Experts ponder H5N1 research moratorium issues

Oct 9, 2012 (CIDRAP News) – The moratorium on research leading to more-transmissible H5N1 avian influenza viruses, originally set for 60 days, has remained in place for 8 months without a clear end in sight, but a series of commentaries in mBio today from experts familiar with the issues offers some clues for possible next steps.

In an introduction to the series, editors of mBio, the journal of the American Society for Microbiology (ASM), wrote that they commissioned the pieces to help crystallize some of the issues that will affect future discussions on the research. The articles argue for and against continuing the moratorium, air biosecurity concerns, and reflect on lessons learned from a similar watershed moment—the Asilomar conference on DNA research in February 1975.

Arturo Casadevall, MD, PhD, editor-in-chief of mBio, and Thomas Shenk, PhD, of the ASM's publications board, wrote that the H5N1 research pause is a historic event in science and that the journal's goal of publishing today's commentaries is to record the events and foster discussions that will "enable decisions that are in the best interests of humanity."

They aired some of the issues that need to be resolved, such as articulating what findings the studies can yield for pandemic preparedness that can't be obtained in any other way. Also, they suggested that an option for navigating some of the difficult issues regarding the risks of the research might be to make safer strains of flu viruses that could allow the research to continue under biosafety level 2 (BSL-2) or BSL-3 conditions.

Drawing parallels to a similar research pause that occurred after the Asilomar conference on recombinant DNA research, Casadevall and Shenk wrote that those events showed that science moved forward and society benefited from a period of cautious studies that documented the safety of the work, which eventually led to the relaxation of most research constraints.

"The challenge now is to find ways of framing questions in the context of the available scientific knowledge to decide what experiments need to be done and when and how to do them," they wrote.

In support of the pause
Stanley Falkow, PhD, one of the scientists who took part in the Asilomar conference and helped draft the DNA research guidelines that resulted, authored a piece that compared the past and present moratoriums and said the H5N1 pause should continue so that stakeholders have time to draw up a roadmap for the path forward. He is a professor of microbiology and immunology at Stanford University.

The Asilomar approach was successful because including nonscientists in policy decisions strengthened the effort and increased public awareness and acceptance of the research, Falkow wrote. He suggested that individual researchers are responsible for thinking through the consequences of their work and that more training for young scientists on responsible research practices could help move past some of the problems. "Mind you, this is not something that needs to await an international meeting," he added.

"In my view, this should not be a government-initiated or -driven problem but rather a standardized program devised by working scientists and the professional organizations to which they belong," Falkow wrote.

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), repeated and expanded on a recommendation he made in July at an influenza meeting that the research moratorium should continue.

He wrote that though he believes the benefits of the lab-modified H5N1 studies outweigh the risks, concerns that have been raised about the work are genuine and legitimate.

Flu virus researchers who have concerns about the moratorium hampering progress could do a better job spelling out the scientific rationale for the experiments before they're performed and should be willing to engage in discussions about the risks, however remote, Fauci said. "We must also not rule out the possibility that in the course of these discussions, a broad consensus might be reached that certain experiments actually should not be conducted or reported."

The US government is planning to strengthen its current guidance on dual-use research of concern and to provide a companion guide to help institutions manage different aspects of the work, he said.

Fauci announced that the US government will host an international workshop by the end of 2012 with input from the National Science Advisory Board for Biosecurity (NSABB), global partners, biosafety and biosecurity experts, scientists, and members of the public. He added that the goal of the meeting is to outline the rationale for and risks of the research. No details from the NIAID on a date or place for the meeting were available to CIDRAP News as of press deadline.

Fauci said the moratorium is providing valuable time and space for researchers and stakeholders. "We all need to work together and get this right, and it should be continued until we do so," he wrote.

A call to resume research
Three researchers who are deeply involved in H5N1 research opposed continuation of the moratorium and wrote that scientists who have approval from their countries should resume the work. They are Ron Fouchier, PhD, of Erasmus University in the Netherlands, Adolfo Garcia-Sastre, PhD, of Mt. Sinai School of Medicine in New York City, and Yoshihiro Kawaoka, DVM, PhD, of the University of Wisconsin and the University of Tokyo.

Two of the authors were involved in the studies that sparked the H5N1 research controversy. Kawaoka headed a group that in reported in a May issue of Nature that as few as four mutations in the H5N1 virus's surface proteins could arm it with the capacity to spread among mammals. Fouchier led a group that reported in a June issue of Science that it takes as few as five mutations to turn the H5N1 virus into an airborne spreader in mammals.

