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Flu meeting opts for openness

Controversial virus studies should be published and oversight of such work strengthened, conference concludes.
Declan Butler

21 February 2012
After weeks of debate, two controversial papers describing forms of the H5N1 avian influenza virus capable of transmitting between mammals should be published in full. That was the unexpected outcome of a meeting convened last week in Geneva, Switzerland, by the World Health Organization (WHO), which also promised to create a more rigorous oversight system for such research.

The decision goes against a recommendation from the US National Science Advisory Board for Biosecurity (NSABB), which the US government has adopted as its official position. In December 2011, the board said that experimental details of the two studies should be redacted from any publications, because of concerns that the information could be used in a bioterror attack. The board also feared that publishing the details would prompt more laboratories to work on the viruses, making an accidental release more likely.

The studies, which created forms of H5N1 that can spread between ferrets through airborne transmission, are likely to be published in a few months. The 22 experts at the meeting, mainly flu researchers, believe that the delay is needed to explain the benefits of the work to the public, and allay concerns about its safety. Meanwhile, a 60-day moratorium on similar research will be extended until a system is put in place to review levels of biosafety and biosecurity. To that end, the WHO intends to convene international discussions among regulators and other bodies in the next few months.

The two researchers at the centre of the controversy say that they are pleased with the outcome. “I was pleasantly surprised by the fact that there were unanimous decisions about most issues, and strong consensus on the others,” says Ron Fouchier, a flu virologist at Erasmus Medical Center in Rotterdam, the Netherlands, whose study has been accepted by the journal Science. Yoshihiro Kawaoka of the University of Wisconsin-Madison, lead researcher on the other study, adds that the meeting allowed him and Fouchier to explain their work, including the potential benefits for surveillance of emerging flu strains (Nature 481, 417–418; 2012) and for vaccine preparation (Nature 482, 142–143; 2012). “We presented why we did these experiments, what we did, what data we obtained, what these data contribute to public health and to the scientific field, and why we think the results should be shared,” says Kawaoka, whose paper has been accepted by Nature. He adds that data he and Fouchier presented on the evolution of H5N1 in the wild clarified the threat from the virus, although he would not be drawn on the details, citing confidentiality.

Microbiologist Paul Keim, who chairs the NSABB and attended the meeting, did not respond to Nature’s request for an interview, but is reportedly “disappointed” by the recommendation to publish the papers.

Nature and Science last year agreed in principle to redact the papers, on the condition that the US government would develop a mechanism to disseminate the full papers to researchers and health officials on a need-to-know basis. But meeting participants concluded that this was impractical, and that the potential public-health benefits of the work outweighed any risk of publishing the papers in full.

Biosafety first

Many flu researchers have already seen the papers, so there was little to be gained by restricting their dissemination, says Richard Ebright, a molecular biologist and biodefence expert at Rutgers University in Piscataway, New Jersey. It is much more urgent, he says, to put in place strict biosafety, biosecurity and oversight provisions for such research.

David Fidler, an expert in international and national security law at Indiana University in Bloomington, points out that the meeting hasn’t actually broken the publication deadlock, because Keim and representatives of the US government still do not agree with publishing the studies in full. “Most of the meeting’s participants appear to have rejected the US position,” says Fidler, “but [have] agreed to the extended moratorium and publication delay in the hope that the US government will change its mind.”

Participants agreed that the mutant viruses should remain in their two containment facilities — rated at ‘BSL-3 enhanced’, the second-highest level of biosafety — and that both should be reviewed before any work restarts. Didier Houssin, president of the French Evaluation Agency for Research and Higher Education, says that the biosafety review of the work must consider whether studies of this kind should be conducted only in labs with the highest biosafety rating of BSL-4, a restriction imposed this month by Canada. Houssin, who attended the meeting, notes that imposing such a restriction globally would curtail similar work because there are just a few dozen BSL-4 labs worldwide. The safety level of BSL-3 labs is very variable, he says, and so any facilities working on such viruses would need to be rigorously assessed.

