If the world finds itself amid a flu pandemic in a few months, it won’t be a big surprise.
“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.
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.
“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.
It won’t be shocking if a flu pandemic breaks out in the world in a few months. 2.3 is a novel clade of the H5N1 avian influenza virus that has been spread by birds. 4.4b, globally since 2021. After infecting cattle in Texas approximately a year ago, the virus has since spread to hundreds of farms throughout the United States. In North America, dozens of human infections have occurred. Additionally, the virus has occasionally displayed the precise mutations that are known to improve its ability to infect and replicate in human cells.
According to Louise Moncla, a virologist at the University of Pennsylvania, “this feels the closest to an H5 pandemic that I’ve seen,” even though there isn’t any conclusive evidence of H5N1 transmission from person to person yet. Seema Lakdawala, an Emory University flu researcher, agrees, “If H5 is ever going to be a pandemic, it’s going to be now.”.
Others are more optimistic, pointing out that comparable dangerous bird flu viruses, like H7N9, have previously waned. According to epidemiologist Caitlin Rivers of the Johns Hopkins Center for Health Security, “why didn’t H7N9 turn out to be easily human-to-human transmissible and cause a pandemic?”. “I think it’s really impossible to predict and it could go either way.”. “.”.
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H5N1 has been on lists of possible pandemic agents ever since it first caused an outbreak in humans in Hong Kong in 1997, killing six people and sickening 18 others who had come into contact with infected poultry. Since then, researchers have developed a picture of the minimal modifications that H5N1 probably needs to spread widely in humans: changes to its polymerase, which is the enzyme that the virus uses to copy its genome, and to its hemagglutinin, which is the H in H5N1 and is the protein that the virus uses to attach to cells. These changes stabilize the virus for airborne transmission and improve its ability to bind to cells in the human upper airways.
Numerous recent studies appear to indicate that there is a greater chance than previously believed that the current H5N1 clade in cattle and birds will cause a pandemic. Many human infections remain undiagnosed, which gives the bovine virus more opportunities to adapt to humans, according to a study that examined blood samples from employees at H5N1-infected dairy farms in Michigan and Colorado. This week’s preprint out shows that clade 2.3 is presently in circulation. Compared to earlier iterations of H5N1, 4.4b viruses are more adept at attaching to human epithelial cells in the airways. Additionally, a Science article published today demonstrates that in laboratory experiments, a single mutation at a single hemagglutinin site, known as 226L, is sufficient to change the virus’ preference for human-type receptors over avian-type cell surface proteins. Many scientists believed that two mutations or more were necessary. According to one of the authors, Jim Paulson of Scripps Research, a switch based on a single mutation “means the likelihood of it happening is higher.”.
How come H5N1 hasn’t caused a pandemic yet?
The virus might simply require additional time to strike the ideal set of mutations, according to one straightforward explanation. According to Paulson, “my rule of thumb is that one in 4000 [virus] particles will have a mutation at the amino acid that you are interested in,” which should help H5N1 win because influenza viruses have a high rate of mutation. Since it results in the amino acid lysine (K) at position 627 of the protein, this polymerase mutation is likely necessary for the virus. It has been identified multiple times in virus strains that infect mammals as well as in the virus isolated from the first human case linked to the U.S. A. disease in dairy cows.
However, the 226L hemagglutinin mutation that would improve H5N1’s ability to bind to human receptors has not yet been detected in viruses in humans, cattle, or birds. Scientists hypothesize that the virus may be hampered by the change and that a second mutation might be required to counteract its drawbacks. Additionally, there may be a specific order in which the two mutations must occur. Mike Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota Twin Cities, compares it to a bank vault’s dial: You turn to the right, then to the left, then to the right, and you have to always get a specific number.
The virus may simply not be able to change an amino acid at position 226 outside of the lab, according to some researchers. Then came the enigmatic case of a seriously ill Canadian teen who has been hospitalized since early November due to H5N1. According to evolutionary biologist Jesse Bloom of the Fred Hutchinson Cancer Center, that patient’s virus sequences indicate that some H5N1s had altered the amino acid at position 226 while others had not. The virus appears to have been evolving toward at least some of the mutations that would have made it more human-friendly during this person’s infection. “.”.
This was not the dreaded 226L mutation: instead of leucine, the amino acid was now histidine. However, “it demonstrated that those locations are changeable in these viruses,” according to Tom Peacock, a Pirbright Institute influenza virologist. Additionally, a second mutation in the same virus at position 190 combined with the glutamine substitution may have the same effect as the 226L. The discovery heightened worries about an impending pandemic for Peacock and others.
The Canadian case may have involved unusual circumstances. The adolescent was admitted to the hospital the week after his symptoms worsened after initially seeking treatment on November 2 for an eye infection, cough, and fever. The prolonged sickness might have contributed to the hemagglutinin alteration by giving the virus more time to find a successful mutation. The type of virus that is presently circulating in birds rather than cattle is perhaps more significant. Presumably in a bird infected with two distinct avian influenza viruses, the bird virus, known as D1.1, has obviously undergone reassortment, or the mixing of different viruses. It gained a new neuraminidase, the protein that the virus uses to separate newly formed virus particles from the cell that produced them, as well as the N in H5N1.
According to some researchers, the virus’s ability to survive depends on a particular combination of neuraminidase and hemagglutinin. Hemagglutinin binds to the same sugar chains on the surface of human cells, aiding the virus in infecting new cells, while neuraminidase cleaves the chains, releasing the newly generated virus from host cells. “You get stuck to the cell that you just budded from if your neuraminidase is too poor and your hemagglutinin is too sticky,” Peacock explains. The virus cannot infect new cells if the balance is skewed in the opposite direction.
The two proteins in the H5N1 variant that is currently circulating in cattle may be so closely related that any alteration to the hemagglutinin is futile since it makes the virus much less effective at infecting cells. Richard Webby, an avian influenza researcher at St. Research Hospital for Jude Children. Osterholm concurs. He says, “The cattle one seems pretty stable and could go on like that for a while.”. It’s D1.1 that concerns me. “”.
According to Paulson, it is possible that scientists have yet to discover another essential alteration that the virus requires in order to spread effectively from one person to another. He states that “the barrier that you can identify as having been overcome may not be the only barrier when you do have a pandemic virus, which is very rare.”. Five or six other people may have been overcome simultaneously, but you may not be aware of them. “”.
More worrisomely, viral immunologist Scott Hensley of the University of Pennsylvania’s Perelman School of Medicine suggests that if more people had been exposed to the virus, it might have had all the necessary components to spread like wildfire. Ultimately, I believe it to be a game of numbers. “”.
