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Science: A single mutation in bovine influenza H5N1 hemagglutinin switches specificity to human receptors
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H5N1: No, we are not one mutation away from a flu pandemic
Published: January 7, 2025 12:56pm EST
Authors
Early last December, a group of researchers published a paper in the journal Science titled “ A Single Mutation in the Bovine Influenza H5N1 Hemagglutinin Changes Specificity to Human Receptors .” Some media outlets exaggeratedly interpreted this to mean that we were just one mutation away from the next flu pandemic .
Although there are currently no documented cases of human-to-human transmission, there is concern that the H5N1 avian influenza virus that has been spreading in cattle in the United States could adapt to human-to-human transmission and eventually trigger an influenza pandemic.
Molecular barriers
One of the barriers to the transmission of avian viruses to humans is the specificity of the binding of the virus's hemagglutinin (HA) to the cellular receptor, a sialic acid molecule of which there are different types. Thus, the HA of avian influenza viruses binds to “avian-type” cellular receptors containing α2-3 sialic acid. In contrast, the HA of human influenza viruses binds to receptors with α2-6 sialic acid, abundant in our upper respiratory tract cells.
For the avian influenza 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 aforementioned study is actually an in vitro experimental assay , not the characterization of a specific isolate of the H5N1 virus circulating in nature. The work consisted of introducing mutations into a specific site of the HA protein of the H5N1 virus and evaluating how they bind to the human-type receptor using different laboratory techniques.
In addition, 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. They observed that a single mutation (specifically, the change of an amino acid from glutamine to leucine at residue 226 of the protein) was sufficient 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 we are one mutation away from a pandemic.
A real 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 via migratory birds, and have diversified into distinct 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. H5N1 viruses 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 geographical spread (it has even been detected in Antarctica), temporal extent (cases are described throughout the year), the number of species that record transmission and the number of animals affected, the avian influenza epidemic can now be considered a true pandemic in the animal world, which is known as panzootic.
In late March 2024, the first case of H5N1 2.3.4.4b infection in dairy cattle was reported in the United States , an unexpected reservoir for the virus. 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 with H5N1 is also widespread, with outbreaks on poultry farms having killed more than 100 million birds in the country. The virus has also been identified in many species of wild mammals and zoo animals, particularly felines.
H5N1 in humans
Historically, human infections with H5N1 have been sporadic and always linked to exposure to infected poultry. As of November 2024, more than 900 human cases have been reported in 24 countries , with mortality rates of more than 30% reported in hospitalized cases. However, this is most likely an overestimate as it does not take into account asymptomatic or unreported infections.
Since March 2024, when the first transmission of the H5N1 virus from cow to person occurred in the United States, 64 human cases have been confirmed in nine states. More than half of these (36) have occurred in California. Detailed clinical information on 46 of these cases identified between March and October 2024 has just been published . Of the 46 patients, 45 were exposed to infected dairy cows (25) or poultry (20). Only one patient could not 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 no one died. Ninety-three percent had conjunctivitis, 49 percent had fever, and only 36 percent had respiratory symptoms, all of which were short-lived. No additional cases of infection were identified among the 97 contacts of these patients, so human-to-human transmission has not been demonstrated. This is consistent with the current lack of evidence of human-to-human transmission of H5N1 in the United States.
Why is it not a pandemic yet?
One simple answer is that the virus may simply need more time to find the right combination of mutations . For the H5N1 avian influenza pathogen to become pandemic, it would need to not only improve its ability to spread through the air between humans and bind to receptors on human cells, but also improve its ability to enter and multiply inside humans.
Furthermore, 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 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 U.S. cases has not shown any changes in the HA gene associated with increased infectivity or transmissibility, and no mutations in other genes have been identified that indicate adaptation to humans. Perhaps a specific mutation that allows H5N1 to better attach to human recipients could harm the virus in some other way.
The One Health Strategy
Getting the right combination of 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 animal health sectors through the collaborative approach called One Health (some sectors have criticized the slowness with which the US authorities are intervening ).
If a susceptible species (pigs, cows, minks, etc.) is infected simultaneously with both human seasonal influenza and avian influenza viruses, a rearrangement of the genomes of both viruses could occur, giving rise to a hybrid that is better adapted to human infection.
Public health efforts should continue to focus on protecting workers exposed to infected animals with preventive measures, such as vaccination, to minimize risk. It is critical to investigate each human case to detect early any changes that may suggest increased 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.
...
