Bird Flu Research to Be Published in Full

February 23, 2012 Project Director

Influenza ward, U.S. Army, Base Hospital No.88, Langres, France. 1918 or 1919, NLM.Recent furor around research on the H5N1 virus strain that has caused influenza in birds and rare cases of severe influenza in people may have died down after last week’s meeting of a group of experts assembled by the World Health Organization. They recommended that two different groups involved in what has come to be seen as controversial research should publish their findings in full. A halt on the bird flu research in question and publication of those data is still in place, however, and will likely last a few months longer.

To date, this H5N1 virus is not efficiently transmissible among humans – in fact, humans generally have been infected only after close contact with infected poultry. But virologist Ron Fouchier at Erasmus Medical Center in Rotterdam manipulated the virus so that it became easily transmissible between ferrets. (Ferrets are a useful standin for humans in influenza studies.) A team headed by Yoshihiro Kawaoka at the University of Madison-Wisconsin accomplished similar results: both papers were under review for publication by science journals before the controversy developed.

The U.S. National Science Advisory Board for Biosecurity in December, along with many other U.S. biosecurity experts, called for the papers to be published only after redaction of key details for security reasons. The NSABB cited concerns that bioweapon developers could reproduce the mutations that made the virus more easily transmitted, and others warned about the potential for the mutated virus to escape from a lab and cause widespread disease. The NSABB recommended that details about the experiments be provided only to approved researchers to avoid widespread reproduction and study of the mutated virus. No mechanism, however, currently exists to determine who would merit approval, or indeed which group would have the authority to issue such approvals.

Many scientists decry what they see as censorship and overreach of security groups. Some see the possibility of malevolent use of the virus as close to impossible; or, as immunologists Peter C. Doherty and Paul G. Thomas wrote in BMC Biology, “Quite frankly, as a tactical, strategic or bioterror weapon, our guess is that 'flu makes little sense….The overwhelming probability is that any 'human pandemic' H5N1 variant will come out of nature, not a laboratory.”

With its recent pronouncement, the group of experts assembled by the WHO has sided against the NSABB and with those calling for openness and free dissemination of the study details. They did, however, ask that the data be published only after 1) a communication plan is developed that addresses public understanding of the issues and 2) the biosafety and security aspects of the studies are reviewed. Presumably, the studies will be published by Science (the Fouchier paper) and Nature (the Kawaoka paper) after those conditions are met.

In support of full publication and continuation of experiments with mutated H5N1, Fouchier, the researcher in the Netherlands said, in an interview for the blog “Science Insider,”

“…[W]e thought there were a number of things that might make an avian influenza virus transmissible between mammals. At the time, that was purely hypothetical. We said the virus probably has to do better in the upper respiratory tract than deep inside the lungs; it must bind to certain mammalian receptors; it has to reproduce in large amounts, to increase chances of transmission; it has to be stable in small droplets, and so on. Now that we have these mutations, we can look at each of these steps to see if they occur. And you will see that for each step, there are multiple options, more possible mutations than just the ones we have found so far. So that's very important.  Something else that has to happen is evaluating existing vaccines and antiviral drugs. Until now, we only have looked in vitro whether these virus's characteristics match existing vaccine strains, and whether the virus is sensitive to antiviral drugs. We haven't tried it in our animal model yet.”

Though he advocated for redaction of key details of the study, Anthony Fauci, MD, head of the National Institutes for Allergy and Infectious Diseases and member of the NSABB, agrees that the research needs to go forward to aid pandemic preparedness. Indeed, Kawaoka stated in an interview with Bloomberg Business Week that some of the mutations created or observed by the two teams have already emerged naturally in circulating H5N1 viruses. Study on the mutations could give scientists a head start on vaccines and antiviral treatments.

In a study whose results were released just today, several researchers have attempted to address the matter of the case fatality rate of bird flu. Media accounts, and researchers themselves, often state that the fatality rate for infection with the virus is nearly 60%. This rate is drawn from the 573 documented cases of H5N1, 58.6% of which have resulted in death. (This is far higher than the 2%-3% case fatality rate of the 1918 Spanish Influenza pandemic that killed more than 40 million people.) That rate of nearly 60%, however, is pinned to a highly specific case definition usually involving a very sick patient who is ill enough to be hospitalized, and from whom the virus is isolated or who shows obvious serological evidence of infection. Some experts argue that the case definition likely excludes anyone who has asymptomatic illness, mild illness, or illness not resulting in hospitalization. Researchers at Mount Sinai School of Medicine hypothesized that the case definition selects for cases that are more likely to result in poor outcomes and does not account for many other, less severe infections. Their review of 20 studies shows that 1-2% of participants had evidence of prior H5N1 infection, and they suggest that the true fatality rate is likely to be lower than generally reported (Wang, ScienceExpress). Even so, the case fatality rate from H5N1 is likely to be far higher than with any other influenza that has circulated in the past.

Continued research into H5N1, including the mutations that allowed the virus to be easily transmissible between mammals, may lead to better surveillance, quicker diagnostic tests, and more effective vaccines. In the event of more widespread disease, these tools will likely be crucial to tracking and controlling disease spread.

Sources and Further Reading

Bennett S. Bird flu research to stay on hold as papers to be published. Bloomberg Business Week. February 21, 2012.

Brundage JF, Shanks GD. Deaths from bacterial pneumonia during 1918-19 influenza pandemic. Emerg Infect Dis [serial on the Internet]. 2008 Aug.

Doherty PC, Thomas PG. Dangerous for ferrets: lethal for humans? BMC Biology. 2012, 10:10.

Enserink M. Flu researcher Ron Fouchier: “It’s a pity that it has to come to this.” Science Insider, January 20, 2012.

Grady D. Despite safety worries, work on deadly flu to be released. New York Times. February 17, 2012.

Ledford H. Call to censor flu studies draws fire. Nature. 481, 9-10 (January 5, 2012).

Palese P. Don’t censor life-saving science. Nature. 481, 115 (12 January 2012).

Wang TT, Parides MK, Palese P. Seroevidence for H5N1 influenza infections in humans: meta-analysis. ScienceExpress. 23 February 2012

Technical consultation on H5N1 research issues: consensus points. WHO Headquarters. 16-17 February, 2012.

WHO case definitions for human infections with influenza A(H5N1) virus.

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