Scientists replicate deadly 1918 flu virus

By STEVE MITCHELL, Senior Medical Correspondent

WASHINGTON, Oct. 5 (UPI) -- Scientists for the first time have reconstructed the 1918 Spanish influenza virus strain that caused the deadliest flu outbreak in history in an attempt to ward off another worldwide pandemic.

The Spanish flu outbreak killed as many as 50 million people at the time, and disease experts think another global flu pandemic is inevitable and due to emerge soon. Currently, public health officials are focusing their attention on a strain of avian flu spreading in Asia and Russia, because it appears to be very lethal to people, killing about 50 percent of those it infects.


Nations around the world have begun to stockpile flu medications and have rushed to manufacture a vaccine to fight the avian flu virus, known as H5N1, but so far the pathogen has not shown signs it has adapted to spread effectively from person to person, and only approximately 60 people have been killed by it.


Using a sample of the 1918 flu virus -- which was extracted from a victim who was buried and frozen in Alaskan permafrost -- a team of researchers led by Terrence Tumpey of the Centers for Disease Control and Prevention in Atlanta used a technique known as reverse genetics to reconstruct the pathogen.

The technique, which they describe in the Oct. 7 issue of the journal Science, involves the use of bacteria to splice together the eight genes of the flu virus with genetic material from another virus to make up for portions of the flu genome that are not available.

Combinations of the genes were then inserted into cell lines that could produce the reconstructed virus.

Tests in animal and human cells showed the virus is extremely virulent and capable of infecting several different species, which is unusual for typical strains of the virus that emerge each flu season. The 1918 virus caused rapid death in mice and chicken eggs and grew rapidly in human lung cells.

There is some good news as well. The flu-fighting drugs oseltamivir and amantadine have been shown to be effective against viruses containing some of the same genes found in the Spanish flu virus.


In addition, the scientists identified regions of the virus that account for its virulence that could be a key target for the development of drugs that could fight it off. These regions consist of a gene that codes for the hemagglutinin protein, or HA, that appeared to be involved in causing the severe lung damage reported in people who were infected with the 1918 flu strain and three other genes that code for enzymes known as polymerases that enable the virus to produce copies of itself.

"Given that HA is responsible for so much pathology in the lung, if we could identify the mechanism for how that happens and then block it, perhaps it would be useful for antiviral development," Tumpey said. "With the identification of the polymerase genes contributing to disease, that represents another set of genes that might also be a good target for prophylactic and therapeutic interventions," he said.

The researchers also reported that vaccines containing the Spanish flu HA gene protected mice.

The decision to both generate the deadly 1918 flu virus and publish the research article describing how it was done was made only after much consideration due to concerns that the virus could be leaked out or the information could be used for nefarious purposes. However, federal officials and other scientists agreed that its public health benefits outweighed the risk.


"We felt we had to recreate the virus and run these experiments to understand the biological properties that made the 1918 virus so exceptionally deadly," Tumpey said. "We wanted to identify the specific genes responsible for its virulence, with the hope of designing antivirals or other interventions that would work against virulent pandemic or epidemic influenza viruses," he added.

"We carefully considered the implications of publishing this research and concluded that the knowledge we're gaining to potentially protect public health far outweighs the risk of working with this virus," Donald Kennedy, editor in chief of the journal, said in a statement.

Kennedy noted that several federal officials arrived at the same conclusion, including Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health in Bethesda, CDC Director Dr. Julie Gerberding and Dr. Amy Patterson, who is with the NIH and also serves as spokeswoman for the National Science Advisory Board for Biodefense.

The scientists said the reconstructed virus is kept under tight safeguards at the CDC.

Even in a typical year, influenza can be quite deadly, causing 36,000 deaths and more than 100,000 hospitalizations in the United States. In a separate study that appears in Nature, scientists reported another advance that may help stop the flu bug in its tracks. Scientists at The Institute for Genomic Research in Rockville, Md., sequenced the genomes of 209 flu-virus samples from patients across New York from 1999 through 2004 to help determine how the virus changes over the course of several flu seasons.


"This study demonstrates that genomics can help us better track the flu virus and develop more effective vaccines," said Elodie Ghedin, who heads TIGR's viral genomics lab. "This is perhaps the most detailed snapshot scientists have gotten of flu's movement through communities."

Nearly all the samples consisted of a flu strain known as H3N2. The researchers identified three distinct variants of the H3N2 strain in the New Yorkers and found indications the variants frequently swapped genetic material, which is a concern because this can lead to new strains that may be more deadly or evade vaccines. Such a swapping phenomenon appears to have led to the formation of a strain last year that quickly spread around the globe but emerged too late to be included in the vaccine.

The genomic screening technique used by TIGR also may enable rapid assessment of the effectiveness of a given vaccine.

"Right in the middle of flu season, we could determine which influenza strains are present in the population, which ones are dominant, and how well a given vaccine works," Ghedin said.


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