Hat tip to Shiloh
Science: A single mutation in bovine influenza H5N1 hemagglutinin switches specificity to human receptors
Translation Google
H5N1: No, we are not one mutation away from a flu pandemic
Published: January 7, 2025 12:56pm EST
Authors
Ignacio Lopez-Goñi Professor of Microbiology. Member of the Spanish Society of Microbiology (SEM), University of Navarra
Elisa Perez Ramirez Veterinary virologist at the Animal Health Research Centre (CISA), Spanish National Research Council (CSIC)
Early last December, a group of researchers published a paper in the journal Science titled “ A Single Mutation in the Bovine Influenza H5N1 Hemagglutinin Changes Specificity to Human Receptors .” Some media outlets exaggeratedly interpreted this to mean that we were just one mutation away from the next flu pandemic .
Although there are currently no documented cases of human-to-human transmission, there is concern that the H5N1 avian influenza virus that has been spreading in cattle in the United States could adapt to human-to-human transmission and eventually trigger an influenza pandemic.
Molecular barriers
One of the barriers to the transmission of avian viruses to humans is the specificity of the binding of the virus's hemagglutinin (HA) to the cellular receptor, a sialic acid molecule of which there are different types. Thus, the HA of avian influenza viruses binds to “avian-type” cellular receptors containing α2-3 sialic acid. In contrast, the HA of human influenza viruses binds to receptors with α2-6 sialic acid, abundant in our upper respiratory tract cells.
For the avian influenza 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 aforementioned study is actually an in vitro experimental assay , not the characterization of a specific isolate of the H5N1 virus circulating in nature. The work consisted of introducing mutations into a specific site of the HA protein of the H5N1 virus and evaluating how they bind to the human-type receptor using different laboratory techniques.
In addition, 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. They observed that a single mutation (specifically, the change of an amino acid from glutamine to leucine at residue 226 of the protein) was sufficient 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 we are one mutation away from a pandemic.
A real 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 via migratory birds, and have diversified into distinct 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. H5N1 viruses 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 geographical spread (it has even been detected in Antarctica), temporal extent (cases are described throughout the year), the number of species that record transmission and the number of animals affected, the avian influenza epidemic can now be considered a true pandemic in the animal world, which is known as panzootic.
In late March 2024, the first case of H5N1 2.3.4.4b infection in dairy cattle was reported in the United States , an unexpected reservoir for the virus. 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 with H5N1 is also widespread, with outbreaks on poultry farms having killed more than 100 million birds in the country. The virus has also been identified in many species of wild mammals and zoo animals, particularly felines.
H5N1 in humans
Historically, human infections with H5N1 have been sporadic and always linked to exposure to infected poultry. As of November 2024, more than 900 human cases have been reported in 24 countries , with mortality rates of more than 30% reported in hospitalized cases. However, this is most likely an overestimate as it does not take into account asymptomatic or unreported infections.
Since March 2024, when the first transmission of the H5N1 virus from cow to person occurred in the United States, 64 human cases have been confirmed in nine states. More than half of these (36) have occurred in California. Detailed clinical information on 46 of these cases identified between March and October 2024 has just been published . Of the 46 patients, 45 were exposed to infected dairy cows (25) or poultry (20). Only one patient could not 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 no one died. Ninety-three percent had conjunctivitis, 49 percent had fever, and only 36 percent had respiratory symptoms, all of which were short-lived. No additional cases of infection were identified among the 97 contacts of these patients, so human-to-human transmission has not been demonstrated. This is consistent with the current lack of evidence of human-to-human transmission of H5N1 in the United States.
Why is it not a pandemic yet?
One simple answer is that the virus may simply need more time to find the right combination of mutations . For the H5N1 avian influenza pathogen to become pandemic, it would need to not only improve its ability to spread through the air between humans and bind to receptors on human cells, but also improve its ability to enter and multiply inside humans.
Furthermore, 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 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 U.S. cases has not shown any changes in the HA gene associated with increased infectivity or transmissibility, and no mutations in other genes have been identified that indicate adaptation to humans. Perhaps a specific mutation that allows H5N1 to better attach to human recipients could harm the virus in some other way.
The One Health Strategy
Getting the right combination of 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 animal health sectors through the collaborative approach called One Health (some sectors have criticized the slowness with which the US authorities are intervening ).
If a susceptible species (pigs, cows, minks, etc.) is infected simultaneously with both human seasonal influenza and avian influenza viruses, a rearrangement of the genomes of both viruses could occur, giving rise to a hybrid that is better adapted to human infection.
Public health efforts should continue to focus on protecting workers exposed to infected animals with preventive measures, such as vaccination, to minimize risk. It is critical to investigate each human case to detect early any changes that may suggest increased 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.
...
