Live debate airs major divisions in H5N1 research battle

Feb 3, 2012 (CIDRAP News) – The controversy over research about potentially dangerous H5N1 viruses heated up last night in a New York City debate that featured some of the leading voices exchanging blunt comments on the alleged risks and benefits of publishing or withholding the full details of the studies.

The debate, sponsored by the New York Academy of Sciences, involved two members of the biosecurity advisory board that called for "redacting" the two studies in question to delete details, along with scientists who want the full studies published and representatives of Science and Nature, the two journals involved.

The 2-hour session, which was live-streamed on the Web, left no clear impression of how the current controversy or future dilemmas over conduct and publication of "dual use" research might be resolved. One of very few points on which the panelists were unanimous was the hope that the current battle won't be repeated.

"I hope that this redaction, which I do feel has some very valuable things associated with it, is a onetime event," said Barbara Jasny, PhD, deputy editor for commentary at Science. "I hope this is not something that'll become institutionalized as a way of dealing with the problem."

The two studies involved the generation of an H5N1 virus and an H5N1-H1N1 reassortant that spread among ferrets via respiratory droplets. In December the National Science Advisory Board for Biosecurity (NSABB), which advises the Department of Health and Human Services (HHS), recommended that the details be deleted from the two reports before they are published. HHS agreed and passed the recommendation to Science and Nature.

The journals have signaled they will go along with the recommendation if a way can be found to provide the details of the reports to scientists with a legitimate need for them. But since the NSABB recommendation was unveiled, scientists, biosecurity experts, and public health officials have vigorously debated the issue in the media and in journal commentaries.

Thursday's discussion covered most or all of the main points of contention, including the magnitude of the H5N1 threat in general and the mutant viruses in particular, the reliability of ferrets as a model for human influenza, the potential public health benefits of the two studies, and government's role in regulating scientific research.

The study under review at Science was led by Ron Fouchier, PhD, of the Netherlands, whose team generated its transmissible H5N1 variant through a combination of genetic engineering and adaptation in ferrets. The study submitted to Nature was led by Yoshihiro Kawaoka of the University of Wisconsin, who created a virus that combined the hemagglutinin gene from an H5N1 virus with seven genes from a pandemic 2009 H1N1 virus. Fouchier's virus is lethal in ferrets, but Kawaoka's is not.

Genesis of NSABB recommendation
In opening the discussion, Jasny said Science's editors recognized early that Fouchier's paper had biosecurity implications, so they convened a group of experts, including some NSABB members, for advice. At the same time, the National Institutes of Health, which funded the study, also brought the paper to the NSABB's attention, she said.

Michael T. Osterholm, PhD, MPH, an NSABB member, said the board set up a working group to consider the two manuscripts and brought in outside expert advisors, including Robert Webster,PhD, of St. Jude Children's Hospital in Memphis and James Curran, MD, MPH, of Emory University. The working group spent "hundreds and hundreds of hours" discussing the problem, leading to unanimous support for the recommendation to withhold the details of the studies. Osterholm is director of the University of Minnesota's Center for Infectious Disease Research and Policy, which publishes CIDRAP News.

Arturo Casadevall, MD, PhD, the other NSABB member on the panel, said he initially thought the studies should be published in full, "but as a result of the deliberative process, I changed my mind." He is a professor of microbiology and immunology at Albert Einstein College of Medicine in the Bronx, N.Y.

When panel moderator Ian Lipkin, MD, later asked Casadevall if any other NSABB members changed their minds during the discussions, he declined comment other than to say there was a long deliberative process. Lipkin is a professor of epidemiology and of neurology and pathology at Columbia University.

Both Osterholm and Casadevall emphasized they were speaking as individuals and not on behalf of the NSABB.

Debate over case-fatality ratio
Much of the debate focused on questions related to how much of a threat the mutant viruses represent. That began early in the session, when Osterholm and Peter Palese, PhD, argued about the case-fatality ratio (CFR) for human H5N1 infections. Palese is a professor of microbiology and chair of the Department of Microbiology at Mount Sinai School of Medicine in New York City.

