The risks and benefits of publishing mutant flu studies

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1 NATURE NEWS: EXPLAINER The risks and benefits of publishing mutant flu studies Research describing two mutant strains of H5N1 avian influenza that spread between mammals is likely to be published in its entirety. Nature examines the controversial decision. Ed Yong 02 March 2012 Two teams of scientists, led by Ron Fouchier of Erasmus Medical Center in Rotterdam, the Netherlands, and Yoshihiro Kawaoka of the University of Wisconsin-Madison, have created mutant strains of H5N1 avian influenza. These laboratory strains could be passed between mammals more easily than wild strains of the virus. News of the research sparked an intense debate about whether the two teams' work should be published in full to aid pandemic preparedness or redacted to prevent misuse by terrorists. A meeting convened by the World Health Organization two weeks ago in Geneva, Switzerland, concluded that the papers should be published in full, despite recommendations to the contrary from a US government advisory board. Nature takes a look at the debate and the science. What is H5N1? 1 of 6 3/8/12 11:26 AM

2 It is a subtype of the influenza A virus the most virulent of the influenza viruses to affect humans. These viruses are classified according to the identity of two of their surface proteins haemagglutinin (H5 in this subtype) and neuraminidase (N1). The subtype behind the 2009 swine flu pandemic is H1N1, which has the same version of neuraminidase as H5N1, but a different version of haemagglutinin. One particular strain of H5N1, called highly pathogenic avian influenza (HPAI), is responsible for the bird flu scares. It circulates regularly among birds and has jumped to humans on occasion. How dangerous is H5N1? Since 2003, the wild virus has infected around 600 people; 59% died. However, the true mortality rate will be lower Related stories because there are probably some milder, unrecorded infections of H5N1. Even so, it seems likely that this virus has a greater mortality rate than either Flu meeting opts for ordinary seasonal flu or possibly the 1918 pandemic H1N1 strain. openness Death-rate row blurs mutant So far, H5N1 has failed to spark a pandemic because it cannot effectively flu debate spread between people. Wild H5N1 viruses cannot latch on to the cells in a Q&A: Reasons for proposed person s nose and throat, but the mutant strains created by Fouchier and redaction of flu paper Kawaoka can spread between ferrets, which are viewed as a good animal model of flu transmission between humans. More related stories How was the virus mutated? Fouchier and his team initially tweaked the virus s genome to create strains that could attach to mammalian nose and tracheal cells, but couldn t spread between individuals. He exposed ferrets to this strain, and used the animals nasal fluids to infect others. After 10 rounds, the virus could spread through the air to infect ferrets in neighbouring cages. The genome of the airborne strain differed from the original one by just five mutations, which have all been spotted individually in wild viruses. Fouchier's paper has been accepted for publication by Science. Kawaoka and his team, whose work has been accepted by Nature, created a chimeric virus with the haemagglutinin protein from H5N1 and the genes from the 2009 pandemic strain of H1N1. It was an artificial version of the same process through which wild viruses shuffle their genes, known as reassortment. Both mutants spread easily among ferrets, but whereas Fouchier s strain reportedly killed all of the animals it infected, Kawaoka s did not. Fouchier later added, however, that his mutant virus does not spread yet like a pandemic or seasonal flu virus and that the ferrets did not die when infected through aerosol transmission. Only when the virus was physically implanted into the trachea or nasal passages of ferrets did the infected animals die. All work on mutant flu strains has been temporarily halted since 20 January 2012, when Fouchier, Kawaoka and 37 others called for a 60-day pause to allow time for an open debate on the risks and benefits of such research. The 2 of 6 3/8/12 11:26 AM

