07 October 2005
Scientists Report Discoveries in Bird Flu and More Common Strains, October 7, 2005 (Findings show deadly 1918 Spanish flu pandemic arose from bird flu-like virus)
By Cheryl Pellerin
Washington File Staff Writer
Washington – With world attention focused on the possibility of a pandemic from bird flu, scientists are working to understand how the virus works and which viral components might be the best targets for flu drugs.
The World Health Organization has confirmed 116 human cases of bird flu and 60 deaths since December 2003.
Only Vietnam, Thailand, Cambodia and Indonesia have reported human cases of the disease caused by the H5N1 virus subtype, which has resulted in the deaths of an estimated 150 million birds in 11 nations.
Many experts say that it is only a matter of time before the virus mutates into a form that can infect people and be easily transmitted from person to person. Such an outbreak could develop into a global pandemic, potentially taking millions of lives.
DISEASES FROM ANIMALS
Bird flu is just one disease that has arisen in animals and mutated to infect people. HIV/AIDS, severe acute respiratory syndrome (SARS), West Nile virus and the Spanish flu of 1918, which is closely related to avian flu, are just a few examples.
The 1918 Spanish flu was a global disaster, killing 20 million to 50 million people, nearly half of them otherwise healthy adults. Spanish flu was an H1N1 virus subtype, many of which still circulate today.
Researchers have partially reconstructed the Spanish flu virus and discovered in part what made the virus so lethal. Such information is essential for influenza drug and vaccine research.
The research, published in the October 7 issue of the journal Science, says the Spanish flu virus is related more closely to avian flu viruses than other human flu viruses.
Therapies against a new flu strain would need to disarm parts of the virus that are most damaging to the body.
RECREATING SPANISH FLU
To learn which virus components would be the best targets for therapies, Terrence Tumpey of the U.S. Centers for Disease Control and Prevention (CDC) and colleagues recreated the 1918 Spanish flu virus.
Using the virus' genome sequence, Tumpey's group created a live virus with all eight of the Spanish flu viral genes. The genome sequence information was recovered in fragments and lung tissues from three flu victims: two U.S. soldiers and a woman who was buried in the Alaskan permafrost in 1918.
The virus is contained at CDC, following stringent safety conditions designed for flu viruses and heightened security elements mandated by the CDC's Select Agent program.
"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,” he added, “with the hope of designing antivirals or other interventions that would work against virulent pandemic or epidemic influenza viruses."
To make the virus, the researchers used an approach called reverse genetics, which involves transferring gene sequences of viral RNA into bacteria and then inserting combinations of the genes – often after manipulating them – into cell lines, where they combine to form a virus.
Like DNA, RNA is a nucleic acid. One of its main functions is to copy genetic information from DNA and translate the information into proteins.
The researchers, who included Jeffery Taubenberger of the U.S. Armed Forces Institute of Pathology, also produced variations of the virus for comparison, replacing certain Spanish flu genes with corresponding genes from other flu viruses.
They then studied the viruses' effects in mice, chick embryos and human lung cells, and identified the genes responsible for the Spanish flu virus's extreme virulence.
More research is needed on antivirals and vaccines for a future flu pandemic, but Tumpey noted encouraging signs.
The FDA-approved flu antiviral drugs oseltamivir (Tamiflu®) and amantadine (Symmetrel®) have been shown to be effective against viruses carrying certain genes from the Spanish flu virus. Vaccines containing other Spanish flu genes were protective in mice.
FLU VIRUS OVERVIEW
Influenza A and B are the two kinds of flu viruses that cause epidemic human disease. Since 1977, according to the CDC, influenza A (H1N1 and H3N2) and influenza B viruses have been in global circulation.
In 2001, H1N2 viruses (probably a combination of H3N2 and H1N1) began circulating widely. Bird flu subtype H5N1 is an influenza A virus. Influenza A is a constantly mutating virus; influenza B does not mutate as rapidly.
Two kinds of vaccines protect against the influenza A and B strains that sweep populations during the winter months.
Each vaccine contains three flu viruses, representing one of the three groups of viruses that circulate among people in a given year.
Each of the three vaccine strains in both vaccines – one A (H3N2) virus, one A (H1N1) virus and one B virus – represent flu vaccine strains that flu experts think will be the dominant strains that year.
The yearly flu shot prepared and administered in the United States is an inactivated vaccine (containing killed virus) that is given with a needle, usually in the arm. The nasal-spray flu vaccine contains attenuated (weakened) live viruses and is sprayed into the nose.
The flu experts formulate their recommendations for the composition of the vaccine each year after much research and some guesswork.
SEQUENCING THE FLU GENOME
At the University of Maryland, Steven Salzberg and co-authors reported in the journal Nature October 5 that they had performed the first large-scale sequencing of 209 complete genomes of influenza A.
It is a technique the authors think can reduce significantly the guesswork scientists have had to rely on to predict which virus will emerge as the dominant starin in approaching flu seasons.
"This is the first-ever large-scale project to sequence the influenza virus," Salzberg said. "It is already giving us remarkable new insights into the rapid evolution of the flu as it moves through the human population."
The initial results are for the Influenza Genome Sequencing Project, a joint project of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and several scientific partners, to help researchers understand how flu viruses evolve, spread and cause disease.
Until now, viruses have been analyzed using an imprecise technique that cannot keep track of influenza A's rapid genetic changes – a viral survival skill that makes it difficult for scientists to prepare an effective vaccine for coming flu seasons.
FLU SURVEILLANCE
"Our sequencing project will help create a new, far more detailed surveillance system for the flu, to help decide which vaccine will be the right one from year to year," Salzberg said. “It promises to give us a more comprehensive picture of the pattern of transmission through human and animal populations."
The ability of influenza A to mutate its genetic code makes it dangerous. The virus mutates from year to year, making it necessary to update flu vaccines annually.
Less frequently, but with deadly results, the virus goes through a major change called an antigenic shift that creates new strains to which humans have no immunity.
This happens when two distinct flu strains exchange genes and is especially deadly when the exchange occurs between human and bird flu. The result can be a worldwide pandemic.
"Our sequencing project will help create a new, far more detailed surveillance system for the flu, to help decide which vaccine will be the right one each year," said Salzberg.
The result will be a more comprehensive picture of the pattern of transmission through human and animal populations, he said.
"The goal,” Salzberg added, “is to sequence thousands of influenza genomes, including avian influenza. By making the data public immediately, we can speed up the process of understanding how the virus is mutating all over the world."
For more information on U.S. and international efforts to combat avian influenza, see Bird Flu.
