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Published Date: 2012-01-25 21:43:11
Subject: PRO/AH> Avian influenza, human (13): transmission studies controversy
Archive Number: 20120125.1021903

AVIAN INFLUENZA, HUMAN (13): TRANSMISSION STUDIES CONTROVERSY
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[1]
Date: Wed 25 Jan 2012
Source: Winnipeg Free Press, The Canadian Press [edited]
http://www.winnipegfreepress.com/arts-and-life/life/health/researcher-at-heart-of-bird-flu-studies-controversy-reveals-details-of-findings-138055808.html

A scientist at the centre of a raging controversy over bird flu [avian A/(H5N1) influenza virus] transmission studies has broken his silence, in the process revealing information about his study that has not been made public previously.

In a commentary in the journal Nature [see transcript below], flu virologist Yoshihiro Kawaoka argued the work he and other high level influenza scientists do to try to puzzle out why some flu viruses spread in humans while others don't is too important to be shelved.

"Our work remains urgent; we cannot give it up," wrote Kawaoka, who up until now has made no comment on the controversy that is pitting flu scientists against the community of biosecurity experts, some of whom insist no further transmission studies on the dangerous H5N1 flu virus should be undertaken.

In his commentary, Kawaoka revealed that his laboratory at the University of Wisconsin-Madison made a hybrid virus, fusing the hemagglutinin protein [gene] (the H in a flu virus's name) from H5N1 into the human H1N1 virus that caused the 2009 pandemic.

The H1N1 virus spreads easily among people, but H5N1 currently does not. They found the viruses came together readily and spread easily among ferrets kept in separate cages. Ferrets are considered the best animal model for predicting how a flu virus will act in humans, and that type of study is meant to replicate the conditions under which flu viruses transmit among humans.

But while it was highly transmissible, the mutant virus did not kill the ferrets, Kawaoka reported. In fact, it was no more pathogenic to the animals than the 2009 H1N1 virus, he said. "Our results ... show that not all transmissible H5 HA-possessing viruses are lethal," he wrote (HA is the short form for hemagglutinin used by flu scientists).

Nature, which plans to publish Kawaoka's paper, acknowledged it had given him dispensation to release information about this work. Normally, journals will not publish studies if the findings have already been reported elsewhere, including in the mainstream media. Spokeswoman Rachel Twinn said Nature decided it was in the public interest to allow Kawaoka to share details of his findings at this time.

Kawaoka -- who also has an appointment at the University of Tokyo -- runs one of 2 labs caught up in this roiling controversy. The other is run by Dutch virologist Ron Fouchier of Erasmus Medical Centre in Rotterdam.

Fouchier has been front and centre in this debate. And before now, much more was known about his work because he reported on it at an influenza conference in Malta in the fall [2011] (Journals' pre-publication bans don't apply to presentations made to scientific conferences.). Fouchier's team forced evolution of an H5N1 virus in ferrets, getting it to the point where it easily transmitted among the animals. It was a full H5N1 virus -- it was not a hybrid -- and it was fatal to at least some of the animals. His paper is to be published in Science.

But before Science and Nature could publish the works, a panel of biosecurity experts urged the U.S. government to ask the journals not to publish the full works, saying to do so would be to print recipes for potential bioterror weapons. The journals and the scientists have grudgingly agreed. But the flu community and some others in the science world have objected to the decision, saying to hold back the full details of the studies will impede science that needs to be done.

In the hopes of creating room for a compromise, last week, 39 leading flu scientists -- including Kawaoka and Fouchier -- announced they would observe a voluntary 60-day moratorium (from 20 Jan 2012) on H5N1 transmission studies. The idea was to give the global community time to sort through the troubling issues the work raises.

The World Health Organization, which has been asked to help mediate the problem, has said it will convene a meeting of technical experts in Geneva in mid February 2012, probably 16-17 Feb 2012. The WHO's point person on the issue, Dr. Keiji Fukuda, has said the meeting will be small, involving fewer than 50 people. The scientists who did the studies as well as scientists from WHO's network of flu laboratories will be invited to attend. A representative of the U.S. biosecurity panel -- the National Science Advisory Board on Biosecurity -- will also be invited to attend, Fukuda has said.

In his commentary, Kawaoka argued that trying to disseminate the full details of his and Fouchier's work on a need-to-know basis -- the U.S. proposal -- will be unworkable. And he said redacting the studies won't eliminate the possibility that the information will become public. "There is already enough information publicly available to allow someone to make a transmissible H5 HA-possessing virus," he warned.

[Byline: Helen Branswell]

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Communicated by:
ProMED-mail Rapporteur Mary Marshall

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[2]
Date: Wed 25 Jan 2012
Source: Nature (2012) doi:10.1038/nature10884 [edited]
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10884.html

Yoshihiro Kawaoka explains that research on transmissible avian flu viruses needs to continue if pandemics are to be prevented.

