NIH panel supports stronger safeguards for H5N1 research

Jan 25, 2013 (CIDRAP News) – A federal advisory committee yesterday recommended increased biosafety precautions for research involving H5N1 avian influenza viruses that can spread among mammals, a step that stems from the ongoing controversy over studies involving lab-modified H5N1 strains that show increased transmissibility in ferrets.

The Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health (NIH) called for a number of additions to enhanced biosafety level 3 (BSL-3) precautions, which scientists have used in recent studies involving more-transmissible H5N1 viruses. The panel discussed the recommendations at an all-day meeting that was webcast.

In calling for further enhancement of BSL-3 precautions, the committee rejected the option of advocating the highest level of biosafety, BSL-4, a standard that only a few labs around the world can meet. Just one member of the panel supported going to BSL-4.

The aim of the recommended steps is to reduce the risk of infections in lab workers and of accidental release of dangerous H5N1 viruses. The steps include things like more personal protective equipment, a "buddy system" for workers, taking baseline serum samples, giving a licensed H5N1 vaccine, if available, to all lab workers, and requiring personnel to avoid contact with susceptible bird species for 5 days after working with the viruses in question.

The recommendations come just a day after 40 leading flu researchers from around the world declared an end to a year-old moratorium on H5N1 "gain of function" research, meaning experiments leading to increased transmissibility or pathogenicity. The researchers announced the moratorium in response to the controversy over whether the details of two such studies should be published.

The stated aim of the RAC meeting was to look at biosafety in research on highly pathogenic avian influenza (HPAI) H5N1 viruses that can spread among mammals by respiratory droplets.

Such were the viruses developed in separate studies led by Ron Fouchier, PhD, of Erasmus Medical Center in the Netherlands, and Yoshihiro Kawaoka, DVM, PhD, of the University of Wisconsin. Publication of their research reports was initially stalled by concerns about biosecurity and biosafety, but they were finally published last May and June in Nature and Science.

The RAC was formed in 1974 to deal with public concerns about the safety of recombinant DNA research. The NIH says it continues to serve as an important public forum for dealing with scientific, ethical, and legal issues raised by recombinant DNA technology.

Yesterday the committee discussed biosafety recommendations that were proposed by a subcommittee serving as a working group. The committee first heard background presentations from a number of experts on H5N1 avian flu, antiviral treatment, H5N1 vaccines, research on mammalian-transmissible H5N1 strains, and the re-creation of the 1918 pandemic flu virus.

Terence Tumpey, PhD, of the Centers for Disease Control and Prevention (CDC), who led the effort to re-create the 1918 virus in 2005, discussed the precautions used in that research. "The virus was handled safely in enhanced BSL-3 conditions, with some additional CDC precautions," he said.

The primary biocontainment barrier used was a biosafety cabinet, Tumpey said. Researchers wore body suits with PAPRs (powered air-purifying respirators) as secondary barriers. They also took prophylactic oseltamivir (Tamiflu) for 2 days before and 10 days after working with the virus.

The RAC working group's recommendations were presented by Jacqueline Corrigan-Curay, JD, MD, who is the committee's executive secretary as well as acting director of the NIH's Office of Biotechnology Activities.

Because the continued effectiveness of antivirals against H5N1 is an important safeguard, she said, higher containment than BSL-3 will be needed if an H5N1 virus isn't sensitive to antivirals. Any experiment designed to increase the virus's drug resistance would require approval from the NIH director or another federal agency, she added.

Concerning personal protective equipment (PPE), Corrigan-Curay said existing BSL-3 specificiations include PAPRs, a protective suit, wrap-back disposable gowns, double gloving, shoe covers, and a shower before leaving the lab. The working group recommended adding the use of protective sleeves over gowns in a biosafety cabinet, spraying or wiping down PPE with disinfectant, and a buddy system, meaning a requirement to have two people in the lab at all times when work is going on.

The working group also recommended a personnel quarantine, meaning workers should avoid contact with susceptible birds for 5 days after working with mammal-transmissible H5N1 viruses. That recommendation imitates a US Department of Agriculture rule for those who work with HPAI viruses.

That suggestion sparked a lengthy discussion about whether personnel should also be told to stay away from mammals for 5 days, since the viruses in question would be contagious in mammals.

The group eventually agreed not to go that route, mainly because of the number of other precautions and the lack of data on whether ferret-transmissible H5N1 strains could also spread in other mammals.

"I don't know how well it transmits to other species if it transmits in ferrets," said Freeda Isaac, DVM, of the US Department of Agriculture's (USDA's) Animal and Plant Health Inspection Service. "Until that's well established, I'm not sure we're ready to do that."

Corrigan-Curay said proper training of lab workers in enhanced BSL-3 precations will be essential. The working group recommended that personnel be required to sign a statement avowing that they understand the safety and incident-reporting requirements. The group recommended that all incidents be reported to institutional authorities immediately and to public health officials within 24 hours.

Another advisory from the working group was that all personnel should receive seasonal flu vaccine, Corrigan-Curay said. Further, if a licensed H5N1 vaccine is available, it should be given to all lab workers, and their immune response should be assessed. "I don' think we can require giving an unlicensed vaccine as policy," she added.

Current NIH guidelines say those exposed to an H5N1 virus should self-isolate at home until infection is ruled out, Corrigan-Curay said. But the working group recommended that for exposure to a mammal-transmissible H5N1 strain, the worker should be isolated in a predetermined facility, not at home.

