Flu Research Clarifies Secrets of Past Pandemics
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As President Bush considers committing the armed forces to help fight a flu pandemic, researchers have reported major strides in understanding why past pandemics happened, how a new one could happen, and what might be done about it.
In a Rose Garden news conference, Bush suggested that the military could be used to enforce quarantines in the event of an avian flu pandemic.
“I’m concerned about what an avian flu outbreak could mean for the United States and the world,” he said. “One option is the use of a military that’s able to plan and move.”
But other options include understanding how the influenza virus mutates and what makes it deadly, researchers said in three reports this week in the journals Science and Nature—knowledge could allow the design of more effective vaccines, and possibly head off a new pandemic.
The three reports:
- Reconstruct the 1918 flu virus that killed as many as 50 million people worldwide.
- Characterize the genes that allowed the 1918 virus to replicate rapidly.
- Chart the evolution of modern flu viruses year after year - and sometimes within a single flu season.
The research has teased out “some of the secrets that will help us prepare for the next pandemic,” said Julie Gerberding, M.D., director of the CDC in Atlanta.
“Science has to be the foundation of our preparedness,” Dr. Gerberding said at a news conference.
The influenza virus uses RNA as its genetic material. Each viral particle has eight segments of RNA that code for genes. Key genes code for the surface proteins hemagglutinin (HA) and neuraminidase (NA).
Researchers led by Jeffery Taubenberger, M.D., Ph.D., of the Armed Forces Institute of Pathology in Rockville, Md., have spent the past nine years sequencing viral RNA isolated from victims of the 1918 flu.
The sequencing of the last three segments - containing more than half of the 1918 virus’s genetic material - “now completes the sequence of the virus,” said Dr. Taubenberger.
Among other conclusions, he said, the new data imply that the 1918 flu was probably an avian strain, like the H5N1 virus now circulating in southeast Asia, which somehow became adapted to humans.
By contrast, he said, the pandemics of 1957 and 1968 involved flu strains with mixtures of human and avian genes. “This suggests that a pandemic can form in more than one way,” he said.
Using the data generated by Dr. Taubenberger’s lab and a technique developed by researchers at New York’s Mount Sinai School of Medicine, scientists at the CDC were able to reconstruct a living version of the 1918 flu strain.
The decision to create the virus anew was not taken lightly, Dr. Gerberding said, but the need to understand how and why it was so deadly outweighed the risk. The work was done in the CDC’s biocontrol labs and workers were carefully isolated from the virus.
“It’s essential that we study these pandemic strains to better design treatment strategies and develop antivirals and other preventive measures,” said Terrence Tumpey, Ph.D., who led the reconstruction team.
Among the findings:
- The key to the extreme virulence of the 1918 virus was its hemagglutinin and polymerase genes.
- The three polymerase genes were essential for maximal viral replication.
- The virus could grow in the absence of the protease trypsin, providing a partial explanation of why it spread so rapidly.
- Taken together, “the constellation of all eight genes” created an exceptionally virulent virus.
- The rebuilt virus was lethal to mice and embryonated chicken eggs, and grew rapidly in human bronchial epithelial cells.
The antiviral drugs Tamiflu (oseltamivir) and Symmetrel (amantadine) have previously been shown to be effective against viruses carrying the 1918 HA and matrix protein genes.
But the current research may lead to new drugs: “Now we have good targets for the development of new antiviral drugs aimed at decreasing the virulence of highly pathogenic influenza viruses,” said Adolfo Garcia-Sastre, Ph.D., of Mount Sinai. Dr. Garcia-Sastre was one of the developers of the technique that allowed Dr. Tumpey and his team to reconstruct the 1918 virus.
Dr. Taubenberger said the changes needed for the 1918 flu to make the jump from birds to people apparently occurred in every gene. “It’s not a single mutation,” he said. “The entire virus had to adapt.”
That may be some comfort to those watching the H5N1 virus with trepidation, but he added that some parallel changes have already been seen in that strain. On the other hand, the new understanding may provide researchers with a checklist of worrisome mutations they could use to guide preventive measures.
In the other paper in Nature, researchers at The Institute for Genomic Research (TIGR) in Rockville, Md., tracked the evolution of more garden-variety flu strains for five years in New York State, discovering that the virus can re-assort or mutate even during the same flu season.
“This is perhaps the most detailed snapshot scientists have gotten of flu’s movement through communities,” said Elodie Ghedin, Ph.D. In the study, she and colleagues sequenced the genomes of 209 isolates of the flu taken from patients who visited county clinics.
The researchers found at least three distinct subpopulations of the flu virus over the five years, and in some cases, they were circulating at the same time. The variants were even able to swap genetic materials.
One such swap, in the 2002-03 flu season, created a new strain late in the year. Because it wasn’t factored into the vaccine for the 2003-04 season, though, that vaccine was less effective than it might have been, Dr. Ghedin and colleagues concluded.
High throughput genomics techniques, though, could catch such emerging strains in real time, she said, and allow for the production of more effective vaccines.
Even in the absence of a pandemic strain, the flu is a major public health issue. In the U.S., the virus kills about 36,000 people in a typical flu season and sends 114,000 to the hospital.
While the research opens new avenues for science, some greeted President Bush’s musings with dismay. Critics said the idea of using the military for police duties amounted to martial law and was probably illegal.
A better plan would be to improve the nation’s ability to produce vaccines, stockpile antiviral drugs, and refurbish the public health system, Irwin Redlener, M.D., associate dean of Columbia University’s Mailman School of Public Health, told reporters.
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