H5N1 Research Moratorium Could Be Over Soon

Risky topic. Researchers Ilaria Capua from Italy, Joseph Sriyal Malik Periris from Hong Kong, and Adel Mahmoud from the United States (right to left) discuss the risks and benefits of research involving the H5N1 avian influenza virus at a me

D. Malakoff/Science

BETHESDA, MARYLAND—The end of a historic, 13-month-long global debate over the safety and wisdom of H5N1 avian influenza research may finally be in sight.

Speaking after a 2-day meeting here, U.S. government officials said today that they are moving rapidly to adopt a new policy for reviewing certain studies involving the H5N1 virus, in a bid to identify high-risk research before it begins. Scientists said the long-discussed move will enable them to soon lift a landmark moratorium on certain kinds of H5N1 research that they voluntarily imposed in January. The controversy was triggered by two studies that showed how to make the virus transmissible in mammals, potentially sparking a deadly human pandemic. Some influenza researchers working outside the United States said that they may even declare the moratorium dead before the U.S. National Institutes of Health (NIH) adopts its new review policy, expected no earlier than next month.

"I suspect that we will be seeing a lifting of the moratorium on the part of people who are not NIH-funded," Anthony Fauci, the head of the National Institute of Allergy and Infectious Diseases (NIAID) said today at the end of a special meeting dedicated to debating, fine-tuning, and test-driving the proposed H5N1 policy. Many of the 39 influenza researchers who arranged the moratorium, he said, have been "patiently waiting for this particular event. … I would not be surprised if they [now say]: 'OK, we've heard it all.' … Some are going to go ahead with their experiments if their country and funder allow it."

"We will be discussing lifting the moratorium very soon. … I'm sure I am going to be seeing lot of e-mails about this tomorrow morning," said virologist Ron Fouchier of Erasmus MC in Rotterdam, the Netherlands, who led one of the research teams that helped spark the controversy and also helped organize the moratorium. "It would be really nice if all 39 of us agree to lift it, or at least 37 or 38. But I think some researchers outside the United States are going to decide to resume" their paused studies even without unanimity, he said.

The latest debate unfolded before some 200 people, including many of the world's top H5N1 researchers, who gathered in an auditorium on the NIH campus to discuss the draft review guidelines. The rules are supposed to help NIH reviewers decide what kinds of H5N1 research the agency should, and should not, fund. Meeting participants also applied the draft, which the U.S. Department of Health and Human Services (HHS) released on 27 November, to four hypothetical studies.

The moratorium and the new rules apply only to a small range of experiments, so-called "gain-of-function" studies, in which researchers use gene engineering or other techniques to make naturally occurring H5N1 viruses more lethal or able to jump to new hosts, such as mammals. Many researchers say that such studies are essential to understanding how the virus might mutate into a form that is capable of sparking a deadly human pandemic, but others argue that the risks of such research outweigh its benefits. The issue came into stark focus in late 2011, when two research teams created H5N1 viruses capable of infecting ferrets. That work sparked a global controversy over whether the results should be published and whether funding agencies should do more to identify problematic studies before they begin.

The review framework is designed to do just that. It spells out seven criteria that a study would have to meet to be eligible for NIH funding. A researcher would have to show that a gain-of-function experiment has "high significance to public health," for instance, and that there were "no feasible alternative methods" for doing it. Scientists would also have to provide "evidence" that the H5N1 virus they want to create "could be produced through a natural evolutionary process in the foreseeable future." A study that fails to meet any one of the criteria would get a more intensive review by HHS and other agencies—and possibly a recommendation that it be transferred to an agency that does classified research, such as the defense or homeland security departments, if reviewers thought the results might be too dangerous to share.

The plan has drawn mixed reviews from scientists, with critics saying that some of the criteria—especially the one that requires researchers to show that their engineered virus could someday appear in nature—are worded too vaguely, and set the funding bar too high. Others worry that the policy could harm international collaboration, especially if other nations don't follow the lead of the United States.

Attendees here had plenty of suggestions for avoiding such problems. One major recommendation that appears to be gaining traction is to limit the extra, HHS-level reviews to only a subset of studies that propose to create especially dangerous H5N1 viruses—specifically, viruses that could infect mammals and be spread through the air, for instance, by droplets of saliva. A "growing chorus" of researchers appears to be endorsing that idea, according to NIH's Amy Patterson, who is helping write the new policy. Such limits, supporters argue, would allow reviewers to sift out less-risky experiments that are easier to contain and harder to tap for evil purposes. Researchers could, for instance, propose experiments that aim to make a virus more infectious or lethal in birds—but not airborne in mammals—without worrying about roadblocks. And the narrower scope would reduce the number of proposals likely to get bogged down in the bureaucracy, they argue.

"As written, a lot of H5N1 studies that were not intended to come to review will get reviewed," said Nancy Cox, a virologist at the Centers for Disease Control and Prevention in Atlanta. "If you read this conservatively, [HHS is] going to have to review 75% of H5N1 studies in the NIH portfolio," added Richard Webby, an H5N1 researcher at St. Jude Children's Research Hospital. Bureaucratic delays, he said, could lead researchers to leave the field or dissuade students from working on the virus.

Patterson and other NIH officials couldn't promise that they'd make that and other suggested changes; the meeting was intended to gather information and not make decisions, they said. And the government plans to release a second version of rules based on public comments it receives through 10 January. But Fauci was clear that he wants to move quickly. "I'm sensitive to the fact that this can't be drawn out over a long time," he said. "We want to expedite this."

The new policy isn't expected to affect many studies. H5N1 gain-of-function studies account for less than $10 million—or fewer than 1%—of NIAID's overall influenza research spending, Fauci said, and fewer than 10% of the grants it gives for research on the H5N1 virus (there are many other influenza viruses).

It is unclear whether other nations will follow the U.S. lead. At the meeting, researchers from Indonesia, Malaysia, and other nations where H5N1 is a simmering problem generally expressed support for gain-of-function studies and concern about policies that might hinder the field. But several said they are more interested in doing studies that characterize natural viruses found in their countries, or more directly assist with drug and vaccine development. Researchers from Europe noted that some of their nations are developing their own systems for reviewing potentially risky research. Many influenza researchers, however, say that lab safety and security requirements in many nations are already strong enough to allow gain-of-function H5N1 studies to proceed.

The voluntary moratorium on such studies, Fouchier said, "has now achieved its purpose." It gave governments, scientists, and the public time to discuss and implement new policies, and to make sure that H5N1 researchers are doing their work safely. It is time, he said, "to get back to work."

Not everyone at the meeting agreed. "I think we should continue the moratorium," said Thomas Inglesby, head of the Center for Biosecurity of the University of Pittsburgh Medical Center. Scientists haven't yet demonstrated that the benefits of gain-of-function studies outweighed the risks, he said. And "if we do decide to proceed, all should acknowledge the extraordinary risk."