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H5N1 Paper Finally Published

Megan Scudellari

Concluding a 7-month controversy, Science publishes a paper detailing how the bird flu virus can be modified to spread through the air among ferrets.

Last December, Ron Fouchier and colleagues at the Erasmus Medical Center in Rotterdam, the Netherlands, submitted a paper to Science detailing their creation of a mutant strain of the avian H5N1 virus that could spread between ferrets via airborne transmission. At the same time, Yoshihiro Kawaoka and his team at the University of Wisconsin, Madison, submitted similar research to Nature. A contentious debate ensued.

Last December, Ron Fouchier and colleagues at the Erasmus Medical Center in Rotterdam, the Netherlands, submitted a paper to Science detailing their creation of a mutant strain of the avian H5N1 virus that could spread between ferrets via airborne transmission. A contentious debate ensued. Source: Science

Because H5N1 is highly pathogenic in humans, killing over 60% of individuals that become infected, the research has the potential to be used as a biological weapon, some scientists and policymakers argued. The journals held off publishing the papers while the National Security Advisory Board on Biosecurity (NSABB), a US panel of scientific and safety advisors, reviewed the work.

Within weeks, the NSABB recommended that portions of the papers be redacted prior to publication after finding “the potential risk of public harm to be of unusually high magnitude." Shortly after that declaration, 39 influenza researchers around the world, including Fouchier and Kawaoka, declared a 60-day moratorium on bird flu transmission research. The World Health Organization subsequently extended that moratorium.

Then, on March 30, after a meeting with flu experts and the papers’ authors, the NSABB reversed their decision. As a result, Kawaoka’s study was published online on May 2 in Nature, and today Science published the Fouchier paper in full(1, 2). In the paper, publically available for the first time, Fouchier and colleagues describe five small changes, mutations in the DNA, that are enough to make H5N1 transmissible in the air between mammals.

The findings are powerful evidence that there is a “real potential” for the bird flu virus to evolve into a pandemic-causing form, said Bruce Alberts, editor-in-chief of Science, at a teleconference June 20 announcing the publication. “It’s our hope that [this] publication will help to make the world safer, particularly by stimulating many more scientists and policymakers to focus on preparing defenses,” he added. The published text retains all the original methods and results, Fouchier confirmed during the announcement, though wording was added to better explain the benefits and risks of the research.

To study how avian influenza viruses might become airborne between mammals, Fouchier and colleagues first genetically modified the virus. After surveying the literature for genetic changes that appeared in the 1918, 1957, and 1968 pandemics, they introduced three of these mutations into the H5N1 virus, but found that the mutated virus did not replicate or transmit effectively between ferrets—a popular mammalian model of flu, as ferrets show similar flu symptoms to humans.

The researchers applied the virus directly into the noses of ferrets, waited a bit, then swabbed the animal’s noses and used those samples to inoculate more ferrets, “passing” the virus from one animal to another. “Already, after a few passages, we found that the virus replicated better in the upper respiratory tract of ferrets,” said Fouchier. After 10 passes, the virus had acquired multiple new mutations, and with them, the ability to transmit between ferrets via aerosol or respiratory droplets. Although airborne, the virus was not lethal to the ferrets, Fouchier emphasized.

The team then analyzed the final viral DNA and identified several previously unknown mutations that allowed the virus to transmit in the air. “As little as five mutations, but certainly less than 10, are sufficient to make H5N1 virus airborne,” said Fouchier. All the mutations have been detected in the virus in nature, just never together, said Fouchier.

Kawaoka’s paper, published a month earlier in Nature, identified similar mutations that cause airborne transmission, but those researchers created a chimeric virus by combining a mutated hemagglutinin protein with genes from the H1N1 virus, which sparked a pandemic in 2009.

The research proves that H5N1 should not be taken lightly, and surveillance programs can now watch out for the newly identified mutations in the wild, in the hopes of stopping a pandemic before it starts. Fouchier’s team also tested a current antiviral and an H5N1 vaccine against the mutated virus, and found that both treatments were effective in ferrets.

The publication of Fouchier’s paper in Science was accompanied by a study by Derek Smith and colleagues at the University of Cambridge assessing the virus’ potential to evolve and transmit via the air naturally. The issue also included six commentary articles on the topic, including suggested strategies on how to prepare for an H5N1 pandemic from vaccine manufacturers (3, 4).


1. Imai, M., et al. 2012. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486:420–428.

2. Herfst, S. et al. 2012. Airborne transmission of influenzaA/H5N1 virus between ferrets. Science 336:1534-41.

3. Russell, C.A., et al. 2012. The potential for respiratory droplet–transmissible A/H5N1 influenza virus to evolve in a mammalian host. Science 336:1541-7.

3. Rappuoli, R., et al. 2012. Influenza: Options to improve pandemic preparation. Science 336:1531-3.

Keywords:  H5N1