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Countering Bioterror:
Smallpox, the "King of Bioterrorism"

by Alicia P. Gregory

The United States stopped mandatory vaccination against smallpox in 1972. "The world was declared free of indigenous smallpox in 1980, and it was thought at the time—naively—that smallpox would be eradicated," says Richard Greenberg, a professor of infectious diseases who is leading the first clinical trial of a new smallpox vaccine at UK.

"The Vector Institute in Russia was creating barrels of smallpox at the same time eradication efforts were being conducted by such famous people as D.A. Henderson, head of the World Health Organization (WHO) global vaccination effort.

"Smallpox is the king of bioterrorism," Greenberg says. "It's the ideal agent in that it's highly contagious. It could easily incapacitate an army."

In 1974 he spent three months with the WHO in Bihar, India, vaccinating people against smallpox. For hundreds of years in that country, small groups of people actually worshipped the virus. "They would take their children and infect them (a religious rite called variolation). They thought that if you gave children a small amount of the virus, they would survive the infection and be blessed by the god of smallpox," Greenberg says. "They would harbor someone with smallpox and not report them for fear that the community would be vaccinated and people would not have a chance to be variolated.

"Of course some of the people who were variolated died. And there have been outbreaks of particularly virulent strains of smallpox in India where over 90 percent of the people have died." On average, 30 percent of people who contract smallpox die, and if you visit India today the ravages of smallpox are still visible on the faces of many people in their 50s and 60s—they bear the unmistakable pitted scars.

Twelve days after exposure to the virus, patients have sudden onset of fever, headaches, backaches, vomiting and even delirium. Two days later the smallpox rash appears on the face and extremities. It begins as tiny pink spots, which enlarge into pustules (or pocks) filled with fluid. The pocks dry up and scab off, leaving sunken scars. The scabs themselves are just as contagious as the pocks. There is no effective antiviral medicine to treat smallpox; all doctors can do is give supportive care: IV fluids and antibiotics for secondary bacterial infections.

Recent articles in JAMA, the journal of the American Medical Association, say that if you are immunized within five days of exposure to smallpox, you won't die.

"The data is pretty soft," Greenberg says. "At the time of a mass outbreak, this may not be the case. You might not be killed, but you're going to be debilitated. Not many people can go to work with a 104-degree temperature and sores all over their skin."

"As a physician and epidemiologist, I personally have a problem with telling the people who work in the ER: 'Go ahead and take care of this patient. The CDC will be here within five days to give you your immunization, and you'll be okay,'" Martin Evans says. "Mass vaccination is being debated now on the national level because 200 million doses of vaccine should be available by the end of the year."

These doses are diluted versions of the old vaccine, which Greenberg says is no longer FDA-approved because some of its ingredients have expired and because it was originally grown on the bellies of cows (a practice now condemned since of the advent of mad cow disease). Greenberg also says they're probably "cutting it close" because scientists aren't sure just how much virus you need in each dose for the vaccine to still be effective.

In June 2002, the Advisory Committee on Immunization Practices, which sets U.S. vaccine policy, recommended against vaccinating all Americans against smallpox. The committee's plan calls for states to designate smallpox response teams—doctors, epidemiologists, nurses, lab workers, and law enforcement officers—who would receive the vaccine. Despite criticism, this decision rings true with the known risks.

The vaccine can, on a rare occasion, cause severe rashes, brain swelling and death in infants or in people with skin disorders (like eczema or psoriasis), HIV/AIDS or who are immunocompromised. Experts estimate that 300 people would die from side effects if the whole nation were vaccinated.

Photo of needle

Smallpox vaccination: a small drop is applied on your upper arm, and 15 needle pricks (with a bifurcated needle like the one above) are made into the drop to transfer the vaccine into the skin.

You can't get smallpox from the vaccine, because it's made from a weakened virus called vaccinia (a distant relative of variola, the virus that causes smallpox), but people whose own defenses can't contain it can have adverse reactions. "We give VIG (vaccinia immune globulin) to kill the vaccinia virus in vaccinated people with immune-compromised conditions—HIV, cancer, organ transplants—or who have it spread to an area of skin that can't defend itself," Greenberg says.