"Highly pathogenic avian H5N1 influenza viruses 1st proved lethal in humans in 1997 in Hong Kong. Since 2003, 578 confirmed infections have resulted in 340 deaths. Now widespread in parts of southeast Asia and the Middle East, H5N1 viruses have killed or led to the culling of hundreds of millions of birds.

To date, H5N1 viruses have not been transmitted between humans. Some experts have argued that it is impossible. But given the potential consequences of a global outbreak, it is crucial to know whether these viruses can ever become transmissible. Work by my group (accepted by Nature) and an independent study (accepted by Science) led by Ron Fouchier of the Erasmus Medical Center in Rotterdam, the Netherlands, suggest that H5N1 viruses have the potential to spread between mammals. As the risks of such research and its publication are debated by the community, I argue that we should pursue transmission studies of highly pathogenic avian influenza viruses with urgency.

To determine whether H5N1 viruses could be transmitted between humans, my team generated viruses that combined the H5 haemagglutinin (HA) gene with the remaining genes from a pandemic 2009 H1N1 influenza virus. Avian H5N1 and human pandemic 2009 viruses readily exchange genes in experimental settings, and those from a human virus may facilitate replication in mammals. Indeed, we identified a mutant H5 HA/2009 virus that spread between infected and uninfected ferrets (used as models to study the transmission of influenza in mammals) in separate cages via respiratory droplets in the air. Thus, viruses possessing an H5 HA protein can transmit between mammals.

Our results also show that not all transmissible H5 HA-possessing viruses are lethal. 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.

Fouchier and his team also generated a transmissible H5 HA-possessing virus, meaning that 2 independent studies have demonstrated the potential for transmissibility of H5 HA-possessing viruses between ferrets. Their mutant H5 HA virus, generated in the genetic background of an H5N1 virus, did kill infected ferrets.

Some people have argued that the risks of such studies -- misuse and accidental release, for example -- outweigh the benefits. I counter that H5N1 viruses circulating in nature already pose a threat, because influenza viruses mutate constantly and can cause pandemics with great losses of life. Within the past century, 'Spanish' influenza, which stemmed from a virus of avian origin, killed between 20 million and 50 million people. Because H5N1 mutations that confer transmissibility in mammals may emerge in nature, I believe that it would be irresponsible not to study the underlying mechanisms.

The new work has implications for pandemic preparedness. There is an urgent need to expand development, production and distribution of vaccines against H5 viruses and to stockpile antiviral compounds. Both studies identify specific mutations in HA that confer transmissibility in ferrets to H5 HA-possessing viruses. 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.

Consequently, I believe that the benefits of these studies -- the knowledge that H5 HA-possessing viruses pose a risk and the ability to monitor them and develop countermeasures -- outweigh the risks. High biosafety and security standards can be met. Our experiments were carried out in a high-containment facility by a small group of highly trained individuals who operate under strict procedures to prevent the accidental release of viruses.

However, the US National Science Advisory Board for Biosecurity (NSABB) has recommended that details of both studies (including the mutations that confer transmissibility) should be restricted and released only to select individuals on a 'need-to-know' basis. I acknowledge the advisory role of the NSABB, but I do not concur with its decision.

The primary justification for the NSABB's recommendation is that publication of our data "could enable replication of the experiments by those who would seek to do harm." But redacting our papers will not eliminate that possibility; there is already enough information publicly available to allow someone to make a transmissible H5 HA-possessing virus.

The mechanism that the US government proposes for releasing data would also be unwieldy. Thousands of applications to access the research are likely to be filed, and potential background checks would create a huge administrative burden. We cannot afford to lose time if we are to combat emerging pandemic threats. Even if an efficient process can be established, it would be difficult to enforce continued confidentiality in the scientific community.

By contrast, wide data dissemination will attract researchers from other areas to contribute to the field. This is crucial, because new ideas are needed to answer some of the most urgent questions. For example, the specific mutations that we identified suggest that influenza transmission is more complex than anticipated and involves not only the receptor-binding properties of HA but other biological and physical properties.

The redaction of our manuscript, intended to contain risk, will make it harder for legitimate scientists to get this information while failing to provide a barrier to those who would do harm. To find better solutions to dual-use concerns, the international community should convene to discuss how to minimize risk while supporting scientific discovery. Flu investigators (including me) have agreed to a 60-day moratorium on avian flu transmission research because of the current controversy. But our work remains urgent: We cannot give up."

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Communicated by:
ProMED-mail <promed@promedmail.org>

[Yoshihiro Kawaoka is at the University of Tokyo and the University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

My admonition in a preceding post (10) in this thread to "watch this space" has come to fruition earlier than I had expected. - Mod.CP]

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