Controversial bird flu research at the University of Wisconsin-Madison finally was published Wednesday in the journal Nature after a months-long international debate about its value to preparedness vs. the risk that key details could be used by terrorists to create a biological weapon.
The study, conducted by an international team of researchers led by the UW's Yoshihiro Kawaoka, shows that relatively few mutations in nature would enable the bird flu virus, also known as avian influenza or H5N1, to be transmissible in mammals.
An advisory panel for the National Institutes of Health in November recommended redacting critical information from the UW study and a second bird flu study done in Holland to protect against bioterrorism. It was an unprecedented request to withhold the methodologies used to make the viruses transmissible and not to identify mutations needed to make the viruses transmissible in mammals.
The board reversed itself last month, citing new information and manuscript revisions that more explicitly state the public health rationale for the work and safety and security precautions used in the research labs in Madison and Holland.
Since late 2003, H5N1 viruses have infected at least 600 humans, mostly in Asia, with about half dying from the disease.
But the virus, acquired through close contact with domestic fowl, does not easily transmit from human to human, which has led some scientists to believe H5N1 poses little threat as a potential agent for a global flu pandemic.
Flu viruses in nature are constantly changing and easily swap genes with other flu viruses, Kawaoka's research noted. So the possibility of 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 professor of pathobiological sciences and leading expert on influenza in the UW-Madison School of Veterinary Medicine.
The study by Kawaoka's group identified the mechanism by which the H5N1 virus transmits.
"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 said in a statement released Wednesday through the UW.
The research also may help governments in some countries justify the significant economic hardship imposed by the mass culling of poultry flocks when potentially dangerous mutations are identified in circulating H5N1 viruses, Kawaoka said.
According to the UW news release:
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 a greater threat to human health.
A subset of the mutations identified by Kawaoka's team 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 says.
Kawaoka cautions there may be other unknown mutations that also enable the virus to transmit in mammals. It's critical to continue research to identify additional mutations that have the same effect, and to understand how they work, he says.
Whether the H5N1 viruses circulating in the world could 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."
The virus engineered in Kawaoka's lab was of low virulence, not deadly. The virus was a laboratory-modified bird flu/human flu hybrid that can become transmissible in an animal model for human infection with just a handful of mutations. The hybrid was less pathogenic than a pandemic H1N1 virus.
Kawaoka's study involved ferrets, commonly used for influenza research. When infected with the flu virus, ferrets sneeze and cough like humans, generating small droplets that can transmit the virus from one animal to another. The ferret respiratory tract also has cellular features similar to those found in humans.
In addition to demonstrating transmissibility, Kawaoka's results showed the experimental mutant virus could be controlled by available medical countermeasures. An H5N1 vaccine as well as oseltamivir, an antiviral drug better known by the trade name Tamiflu, both proved effective, Kawaoka found.
The other bird flu study at the center of the international debate, from Holland, was cleared last week to be published in the journal Science, now that the researcher has an export permit from the Dutch government. It's unclear when that study will be published.
Both studies faced unprecedented government scrutiny and were funded by the National Institutes of Health.
Research on transmission of viruses from animal reservoirs has been deemed a priority by the United States National Institute of Allergy and Infectious Disease and the World Health Organization.
The UW research was conducted under strictly controlled conditions with multiple layers of safety and security precautions, according to the university.
Research involving agents such as highly pathogenic influenza viruses undergoes rigorous federal and institutional oversight including frequent and unannounced inspections. The laboratories such as the one where the new work was conducted are designed to strict specifications and operated to ensure safety, the university said.
The UW study involved scientists from the University of Tokyo, where Kawaoka is also on the faculty, Kobe University and Chubu University.
WHAT IT MEANS
The research may help governments in some countries justify the significant economic hardship imposed by the mass culling of poultry flocks when potentially dangerous mutations are identified in circulating H5N1 viruses.
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