"We know what the side effects are. We have almost two centuries' worth of data on what kind of people won't do well if they get vaccinated. Those people shouldn't be involved in clinical research and we screen them out.

"It's important for people who get vaccinated to protect the vaccination site not only from the elements, but from their hands and other people until the scab has fallen off," he says. "This doesn't mean hospital staff can't go back to work after being vaccinated; they just need to take precautions."

UK's Smallpox Trial
A detailed list of these precautions was included in the 16-page consent form the 150 volunteers had to sign to join the smallpox vaccine trial. UK is the exclusive site for this clinical trial and was chosen, according to Terry Irgens, president of DynPort Vaccine Company in Virginia, because of the university's excellent reputation and Greenberg's expertise.

Claire Pomeroy, chief of the Division of Infectious Diseases and associate chief of staff at the Chandler Medical Center, says, "Dr. Greenberg's team has a long track record of doing vaccine studies, and those skills are being brought to bear on this challenge." Greenberg, who conducted his first trial in 1978, has conducted clinical trials at UK since 1989. He currently has two other vaccine trials under way for the prevention of shingles and HIV.

"About a year ago DynPort, the vaccine contractor for the military, wanted to know if anyone in the country was willing to do trials of their new smallpox product to get FDA approval," Greenberg says. "They visited us last summer, and we helped them write the protocols for the study.

"This is probably as important a project as I've ever tackled. Since 9/11 everybody has felt a little smaller, a little weaker, and a little bit more vulnerable to the crazy people on Earth. This is our way to contribute."

Beth Plummer, a clinical researcher at UK since 1989 and Greenberg's "right-hand" in this project, says this is a unique opportunity for Kentuckians. "This is clinical research where the volunteers can gain a tangible benefit from participating—immunity against smallpox. Plus they are contributing to medical knowledge that can get this vaccine approved."

"This study is moving the national agenda forward," Pomeroy says. "No one can take the next step, deciding whether we should vaccinate the nation, until we have proven that we have a safe vaccine to offer people. We need to have these answers. The national spotlight is on Kentucky."

This trial, designed to compare the safety and effectiveness of DynPort's new smallpox vaccine (CCSV) to the existing smallpox vaccine (Dryvax), enrolled 150 healthy, previously unvaccinated volunteers between the ages of 18 and 30. Fifty volunteers were randomly selected to receive the existing smallpox vaccine; the remaining 100 received the new vaccine. All volunteers were followed for 180 days, and a group of 60 volunteers will be followed for three years. Volunteers' blood will be tested for antibodies specific to smallpox at various points throughout the study.

"This is the first time we've followed people to study how long the smallpox vaccination lasts," Greenberg says. Experts estimate that the immunity provided by the old vaccine may last up to 10 years. "We know that if you take cells out of people who've been vaccinated 50 years earlier, they still have a response to the antigens in the test tube, but we don't know how vigorous that response is."

Greenberg says they'll probably have to do two additional clinical trials, involving 4,000 more people, before FDA approval. The next trial will have much looser criteria: people ages three through 75.

What makes this vaccine new is technology: this product is grown in a laboratory versus being grown on the skin of cattle or sheep.

"The vaccinia virus used in the new vaccine originally came from camels and water buffalos. It has been used for human vaccination since the late 1920s," Greenberg says. "The virus is cultivated and harvested from layers of cells using Nunc® cell factories." The result: a "cleaner" vaccine with fewer animal byproducts.

DynPort is working on this vaccine for the U.S. military, and the federal government selected Acambis Corporation in Massachusetts as its contractor for vaccines for the civilian population.

"Our main challenge in recruiting for this trial was educating 18- to 30-year-olds about the importance of this study," Plummer says.

"There is definitely a generation gap between people over 30 and under 30," Greenberg says. "This younger group has no connection with smallpox—grew up in an era with no TV coverage of epidemics—and has no idea what it is."

He says the benefits of developing this vaccine are twofold: it's an obvious deterrent against bioterrorism, and, if more people are vaccinated, it will be easier to manage an outbreak if it happens.

"Smallpox is the ideal weapon to hold this country hostage," Greenberg says. "If we go into a country harboring terrorists, that country could threaten to release smallpox if we invade. Then who would be the bad guy?"

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