NSABB: Studies show how H5N1 can jump natural barrier

Jan 31, 2012 (CIDRAP News) – The core of a US biosecurity advisory board's concern about two controversial, as-yet-unpublished studies on H5N1 viruses is that the studies have shown how to remove the apparent natural barrier that keeps the viruses from spreading efficiently in mammals, members of the board said in statements published today.

Removal of this barrier creates the potential for a catastrophic pandemic if such mutant viruses were released by bioterrorists or by accident, said members of the National Science Advisory Board for Biosecurity (NSABB), which has focused mainly on the perceived risk of bioterrorism. The board has recommended withholding details of the studies from publication.

"The artificial evolution of a new mammal-adapted H5N1 virus, as reported in these two papers, has removed the natural barriers that might have existed. Accomplishing this in the lab, however, doesn't mean that it can occur naturally," said Paul Keim, PhD, acting chair of the NSABB, in a question-and-answer interview published in Nature.

A statement signed by all the NSABB members was published simultaneously in Nature and Science. The findings of the two studies are "very important because, before these experiments were done, it was uncertain whether avian influenza A/H5N1 could ever acquire the capacity for mammal-to-mammal transmission," the statement says.

"Now that this information is known, society can take steps globally to prepare for when nature might generate such a virus spontaneously."

Although NSABB members have talked to reporters in recent weeks, today's publications were the first formal statements from the board since its recommendation against full publication was announced by the US National Institutes of Health (NIH) on Dec 20. The Department of Health and Human Services (HHS) endorsed the board's recommendation and forwarded it to Science and Nature, the journals considering publishing the studies.

Though often fatal, human infections with H5N1 are rare—fewer than 600 cases have been documented since 2003—and transmission from person to person is even rarer. In the two studies in question, researchers generated a mutant H5N1 virus and an H5N1-H1N1 hybrid virus that spread by airborne droplets among ferrets, which are considered the best animal models for studying human flu.

Ron Fouchier, PhD, of Erasmus Medical Center in Rotterdam led a team that generated mutations in an H5N1 strain and then allowed it to evolve naturally in ferrets, leading to more mutations that produced a variant that was efficiently transmissible and remained lethal to the ferrets. The study was submitted to Science.

In the other study, a team led by Yoshihiro Kawaoka, DVM, PhD, of the University of Wisconsin and the University of Tokyo combined the hemagglutinin (HA) gene from an H5N1 virus with seven other genes from a pandemic 2009 H1N1 virus. This, too, produced a virus that could spread by air, but it was no more pathogenic than the 2009 H1N1 virus and did not kill any of the ferrets, Kawaoka has said.

Rationale for targeting Kawaoka study
Much of Keim's interview today dealt with why the NSABB included Kawaoka's study in its recommendation, given that it involves a virus that was not lethal in ferrets and was a reassortant rather than a strictly H5N1 strain.

Responding to questions from Nature's editors, Keim wrote that though the reassortant is no more pathogenic than the 2009 H1N1 virus, "we believe that the techniques described could be used to generate other viruses with H5 HA that have potentially much greater pathogenicity." In addition, the fact that people have had no previous exposure to H5 viruses could lead to a much broader pandemic than that of 2009, he said.

The editors said the mutations described in Kawaoka's paper are insufficient to provide a blueprint for a transmissible, highly pathogenic, wholly avian H5N1 virus, suggesting that publishing the full study is not risky.

Keim replied, "The fact that Kawaoka's specific virus and mutations might not be the feared H5N1 pandemic strain is not the point. It is that this laboratory created a virus that has now bypassed apparent barriers to evolution in the wild. If this virus were to escape by error or by terror, we must ask whether it would cause a pandemic. The probability is unknown, but it is not zero."

He added that Kawaoka's study "significantly advances the ability to construct an H5 virus with catastrophic potential. This altered H5 HA gene could be combined with other influenza virus genes possibly leading to a pandemic."

The Nature editors also said independent advisers voiced doubt that Kawaoka's virus could be exploited by bioterrorists, since it couldn't be aimed at a specific population and because vaccines and drugs are available.

Keim acknowledged that bioterrorist uses of the virus would be "low-probability events, but they could introduce a new evolutionary seed into the environment that seems not to exist in nature. This might not cause a pandemic instantly, but it could start the virus on a new path for pandemic evolution." He also agreed that H5N1 vaccines and flu antivirals exist, but said supplies are not sufficient anywhere in the world.

Keim also was one of three commentators today writing on the issue in the open-access journal mBio (see related CIDRAP News story).

NSABB statement more general
The statement from the full NSABB is more general than Keim's comments and does not cover much new ground. The article focuses mainly on the risk of bioterrorism, with little mention of the risk for release of dangerous H5N1 viruses through lab accidents.

"We found the potential risk of public harm to be of unusually high magnitude," the board said, adding that the members were unanimous in concluding that the full details of the two studies should not be published.

"Our concern is that publishing these experiments in detail would provide information to some person, organization or government that would help them to develop similar mammal-adapted influenza A/H5N1 viruses for harmful purposes," the statement says.

But the board also sees the studies as clearly beneficial in that they alert the world to the threat of readily transmissible H5N1 and should spur greater preparedness and research on better defenses. Publishing the basic findings but not the full details will maximize the benefits and minimize the risks, the panel said.

As members have commented before, the board also called for a broad international discussion aiming for a consensus policy on dual-use research on H5N1. The World Health Organization recently said it would take the lead on such efforts and expressed the hope of holding a conference on the issues in February.

The board drew a parallel between the current situation and the controversy over recombinant DNA research in the 1970s. At that time researchers voluntarily imposed a moratorium on the work until they could develop guidelines on how to do it safely and responsibly.

Leading flu researchers announced on Jan 20 their own moratorium on studies that could lead to the generation of more-transmissible H5N1 viruses. The 60-day break is intended to allow time for discussion of the risks, benefits, and oversight.

Meanwhile, Science has agreed to postpone publication of the Fouchier study until March, "to allow the international conversations about the research to move forward," spokeswoman Kathy Wren told CIDRAP News today. She said no publication date has been set, however. Nature officials declined to comment on the timeline for publishing the Kawaoka report.

Fouchier expressed disappointment with the NSABB statement today, according to a Canadian Press (CP) report.

"I was hoping for an explanation of the risks of communicating the results of our study via normal publication. There is none," he told the CP. "Our information is useless to small bioterrorist groups, and larger organizations and rogue countries can replicate our work without our manuscript."

See also:

Jan 31 NSABB statement in Nature and Science

Introduction to Jan 31 Paul Keim comments in Nature

Jan 31 CP story quoting Fouchier

Jan 31 CIDRAP News story "Experts continue to clash over NSABB recommendation"

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