Although there are currently no documented cases of human-to-human transmission, there is concern that the H5N1 bird flu virus that has spread in cattle in the United States could adapt to human-to-human transmission and end up triggering a flu pandemic. .
One of the barriers to transmission of avian viruses to humans is the specificity of the binding of the hemagglutinin (HA) of the virus with the cellular receptor, a sialic acid molecule of which there are different types. Thus, HA from avian influenza viruses binds to “avian-like” cellular receptors containing α2-3 sialic acid. In contrast, HA from human influenza viruses binds to α2-6 sialic acid receptors, abundant in our upper respiratory cells.
For the avian flu virus to be transmitted from person to person, the first step would therefore be for it to be able to bind effectively to human receptors.
The different influenza viruses differ in the envelope proteins hemagglutinin and neuraminidase, of which there are 18 and 11 different types, respectively.
The aforementioned study is actually an in vitro experimental test, not the characterization of a specific isolate of the H5N1 virus that is circulating in nature. The work consisted of introducing mutations in a specific site of the HA protein of the H5N1 virus and evaluating how they bind to the human receptor using different laboratory techniques.
Additionally, the scientists determined the crystal structures of these mutant proteins to understand the molecular basis of the specific binding between the HA proteins and the receptors. Thus they observed that a single mutation (specifically, the change of an amino acid glutamine for a leucine at residue 226 of the protein) was enough for the virus to bind to the human receptor in the laboratory.
In theory, the appearance of this single mutation could be an indicator that the virus can be transmitted between people. In addition, the researchers found that a second mutation further improves binding to the human receptor. But that does not mean that we are one mutation away from a pandemic.
A true pandemic in the animal world
The first highly pathogenic avian influenza virus of the H5N1 subtype emerged in China in 1996. Since then, H5 viruses have spread widely in Europe, Africa, North America and Asia through migratory birds, and have been diversifying into different genetic types (clades and subclades).
In 2020, the clade called 2.3.4.4b emerged, which arrived in North America at the end of 2021. Viruses H5N1 belonging to this group have been able to infect more than 350 species of birds and more than 50 species of marine and terrestrial mammals, including humans. Due to its geographic extension (it has even been detected in Antarctica), its temporal extension (cases are described throughout the year), the number of species that register transmission and the number of animals affected, the avian flu epidemic can now be considered a true pandemic. in the animal world, what is known as panzootic.
In late 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, this pathogen has been detected in more than 900 dairy farms in 16 states, with California having the highest incidence (about 80% of cases).
Infection of wild birds by H5N1 is also widespread and outbreaks in poultry farms have caused the death of more than 100 million birds in the country. In addition, the virus has been identified in many species of wild mammals and zoo animals, especially felines.
H5N1 in humans
Historically, human H5N1 infections have been sporadic and always related to exposure to infected poultry. As of November 2024, more than 900 human cases have been reported in 24 countries and mortality rates of more than 30% have been reported in hospitalized cases. However, this is most likely an overestimation, since asymptomatic or unrecorded infections are not taken into account.
Since March 2024, when the first cow-to-human transmission of the H5N1 virus occurred in the United States, 64 human cases have been confirmed in nine states. More than half of them (36) have occurred in California. Detailed clinical information has now been released on 46 of those cases identified between March and October 2024. Of the 46 patients, 45 were exposed to infected dairy cows (25) or poultry (20). In only one of the patients has it not been possible to identify the source of infection (he was hospitalized with non-respiratory symptoms, had no complications and was discharged three days after admission).
Among the 45 patients with animal exposure, all had mild illness, none were hospitalized, and none died. 93% suffered conjunctivitis; 49%, fever, and only 36%, respiratory symptoms, always of short duration. No additional cases of infection were identified among the 97 contacts of these patients, so it has not been possible to demonstrate human-to-human transmission. This is consistent with the current lack of evidence of human-to-human transmission of the H5N1 virus in the United States.
Why isn’t it a pandemic yet?
A simple answer is that the virus may simply need more time to find the right combination of several mutations. For the H5N1 avian flu pathogen to become a pandemic, it should not only improve its ability to be transmitted by air between humans and bind to receptors on people’s cells, but also improve its ability to enter and multiply in them.
Additionally, it should be able to evade the human immune system. It cannot be ruled out that part of the population already has some acquired immunity against influenza viruses with neuraminidase type 1 (such as H5N1) through contact with other human influenza viruses such as H1N1, or that influenza vaccines seasonally have some protective value.
At the moment, sequencing of the H5N1 viruses from cases in the United States has not shown changes in the HA gene associated with greater infectivity or transmissibility, and no mutations have been identified in other genes that indicate adaptation to humans. Perhaps a particular mutation that allows H5N1 to adhere better to human receptors could harm the virus in some other way.
The One Health Strategy
Producing the correct combination of several mutations is complicated… but not impossible. The flu virus is the champion of variability and recombination. The intense global circulation of the H5N1 virus in the animal world is bad news.
Although the risk to the general public is currently low, it is essential to improve biosecurity on farms, intensify veterinary surveillance not only in poultry but also in cattle and pigs, and promote effective coordination between the public health and sanitation sectors. animal through the collaborative approach called One Health (some sectors have criticized the slowness with which US authorities are intervening).
If a susceptible species (pigs, cows, minks…) is infected at the same time with human seasonal flu viruses and avian flu, a rearrangement could occur between the genomes of both viruses, giving rise to a hybrid that is more adapted to the virus. human infection.
Public health efforts should continue to focus on protecting workers exposed to infected animals with prevention measures, such as vaccination, to minimize risk. It is essential to investigate each human case to detect early any changes that may suggest greater pathogenicity, virulence or transmissibility between people.
Furthermore, research into new therapeutic strategies and the development of universal vaccines, effective against all influenza subtypes, remain a priority. We are not one mutation away from a pandemic, but the H5N1 virus is getting closer.
Article published in The Conversation
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