Scientists unravel SARS' gene code
Sequencing speeds vaccine research
By Jeremy Manier
Tribune staff reporter
Published April 13, 2003
In a new laboratory at the National Institutes of Health in Maryland, researchers began working in the last few days with the virus thought to cause the respiratory disease SARS in hopes of developing a vaccine for an illness no one yet truly understands.
Although any useful vaccine likely is years away, teams already have started using special tissue cultures to grow a weakened form of the virus, which has not yet been conclusively proven to cause SARS. Making a weakened virus is the first step toward a potential vaccine, NIH officials say.The fledgling vaccine effort seeks to combat a mysterious, deadly disease first identified only last month.
Yet research on the new illness already is advancing at a pace that has left many experts in awe. Federal scientists say they nearly have completed the genetic sequencing of the previously unknown coronavirus thought to cause SARS--the fastest such genetic cataloging ever has been done for a new organism, experts say.
The rapid collection of information could be crucial in designing vaccines for the disease, which has infected more than 2,700 people worldwide and has killed 111. World Health Organization official David Heymann said Friday that SARS' unusual potential for quick spread could make it "the first severe new disease of the 21st Century with global epidemic potential."
With such an urgent threat, researchers can't afford to wait until they're sure of the cause to start formulating vaccines, experts say.
"This is all being done simultaneously, like a center fielder who has to start moving at the sound of the bat before he knows where the ball will be," said Dr. Michael Osterholm, director of the center for infectious disease research and policy at the University of Minnesota.
Much of the early work on a SARS vaccine will be guided by vaccines made for other known coronaviruses--which take their name from their crown-like exterior--that affect animals such as chickens and pigs. Virtually every chicken in the developed world is vaccinated against the coronavirus that causes avian infectious bronchitis.
"They use billions of doses every year," said Dave Cavanagh, a coronavirus expert and vaccine researcher at the Institute for Animal Health in Britain.
But researchers likely will need to break new ground as well. Early genetic sequencing of the suspected SARS virus indicates it has only 50 to 60 percent of its genetic material in common with other related germs.
"It's that new, that we don't recognize any close relationships with existing, well-known coronaviruses," Cavanagh said.
Scientists are not yet certain that the coronavirus causes SARS. Although they have found the virus in samples from many patients, they do not know whether another virus or some other agent is required to produce the illness.
Until enough time has passed to gauge the global spread of SARS, it is impossible to know who would receive any potential vaccine or whether it would be distributed widely, like flu shots.
But experts say a vaccine could be essential if the disease gains a permanent foothold among humans, as many researchers fear. Those experts note that HIV, though far more deadly than SARS, also began as a modest epidemic. In July 1982, one year after that disease had been identified, only 452 AIDS cases had been reported in the U.S.
Some of the steps needed to confirm that the suspect coronavirus causes SARS--short for severe acute respiratory syndrome--also will be crucial in developing a vaccine, experts say.
A key test under way is to experimentally infect animals with the coronavirus and see whether they get SARS, said Julie Gerberding, director of the federal Centers for Disease Control and Prevention. Researchers then must check to see whether the diseased lung tissue contains coronavirus.
Finding an animal that the virus can infect would be central to making a vaccine, Gerberding said. Federal officials said they are looking at mice and monkeys as possible animal models for the disease.
"The fastest way to get from where we are now to a first-generation vaccine is to do the old-fashioned methodology, which is basically growing the virus in a certified cell line, killing it, and then inoculating an animal to see if it offers protection against exposure," Gerberding said at a news briefing last week.
As with other vaccines, the principle behind a SARS vaccine would be to train the recipient's immune system to recognize the invading virus and fight off an infection.
The challenge is making something that is similar enough to the target virus to induce a protective immune response without causing the disease.
Vaccines containing live viruses often yield more powerful protection than killed viruses, though they also bring risks. Cavanagh said only a live-virus vaccine can provide immunity to the coronavirus that sickens chickens.
