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NSABB Members React to Request for Second Look at H5N1 Flu Studies

Members of a U.S. government biosecurity advisory board are offering a range of reactions to the news that they are being asked to take a second look at two controversial flu studies. Some have not previously spoken publicly about the issue, which has sparked a global debate about biosecurity versus scientific freedom. And several say they are skeptical that the new review will reverse their opposition to fully publishing the methods and results of the two experiments.

The comments below come after months of rapid-fire developments in the H5N1 flu research controversy. It began late last year, when the National Science Advisory Board for Biosecurity (NSABB) recommended that two science teams delete key details from papers submitted to Science and Nature that describe how researchers made the H5N1 avian influenza more transmissible between mammals, possibly providing a blueprint for starting a flu pandemic. The risks posed by the research outweighed its potential benefits, the 23 voting members of the panel unanimously concluded after what they described as hundreds of hours of discussion. The NSABB's voting members are mostly scientists drawn from a wide range of disciplines and institutions, including universities and companies. (There are also 18 non-voting ex-officio members from federal agencies.)

The researchers and the journals agreed to follow NSABB's recommendation, provided that the U.S. government comes up with a mechanism to share those details with bona fide researchers and public health experts. The deal sparked extensive criticism, however, with some scientists saying the redactions went too far, and others arguing the research should not have been conducted in the first place.

Then, in January, flu researchers—including the leaders of the two research teams, Ron Fouchier of Erasmus Medical College in the Netherlands and Yoshihiro Kawaoka of the University of Wisconsin, Madison—announced a 60-day moratorium on many kinds of studies involving the virus. That moratorium, currently set to expire 20 March, was designed to ease tensions and public concern, and allow time for international discussion of the issue.

Last month, the World Health Organization (WHO) convened a group made up mainly of flu experts for 2 days in Geneva to examine the studies. Many of the 22 people at the WHO meeting, however, rejected NSABB's conclusions and argued that the papers should be published in full. That meeting included talks by Fouchier and Kawaoka, who presented "new data" and, in the case of Fouchier, "clarified older data," according to Anthony Fauci, head of the National Institutes of Health's National Institute of Allergy and Infectious Diseases, which funded the two studies. Fauci, who attended the Geneva meeting, says members of the group also asked the researchers to revise and resubmit their manuscripts to NSABB.

Fauci announced that the U.S. government has asked NSABB to review the new manuscripts on 29 February at an early-morning panel discussion on the H5N1 controversy organized by the American Society for Microbiology (ASM) in Washington, D.C. NSABB "needs an opportunity to see all of the data we saw in Geneva … and have some time to talk it over," Fauci told ScienceInsider.

The reconsideration request apparently caught many NSABB members and Washington policy-makers by surprise. Sources familiar with the planning say the NSABB meeting—tentatively scheduled for later this month—could last 2 days. It also hopes to include presentations by Fouchier and Kawaoka, so that NSABB members could speak to them "face-to-face," unlike the teleconferences that characterized many of the earlier discussions of the flu studies.

Acting NSABB Chair Paul Keim of Northern Arizona University in Flagstaff, who moderated the ASM discussion, declined to speculate on how the panel might view the new versions of the two studies. But "the recommendations from NSABB can clearly be changed in the future," said Keim. "We can go back and reverse this if that is the best course of action."

The ASM meeting also included an extensive presentation by Fouchier of virus transmission and lethality data apparently drawn from his Science manuscript. In general, Fouchier said the data showed that his version of the engineered H5N1 virus was, in contrast to press reports, not lethal when inhaled by ferrets and would not spread "like wildfire" through the air. (Kawaoka had publicly said earlier that his version of the mammal transmissible virus was not lethal in ferrets.)

In the wake of the ASM meeting, ScienceInsider attempted to contact all 23 voting members of the NSABB. Seven agreed to e-mail, telephone, or in-person interviews—with several emphasizing that they were speaking for themselves, not NSABB. They included:

David Relman, Professor of Microbiology & Immunology, and of Medicine, Stanford University School of Medicine, Stanford, California

"My bottom line: Fouchier started with a highly worrisome and sometimes-lethal virus for humans, and appears to have enhanced its transmissibility by the respiratory route. Nothing said in recent days changes these facts, [and] not my assessment of the risk-benefit ratio. To me the most important issue about [Fouchier's] studies of transmissibility in the ferret model is the direct comparison of the starting strain (H5N1 wildtype) and his engineered strain(s). And the latter is/are more transmissible via [respiratory] route than the former." Kawaoka's paper "also provided clear guidance on how to enhance the transmissibility of H5N1 viruses," he writes, and other issues, such as virulence and lethality, were less important.

Susan Ehrlich, Retired Judge and Adjunct Professor, Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston

"I heard nothing new so much as a different emphasis during the ASM meeting. This would be expected, however, for two reasons: The NSABB members, particularly those of us working group members, have spent hundreds of hours discussing these manuscripts after having reviewed them, and this was a public meeting. And of course none of us has yet seen the revised manuscripts, which I have no doubt will be reviewed with completely open minds, remembering that the first thought of each of us is that scientific research should be freely and completely communicated, a point made evident in each of the NSABB's several reports and specifically in the June 2007 Proposed Framework for the Oversight of Dual Use Life Sciences Research: Strategies for Minimizing the Potential Misuse of Research Information."

