The deadly avian influenza virus is as little as three mutations away from easily spreading from mammal to mammal, which might include humans, researchers reported today.
The controversial studies, held up for eight months after the U.S. government raised concerns about the potential misuse of the information, were released in full to help raise awareness, spur greater surveillance for changes in the virus and highlight the need to prepare for a potential pandemic, officials said.
The reports were released today in a special section of the journal Science with all of the details about the specific mutations that caused the avian influenza A H5N1 to become more easily transmissible in ferrets, a stand-in animal model for humans in influenza studies.
"It is our hope that (today's) publication will help to make the world safer ... by stimulating many more scientists and policy-makers to focus on preparing defenses," said Dr. Bruce Alberts, editor-in-chief of Science. "This is going to require a great deal of new innovation and making the new data as widely available as we are (now) greatly increases the chances that this innovation will happen."
Since the 1990s, the avian influenza A H5N1 has led to the destruction of millions of birds in Asia, Africa, the Middle East and Europe as the virus has spread. Since 2003, the virus has infected more than 600 people, resulting in 357 deaths, for a fatality rate of almost 60 percent, according to data from the World Health Organization. But there has been little human-to-human transmission of the virus, in part because it did not appear to be able to infect mammals through airborne droplets, a key characteristic of pandemic influenza strains, according to the Science study.
Dr. Ron A.M. Fouchier and colleagues at the Erasmus Medical Center in the Netherlands took a strain of influenza A H5N1 from Indonesia and then reverse engineered into it three mutations that helped lead to pandemic influenza outbreaks in 1918, 1957 and 1968. With these three mutations, however, the virus still did not spread by airborne transmission. The researchers then infected one group of ferrets, then infected the next group of ferrets with a virus from the first group, and so on through 10 cycles of infection as a way to force the virus to evolve to a new host.
"Such experiments are well known in the virology field to lead to further adaptation of viruses based on the theory of natural selection," Fouchier said.
After 10 cycles, that mutant H5N1 virus was found to have at least two new mutations not known to be involved previously in airborne transmission, in addition to the original three, he said. And when ferrets infected with that strain were placed near but not in contact with uninfected ferrets, the virus was able to infect the new ferrets through airborne droplets.
"Our main conclusion is that the H5N1 bird flu virus can acquire the ability of aerosol transmission between mammals," Fouchier said. "And we show that as little as five mutations but certainly less than 10 are sufficient to make H5N1 virus airborne."
However, not one of the ferrets who were infected by airborne transmission was killed by the virus, perhaps because it is less likely to cause a deep infection in the lungs that can lead to pneumonia, he said. And the airborne virus seemed to be susceptible to the antiviral oseltamivir and antigenically similar to the H5N1 vaccine, Fouchier said.
The big question is how quickly and how easily the necessary mutations to become airborne will happen, said Dr. Derek Smith of the University of Cambridge, who is also involved in the Erasmus lab. In studying nearly 4,000 avian influenza genetic sequences, "we found that two of the mutations are already seen frequently, including in combination with each other," he said. If only five of the mutations are needed to become airborne, "it's possible that it could be as few as three" new mutations.
Smith likened the ability to gauge when or if that would ever happen as similar to trying to forecast earthquakes, but "we now know that we are living on a fault line," he said. The research published in Science and an earlier study show "that it is an active fault line," Smith said. "It really could do something."
The probability of hitting that right combination might also work against the airborne virus, he said.
"If it takes four or five mutations, then of course it is more difficult," Smith said. "And at five mutations, it really does look like it is pretty difficult. But we don't yet know how likely it is."
Some of the mutations appear to be more common in human cases of avian influenza than the bird strains, Fourchier said.
"So there might be a link between bird to human transmission and some of these mutations," he said.
All of this points toward greater need for increased surveillance for the mutations, particularly in human cases where a mutation might be hidden in a lesser strain than the dominant one causing the infection, Smith said. It points toward the need for greater surveillance in general, particularly if the virus does begin to spread more easily, said Dr. Rino Rappuoli of Novartis Vaccines and Diagnostics in Siena, Italy.
"Once the pandemic comes, I think it would be very important to have a very active surveillance that would pick the virus before it spreads," he said. "Detecting the virus early is very important."
It also points to the need to change vaccine manufacturing, from the egg-based approach to cell-based processes that are much quicker and can respond more rapidly to an unknown strain, Rappuoli said. That could also mean changing the process that regulates how vaccines are licensed and distributed, he said.
The decision to make all of the information public came after much debate and is not without some risk, said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. The benefit of full disclosure "in my mind far outweighs the risk of nefarious use of this information," he said. "Being in the free and open literature would make it much more easy to get a lot of the good guys involved than the risk of getting the rare bad guy involved."
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