Bird-Flu Study Shows Virus's Pandemic Potential

Nigeria reported the first human death from bird flu in West Africa on Wednesday, January 31, 2007. In the UK 160,000 turkeys have been ordered culled after 2,500 turkeys were reported infected with the H5N1 virus in this European country., a photo by Pan-African News Wire File Photos on Flickr.

New Bird-Flu Study Shows Virus's Pandemic Potential

By GAUTAM NAIK
Wall Street Journal

In a new experiment showing how the virus that causes bird flu might spark a human pandemic, scientists induced five genetic changes in the bug, transforming it into a type capable of airborne transmission between mammals.

The findings signal how the virus, which has killed nearly 60% of about 600 people known to have been infected in more than a dozen countries since 2003, could pose a much greater public-health risk in the future. Two of the mutations the scientists created already circulate in birds and people, and natural evolution could bring about the remaining three, researchers said.

The findings appear in the journal Science, which on Thursday published several papers and commentaries about the virus—also known as H5N1. The studies were funded by the U.S. National Institutes of Health and other groups.

The genetic-alteration paper in Science is one of two experiments whose planned publication sparked fears it would give terrorists a blueprint for making a biological weapon. The first such paper described an alternative genetic technique for creating a pandemic version of H5N1 and appeared in Nature in May.

A government advisory panel that had recommended against the papers' being made public reversed course after learning about findings in the work that could help health agencies better monitor for bird flu. If officials know which bird-flu genetic signatures to look for, they can obtain swabs from people infected with H5N1 and see whether the critical mutations have started to accumulate.

The flu-surveillance benefit of the research "far outweighs the risk of nefarious" use posed by terrorists or anyone else pursuing a biological-weapons program, said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, part of the NIH. Dr. Fauci and NIH director Francis Collins co-authored one of the commentaries in Science examining the benefits and risks of flu research.

The authors of the latest studies cautioned they can't predict when or if the remaining three genetic mutations might emerge. Nor are these the only possible mutations that could start a pandemic, they said. "We only know that it's within the realm of possibility that the [three mutations] could evolve in a human or other mammalian host," said Derek Smith of the University of Cambridge. I

In one of the Science papers, co-authored by Dr. Smith, a 15-year analysis of surveillance data found that two of the five mutations seen in the lab-engineered viruses had occurred in several existing bird flu strains.

The H5N1 virus can move from birds to people through close contact. But it isn't yet efficient at jumping from person to person, a necessary ingredient for triggering a pandemic.

The latest studies also indicate that the risk of an H5N1-pandemic may be greater than previously believed.

In the experiment published in Nature in May, scientists combined H5N1 and swine flu and came up with a hybrid bug that could leap from mammal to mammal. That experiment was based on the long-held notion that a pandemic strain is more likely to emerge when a flu virus mixes its genes with another virus in an animal host, such as a pig. But one of the Science studies suggests that such "re-assortment" may not be necessary to give rise to a pandemic strain, and that it might emerge from mutations in H5N1 alone.

Scientists first changed three amino acid molecules of H5N1 in a way they believed would boost the bug's affinity for human hosts, then infected ferrets with the mutated virus. Ferrets are a good model because they sneeze like humans and show similar symptoms when infected by flu.

The researchers swabbed the noses of the infected ferrets and used virus samples from their bodies to infect another round of ferrets, thus "passaging" the virus several times through different ferrets. At each stage, they took tissue samples from the ferrets to see how H5N1 was evolving.

"After about 10 passages, we found the virus had acquired the ability to transmit" from animal to animal, said Ron Fouchier of the Erasmus Medical Center in Rotterdam, Netherlands, and study co-author. That suggests that "in humans it would take a low number of transmissions for the mutations to accumulate."

Five mutations gave the virus the ability to jump from ferret to ferret: three of the initial amino-acid changes; plus two that emerged through evolutionary selection in the animals' bodies.

Four of the genetic substitutions were in hemagglutinin, a protein on the surface of H5N1 that helps it to enter host cells. The fifth was in the polymerase 2, a protein that helps the virus replicate its genetic material.

Most of the infected ferrets recovered from the lab-made virus. The animals succumbed only when large doses of the mutant virus were introduced directly into their throats.Experiments also suggested the engineered virus responded to an antiviral drug and to antibodies from ferrets that had received experimental H5N1 vaccines. People infected with H5N1 are treated with antivirals.

Write to Gautam Naik at gautam.naik@wsj.com