Fidler and other experts note that the meeting did not address the overall risks and benefits of the work, or how similar research might be overseen in future. Keiji Fukuda, WHO Assistant Director-General for Health Security and Environment, explains that later meetings will deal with these topics and will have wider participation.

Meanwhile, the meeting agreed that it was “critical” for the WHO to form a communications plan over the next few months to increase public awareness and understanding of the importance of the flu work, and to alleviate public anxieties. But Peter Sandman, a risk-communications consultant in Princeton, New Jersey, advises against any attempt by the WHO to “educate” the public out of its concerns. As a strategy, he says, it “is thoroughly discredited, because it doesn’t work”.
Nature482,447–448(23 February 2012)doi:10.1038/482447a

http://www.nature.com/news/flu-meeting- ... ss-1.10067

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The NSABB should be more focused on teh composition of its board, which clear lacks the expertise to understand the key issues associated with efficient H5N1 transmission.

The recommendations by the NSABB lacked a scientific basis, and was appropriately rejected (although the rejection should have been more immediate).

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Most recent clade 2.1 target is from 2005

http://www.who.int/influenza/resources/ ... update.pdf

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The chair of the US biosecurity advisory board that recommended withholding details of two studies on H5N1 virus transmissibility today expressed a mixed reaction to last week's international meeting in which scientists and officials involved in the controversy called for eventually publishing the full studies.

Paul S. Keim, PhD, chair of the National Science Advisory Board for Biosecurity (NSABB), said he was pleased that the international group favored extending a current moratorium on research on lab-generated H5N1 viruses, but he was disappointed that it opposed publishing the papers in redacted form in the near future.

Meanwhile, Keiji Fukuda, MD, the World Health Organization (WHO) official who led the meeting, in an e-mail message to scientists after the meeting, said the session was not intended to "second guess" any previous meetings.

The WHO organized the meeting, held Feb 16 and 17 in Geneva, as a first step to sort out issues raised by two US-funded studies in which researchers generated mutant H5N1 viruses and reassortants that spread among ferrets by airborne droplets, unlike natural H5N1 strains. The studies have triggered concern that the viruses, if unleashed, could cause a devastating human pandemic.

In December the NSABB recommended that Science and Nature, the journals intending to publish the studies, omit key details that could allow others to replicate the experiments. The US Department of Health and Human Services endorsed the recommendation.

The journals subsequently signaled they would go along with the advice if, as also recommended by the NSABB, a way could be found to provide the details to scientists with a legitimate need for them.

The ensuing debate included calls for international discussions on the regulation and dissemination of "dual use" life-sciences research, and Fukuda announced in January that the WHO would organize a meeting. He is assistant director-general for health security and environment at the agency.

Shortly after that, on Jan 20, 39 leading flu scientists from around the world announced a 60-day moratorium on research leading to the generation of H5N1 viruses with increased transmissibility in mammals. The signers included the lead authors of the two controversial studies, Ron Fouchier of Erasmus Medical Center in the Netherlands and Yoshihiro Kawaoka of the University of Wisconsin.

At last week's meeting, a group of public health and flu experts invited by the WHO agreed that the research moratorium should continue but that the two studies should be published in full at a later date, the WHO announced after the meeting. The group recommended that publication should be preceded by an effort to increase public awareness and understanding of the studies and the rationale for publishing them and by a review of the related biosafety and biosecurity issues.

Participants in the meeting included Keim, Fouchier, and Kawaoka, among others. Keim, a microbial geneticist at Northern Arizona University, and Anthony Fauci, MD, director of the US National Institute of Allergy and Infectious Diseases, were the only participants who disagreed with the recommendation to publish the full studies, according to previous reports.

Keim offered some reactions to the meeting today in an e-mail to CIDRAP News, commenting, "The meeting was a very important part of the global dialogue that is needed on this topic. This is an important group of flu scientists and their opinion is critical. They are, however, only part of the global community that needs to be engaged, and more meeting are in the offing.

"I was pleased that they recommended extending the moratorium on research and that they would not be pushing for publication of the work during this time frame. It also became clear that additional biosafety and biosecurity reviews have or are being performed at these institutions [involved in the research]. Given the phenotypic changes in the pathogen, this seems appropriate.

