Post by Nadica (She/Her) on Dec 7, 2024 3:28:05 GMT
Why hasn’t the bird flu pandemic started? - Published Dec 5, 2024
By Kai Kupferschmidt
If the world finds itself amid a flu pandemic in a few months, it won’t be a big surprise. Birds have been spreading a new clade of the H5N1 avian influenza virus, 2.3.4.4b, around the world since 2021. That virus spilled over to cattle in Texas about a year ago and spread to hundreds of farms across the United States since. There have been dozens of human infections in North America. And in some of those cases the virus has shown exactly the kinds of mutations known to make it better suited to infect human cells and replicate in them.
No clear human-to-human transmission of H5N1 has been documented yet, but “this feels the closest to an H5 pandemic that I’ve seen,” says Louise Moncla, a virologist at the University of Pennsylvania. “If H5 is ever going to be a pandemic, it’s going to be now,” adds Seema Lakdawala, a flu researcher at Emory University.
Others are more sanguine, noting that similarly menacing avian flu viruses, such as one called H7N9, have petered out in the past. “Why didn’t H7N9 end up being easily human-to-human transmissible and cause a pandemic?” asks Caitlin Rivers, an epidemiologist at the Johns Hopkins Center for Health Security. “I feel like there’s really no way to estimate and it could go either way.”
Ever since H5N1 first caused an outbreak in humans in Hong Kong in 1997, sickening 18 who had been in contact with infected poultry and killing six, the avian virus has been high on lists of potential pandemic agents. Scientists have since built up a picture of the minimum changes H5N1 likely needs to spread widely in humans: mutations in its polymerase, the enzyme the virus uses to copy its genome, and in its hemagglutinin—the H in H5N1—the protein the virus uses to attach to cells, to stabilize it for airborne transmission and help it better bind to cells in the human upper airways.
A slew of recent findings all seem to suggest the risk of the current H5N1 clade in cattle and birds causing a pandemic is actually higher than previously thought. A study looking at blood samples from workers at H5N1-infected dairy farms in Michigan and Colorado found that many human infections go undetected, each one offering the bovine virus more chances to adapt to us. A preprint out this week indicates currently circulating clade 2.3.4.4b viruses are better at binding to human epithelial cells in the airways than previous versions of H5N1. And a Science paper out today shows in lab studies that a single mutation at one hemagglutinin site, dubbed 226L, is enough to shift the virus’ preference from the avian-type cell surface protein to human-type receptors. Many scientists had thought at least two mutations were required. A switch based on just one mutation “means the likelihood of it happening is higher,” says Jim Paulson of Scripps Research, one of the authors.
So why hasn’t H5N1 touched off a pandemic yet?
One simple answer is that the virus may just need more time to hit the right combination of mutations. The high mutation rate of influenza viruses should tip the odds in H5N1’s favor: “My rule of thumb is that one in 4000 [virus] particles will have a mutation at the amino acid that you are interested in,” Paulson says. Indeed, one polymerase mutation the virus likely needs, dubbed 627K because it leads to the amino acid lysine (K) at position 627 of the protein, has been found several times in strains infecting mammals but also in virus isolated from the first human case associated with the U.S. outbreak in dairy cows.
On the other hand, the viruses in birds, cattle, and people so far show no signs of the 226L hemagglutinin mutation that would allow H5N1 to better latch onto human receptors. Researchers speculate that change might hamper the virus in some way, and a second mutation may be needed to offset its disadvantages. The two mutations might also have to come in a particular order. “It’s like a dial on a bank vault: You go to the right, then you go to the left, then you go to the right and you’ve got to get a certain number every time,” says Mike Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota Twin Cities.
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In fact, some researchers thought the virus might just be unable to swap an amino acid at position 226 outside the lab. But then came the mysterious case of a severely sick teenager in Canada who has been hospitalized with H5N1 since early November. Virus sequences from that patient suggest some H5N1s had changed the amino acid at position 226 whereas others had not, says Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Center. “It looks like during the infection of this individual, the virus could have been evolving towards at least some of the mutations that would adapt it to humans.”
This was not the feared 226L mutation: The amino acid had changed to a histidine instead of leucine. Still, “It showed that those sites are mutable in these viruses,” says Tom Peacock, an influenza virologist at the Pirbright Institute. And the glutamine substitution, together with another mutation in the same virus at position 190, could have the same effect as the 226L. For Peacock and others, the finding upped concern about an imminent pandemic.
