05/02/2012 01:04 EDT | Updated 07/02/2012 05:12 EDT

Three mutations might give hybrid bird flu virus ability to transmit to humans: study

A bird flu study that was blocked from publication for months after biosecurity experts questioned if it was unsafe to put it in the public domain has finally been published.

The work, conducted by a team led by influenza virologist Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo, suggests that as few as three changes to the main gene on the surface of some H5N1 flu viruses might allow the virus to transmit efficiently among mammals — perhaps even humans.

Kawaoka and his team managed to create a hybrid virus that would transmit through the air, passing from infected to healthy ferrets, which were used in the experiment as a stand in for people. The newly transmissible virus needed four mutations in the surface gene, the hemagglutinin, which gives a flu virus the H portion of it name.

One of the mutations is already seen in viruses in the Middle East, Africa and parts of Asia and Europe, potentially leaving the need for only three more, if the virus were to take this route to gain the capacity to pass from human to human.

"Our study shows that relatively few amino acid mutations are sufficient for a virus with an avian H5 hemagglutinin to acquire the ability to transmit in mammals," Kawaoka said in a press release.

Science currently has no way to gauge how likely or unlikely it is that this would happen. And experts warn there are likely other paths the virus could take to adapt to spread among mammals.

Kawaoka's paper, published in the journal Nature, is one of two that have been at the center of a protracted fight that has pitted biosecurity experts against influenza scientists.

The U.S. National Science Advisory Board for Biosecurity argued publishing the paper could threaten national security and public health. But flu research establishment countered that sharing the data is critical to both shore up a new and delicate international flu virus sharing agreement and to monitor H5N1 viruses in the wild for dangerous changes.

The second study, by Dutch virologist Ron Fouchier, was only cleared for publication by the Dutch government late last week. It is to be published in Science, though a date has not yet been announced.

In the world of influenza research, Kawaoka is rock star, known for elegant studies that grace the pages of the top scientific journals.

This one is no exception, flu scientists say. The intricate work involved creating a reassortant or hybrid virus with a mutated hemagglutinin gene from H5N1 fused to the seven remaining genes from the H1N1 virus responsible for the 2009 pandemic.

"It really is a wonderful study," said Richard Webby, director of a World Health Organization collaborating center that focuses on studies of animal and bird influenza viruses at St. Jude Children's Hospital in Memphis, Tenn.

Webby suggested the mutations that pushed Kawaoka's virus to become transmissible in mammals will likely not come as a surprise to others doing this type of work.

They change functions the field has known for some time are key for avian flu viruses to make the leap to be able to infect humans. Those include changing the type of cell receptors the viruses bind to, from receptors that are typically found in people only deep in the lungs to ones found in the upper respiratory tract, where human flu viruses attach.

But the work is valuable in helping flu scientists figure out the mechanism by which the mutations help the virus become more efficient at mammal-to-mammal spread, said Adolfo Garcia-Sastre, a flu virologist at Mount Sinai Hospital in New York City.

He cautioned against reading too much into the results though, saying that a virus that transmits easily among ferrets may still not do so among people.

But Garcia-Sastre suggested the findings will be useful for scientists and public health experts who are monitoring H5N1 viruses for changes that might make the viruses more of a threat to humankind. For instance, bird flu outbreaks caused by viruses bearing the mutations Kawaoka used could be prioritized for control over others that don't, he said.

Though the NSABB questioned whether flu surveillance is sufficiently strong to pick up these kinds of signals in real time, the World Health Organization's point person for flu agreed with Garcia-Sastre's assertion.

"If we detect certain patterns out there — and I believe that the systems and the data are good enough to pick up certain patterns — then again it may give us a leg up upon important changes taking place among viruses," said Dr. Keiji Fukuda, the WHO's assistant director general for health security and environment.

The authors of a commentary published by the journal noted that none of the ferrets infected with the hybrid virus died, a fact they called "intriguing."

Flu experts Malik Peiris and Hui-Ling Yen of the University of Hong Kong raised the possibility that the receptor binding changes the virus had to undergo to adapt to mammalian transmission may lead to less severe disease in mammals.

But Peiris acknowledged in an email that there is no evidence in Kawaoka's paper to either support or refute the idea. He suggested another potential explanation for why the hybrid was not fatal when H5N1 viruses are might be due the fact the hybrid lacks the internal genes of the whole bird flu virus. Those genes may play a major role in H5N1's virulence, he said.

The publication of Kawaoka's paper closes a chapter in a difficult saga for influenza science. But flu scientists know it's unlikely the story is over.

Webby said flu research will likely come under more oversight going forward, with far more attention paid to any work that might potentially be seen as so-called dual use research of concern — science that could be used for good or for evil.

He said that will probably lead to "much more prior approval or ongoing monitoring of this type of research."

"There's certainly going to be more paperwork. But in the long run it's surely going to be a whole lot easier than what we've just been through since December of last year."

And Fukuda said he hopes the flu community learns lessons from the experience, suggesting it is would be wise for researchers to discuss among themselves about how to conduct this type of research responsibly before they lift a self-imposed moratorium on H5N1 transmission studies.

"I hope it hasn't been lost on everybody that we've had this four months of very intense discussions because there are real concerns and that it is not simply a matter of 'Let's have a moratorium,' 'Let's stop the moratorium," Fukuda said from Geneva.

"The real issue is that there are concerns about the transmissibility of H5 viruses, there are concerns about the way the studies are being done, (and whether) the safeguards are adequate."