"I was disappointed that they did not want to publish the redacted papers quickly and during the moratorium," Keim added. "NSABB thought that redacted publication could help guide policy makers toward increasing the flu-fighting infrastructure."

In a statement issued after the meeting, the WHO said the meeting participants opposed publishing the redacted manuscripts mainly on the grounds that it would be too difficult to quickly find a way to share the full details with scientists in need of them, given the legal complexities involved.

Fukuda described the results of the meeting in a press briefing at its end. Later, he commented further on several aspects of the meeting in an e-mail that he sent to a number of scientists. Laurie Garrett, PhD, senior fellow for global health at the Council on Foreign Relations, posted a copy of the message on her blog (see link below).

In the message, Fukuda said he was aiming to provide "perspective and insight" on the meeting. He said the reason for holding the session in secrecy was that it included a review of sensitive unpublished data that are "at the heart of the controversy." The participants were chosen largely because they had some role in the research or in sending the original viruses to the WHO or because they were "considered to have a potential role in implementing solutions."

Echoing some of his pre-meeting comments, Fukuda said the meeting was not intended to be a "broad debate on the relative merits of research and publication versus security or safety as many seem to have assumed." Rather the aim was to focus on the "most acute issues," mainly "what can be said about the manuscripts / information and . . . what can be agreed upon related to the new lab modified H5N1 viruses held at the two universities and research on them."

"Moreover, the starting premise was that research and availability of information is essential but that research takes place in a social context and that social safety and security concerns are of equal importance," he added.

"Therefore, we did not enter into a debate over the respective perspectives but said the real issue is [to] find ways in which both concerns can be balanced and accommodated. Importantly, the meeting was not set up to discuss or second guess . . . other previously held discussions or meetings."

WHO spokeswoman Christy Feig, MPH, cautioned today against assuming that Fukuda's message was intended to counter any specific criticisms or misinformation about the meeting.

"Don't read too much into Keiji's e-mail," she commented. "He was simply trying to communicate to a larger group in the scientific community about the outcome of the meeting since it ended late on Friday. He received an e-mail with a link to a news story about the meeting and the e-mail was to a large group, so he just used it as a moment to report out to them the outcome and context of the meeting."

Garrett, in comments to CIDRAP News, said she had no inside information, but she speculated that Fukuda and the WHO might have been criticized for overstating the degree of consensus at the meeting. She said the debate has put the WHO in a very difficult position and noted that Fukuda repeatedly described the meeting in terms such as "heated" and "difficult."

"My sense is that he erred in saying that the six resolutions that WHO has posted on its website were 'unanimous,'" Garrett said. "Even the word 'consensus' is dicey, as some use the word to mean unanimity, while others use it to mean the majority of a group felt a particular way (a vote, without voting). Blowback may have come from meeting participants when they read press coverage, especially for the Americans that were described as going along with a position that contradicted NSABB."

She added that Fukuda hesitated when he was asked directly whether NSABB members had supported a position contrary to that of their own committee.

See also:

Feb 17 CIDRAP News story "WHO H5N1 study group extends moratorium, calls for full publication"

Feb 17 Garrett blog
http://www.cidrap.umn.edu/cidrap/conten ... ho-jw.html

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Dear All,


Given this rather extraordinary email list from [NAME REMOVED by me], I would like to take advantage and provide perspective and insight on the recent H5N1 research meeting held at WHO 16-17 February 2012 in Geneva at WHO.

1. The meeting was held under confidential conditions because it included a review of unpublished data that was considered sensitive and at the heart of the controversy. The premise was that holding a discussion based on facts -- including the manuscripts and information at the heart of the controversy -- was best. Although there have been a number of informed editorials and opinion pieces, we wanted to base the discussion on more than just opinion and concerns.

2. The participants -- whose names were posted on the first day of the meeting -- largely were asked to participate largely because they had a role in some aspects of the research (conduct, review, funding, oversight, publication etc), or in sending the viruses to WHO or were considered to have a potential role in implementing solutions.

