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Original article: https://theconversation.com/no-were-not-one-mutation-away-from-an-h5n1-bird-flu-pandemic-here-are-the-facts-247139
In early December 2024, a group of researchers published an article in the journal Science, entitled “A single mutation in bovine influenza H5N1 hemagglutinin switches specificity to human receptors”. Some media outlets somewhat exaggeratedly took this to mean that we are one mutation away from bird flu “becoming the next COVID”.
There are currently no documented cases of human to human transmission of bird flu, also known as avian flu H5N1, though there is concern that the virus, which has spread among farm cows in the US, may mutate and spread to humans, leading to a flu pandemic.
Molecular barriers
One of the barriers currently preventing avian viruses from spreading to humans has to do with the way different flu viruses bind to their host. This happens when a flu virus’ haemagglutinin (HA) binds to a receptor. In the case of flu, the receptor contains sialic acid molecules.
However, there are various types of virus receptors. The HA of avian influenza viruses binds to “avian-type” receptors containing α2-3 sialic acid. However, HA from human influenza viruses binds to different receptors – those with α2-6 sialic acid – which are abundant in our upper respiratory tract cells.
For the avian flu virus to be transmitted from one human to another, it would first have to develop the ability to successfully attach itself to human receptors.
The aforementioned study did not identify a specific H5N1 isolate currently circulating in the real world. It was an experimental in vitro test that, via a range of different laboratory techniques, introduced mutations at a specific point in the HA protein of the H5N1 virus, and then assessed how they bound to the human-type receptor.
The researchers also determined the crystal structures of these mutant proteins in order to figure out the molecular basis of how the HA proteins bind to the receptors. They found that a single mutation (specifically, a single glutamine to leucine mutation at residue 226 of the virus hemagglutinin) was enough to make the virus bind to the human receptor in the laboratory.
In theory, the appearance of this single mutation would allow the virus to be transmitted from person to person. In addition, the researchers found that a second mutation would further enhance binding to the human receptor. However, none of this means we are “one mutation away” from a pandemic.
A pandemic in the animal world
The first highly pathogenic avian influenza virus of subtype H5N1 emerged in China in 1996. Since then, H5 viruses have spread widely in Europe, Africa, North America and Asia via migratory birds, and have diversified into different genetic types (clades and subclades).
In 2020, clade 2.3.4.4b emerged, and it reached North America in late 2021. H5N1 viruses belonging to this group have managed to infect over 350 species of birds and more than 50 species of marine and terrestrial mammals, including humans.
Because of its geographical spread (it has even been detected in Antarctica), its temporal spread (cases are described throughout the year), the number of species showing transmission, and the number of animals affected, the avian influenza epidemic can already be considered a pandemic in the animal world. This is known as a panzootic.
At the end of March 2024, the first case of H5N1 2.3.4.4b infection in dairy cattle, an unexpected reservoir of the virus, was reported in the United States. Since then, the pathogen has been detected in more than 900 dairy farms in 16 states, with California having the highest incidence (about 80% of cases).
H5N1 infection of wild birds is also widespread, and outbreaks in poultry farms have caused the deaths of more than 100 million birds in the US. In addition, the virus has been identified in many species of wild mammals and zoo animals, particularly felines.
H5N1 in humans
Historically, human H5N1 infections were sporadic and always related to exposure to infected poultry. As of November 2024, more than 900 human cases in 24 countries had been reported, with mortality rates of over 30% in hospitalised cases. However, this is most likely an overestimate, as asymptomatic or unrecorded infections are not taken into account.
Since March 2024, when the first cow-to-human transmission of H5N1 occurred in the United States, 64 human cases have been confirmed in nine states, more than half of them (36) in California. Detailed clinical information on 46 of those cases identified between March and October 2024 has recently been released – out of 46 patients, 25 had been exposed to infected dairy cows, and 20 to poultry.
In just one of the patients, the source of infection was unclear. The patient was hospitalised with non-respiratory symptoms, had no complications, and was discharged three days after admission.
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Among the 45 patients with animal exposure, all had mild illness, none were hospitalised, and none died (though a separate death from H5N1 infection has since been reported in the US). Conjunctivitis occurred in 93%, fever in 49%, and respiratory symptoms in only 36%, all of which were of short duration.
No additional cases were identified among the 97 contacts of these patients, so no person-to-person transmission could be demonstrated. This is consistent with the current lack of evidence of human-to-human transmission of the H5N1 virus in the United States.
Why is it not a pandemic yet?
A simple answer is that the virus may just need more time to find the right combination of mutations. For the H5N1 avian influenza virus to become pandemic, it would not only need to improve its ability to become airborne between humans and to bind to receptors on people’s cells – it would also need to improve its ability to enter these receptors and multiply within them.
In addition, it would need to get round the human immune system. We cannot rule out the possibility that part of the population already has some acquired immunity to neuraminidase type 1 influenza viruses (such as H5N1) through contact with other human influenza viruses such as H1N1, or that seasonal influenza vaccines have some protective value.
So far, sequencing of H5N1 viruses from US cases has shown no changes in the HA gene associated with increased infectiousness or transmissibility, and no mutations in other genes have been identified that would indicate adaptation to humans.
The is also the possibility that a particular mutation that allows H5N1 to better bind to human receptors could harm the virus in some other way, making it less effective.
The One Health approach
Getting the right combination of mutations is tricky, but not impossible. The influenza virus is a champion of adaptability and recombination, and the H5N1 virus’ widespread global circulation among animals is undeniably bad news.
While the risk to the general public is currently low, it is imperative that we improve biosecurity in farming. We also have to intensify veterinary surveillance in cattle and pigs as well as poultry, and to promote effective coordination between the public and animal health sectors through the collaborative approach known as One Health. The US authorities’ slow response has come under heavy criticism from the scientific community in recent months.
If a susceptible species (pigs, cows, mink, etc) were infected with both human seasonal and avian influenza viruses, reassortment between the genomes of the two viruses could occur, resulting in a hybrid that is better adapted for human infection.
Public health efforts should continue to focus on protecting workers exposed to infected animals with preventative measures, such as vaccination, to minimise risk. It is essential to investigate each human case to swiftly detect any changes that may suggest increased virulence or human-to-human transmissibility.
In addition, research into new therapeutic strategies and the development of universal vaccines (i.e. those effective against all influenza subtypes) remain a priority. We are not one mutation from a pandemic, but the H5N1 virus is certainly not getting any further away.