The World Health Organization (WHO) lists 583 confirmed H5N1 cases with 344 deaths since 2003, for a CFR of 59%. Palese contended, as he has previously in other forums, that this ratio is too high, because only severe cases are being counted.

"Only hospital cases are counted. People who are asymptomatically infected are not being counted," he said. "The unfortunate WHO estimate is very high."

Flu researchers have sought to detect unreported and asymptomatic H5N1 cases by looking for H5N1 antibodies in the blood of people with potential past exposures to the virus. Palese said that in 10 studies with at least 500 subjects each, the infection rates ranged from 0.2% to 5.6%. If one assumes a 2% infection rate for people who are exposed to the virus but don't have recognized cases, "the case-fatality with H5N1 really is much lower than what the WHO tries to say," he asserted.

Osterholm replied, "You can't have your own facts, and you've been constantly putting your own facts on this." He said that in 13 studies that met the WHO criteria for H5N1 serology, only 26 of 5,533 subjects were positive for H5N1 antibodies, for a rate of 0.469%.

"But none of this is critical, because if this virus was 20 times less virulent than it is now, it would still be worse than [the] 1918 [pandemic flu virus]," he added. "The data are clear and compelling. It'd still be the worst flu pandemic in history."

"I'm not saying anything other than what's published in the literature," replied Palese.

Ferrets on trial
Participants also disagreed about the reliability of ferrets as models of flu effects in humans. Virologist Vincent Racaniello, PhD, a professor of microbiology and immunology at Columbia University's College of Physicians and Surgeons, said that when he began studying viral pathogenesis under Albert Sabin and other eminent experts, "The first thing they said was when you study viruses in animals, don't think you'll learn much about what happens in humans."

Casadevall agreed that transmissibility in ferrets doesn't necessarily predict transmissibility in humans, but he said it was "striking" that so many flu experts view ferrets as a suitable model for studying human flu.

The NSABB contacted many flu experts from around the world, and with few exceptions, they said the ferret model "is a reasonable estimate of what might happen," said Osterholm. Moreover, Fouchier himself, when he discussed his study at a European meeting last September, ended his talk saying, "'This is now a very dangerous virus,'" Osterholm added.

Laurie Garrett, PhD, senior fellow for global health at the Council on Foreign Relations, commented, "The public health asset argument is that these experiments provide predictive value to help public health and identify genetic changes that should be monitored. If the ferret is useless, with no predictive value, then I do not understand why the experiment was ever done."

Palese responded, "In fact the ferret is much too sensitive as an animal model, so I think an animal model is just that, an animal model, and not predictive."

In other exchanges about how dangerous the mutant H5N1 viruses might be, Osterholm contrasted H5N1 with smallpox.

"I would not like to see smallpox get out of a BSL-4 [biosafety level 4, the highest level] lab, but it wouldn't be overly concerning" in view of the vaccine and other countermeasures available, he said. He noted that the WHO had a quick-response plan to contain an incipient flu pandemic, but the 2009 pandemic showed its futility. "Once [flu] is out, it's gone, it's a worldwide issue," he said.

Palese responded, "I'm shocked to hear that you wouldn't be concerned if smallpox got out. Two hundred million people died [of smallpox] in the 20th century, 500 for H5N1. H5N1 virus is so much less dangerous from what we know than smallpox."

Casadevall defended Osterholm's position, commenting, "We have a smallpox vaccine, and there's a long period of incubation." The last outbreak in Europe was stopped with a quick vaccination campaign, he added.

Some of the discussion focused on the potential benefits of the H5N1 studies and full publication of the details. Garrett questioned the benefits, saying, "One of the other great arguments in favor of public health benefits is that they tell us what we should watch for in nature. . . . Nothing could be further from the truth. Most of the viral samples of H5 are fragmentary, and there's no routine capacity, especially in developing countries."

In response to an assertion from Osterholm that both the risks and benefits of research must be carefully weighed, Racaniello said, "For much of science you can't do a risk-benefit analysis. If you think you can, you're wrong." He pointed to the 1950s discovery of restriction enzymes used by E coli to cut up the genes of viruses. The discovery drew little notice at the time, but eventually it turned out to be a key to the biotechnology revolution, he said.

