PHILADELPHIA — PHILADELPHIA - Smallpox once was mankind's most deadly natural enemy, having killed more people in history than any other disease - 300 million in the 20th century alone.
Though it was officially eradicated in 1980, concern over its use as a biological warfare agent has prompted the U.S. government to take an enormous interest in the virus.
"One day there was this slew of poxvirus requests for applications," said Stuart Isaacs, a virologist at the University of Pennsylvania. "I nearly fell out of my chair."
Now, Isaacs and colleague John Lambris have a $1.1 million grant from the National Institutes of Health to study new strategies to fight the virus, as well as ways to prevent complications that could arise if the nation decided to renew mass vaccinations.
Scientists across the country are looking at other ways to deal with smallpox.
The eradication of smallpox, an international effort headed by the World Health Organization, was considered one of the great achievements of the century. Workers traveled from continent to continent, chasing down pockets of the disease and vaccinating everyone within a wide radius. The virus, which needs human hosts to survive, was cornered and eliminated.
Eliminated for 30 years
With smallpox gone from the United States for more than 30 years, mass vaccinations have long since ended.
Today's predicament stems from that - and from one of two small frozen vials of smallpox virus, known as the variola virus, that were kept under lock and key in the United States and the former Soviet Union.
In the mid-1990s, Russian defector Ken Alibek sent up the alarm when he testified that his laboratory in Koltsovo, the State Research Center of Virology and Biotechnology, had turned its small vial of experimental virus into tons of virus that could be used as a biological weapon - and had gone so far as to figure out how to launch it on a missile.
With the dissolution of the Soviet Union, no one can be sure of the location of all of this deadly pathogen.
"It is a very worrisome situation," said D.A. Henderson, director of the original worldwide eradication effort and now the head of the Johns Hopkins Center for Civilian Biodefense Studies in Baltimore. "As we look at the agents that might be used for biological warfare, smallpox is at the top of the list."
The idea is not new. Some records show that the British used smallpox as a germ-warfare agent in 1763 in the French and Indian War. They were thought to have intentionally given smallpox-infested blankets to American Indians, who had weaker resistance to the disease than did Europeans. Some people believe the U.S. government continued that practice into the 1800s.
Even from a terrorist's standpoint, smallpox - one of a class of genetically similar poxviruses that are specific to different animals - would be risky and hard to control. It can be spread to humans through the air, and just a few particles are needed to get the disease. Victims develop a fever and then severe aches and pains. After a few days, spots appear on the skin, growing into painful pustules the size of peas.
In extreme forms of the infection, the pustules cause the skin to slide off in sheets, and can create severe internal hemorrhaging that destroys the lining of the intestines. There is no effective treatment.
30% of victims die
About 30 percent of all victims die, although how the disease kills them is not completely understood. Most of the survivors are left with deep scars.
At the NIH, scientists are looking at ways to protect against both anthrax and smallpox, considered the two biggest germ-warfare threats, said James Meegan, program officer for acute viral diseases. "Of those two, smallpox is the only one that could spread into a worldwide epidemic," he said. "It was one of the biblical plagues."
For the time being, he and other experts agree that the United States is dangerously unprepared. No one born after the mid-1970s has been vaccinated. And since full immunity only lasts for about 10 years, no one is completely safe. "We have at least a generation with no protection at all and an older generation that has waning protection," Meegan said.
Once the eradication was complete, the United States stopped making the vaccine, so all that's left are 10 million doses, stored in a freezer housed in a Wyeth-Ayerst warehouse in Lancaster County. Experts say at least 40 million doses would be needed to protect against a possible regional attack.
The smallpox vaccine dates back to the 1700s. It contains a live virus called vaccinia, whose origin is not fully known. The original smallpox vaccine was simply a dose of cowpox, which appeared to give smallpox immunity to dairy maids who contracted this lesser pox from their infected cows. Over the years that virus may have "recombined" - exchanged genetic material - with actual smallpox, leaving doctors with a new virus, which they dubbed vaccinia.
The vaccinia stored by Wyeth-Ayerst was made by infecting calves with vaccinia and scraping off pustules that formed on their sides. That method, Penn's Isaacs said, "would never get past the rigmarole of [the Food and Drug Administration] today."
With more modern and sanitary methods now available, the government has contracted out the job to replenish the vaccine to a small biotech firm called BioReliance Corp., based in Rockville, Md. Cell cultures would be used instead of calves.
Even if scientists succeed in creating a new supply of the vaccine, however, the live vaccinia virus could itself cause a severe or even deadly infection in those with HIV or other immune-compromising conditions including people with organ transplants who must take immune-suppressing drugs. Some people died from the vaccine in the past, too, but the risk of getting smallpox was far greater than the risk from the vaccine.
One of the goals at the Penn labs is to find ways to protect vulnerable people against the harsh vaccine. The only current treatment for bad reactions to the vaccine is a particular type of immune globulin, said Isaacs, who has long been researching vaccinia and other related viruses as vehicles for numerous vaccines. But immune globulin, a human protein, is in short supply and difficult to make.
Isaacs and Lambris, who is an expert in the interactions of proteins associated with viruses, are looking at the survival mechanisms used by both vaccinia and smallpox. If they can find ways to outwit these viral survival strategies, they might be able to develop a remedy for either a bad vaccinia reaction or, perhaps, a treatment for smallpox itself.
As part of their survival equipment, both viruses carry a protein called VCP. It helps these viruses evade the immune system in organisms ranging from invertebrates to humans.
Oddly, the VCP protein is produced by a viral gene that is similar to a gene found in many mammals, Lambris said. Humans use the gene and its related protein to protect our own cells from getting chewed up by our immune system.
Chances are, Lambris said, that somewhere back in its history the virus actually stole this gene from a host animal and turned it to its own advantage.
If the scientists can find a way to block this protein, they might render both smallpox and vaccinia more vulnerable to the body's immune system.
The other target for Lambris and Isaacs is a protein called B5R, which these poxviruses carry on their surfaces to enter and infect new cells. The researchers are producing what are called monoclonal antibodies - other proteins that are custom-shaped to bind to B5R and disable it.
"These are potential therapeutics to battle the vaccine reactions," Isaacs said, "but they may have application in treatment in smallpox infection itself."