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Landmark study on avian flu transmission gets published

Wednesday May 2, 2012
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After a lengthy debate over a pair of studies that show how the avian H5N1 influenza virus could become transmissible in mammals, and an unprecedented recommendation by a government review panel to block publication, one of the studies will finally and fully be published May 3 in the journal Nature.

The publication caps an extended conversation that pitted infectious diseases experts against flu and public health researchers who argued that publication was not only important, but also essential to informing influenza surveillance and preparedness for a virus that could evolve to infect humans and cause a global pandemic.

"Our study shows that relatively few amino acid mutations are sufficient for a virus with an avian H5 hemagglutinin to acquire the ability to transmit in mammals," Yoshihiro Kawaoka, PhD, a flu researcher with the University of Wisconsin-Madison whose study of H5N1 virus transmissibility was at the center of the debate, said in a news release.

"This study has significant public health benefits and contributes to our understanding of this important pathogen. By identifying mutations that facilitate transmission among mammals, those whose job it is to monitor viruses circulating in nature can look for these mutations so measures can be taken to effectively protect human health."

Kawaoka cautioned there may be other unknown mutations that also enable the virus to transmit in mammals. Continued research to identify additional mutations that have the same effect, and to understand how they work, is therefore critical, he said.

The study, conducted by an international team of researchers led by Kawaoka, a UW-Madison professor of pathobiological sciences and a leading expert on influenza, showed that some viruses circulating in nature require just four mutations to the hemagglutinin protein, which sits on the virus surface and enables it to bind to host cells, to become an even greater threat to human health.

A subset of the mutations identified by the group has, in fact, already been detected in some viruses circulating in poultry flocks in Egypt and parts of Southeast Asia, underscoring the urgency of science-based surveillance, Kawaoka said.

In the Nature report, Kawaoka’s group described a laboratory-modified bird flu/human flu hybrid virus that can become transmissible in an animal model for human infection with only a handful of mutations. Because flu viruses in nature are constantly changing as they circulate and easily swap genes with other flu viruses, the possibility of circulating H5N1 viruses hitting the right combination of mutations and becoming a bigger threat to human health is greater than many experts believed, said Kawaoka, a faculty member in the UW-Madison School of Veterinary Medicine.

"H5N1 viruses remain a significant threat for humans as a potential pandemic flu strain," he said. "We have found that relatively few mutations enable this virus to transmit in mammals. These same mutations have the potential to occur in nature."

Since late 2003, the H5N1 viruses have infected at least 600 humans, mostly in Asia, and killed more than half of the people infected. But the virus, which can be acquired through close contact with domestic fowl, does not easily transmit from human to human, leading some scientists to believe H5N1 posed little threat as a potential agent for a global flu pandemic.

However, research on transmission of viruses from animal reservoirs was deemed a priority by the National Institute of Allergy and Infectious Disease, part of the National Institutes of Health, in a 2006 Blue Ribbon Panel report and by the World Health Organization in its 2009 Public Health Research Agenda.

In addition to demonstrating transmissibility, Kawaoka’s results showed the experimental mutant virus could be controlled by available medical countermeasures. An H5N1 vaccine and oseltamivir, an antiviral drug better known by the trade name Tamiflu, both proved effective.

Whether or not the H5N1 viruses currently circulating in the world can easily acquire the additional mutations needed to cause a pandemic is an open question, according to Kawaoka: "It is hard to predict. The additional mutations may emerge as the virus continues to circulate."

In December 2011, a NIH advisory panel, the National Science Advisory Board for Biosecurity, recommended redacting critical information from the Kawaoka lab’s report and from a similar study conducted in Holland. The unprecedented request was to withhold the methodologies used to make the virus transmissible and to not identify the mutations needed to make the virus transmissible in mammals.

This month, the NSABB reversed itself, citing new information and manuscript revisions that more explicitly state the public health rationale for the work as well as the safety and security precautions in place in the labs in Wisconsin and Holland.

The study is available to read on the Nature website at http://bit.ly/JNPFNx.

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