"Keeping in mind that I have not read the revised manuscripts, I do have certain concerns. Dr. Fouchier emphasized ferret response during the meeting, but the larger issue is that of transmissibility. H5N1 admittedly is a dangerous virus, and it now has been made more so. Its host range was extended. The research on the modified virus was conducted at the same biosafety level as research on the parent virus. These concerns underlie my thoughts about the communication of this research in the context of the NSABB's responsibility to the public should there be an accident (bioerror) or an incident of deliberate misuse (bioterror), and so I want to continue to proceed with caution."

Stanley Lemon, Professor of Medicine and Microbiology & Immunology, University of North Carolina, Chapel Hill

"The major concern has been about acquisition of the capacity for aerosol transmission of the virus to a mammal."

Lynn Enquist, Professor and Chair, Department of Molecular Biology, Princeton University, New Jersey

"Here is my take home message. Both groups did experiments that are on the 'seven experiments of concern' described in detail in the Fink report [the 2003 National Academies report Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma] and our own recommendations. They not only changed the host range of a dangerous pathogen, they also changed its mode of transmission. "

"All the other differences in methods, or new or clarified work on virulence in ferrets, does nothing to change those facts."

"While there is no doubt that work must be done to study H5N1, and all the debate so far shows how necessary further work is, these new derivatives are novel entities with unknown consequences if they move into the ecosystem."

"How should work on these new agents proceed? How many labs should be working along these same directions? How should this work be communicated now and in the future? Those are a few of the central questions in my opinion."

"The NSABB should not be making these decisions or reviewing the details of the science. We called attention to the fact that these experiments are dual use research of concern."

Arturo Casadevall, Chair, Division of Infectious Diseases, Albert Einstein College of Medicine, New York, New York

Casadevall noted that he went into the original NSABB discussions of the two papers thinking: "Science should be free and nothing should be redacted, but then it became clear to me that there was almost no public good in [publishing] the details." Now, he says: "I'm going to go to the next meeting with an open mind and listen to everything. This process is supposed to be deliberative. And this process is one in which you can think through it and change your mind."

But "the central issue for me is the transmissibility. Unless Ron [Fouchier] gets up there and says this is no longer mammalian transmissible," Casadevall is unlikely to reverse his opposition to full publication. "Having transmissibility is a new characteristic for H5N1," he adds, noting that "this virus has the capacity to recombine and we have no idea what will come out." He sees the virulence and lethality of the new engineered viruses as "mini-debates" that are less important. "We need to be very cautious. We're dealing with an organism that we know can cause pandemics and can kill a lot of people. And we know that we don't have immunity to H5. I would urge caution." Casadevall also notes that "I'm from Cuba. I know something about redaction."

Michael Osterholm, Director, Minnesota Center of Excellence for Influenza Research and Surveillance, University of Minnesota, Twin Cities

"The information that I saw [on 29 February] in no way changed the underlying issue of concern for NSABB, and that was the issue of transmissibility. Expanding the host range of a dangerous pathogen is one of the [seven types of experiments identified as raising dual use concerns by the Fink Report]. … I have not seen anything that fundamentally changes anything about the NSABB position. … I feel very confident that the criteria we used for calling for the redaction of this paper based on the transmissibility issue was straightforward and I'm not convinced that additional face-to-face conversation would make any difference."

Michael Imperiale, Professor, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor.

"What Ron [Fouchier] is saying now is not what was in the paper. We were led to believe by the paper that aerosol transmission is also lethal." He also says it was news to him that the mutated virus did not spread between ferrets via the aerosol route as readily as seasonal strains, as Fouchier showed at the ASM meeting "That really didn't come across to me in the paper," he says. "I didn't see that kind of comparison."

Then again, he is uncertain the new information will influence his thinking about redaction. "Based on bare minimal facts, from what I heard Fouchier say on Wednesday, I'm not sure it would matter. The lethality in ferrets is the same as the starting virus and now it can be transmitted." Specifically, noted Imperiale: "If the starting H5N1 virus is injected intratracheally into ferrets, it kills them. What [Fouchier's] done is changed it so it's no longer fecal-oral spread, but aerosol. He injects that intratracheally, and it kills them. So it's just as lethal, plus now it can be spread by aerosol. You have a virus that kills X percent of the humans it infects. Based on the ferret data, we'd expect it to kill the same exact percent of humans, and now it can be transmitted from human to human. Obviously, I'd need to see that revised paper, but I don't it know that it changes anything."

Imperiale says, ultimately, there's just too much uncertainty to take the risk of publishing all the details of the experiments. "Given the uncertainty, I say go with the precautionary principle. And you wait until you can get rid of that uncertainty. If you redact, it's not a permanent action. If you let it out, that's permanent."