3 moratorium has since been extended until a system to review the Research safety of into such mutant work strains and its of avian consequences influenza for security is put in place. (white) aims to reveal more about flu transmission mechanisms. Why did they do the research? MEDICAL RF.COM/SCIENCE PHOTO LIBRARY The studies provide basic knowledge about the potential of H5N1 to mutate into a more transmissible form. Kawaoka notes that H5N1 viruses already circulate in nature, mutate constantly and could cause pandemics. I believe that it would be irresponsible not to study the underlying mechanisms, he says. More practically, the research could allow public-health workers to monitor wild viruses for similar mutations that make H5N1 more dangerous to humans. In response, health agencies could then advise manufacturers of flu drugs and vaccines to ramp up production, or could instigate stricter public-health measures to prevent transmission. Would that actually work? For now, probably not. It seems unlikely that manufacturers will pre-emptively produce more vaccine on the basis of a potential threat. And the benefits of improved surveillance may be overplayed because tracking flu mutations is logistically difficult. Surveillance is patchy, especially in poorer countries where H5N1 is most common. There are also many potential ways for H5N1 to become transmissible, and focusing on Fouchier s five mutations could lead to a false sense of security. Nonetheless, Fouchier and others hope that the current controversy will stimulate more funding of flu-surveillance systems. Could the viruses be used in bioterrorism? Unlike most other bioterror agents, H5N1 can be fought with vaccines and drugs, and cannot be targeted to a specific population. However, Paul Keim, acting chair of the US National Science Advisory Board for Biosecurity (NSABB) which recommended that the mutant-flu work should not be published in full cautions that there are not enough flu vaccines or drugs worldwide, and a rapid pandemic would overwhelm our ability to manufacture more. There are also signs that some wild strains of H5N1 have developed resistance to antiviral drugs. Could the mutant viruses escape from laboratories? Worries about escaping viruses are not unfounded. Accidental infections of SARS have affected staff at four biosafety level-3 (BSL-3) and BSL-4 labs in mainland China. The experiments that created the mutant H5N1 strains were done in BSL-3 'enhanced' labs. But some virologists believe that research on the mutant strains should be confined to BSL-4 labs, where the most dangerous viruses, such as Ebola, are studied. Only a few dozen such facilities exist. They use extra safety protocols, including different suits, more rigorous decontamination and more security measures such as bomb-proofing and video surveillance. Will the studies now be published in full? At the recommendation of a US advisory board, Nature and Science considered redacting both papers. However, attendees at the WHO Geneva meeting agreed that redaction would be ineffective, and that it would be impossible to distribute full details to only selected researchers. Owing to the substantial immediate risk posed by wild H5N1 strains, which is greater than previously thought, the delegates concluded that both studies should be published in 3 of 6 3/8/12 11:26 AM

4 full. Meanwhile, the National Institutes of Health has asked the NSABB to reconsider the fate of the two studies in the light of unpublished data presented by both groups at the WHO meeting. Nature doi: /nature Related stories and links From nature.com Flu meeting opts for openness 21 February 2012 Death-rate row blurs mutant flu debate 13 February 2012 Q&A: Reasons for proposed redaction of flu paper 31 January 2012 Researchers defend benefits of mutant flu research 26 January 2012 Pause on avian flu transmission studies 20 January 2012 Call to censor flu studies draws fire 03 January 2012 Fears grow over lab-bred flu 20 December 2011 Mutant flu news special Nature Reports avian flu Web focus: 1918 influenza pandemic Comments 4 of 6 3/8/12 11:26 AM

5 :50 AM Stephen Stewart said: The recent recommendation of the World Health Organization (WHO) to publish unredacted versions of the Â reports of the H5N1 avian influenza research conducted byâ Yoshihiro Kawaoka at the University of Wisconsin-MadisonÂ andâ Ron Fouchier at the Erasmus Medical Center in RotterdamÂ conflicts with the recommendations of theâ US National Science Advisory Board for Biosecurity (NSABB). Paul Keim, who chairs the NSABB and attended the meeting, is reportedly â œdisappointedâ! by the recommendation to publish the papers.â David Fidler, an expert in international and national security law at Indiana University in Bloomington, points out that the meeting hasnâ t actually broken the publication deadlock, because Keim and representatives of the US government still do not agree with publishing the studies in full. â œi believe that it would be irresponsible not to study the underlying mechanisms,â! says Yoshihiro Kawaoka. Yet whereas the chimeric virus Â Kawaoka'sÂ team created did not kill any of the infected ferrets, the mutant strain of H5N1 developed byâ Ron Fouchierâ s team reportedly killed all of the infected ferrets.â There are many ways for H5N1 to become transmissible. Finding one presents an immediate risk without improving security. The arguments thatâ this research could allow monitoring of wild H5N1 viruses for similar mutations and allow manufacturers to ramp up production of vaccines seem facile and self-serving.â AsÂ Ed Yong has noted, "the benefits of improved surveillance may be overplayed because tracking flu mutations is logistically difficult" and "it seems unlikely that manufacturers will pre-emptively produce more vaccine on the basis of a potential threat." Ed Yong also says, "worries about escaping viruses are not unfounded." In fact, given the history of biosecurity breaches, the issue is not whether these H5N1 virusses will escape containment facilities, but when. The mutant strain of H5N1 developed byâ Ron Fouchier at the Erasmus Medical Center in Rotterdam may be more virulent than any yet encountered in the wild. If it killed every infected ferret it should be destroyed immediately :53 AM Stephen Stewart said: My previous comment was initially deleted and I was unable to post further comments. When I queried this by , I was told it was an error. My comment appeared, with the addition of a variety of characters embedded in the text. Oh well. You need to be registered with Nature and agree to our Community Guidelines to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. See other News & Comment articles from Nature 5 of 6 3/8/12 11:26 AM

The Controversy About the H5N1 Transmissibility Experiments. resumes on lethal flu strains

The Controversy About the H5N1 Transmissibility Experiments http://www.nature.com/news/work resumes on lethal flu strains 1.12266 3 M AY 2 0 1 2 VO L 4 8 5 N AT U R E 1 3 Learning Objectives Participants