Questions about governmental role
On the question of the governmental role in regulating dual-use research, Garrett said basic notions about the purposes of government lead to a contradiction. One of the prime duties of government is to protect the public from perceived threats, she said.

"If you define the threat as a natural pandemic, you could argue that government should promote this kind of research, because it can lead to defenses," she said. "But if you define the threat as bioterrorism or biosecurity or lab leaks, then government has an absolute mandate to intervene to control that research."

If the question is difficult at the national level, it's even more so at the international level, Garrett said. "If you go to the international level, we have only the International Health Regulations and the 2011 virus-sharing agreement" hammered out by the WHO, she said. "We have absolutely no consensus as to what is the appropriate role of international governing bodies."

Later she added that the controversy puts the WHO in a very difficult position, "because the whole debate over virus sharing and who should have access was arguably the most emotional that's gone on at WHO in my lifetime." She referred to the 2011 agreement on international sharing of influenza and other viruses, particularly those collected in developing countries. Indonesia and other countries had protested the sharing of viruses, arguing that drug companies used the isolates to make vaccines that were unaffordable for the source countries.

Casadevall voiced concern about the overregulation of science, especially clinical research. "I have to write a 100-page animal [research] protocol to do something to help society, when you can walk into a Home Depot and find many ways to kill a mouse without any protocol," he said. "With this system in place, you're going to kill science."

On the question of publication versus secrecy, Jasny estimated that about 1,000 people have already seen Fouchier's data, including 800 who attended the European meeting where he discussed it, plus government officials and editors.

Osterholm and Casadevall said the NSABB hasn't suggested that the details can be kept secret for long, but they argued that withholding them nonetheless has short-term value.

"Everyone knows you can make a fertilizer bomb. But I don't think they want you to have the exact specifications on how to make a fertilizer bomb," said Casadevall.

When Lipkin raised the issue of lab security and containment levels, the debate turned heated once again.

Osterholm said significant lab leaks of infectious agents don't happen often, but added, "We can't un-ring a bell. One day maybe it'll be shown that this can't transmit to people, but if we're wrong and we find it does end up being transmitted . . . it'll be just like 9/11. I don't understand why it's not going to be put into BSL-4 until we understand what we're doing."

Palese, who had said earlier that the type of research in question is already very restricted, reiterated his argument that all the existing evidence does not suggest the mutant H5N1 would spread among humans.

"There are many reasonable scientists who disagree with you," Osterholm replied. Referring to the Sep 11 attacks, he added, "Damn it, this is a real possibility, and if we are wrong, the consequences could be so catastrophic that we'll all go back and ask ourselves why did we let it happen."

Garrett warned that the debate over the research needs to include representatives of the general public, not just scientists. If an upcoming conference being planned by the WHO leads to some sort of agreement based only on discussion among scientists, she said, "It's all going to backfire. It's going to explode in our face."

The WHO has scheduled the conference for Feb 16 and 17, but the agenda and participants are still being firmed up, spokesman Gregory Hartl told CIDRAP News today.

The value of a gutted paper
In response to question from Lipkin, Veronique Kiermer, PhD, executive editor of Nature, said the two H5N1 studies are worth publishing even if the details must be left out.

"I think these two papers are very important and the overall message needs to be published," she said. "Also the scientists who have done this work deserve to have credit."

She added that it will be important for any mechanism for disseminating the details to be fair, so that anyone with a real need to know can get the data. But how to define who those people are remains to be worked out, she acknowledged.

Jasny commended the authors of the two H5N1 studies for being very responsible. "They could've withdrawn the papers and published them elsewhere if they so chose. They're tried to work through the system, realizing the problems that are inherent in the situation. That's another reason to publish a redacted manuscript, because they've played fair."

See also:

Information on Feb 2 NYAS symposium on H5N1 dual use research

Feb 7 pre-debate interviews from Nature with panel members

List of panelists

Dec 23, 2011, CIDRAP News story "Fears about mutant H5N1 hinge on ferrets as flu model"

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