the necessary actions and the concern that these interfere with other human activities.
Bird flu is a sword of Damocles hanging over our heads. And we’re not really doing everything we can to prevent it from falling sooner or later.
