Virus in one controversial H5N1 study wasn't lethal

Jan 25, 2012 (CIDRAP News) – Breaking a prolonged silence, the author of one of two controversial studies dealing with mutant H5N1 viruses said today that the virus his team created went airborne to spread among ferrets, but it didn't kill them.

In a commentary in Nature, Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo said the mutant virus was actually a hybrid combining the hemagglutinin (HA) gene from an H5N1 strain with other genes from a pandemic 2009 H1N1 virus.

Kawaoka's study is one of two that sparked a Dec 20 recommendation by the National Science Advisory Board for Biosecurity (NSABB) that journals publish only the general findings, minus details that could enable others to replicate the studies. The board's concern is that the full reports could lead to intentional misuse of the data or accidental release of the viruses.

The journals involved, Nature and Science, have indicated they plan to comply with the recommendation if a method can be devised to share the full studies with scientists who need them for legitimate research.

In a related development today, several experts quoted in a news report in Nature said the two controversial studies are unlikely to yield immediate public health benefits, contrary to the assertions of the authors and other scientists who have argued for publication of the full details. The other study was conducted by a team led by Ron Fouchier of Erasmus Medical Centre in the Netherlands.

Two studies differ
Kawaoka's commentary marks the first release of any substantive information about his study. Previous reports have indicated that his study was generally similar to Fouchier's, but the commentary indicates that there are noteworthy differences.

Fouchier gave a general description of his findings last September at a flu conference in Malta and has talked to journalists about them a number of times since. According to those accounts, his team, aiming to determine which mutations could render H5N1 viruses more transmissible, engineered certain mutations in H5N1 strains and then infected ferrets with them. Ferrets are considered the best animal model of human flu.

The resulting virus still didn't spread easily, so Fouchier's team then passed the strain through a series of ferrets by infecting one, waiting until it got sick, and then using a sample from it to infect another. After ten such "passages," the virus had acquired five additional mutations and was able to spread via airborne droplets, according to the accounts. The virus reportedly killed the ferrets in all cases.

Kawaoka's team, unlike Fouchier's, fused the HA gene from an H5N1 strain with the remaining genes from a 2009 H1N1 virus. "We identified a mutant H5 HA/2009 virus that spread between infected and uninfected ferrets . . . in separate cages via respiratory droplets in the air," he writes. "Thus viruses possessing an H5 HA can transmit between mammals."

"Our results also show that not all transmissible H5 HA-possessing viruses are lethal," he adds. "In ferrets, our mutant H5 HA/2009 virus was no more pathogenic than the pandemic 2009 virus—it did not kill any of the infected animals. And, importantly, current vaccines and antiviral compounds are effective against it."

Besides describing his study, Kawaoka uses the commentary to assert the need for such research and to voice disagreement with the NSABB recommendation.

He writes that his study and Fouchier's identify particular mutations that make H5-HA-containing viruses transmissible in ferrets, adding, "A subset of these mutations has been detected in H5N1 viruses circulating in certain countries. It is therefore imperative that these viruses are monitored closely so that eradication efforts and countermeasures (such as vaccine-strain selection) can be focused on them, should they acquire transmissibility."

Kawaoka asserts that omitting the details of the two studies will not eliminate the risk that malefactors could use the data to do harm, because enough information is already available to allow someone to make a transmissible virus containing H5 HA. At the same time, the step will make it harder for legitimate scientists to get the information, he writes.

Kawaoka notes that he is one of 39 flu researchers who last week announced a voluntary 60-day moratorium on H5N1 transmission research to allow time for discussion of the issues. "But our work remains urgent—we cannot give up," he concludes.

Given that the virus generated by Kawaoka's team was not lethal in ferrets, it was not clear today why the NSABB included his study in its recommendation against full publication. NSABB members who were queried by CIDRAP News today did not comment specifically on that question, but one of them said the board would publish information next week in Nature and Science that will address such questions.

"The NSABB has written several statements and responses to questions from Nature and Science editors that are about to be published in Science and Nature that have answers to these questions. This is all in press and should be out in a week or so," said Lynn W. Enquist, PhD, who is Henry L. Hillman professor and chair of the Department of Molecular Biology at Princeton University.

Doubts about early payoff
In the Nature news article, a number of flu experts said the controversial studies have value but, because of the world's limited flu surveillance capabilities, they are not likely to yield immediate benefits.

Knowledge of the specific H5N1 mutations linked to increased transmissibility in ferrets will make it possible to watch for them in birds and other animals, potentially leading to an early warning of a pandemic, according to Kawaoka, Fouchier, and others.

"That claim is meeting with skepticism, however," says the story by Nature reporter Declan Butler. "More than a dozen flu experts contacted by Nature say they believe that the work opens up important vistas in basic research, and that it sends a valuable warning about the potential for the virus to spark a human pandemic. But they caution that virus surveillance systems are ill-equipped to detect such mutations arising in flu viruses. As such, work on the viruses is unlikely to offer significant, immediate public-health benefits, they say."

Michael T. Osterholm, PhD, MPH, and other researchers said the idea that the research offers a guide to dangerous strains that could be stamped out before they spread is unrealistic, according to the story.

"In order to even consider the possibility of reducing the animal reservoir of an emerging pandemic virus, one would need rapid and complete detection of virus in all geographical areas," said Osterholm, who is director of the University of Minnesota's Center for Infectious Disease Research and Policy, publisher of CIDRAP News, and an NSABB member.

Such an achievement is unlikely, since surveillance of H5N1 in poultry worldwide is patchy, especially in poorer countries, where the virus is prevalent, the story said.

In addition, Butler wrote, few flu virus samples are ever sequenced: "Last year, global surveillance resulted in partial sequences from just 160 H5N1 isolates being submitted to GenBank, the main repository of such data . . . . And virus isolates are often sequenced months or years after they are collected—hardly the swift turnaround of a pandemic alert system."

"Could we pick up a mutation in real time and stop a pandemic? Not with the surveillance we have now,” said Ilaria Capua, an animal flu expert at the Experimental Animal Health Care Institute of Venice in Legnaro, Italy.

See also:

Kawaoka commentary in Nature

Declan Butler report in Nature

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