"That might indicate to us that a live virus would be the one you'd need to get immunity" from SARS, Cavanagh said.
To keep such vaccines from causing disease, researchers grow the virus in a medium that forces it to adapt and lose its virulence. For example, scientists have made a live influenza vaccine by growing flu virus in a relatively cold environment, so the virus can survive in the respiratory tract but not in the warmer body tissues where it causes the most damage.
But such viruses, also called live attenuated vaccines, carry the risk of changing back into a dangerous form. That's a distinct threat with coronaviruses, which tend to mutate and recombine their genes frequently, increasing the chance that some variant will be virulent.
"It's an ever-present downside to making a live attenuated vaccine," Cavanagh said. "Killed vaccines are much safer, but with respiratory infections, killed vaccines tend not to work."
If a live vaccine turns out to be the best option for preventing SARS, officials will have to consider such risks before using it, Cavanagh said.
"You don't want to create a new problem in your attempt to solve a problem," Cavanagh said.
Despite the constant mutations of coronaviruses, it may be possible to develop a SARS vaccine that would protect against a broad variety of strains, said Susan Baker, a coronavirus researcher at Loyola University Medical Center.
The vaccine would need to contain proteins or other parts of the virus that do not vary from one strain to another, thus producing a widely effective immune response.
"What we'd like to do is find a region [of the virus] that's more conserved, that can't change, and immunize against that region," Baker said.
Baker and other researchers said they are eagerly awaiting the completion of genetic sequencing for the SARS coronavirus for clues about where the new germ came from.
Specifically, they will be looking for areas of the sequence that appear transposed, or recombined, from another coronavirus--possibly one that originally infected only animals. Scientists already have sequenced the genes of more than a half-dozen other coronaviruses that could be used for comparison, including one that causes about one-third of common colds.
Understanding such relations could offer insights into the pathology and treatment of SARS, Baker said.
Further down the road, experts said, it may be possible to develop genetically modified versions of the SARS virus for use as vaccines. Cavanagh, who has worked on such vaccines for animal coronaviruses, said the experimental approach has potential advantages over the use of live vaccines.
Increasing knowledge about how genes function makes it possible for scientists to find all the genes that make a virus dangerous and remove them.
Once a virus has been so dramatically modified, Cavanagh said, "the chances of it mutating back to a pathogenic form are much less."
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Researchers work toward SARS vaccine
Federal researchers could examine existing vaccine methods in an effort to create one that would control the mystery illness called severe acute respiratory syndrome (SARS). Experts believe that the new disease, which was discovered in Asia and has spread around the world, is caused by a previously unknown form of coronavirus.
VACCINE METHODS
VACCINE TYPE: Subunit
HOW IT'S MADE: Copies of the virus are grown, then dissolved into harmless pieces. The virus' protein coat is removed.
HOW IT WORKS: The vaccine will stimulate the immune system to attack the protein coat.
VIRUSES IT'S USED ON: Used for hepatitis B, influenza
VACCINE TYPE: Live-attenuated
HOW IT'S MADE: Growing live virus in a special medium produces weakened copies of the virus.
HOW IT WORKS: The body's immune system learns to recognize the virus.
VIRUSES IT'S USED ON: Used for measles, mumps and rubella in humans, infectious bronchitis in chicken
VACCINE TYPE: Naked DNA
HOW IT'S MADE: Genetic material from the germ is removed and modified so it contains only a fragment of its original genetic material.
HOW IT WORKS: The body's own cells will use the "naked" DNA to generate antigens for the disease.
VIRUSES IT'S USED ON: Being tested for HIV, malaria, influenza
VACCINE TYPE: Genetically engineered
HOW IT'S MADE: A virus' key gene is snipped out, allowing the organism to induce immunity but not disease.
HOW IT WORKS: The modified germ has enough in common with the pathogen's original form to create immunity.
VIRUSES IT'S USED ON: Still being tested
Sources: Centers for Disease Control and Prevention; Princeton University; pbs.org
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