[Example] H5N1 avian flu could cause a human pandemic

ON JULY 14TH America’s Centres for Disease Control and Prevention (CDC) reported five new cases of the H5N1 avian flu virus in humans, bringing the total number of cases reported since April to nine. All five were involved in culling infected poultry in Colorado, and appear to have the same strain that has been spreading in dairy cows across the country since December. So far, there is no evidence the virus has adapted to spread between humans, a prerequisite for a flu pandemic. But things can change quickly—the more the virus circulates in animals that come in close contact with humans, the bigger the risk that a pandemic strain will emerge.

Should H5N1 go down this path, would the world be prepared? When SARS-CoV-2 emerged in 2019, humans had no natural immunity, drugs or vaccines. All three exist for H5N1, though how well any of them would work against a possible pandemic virus remains unclear.

H5N1 was identified in wild geese in 1996 and has been circulating in birds ever since. The virus is deadly for poultry and hundreds of millions of chickens have been culled over the decades to prevent its spread on farms. Occasionally, birds with H5N1 have infected mammals, including humans. Luckily, these have been dead-end infections, with no further spread. In 2023, however, the H5N1 virus acquired genetic changes allowing it to spread between marine mammals. This is the kind of adaptation the virus needs to begin spreading between humans, says Malik Peiris, a virologist at the University of Hong Kong. If the current outbreak in cows in America continues, he says, then mutations to ease its transmission between humans will almost certainly arise.

Alternatively, someone infected with a seasonal flu virus could become infected with a bovine H5N1. That bovine H5N1 virus could then pick up the gene segments from the seasonal flu virus that makes it contagious between humans, a gene-swap trick that flu viruses are particularly adept at. Known as viral reassortment, this kind of swap happens particularly easily in pigs because they can become infected with both avian and human flu viruses simultaneously, acting as melting pots for viral evolution.

H5N1 adapting to pigs is “the really scary thing” says Dirk Pfeiffer, a veterinary epidemiologist at the City University of Hong Kong. Pigs infected with flu viruses are often asymptomatic, so by the time any H5N1 virus adapted to humans could be found in them, it would have already spread in people, he says. The recent mammalian adaptations of H5N1, as well as its presence on dairy farms, make scientists think it is only a matter of time before it adapts to pigs.

It is not possible to predict how deadly a pandemic strain of H5N1 could be. Since the virus first emerged, around 900 human infections have been confirmed. Half were fatal, but asymptomatic infections would have gone uncounted, making the true fatality rate lower. The nine H5N1 cases in dairy and poultry workers found in America since April this year were all mild, though that will not necessarily hold true for future infections. To understand how widespread human infections are, the CDC is now testing for antibodies in people on farms that have had H5N1 outbreaks.

There are several reasons to believe that, should an H5N1 pandemic occur, things may be less dire than they were with covid-19. No one had immunity against covid when it emerged, for example. By contrast, studies suggest that most people have some degree of flu-related immunity that could prevent severe H5N1 infections.

Antibodies for the flu are primarily directed against the two proteins on the surface of the influenza virus, hemagglutinin (H) and neuraminidase (N). Most potent is the protection directed at the H protein. Antibodies for H5, the form of H present in H5N1, are rare in people because it is not found in seasonal flu viruses.

But Michael Worobey, an evolutionary virologist at the University of Arizona, and his colleagues have discovered that someone whose first-ever flu infection was with an H1 or H2 flu virus will probably have some protection against avian H5N1. This effect is due to an outsize “immune imprinting”, probably by the flu strain in global circulation in the year after they were born. Using historical data on seasonal flu strains, Dr Worobey’s team estimates that most people born before 1968 may have this type of immune protection against H5N1. Most of those born subsequently—and especially in the past decade—will not. Though this immunity may not prevent infection, there is a good chance that it will shape the severity of disease, says Dr Worobey, and “make a big difference in terms of who lives and who dies”.

Similar, though less powerful, immunity may arise from previous exposure to the N1 component, as well as from T-cells primed to attack other types of flu virus. These, too, may mitigate the severity of a new flu pandemic, says Dr Peiris.

It is not only the human body that is better prepared to face H5N1 than covid. Pharmaceutical companies are too. Existing antiviral drugs used for seasonal flu are likely to work against H5N1 because they target a virus’s replication mechanism, which is similar across strains.

Vaccine development is also more advanced. Many countries, including America, have a stockpile of H5N1 vaccines as part of their generic pandemic preparedness plans, reserved for those at the highest risk of becoming infected. Fifteen European countries are also adding the vaccines to their stockpiles. Finland, for its part, has started offering the jabs to farm workers most at risk, such as those working with poultry, foxes and mink. As the vaccines are thought to primarily prevent severe disease, rather than infection, American officials have not followed suit.

A pandemic, however, will require billions of vaccine doses. The fastest way to make them would be to use mRNA technology, which uses a section of the virus’s genetic material, rather than the whole virus, to provoke an immune response in the host’s body. These can be made in four weeks, compared with the six months needed for the typical seasonal flu jabs. The American government has commissioned Moderna, a pharmaceutical company, to develop an mRNA vaccine for H5N1. GlaxoSmithKline and CureVac, both biopharmaceutical companies, are also in the early stages of developing such a vaccine. Drew Weissman, who won a Nobel prize in 2023 for developing mRNA technology, is testing a rival mRNA vaccine with colleagues at the University of Pennsylvania.

Dr Weissman also hopes to develop an mRNA vaccine that can be administered to animals in the form of an oral tablet or patch. This would simplify mass vaccination of poultry and cattle, preventing further spillovers. At the moment, no H5N1 vaccine has been approved for animal use in America or Europe.

All this vaccine development will take time, as will building up the stockpiles needed to prepare for a large outbreak in humans. Such time would be well-spent. Should H5N1 become a human pandemic, it is possible—assuming vaccine supplies ran low or existing stocks could not be speedily deployed—that it could kill as many people as covid did. The lack of aggressive measures to halt the outbreak in cows in America is exacerbating matters. The risk, says Dr Peiris, is that the virus will become permanent and eventually spread beyond the country. “Then,” he adds, “there is no stopping it.” ■