Based on those findings, research must resume to allow scientists to fully assess the pandemic potential of H5 viruses, the three scientists wrote.

They pointed out that part of the reason for the research moratorium was to allow governments to clarify biosafety and biosecurity requirements for facilities that conduct the H5N1 studies, and said that countries such as the Netherlands and Canada have already clarified containment issues.

The three researchers revealed that the US Intergovernmental Select Agents and Toxins Technical Advisory Committee has reviewed the conditions for H5N1 transmissibility research and is expected to release its recommendations in the Federal Register shortly.

On Oct 5 the US Department of Agriculture (USDA) released its biennial review and final rule on select agents and toxins in the Federal Register, noting that one commenter suggested adding mammalian-transmissible H5N1 to a list of select agents and toxins.

The USDA said its select agent program is considering the issue and may address it in future rulemaking. "Given the stage these discussions are in, however, we are not making any changes in this final rule based on this comment," the agency said in the notice.

Fouchier and his coauthors listed some examples of possible future H5N1 experiments and their benefits, which include identifying other mutations that allow the virus to adapt to mammals that could be monitored through surveillance, and defining molecular mechanisms of transmission and pathogenicity that could help determine if adaptation could make the virus less virulent.

"The benefits of H5N1 virus transmission may or may not result in immediate applications—accumulating knowledge in basic research is an incremental process," they wrote.

Biosafety concerns
Two other commentaries targeted biosafety and biocontainment issues that have been raised by the H5N1 research debates.

Ian Lipkin, PhD, director of Columbia University's Center for Infection and Immunity, raised concerns about biocontainment conditions for H5N1 transmission studies going forward. He said his views reflect the work he did on West Nile virus in 1999 and on the SARS outbreak in 2003.

He commented that for BSL-3 or enhanced BSL-3 labs, training, monitoring, and access controls aren't as rigorous as for BSL-4 labs. And while labs now working on lab-modified H5N1 viruses are "state of the art," other groups working at that level might not be as well equipped or experienced.

Instead of shifting the work on the viruses to the BSL-4 level, Lipkin suggested that an international group such as the World Health Organization (WHO) could develop specific requirements for research at enhanced BSL-3 labs on agents that have pandemic potential, especially when the experiments address virulence and transmissibility.

"Given the implications for humankind, whatever course we pursue must be developed with global consultation and oversight," Lipkin wrote.

Meanwhile, two infectious disease experts from Harvard University's School of Public Health suggested that several steps are needed before work on pathogens such as mammalian-transmissible H5N1 is funded, including an explicit risk-benefit analysis and improved biosafety practices and enforcement. The authors are Marc Lipsitch, PhD, professor of epidemiology, and Barry Bloom, DSc, PhD, professor in the Department of Immunology and Infectious Diseases.

For potential pandemic pathogens such as SARS, smallpox, and highly transmissible, pathogenic flu viruses, national and international bodies should establish specific and more stringent criteria for work with the agents, they wrote, adding that the moratorium affords an opportunity to define measures to minimize the risk of lab-related infections or epidemics.

Other suggestions from Lipsitch and Bloom include engaging in public discussions such as the Asilomar meeting, revising agent classification and categories, revising safety guidelineto put more emphasis on lab training, a cross-government agency to review research proposals on potential pandemic pathogens, and global guidelines to oversee international labs that work on these pathogens.

Casadevall A, Shenk T. The H5N1 moratorium controversy and debate. mBio 2012 Oct 9 [Abstract]

Falkow S. The lessons of Asilomar and the H5N1 "affair." mBio 2012 Oct 9 [Abstract]

Fauci AS. Research on highly pathogenic H5N1 influenza virus: the way forward. mBio 2012 Oct 9 [Abstract]

Lipsitch M, Bloom BR. Rethinking biosafety in research on potential pandemic pathogens. mBio 2012 Oct 9 [Abstract]

Fouchier R, Garcia-Sastre A, Kawaoka Y. The pause on avian H5N1 influenza virus transmission research should be ended. mBio 2012 Oct 9 [Abstract]

Lipkin WI. Biocontainment of gain-of-function infectious disease research. mBio 2012 Oct 9 [Abstract]

See also:

Jul 31 CIDRAP News story "Fauci urges continuing pause on risky H5N1 studies"

Oct 5 USDA Federal Register notice

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