A wide-ranging discussion followed Corrigan-Curay's presentation of the recommendations, which were received mostly favorably.

Stephen Redd, MD, of the CDC, a visiting expert, suggested that the precautions be strengthened further by including active health monitoring of personnel, "with periodic notifications that a person doesn't have an illness," and increasing the frequency of PAPR testing. He also endorsed using licensed H5N1 vaccines when they're available.

Joseph Kanabrocki, PhD, of the University of Chicago, a guest expert, supported the enhanced BSL-3 approach, saying, "There are very few BSL-4 labs in the world, and they're very, very expensive to operate. I just think it [requiring BSL-4] would bring influenza research to a halt."

But Dawn Wooley, PhD, an associate professor in neuroscience, cell biology, and physiology at the Wright State University School of Medicine in Dayton, Ohio, said she thinks the research calls for BSL-4 rules.

In her view, the virus strains in question fall into NIH "risk group 4," meaning pathogens that can cause lethal or serious disease and for which no prevention or treatment is available. She said a common theme is that risk group 4 means both high individual and high community risk, adding, "I can't rationalize how this is a low community risk."

By calling for BSL-3, "We're telling taxpayers we're doing this in less than the safest conditions," she said.

Laurie Zoloth, PhD, a professor of medical humanities and bioethics at the Feinberg School of Medicine at Northwestern University, also expressed some misgivings. Because there's "a level of mistrust" about vaccines, if an accident resulted in a need for mass vaccination, the vaccine uptake might not be good, she said.

"I think it's taking a significant risk to do this work," she said.

But Daniel Perez, PhD, of the University of Maryland, a flu researcher and guest expert, argued that doing the research in level 3 conditions is no less safe than in level 4. If the research is confined to BSL-4 labs, of which there are so few, they may be overused, he added.

Perez and Robert Webster, PhD, of St. Jude Children's Research Hospital in Memphis, one of the world's leading flu researchers, said Fouchier, Kawaoka, and others had tried for years to determine what would increase H5N1 transmissibility before they finally succeeded.

"I don't think people realize that Kawaoka and Fouchier spent about 10 years trying to get transmissible viruses, and it's not easy," Webster said. "The number of labs trying to do it were responding to the requests of the world. They were not doing anything against what we should be doing."

One working group recommendation that prompted a long debate was that lab workers should be given an antiviral drug only after medical evaluation and that the drugs should not be provided in advance.

Corrigan-Curay wondered if some flexibility should be allowed on that point, such as for a lab worker who was going to travel and would not have access to antivirals in case of illness.

Some panel members liked the idea, but others voiced concern that that approach would encourage people to take a potentially dangerous situation too casually and not seek immediate medical attention. Eventually the group decided to accept the original recommendation.

When the committee finally voted on the set of recommendations, Wooley was the only one who voted no, although Zoloth expressed her vote as "a guarded, grumpy yes."

Renate Myles, an NIH spokeswoman, said today that it will be up to the NIH to decide if the RAC recommendations become official guidelines.

The meeting included considerable discussion of H5N1 vaccines and their possible use in researchers who handle H5N1 viruses.

Armen Donabedian, PhD, of the US Department of Health and Human Services' (HHS's) Biomedical Advanced Research and Development Authority (BARDA), gave an update on the HHS stockpile of H5N1 vaccine, part of pandemic preparedness efforts.

The stockpile contains vaccines against four H5N1 clades, which "covers in general the major families which are circulating now," he said. "There are quite a bit more than 40 million doses" in the stockpile, he added, and the potency of bulk antigen that has been in the stockpile for 5 to 8 years is over 75%.

Donabedian said a vaccine for an Indonesian strain (clade 2.1.3) used in research will be made available soon to at-risk lab and manufacturing workers. "We're looking to set that up within the next month," he said, without offering further details.

In response to a query today, Dr. Robert Huebner, active director of the BARDA Influenza Division, told CIDRAP News that the agency is working with a manufacturer to finalize details on an H5N1 immunization program and will share information about it when it's ready. Currently there is no vaccine program for workers at risk for H5N1 exposure, he said. .

At the meeting, Donabedian also commented that a manufacturer applied to the US Food and Drug Administration (FDA) last March for approval of an adjuvanted H5N1 vaccine. "FDA has been reviewing that assiduously and we expect they'll make a ruling in several weeks," he said.

Webster commented that he and everyone in his lab received the H5N1 vaccine when it became available. "Let's make sure that the workers in all the labs are vaccinated at least with an H5 [vaccine], because we are primed with H5 and you cross-react to the other clades," he said.

See also:

NIH RAC homepage
http://oba.od.nih.gov/rdna_rac/rac_about.html

Jan 24 RAC meeting agenda
http://oba.od.nih.gov/oba/RAC/meetings/Jan2013/RAC_H5N1_2013_agenda_FINAL.pdf

RAC roster
http://oba.od.nih.gov/oba/RAC/roster/RAC_Roster_2012_09.pdf

Dec 17 CIDRAP News story about NIH funding framework for gain of function research
http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/dec1712durc.html

Dec 3 CIDRAP News item about draft NIH funding criteria for studies that could increase H5N1 transmissibility
http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/dec0312scan.html

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