With new data, NSABB may revisit H5N1 studies

Feb 29, 2012 (CIDRAP News) – The mutant H5N1 virus generated in one of two controversial studies was less lethal and contagious than has been generally understood, and the US government's biosecurity advisory committee will be asked to examine new and clarified data from the study, scientists and government officials revealed today.

Ron Fouchier, PhD, lead author of one of the studies, said the mutant H5N1 virus generated in his experiment was not highly lethal when it spread among ferrets via coughing and sneezing, though it was lethal when intentionally introduced into the ferrets' lungs in high doses. He spoke at a panel discussion hosted by the American Society for Microbiology (ASM) and streamed over the Web.

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), said new data and clarifications of existing data emerged Feb 16 and 17 at a meeting of flu experts and public health officials hosted by the World Health Organization (WHO) in Geneva.

Fauci said the National Institutes of Health, which includes the NIAID, now supports a revision of the manuscripts to include the new and clarified data and hopes to reconvene the National Science Advisory Board for Biosecurity (NSABB) to look at the new version.

Fauci referred mainly to the Fouchier study, saying there was "substantial clarification" of his data at the WHO meeting. He did not make clear if there was significant new data from the other study, led by Yoshihiro Kawaoka, DVM, PhD, of the University of Wisconsin.

The NSABB recommended in December that key details of both studies be withheld from publication, out of concern that bioterrorists could use the information to generate a highly dangerous virus. Both studies involved the generation of H5N1 viruses that could spread among ferrets by the airborne route.

The studies were submitted to Science and Nature, and the journals have said they would go along with the NSABB recommendation if a method can be devised to share the full details with legitimate scientists who need them.

Paul Keim, PhD, who moderated today's discussion and is acting chair of the NSABB, declined to say if he thought the committee's new review of the findings might lead to a different recommendation. "We can't say anything about that," he said. Keim is a microbial geneticist at Northern Arizona University in Flagstaff.

Fouchier, who was one of four panelists, gave background on his team's work at Erasmus University Medical Center in the Netherlands and a general description of his study, which involved introducing mutations into an H5N1 virus and then allowing it to evolve in ferrets. The study produced a virus that could spread between ferrets without direct contact.

"We now know exactly which mutations and which biological traits are necessary for H5N1 to become aerosol transmissible between ferrets," Fouchier said.

He said the heavy press coverage of the controversy has created "a lot of misperceptions" about his team's findings, particularly on the transmissibility and lethality of the virus. Reports have generally indicated that all or most of the ferrets exposed to the H5N1 virus died.

"The first thing [misperceived] is that the virus would spread like wildfire if it came out of our facility. We don't believe this is the case," he said.

He showed charts indicating that the pandemic 2009 H1N1 virus spreads much more efficiently in ferrets than the mutant H5N1 virus does. The H5N1 strain "doesn’t transmit in 100% of cases," he said. "The virus titers being shed are much lower, and thirdly a lot of the animals don't start shedding until day 3, 4, or 5."

"The second misperception is that the virus would be highly lethal," Fouchier said. "It's absolutely clear that H5N1 is highly pathogenic for chickens, but in mammals this is simply not the case."

When ferrets are inoculated with very high doses of the mutant H5N1 strain in the lower respiratory tract, they die, but when they are simply exposed by the nasal route, "they might get sick but they don't die," he said.

Fauci and Fouchier commented further on the point in a question period later. At the WHO meeting, Fauci said, most participants thought that the mutant H5N1 virus spread easily among ferrets via sneezing and that all the infected ferrets died. "That is not what happens," he said. "When a ferret sneezes on another ferret, that ferret gets sick but does not die."

Fouchier added, "This virus does not kill ferrets when they are sneezed upon." He said he has never seen "severe disease" in ferrets infected by the aerosol route.

Regarding transmissibility, he said, "If anything, our data suggests that this virus spreads poorly. . . . Whether this virus if it would escape our laboratory would start spreading, we don't know."

Today's revelations suggest that Fouchier's virus may be similar to Kawaoka's virus in its virulence. In a commentary published in January, Kawaoko said the virus his group generated did not kill any of the ferrets it infected.

Fauci, in mentioning plans to reconvene the NSABB to look at the new data, said, "We wanted to give them the benefit of the same discussion that took place in Geneva."

The WHO meeting brought forth "a combination of old data that was clarified and new data that was juxtaposed with the old data," he said. "I'd love to tell you, but the deliberations that took place in Geneva were under a confidentiality agreement" and complex legal restrictions that barred participants from discussing what went on.

After the meeting, as reported previously, the WHO announced that the majority of the participants favored publishing the two studies in full after allowing time for a public information campaign, while extending a current moratorium on research involving lab-generated H5N1 viruses.

Another panelist in today's discussion was Bruce Alberts, PhD, editor-in-chief of Science, who said he was surprised to learn after the NSABB made its recommendation that there was no mechanism already in place for providing the details of the two studies to scientists with a need to know. "So we asked that a mechanism be developed as part of the agreement for redaction" of the studies, he said.

"The NSABB will be meeting again to consider some new data," he said. "It's my intention to try to comply with the NSABB recommendation, provided we can have a mechanism for selective access to the information by those with a need to know."

Alberts said he was involved in a similarly difficult publication case in 2005, when Science received a manuscript about how terrorists might use botulinum toxin to contaminate the US milk supply.

"I was approached by many in the US government and urged not to publish it," he said. He would've sought advice from the NSABB, but the board was new and had not yet met, so he had to make the decision, which was to publish, he recounted.

Also on the panel was Michael T. Osterholm, PhD, MPH, an NSABB member, who outlined the process that led to the board's recommendation to withhold details of the two studies. He noted that after hundreds of hours of deliberations, the board's vote on the recommendation was unanimous.

"Our rationale for all of this is that if H5N1 acquires the capacity for mammalian transmission, the world could face a significant pandemic," said Osterholm, who directs the University of Minnesota's Center for Infectious Disease Research and Policy, publisher of CIDRAP News.

He said the NSABB has made clear that its recommendation on the two studies is just the beginning of discussions on how dual-use research should be handled. "The NSABB never saw itself as the court of final vote; it saw itself as the court of the first vote," he said.

See also:

Video of Feb 29 ASM discussion

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

Jan 25 CIDRAP News story "Virus in one controversial H5N1 study wasn't lethal"

Dec 20, 2011, CIDRAP News story " US government urges journals to omit details of two H5N1 studies"

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