3. The purpose of the meeting was not hold broad debate on the relative merits of research and publication versus security or safety as many seem to have assumed. Instead, it was based on the idea that there are a very large number of extremely complex considerations, and focusing discussions on the most acute issues related to the specific situation would be most useful and productive. These issues were largely:

1) what can be said about the manuscripts / information and

2) what can be agreed upon related to the new lab modified H5N1 viruses held at the two universities and research on them.

Moreover, the starting premise was that research and availability of information is essential but that research takes place in a social context and that social safety and security concerns are of equal importance. Therefore, we did not enter into a debate over the respective perspectives but said the real issue is find ways in which both concerns can be balanced and accommodated. Importantly, the meeting was not set up to discuss or second guess and other previously held discussions or meetings.

4. Every participant was asked to partake in the discussions from this perspective, and in this spirit. Despite the widely varying backgrounds of the participants, they did so which is why several agreements were reached.

5. The results and agreements among the participants have been posted and I will not comment further on those points.

6. The related issues which are being debated in various fora are part of a historical continuum. Some aspects are similar to what was discussed back in the 1970's with recombinant DNA technology and later events such as the anthrax attacks. But other considerations are new, including the fact that the world now has a Pandemic Influenza Preparedness Framework whose existence and implementation are important.

In ending this note, this meeting was not intended to answer all questions and did not do so. But it showed that participants with widely varying opinions, priorities and backgrounds could come together and find common ground when the discussions were based on facts and mutual good will. Since I am overloaded with emails, many related to this meeting, I most likely will not respond to individual comments generated by these comments so my apologies in advance.

Thank you,

Keiji Fukuda
http://www.lauriegarrett.com/index.php/en/blog/3143

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Publish lethal flu virus work, says WHO
22 February 2012 by Debora MacKenzie
Magazine issue 2853. Subscribe and save
For similar stories, visit the Epidemics and Pandemics and Bird Flu Topic Guides




BATTLES continue over whether or not to publish research in which H5N1 bird flu transmitted readily among mammals.

Last week, a group of flu virologists, public health experts from countries where H5N1 circulates, bioethicists and the World Health Organization advised that the work should be published - even though the top US biosecurity panel has advised against it.

The US National Science Advisory Board for Biosecurity (NSABB) feared publication would hand hostile forces a fearsome bioweapon. The WHO, which hosted the meeting in Geneva, Switzerland, decided it was impossible to stop publication yet make details of the work available to protect public health. New Scientist has found that publication might add little to what is already openly available in the scientific literature.

H5N1 has killed over half the people known to have caught it since it spread worldwide in birds in 2004. Inability to pass readily between people has so far kept it from going pandemic. The current dispute concerns two pieces of research that created H5 viruses that spread through the air among ferrets - the best test-animal - like normal flu.

Ron Fouchier and colleagues at the Erasmus Medical Centre in Rotterdam, the Netherlands, created transmissible H5N1 by putting two mutations into the HA surface protein of an H5N1 virus, and one into its polymerase enzyme, before exposing ferrets to it. It spontaneously acquired two more significant mutations, and remained lethal. In the other research under scrutiny, Yoshi Kawaoka at the University of Wisconsin-Madison also created transmissible H5 flu.

However, a paper that shows how to makes H5 readily transmissible had already been published in September last year by Reuben Donis and colleagues at the US Centers for Disease Control and Prevention in Atlanta, Georgia. His team equipped a different H5N1 with the same two mutations as Fouchier. He also added a third mutation, and switched other genes to make it transmissible among ferrets.

While Fouchier concluded from his work that transmissible H5N1 might readily emerge naturally, Donis said it could be difficult. "Research must continue for such differences to be resolved, and for the world to understand the threat posed by H5N1," says Ab Osterhaus, head of the Rotterdam lab. Yet the dispute over publication of Fouchier's and Kawaoka's papers has led to an indefinite moratorium on such research.

