Some bird flu strains only three mutations away from a pandemic, researchers find

A new study raises concerns that it may be possible for airborne transmissible, human-to-human avian H5N1 flu viruses to evolve in nature.

The study looked at five mutations identified previously in the controversial bird flu studies published in the journals Nature and Science—led by Yoshihiro Kawaoka of the University of Wisconsin and Ron Fouchier of Erasmus Medical Center in Rotterdam, the Netherlands, respectively—which would make it possible for bird flu to spread from human to human.

In those studies, the researchers experimented with bird flu strains to show which mutations would be necessary for the virus to evolve to become transmissible between mammals.

The papers revealed with only five mutations (amino acid substitutions), or four mutations plus reassortment, bird flu can become transmissible between mammals – and potentially humans.  Currently, bird flu can be transmitted from birds to humans, but not from humans to humans.

U.S. federal officials initially asked the journals to withhold publishing the papers, based on bioterrorism fears, but relented after an independent panel of experts determined there was no threat to public health.

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Now, in an accompanying study, led by Professor Derek Smith and Dr. Colin Russell at the University of Cambridge, researchers analyzed all the surveillance data available on avian H5N1 flu viruses in the past 15 years and discovered two of the five mutations needed to make bird flu transmissible between mammals had already occurred in numerous avian flu strains that exist in nature.

Not only that, but a number of the virus strains had both of the mutations, the researchers added.

"Viruses that have two of these mutations are already common in birds, meaning that there are viruses that might have to acquire only three additional mutations in a human to become airborne transmissible,” Russell said in a released statement. “The next key question is, 'Is three a lot, or a little?'"

In order to address the question, the researchers used a mathematical model of how viruses replicate and evolve in mammals to see which factors would increase the likelihood of the three mutations occurring spontaneously in nature.

According to the model, factors that increased the likelihood of the virus evolving included random mutations and positive selection.  Viruses can replicate billions of times within a single host, sometimes imperfectly, leading to random mutations.  Positive selection may favor some of these mutations if they help the virus adapt to mammals and spread.

A long period of infection can also increase the likelihood of the virus evolving, because the longer a person is infected, the more the virus replicates and mutations can accumulate.  According to the researchers, it is also likely that there are other mutations not identified by the Fouchier and Kawaoka papers, which can act as functional substitutes for the three remaining mutations.

Finally, the diversity of the virus within the bird population can spell trouble for humans as well.  The more mutations there are within the bird population, the higher probability there is that a key mutation may be missed by routine surveillance.

However, even after identifying those factors, as well as a few factors that may actually decrease the likelihood of bird flu evolving, the researchers said it was impossible to determine the exact risk.

“You can’t put a number on it,” Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Disease at the National Institutes of Health, told “ But nature has already told us this is very unlikely—not impossible, but unlikely.”

According to Fauci, health officials first noticed the bird flu virus in 1997 and started following it closely since 2003.

“In nine years, there have been 600 cases in that period, and the virus has not naturally mutated to get to the point where investigators got it in [the papers by Kawaoka and Fouchier],” Fauci said.  “…But some of the mutations induced experimentally are to a certain extent occurring naturally in the wild, so the bottom line is, it is feasible.”

The U.S. Department of Agriculture continually does surveillance on chickens for traces of H5N1, while the Centers for Disease Control and Prevention periodically samples influenza strains in people, according to Fauci—who added that no potential pandemics have been observed as intensively as this one in the past.  So far, there have been no reported cases in the U.S. of H5N1 in humans.

The Cambridge researchers recommended continued surveillance of the bird flu virus, particularly in regions where mutations necessary for human transmission have occurred, as well as in regions connected to those by bird migration and trade.  They also called for additional studies and deep sequencing of bird flu viruses to identify any other mutations that may play a role in human-to-human transmission.

In a statement, Smith compared the situation to assessing the risk of an earthquake or tsunami. “We don't know exactly when and where, but by increasing monitoring and research – some of which is already underway – scientists and public health officials will be able to increase the accuracy with which the risk can be assessed and to minimize those risks."

Fauci added: “If in fact the mutations can happen, you want to get an idea of what the virus would look like in order to have better surveillance, determine its sensitivity to current drugs and see if the vaccine still protects against it."

The study will be published in the journal Science.