Unusual factors may have been at play in the Canadian case. The teenager first sought care on 2 November for an eye infection and cough and fever and was hospitalized the week after, when symptoms worsened. The protracted illness may have played a role in the hemagglutinin change, allowing the virus time to hit on a winning mutation. Perhaps more important, the teenager’s virus is the variety that is currently circulating in birds, not cattle. The bird virus, designated D1.1, has clearly gone through reassortment, a mixing of different viruses, presumably in a bird infected with two different avian influenza viruses. In the process it acquired a new neuraminidase, the N in H5N1 and the protein the virus uses to detach new virus particles from the cell that produced them.
Some researchers believe a specific neuraminidase and hemagglutinin combination is crucial to the virus’ success. The two proteins have opposing effects on the same sugar chains on the surface of human cells: Hemagglutinin attaches to these chains, helping the virus infect new cells, whereas neuraminidase cuts those chains, freeing newly formed virus from host cells. “If your hemagglutinin is too sticky and your neuraminidase is too poor, you get stuck to the cell that you’ve just budded from,” Peacock says. If the balance skews the other way, the virus can’t infect new cells.
In the H5N1 variant now circulating in cattle the two proteins may be so well matched that any change in the hemagglutinin is a dead end because it makes the virus much worse at infecting cells. But the newly combined genotype of the bird strain that infected the teenager may have more flexibility to transform into a pandemic virus, says Richard Webby, an avian influenza researcher at St. Jude Children’s Research Hospital. Osterholm agrees. “The cattle one seems pretty stable and could go on like that for a while,” he says. “D1.1 is the one I worry about.”
It is possible that researchers have not yet identified some other crucial change the virus needs to transmit well from humans to humans, Paulson says. “When you do have a pandemic virus, which is very rare, the barrier that that you can identify as having been overcome may not be the only barrier,” he says. “You might be unaware of five or six others that were also overcome at the same time.”
Or, more disturbingly, the virus in the Canadian teenager might actually have had all it needed to go pandemic if only more people had been exposed to it, says viral immunologist Scott Hensley of the University of Pennsylvania’s Perelman School of Medicine. “At the end of the day, I think it is a numbers game.”
By Kai Kupferschmidt
If the world finds itself amid a flu pandemic in a few months, it won’t be a big surprise. Birds have been spreading a new clade of the H5N1 avian influenza virus, 2.3.4.4b, around the world since 2021. That virus spilled over to cattle in Texas about a year ago and spread to hundreds of farms across the United States since. There have been dozens of human infections in North America. And in some of those cases the virus has shown exactly the kinds of mutations known to make it better suited to infect human cells and replicate in them.
No clear human-to-human transmission of H5N1 has been documented yet, but “this feels the closest to an H5 pandemic that I’ve seen,” says Louise Moncla, a virologist at the University of Pennsylvania. “If H5 is ever going to be a pandemic, it’s going to be now,” adds Seema Lakdawala, a flu researcher at Emory University.
Others are more sanguine, noting that similarly menacing avian flu viruses, such as one called H7N9, have petered out in the past. “Why didn’t H7N9 end up being easily human-to-human transmissible and cause a pandemic?” asks Caitlin Rivers, an epidemiologist at the Johns Hopkins Center for Health Security. “I feel like there’s really no way to estimate and it could go either way.”
Ever since H5N1 first caused an outbreak in humans in Hong Kong in 1997, sickening 18 who had been in contact with infected poultry and killing six, the avian virus has been high on lists of potential pandemic agents. Scientists have since built up a picture of the minimum changes H5N1 likely needs to spread widely in humans: mutations in its polymerase, the enzyme the virus uses to copy its genome, and in its hemagglutinin—the H in H5N1—the protein the virus uses to attach to cells, to stabilize it for airborne transmission and help it better bind to cells in the human upper airways.
A slew of recent findings all seem to suggest the risk of the current H5N1 clade in cattle and birds causing a pandemic is actually higher than previously thought. A study looking at blood samples from workers at H5N1-infected dairy farms in Michigan and Colorado found that many human infections go undetected, each one offering the bovine virus more chances to adapt to us. A preprint out this week indicates currently circulating clade 2.3.4.4b viruses are better at binding to human epithelial cells in the airways than previous versions of H5N1. And a Science paper out today shows in lab studies that a single mutation at one hemagglutinin site, dubbed 226L, is enough to shift the virus’ preference from the avian-type cell surface protein to human-type receptors. Many scientists had thought at least two mutations were required. A switch based on just one mutation “means the likelihood of it happening is higher,” says Jim Paulson of Scripps Research, one of the authors.