The journals Nature and Science both agreed to publish redacted versions of the papers, without details of the methods or mutations - but only if means were found to get those details to the people who need them. These include researchers working with H5N1, who must guard against inadvertently creating such viruses, and public health agencies.

Last week Keiji Fukuda of the WHO said there was "unanimous" agreement that this could not readily be done. He said it was impossible to decide who should grant access to the information.

US officials at the meeting stated that they still supported the NSABB's stance, although Fukuda says everyone there agreed there was no way to meet the journals' conditions. The group advised postponing publication while it raised "understanding in non-scientific groups" about the risks. Tony Fauci, head of the US National Institutes of Allergy and Infectious Disease, says there is "no way we can require the journals not to publish".


Meanwhile, back in the pig pen

While the world's flu scientists and biowarriors face off over publishing research on H5N1 bird flu, other flu continues to evolve among pigs. And it may just have taught us something disconcerting about bird flu.

The "triple reassortants" of bird, pig and human flu viruses circulating in pigs were the source of the 2009 human pandemic. Some carry surface proteins from human H3N2 flu from the early 1990s, and few people born since then have antibodies to them. In the past two years 17 people are known to have caught these viruses from pigs, but it never spread far.

Terrence Tumpey at the US Centers for Disease Control and Prevention in Atlanta, Georgia, can't explain why. He has shown that the pig viruses from those human cases bind to human receptors, spread readily among ferrets, and replicate better than current human H3N2 viruses in human airway cells in culture (Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.1119945109). This suggests that adapting to humans is only part of the pandemic process. Some virologists argue that because transmissible H5N1, such as the viruses created in the lab (main story), has not been seen in nature, it cannot occur. But perhaps it hasn't yet had the opportunity: an adapted virus may need other things to take off, such as enough susceptible humans, says Tumpey.
http://www.newscientist.com/article/mg2 ... s-who.html

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In contrast, when the ferrets
were infected with EG06-196R/226L/228S virus, viral shedding was
detected in the nasal secretions of direct contact ferrets, although
no infection was evident in ferrets exposed to respiratory droplets
(Table 2). The results suggest that a measurable increase in H5N1
virus transmission via direct contact in ferrets can be imparted by
modification of HA molecules approximating a human virus receptor
specificity.

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The above comments strongly suggest Fouchier started with Q226L/G228S on H5 and E627K on PB2.

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Virology. 2012 Jan 5;422(1):105-13. Epub 2011 Nov 5.
In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity.
Chen LM, Blixt O, Stevens J, Lipatov AS, Davis CT, Collins BE, Cox NJ, Paulson JC, Donis RO.
SourceInfluenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, United States.

Abstract
Acquisition of α2-6 sialoside receptor specificity by α2-3 specific highly-pathogenic avian influenza viruses (H5N1) is thought to be a prerequisite for efficient transmission in humans. By in vitro selection for binding α2-6 sialosides, we identified four variant viruses with amino acid substitutions in the hemagglutinin (S227N, D187G, E190G, and Q196R) that revealed modestly increased α2-6 and minimally decreased α2-3 binding by glycan array analysis. However, a mutant virus combining Q196R with mutations from previous pandemic viruses (Q226L and G228S) revealed predominantly α2-6 binding. Unlike the wild type H5N1, this mutant virus was transmitted by direct contact in the ferret model although not by airborne respiratory droplets. However, a reassortant virus with the mutant hemagglutinin, a human N2 neuraminidase and internal genes from an H5N1 virus was partially transmitted via respiratory droplets. The complex changes required for airborne transmissibility in ferrets suggest that extensive evolution is needed for H5N1 transmissibility in humans.

http://www.ncbi.nlm.nih.gov/pubmed/22056389

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Remarkably, the EG06-196R/226L/228S virus exhibited little α2-3 sialoglycan binding and strong binding to α2-6 sialoglycans (Fig. 4). Thus, unlike the natural human H5N1 isolates that exhibit weak binding to α2-6 sialosides and strong binding to α2-3 sialosides, this mutant exhibits a nearly complete switch in specificity, characteristic of the pandemic human influenza viruses of 1957 and 1968.

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