Acambis Inc. is more than halfway along in human trials of a new-generation smallpox vaccine.

The Cambridge, Mass., company's chief scientific officer, Thomas Monath, is senior author of an article in the September 2003 issue of Nature Medicine. It's titled "Clonal vaccinia virus grown in cell culture as a new smallpox vaccine."

"The first point of our finding," Monath pointed out, "is that this is a clonal vaccine. In other words, it represents vaccine that's derived from a single virus particle, whereas the earlier Dryvax vaccine is a mixture of multiple subpopulations. We show in this Nature Medicine paper that some of those pre-eradication vaccines are quite unacceptable. So it's likely that the side effects of smallpox vaccination are due to the emergence in an individual who has higher virulence.

"There's a range of side effects, including encephalitis - one of the most feared. We showed in animal models that our vaccine is less likely - less virulent in terms of ability - to cause that brain infection. By using clonal vaccine, we avoid that problem. But one can't demonstrate that until we have very large and complete clinical trials.

"So far," Monath told BioWorld Today, "we have tested 1,200 human subjects in six different Phase I and Phase II trials, starting about February last year. Phase II tested dosage levels and safety. Healthy adult volunteers entered those trials in exactly the way all new vaccines and drugs are tested. We're at the stage now of going on to Phase III for efficacy. We started with mice because they are traditional and easy, then moved up to monkeys. Challenging those mice with virus that causes a lethal outcome showed us that our clonal vaccine was as protective as Dryvax."

Monath explained the need for undertaking this clonal vaccine project a quarter-century after the World Health Organization proclaimed the total eradication of smallpox, on May 8, 1980. "In that year," he said, "remaining Dryvax vaccine, made by Wyeth Laboratories, was one of the licensed smallpox vaccines used routinely in the U.S. It's still the only vaccine under license. The old stocks, which were made in the 1970s up to about 1982, were owned by the CDC [Centers for Disease Control and Prevention in Atlanta]."

Controversy: Vaccinate Before Or After Attack?

"That stockpile - perhaps 10 million doses - is still held by the CDC. That's the original stockpile for which they are responsible in the event that smallpox came back. But in the present context of viral terrorism, that quantity is far insufficient because today there are 280 million Americans, and in the event of a bioterror smallpox attack there wouldn't be enough vaccine.

"That was the rationale for the contract we won from the CDC to manufacture a new and much larger national stockpile of smallpox vaccine for the purpose of countering the threat of bioterrorism. The challenge after the Twin Towers attack on 9/11 was to make one vaccine dose for every American as quickly as possible. The CDC contract," Monath said, "was for 209 million doses. They now exist physically.

"The public has been informed," he continued, "that a number of rogue states that respond to terrorists have got smallpox material. Officially, the only countries that have it [Variola orthopoxvirus] are the former Soviet Union and the United States. There is public evidence," Monath went on, "that the Soviets did weaponize smallpox, and delivered a variety of these agents into a series of weapon systems - such as warheads on long-range intercontinental missiles, or bombs. Officially, the Russians stated that they dismantled all that, but there is no absolute evidence this is so.

"We don't know what's going on in other countries," Monath added. "You read in the newspapers about Iraq. We haven't found anything there yet. But the smallpox threat is still considered the primary weaponized threat agent, because it's so communicable. It could cause an attack in one place that might lead to a global pandemic.

"There's a lot of controversy," Monath observed, "as to how to use this new vaccine stockpile. The present U.S. policy is not widespread immunization, but to vaccinate individuals at very high risk. Health care workers are most likely the first to encounter patients with smallpox, if there were any events. Only after that would there be a wider use of vaccine - probably in a test burst containing the outbreak by immunizing the population surrounding the cases - so-called ring vaccination.' Then if that fails, one could possibly try to immunize much larger populations - or the entire population. The plans are laid to do that, but the response is scaled to the event. Some people are proponents of vaccinating everyone in advance of a smallpox attack, but this is not the U.S. government's policy."

Scarified Skin Proves Vaccine's Efficacy

"Mechanically," Monath recounted, "to administer the modern vaccine, a device was developed in the 1960s called the bifurcated needle.' It looks like a large sewing needle, and has a two-pronged head, which you dip into the liquid vaccine. Some of that liquid is suspended between the two points of the bifurcated needle. You simply put a drop on the skin and then poke holes in its surface with that two-point needle. That introduces the virus into the epidermis, the most superficial layer of the skin, where there are certain white blood cells that are susceptible to local infection. The virus replicates locally, which leads to immunity. The vaccine comes in a 100-dose vial. You take 100 needles, dip them out and immunize 100 people with every vial. Manufacturing was upgraded in the early 20th century by freeze drying.

"If you're successfully vaccinated," Monath pointed out, "you get a scarified pock pustule on your arm, confirming that you're protected against smallpox for three to five years. That's an observation. There have not been any clinical trials for efficacy. Retrospective analyses in populations have examined the difference between vaccinated and unvaccinated people in the incidence of smallpox during outbreaks. Vaccination proves very effective, particularly if done in multiple immunizations, or relatively recently. But in our trials," he concluded, "we can't look at protection, because there's no more smallpox - thank God!"