So why hasn’t H5N1 touched off a pandemic yet?
One simple answer is that the virus may just need more time to hit the right combination of mutations. The high mutation rate of influenza viruses should tip the odds in H5N1’s favor: “My rule of thumb is that one in 4000 [virus] particles will have a mutation at the amino acid that you are interested in,” Paulson says. Indeed, one polymerase mutation the virus likely needs, dubbed 627K because it leads to the amino acid lysine (K) at position 627 of the protein, has been found several times in strains infecting mammals but also in virus isolated from the first human case associated with the U.S. outbreak in dairy cows.
On the other hand, the viruses in birds, cattle, and people so far show no signs of the 226L hemagglutinin mutation that would allow H5N1 to better latch onto human receptors. Researchers speculate that change might hamper the virus in some way, and a second mutation may be needed to offset its disadvantages. The two mutations might also have to come in a particular order. “It’s like a dial on a bank vault: You go to the right, then you go to the left, then you go to the right and you’ve got to get a certain number every time,” says Mike Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota Twin Cities.
In fact, some researchers thought the virus might just be unable to swap an amino acid at position 226 outside the lab. But then came the mysterious case of a severely sick teenager in Canada who has been hospitalized with H5N1 since early November. Virus sequences from that patient suggest some H5N1s had changed the amino acid at position 226 whereas others had not, says Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Center. “It looks like during the infection of this individual, the virus could have been evolving towards at least some of the mutations that would adapt it to humans.”
This was not the feared 226L mutation: The amino acid had changed to a histidine instead of leucine. Still, “It showed that those sites are mutable in these viruses,” says Tom Peacock, an influenza virologist at the Pirbright Institute. And the glutamine substitution, together with another mutation in the same virus at position 190, could have the same effect as the 226L. For Peacock and others, the finding upped concern about an imminent pandemic.
Unusual factors may have been at play in the Canadian case. The teenager first sought care on 2 November for an eye infection and cough and fever and was hospitalized the week after, when symptoms worsened. The protracted illness may have played a role in the hemagglutinin change, allowing the virus time to hit on a winning mutation. Perhaps more important, the teenager’s virus is the variety that is currently circulating in birds, not cattle. The bird virus, designated D1.1, has clearly gone through reassortment, a mixing of different viruses, presumably in a bird infected with two different avian influenza viruses. In the process it acquired a new neuraminidase, the N in H5N1 and the protein the virus uses to detach new virus particles from the cell that produced them.
Some researchers believe a specific neuraminidase and hemagglutinin combination is crucial to the virus’ success. The two proteins have opposing effects on the same sugar chains on the surface of human cells: Hemagglutinin attaches to these chains, helping the virus infect new cells, whereas neuraminidase cuts those chains, freeing newly formed virus from host cells. “If your hemagglutinin is too sticky and your neuraminidase is too poor, you get stuck to the cell that you’ve just budded from,” Peacock says. If the balance skews the other way, the virus can’t infect new cells.
In the H5N1 variant now circulating in cattle the two proteins may be so well matched that any change in the hemagglutinin is a dead end because it makes the virus much worse at infecting cells. But the newly combined genotype of the bird strain that infected the teenager may have more flexibility to transform into a pandemic virus, says Richard Webby, an avian influenza researcher at St. Jude Children’s Research Hospital. Osterholm agrees. “The cattle one seems pretty stable and could go on like that for a while,” he says. “D1.1 is the one I worry about.”
It is possible that researchers have not yet identified some other crucial change the virus needs to transmit well from humans to humans, Paulson says. “When you do have a pandemic virus, which is very rare, the barrier that that you can identify as having been overcome may not be the only barrier,” he says. “You might be unaware of five or six others that were also overcome at the same time.”
Or, more disturbingly, the virus in the Canadian teenager might actually have had all it needed to go pandemic if only more people had been exposed to it, says viral immunologist Scott Hensley of the University of Pennsylvania’s Perelman School of Medicine. “At the end of the day, I think it is a numbers game.”