By Shannon Brownlee

Page 2 of 2 (Page 1)

Henderson worries that an outbreak of smallpox in the United States today could be similarly explosive. "We've looked at what would happen in a small outbreak, 100 cases, in Baltimore," he says. "The first place you would see patients is in the hospital." There would be little to do for them, he says, except provide comfort and IV fluids, and place them under strict quarantine.

To prevent the outbreak from spreading, health officials would need to vaccinate all people with whom the patients had had face-to-face contact, a task that would be more difficult than it was 30 years ago in Africa and on the Indian subcontinent, where most people still traveled on foot.

Today, Americans could be across the country, if not in Paris or Tokyo, within a day after being exposed. By the time they were tracked down, at least some of that first round of contacts would already be sick, says Henderson. It would be too late to vaccinate them.

"Our guess is that in four to five weeks, all 8 million doses of vaccine in the current US stockpile are gone," says Henderson. He tips back in his chair for a moment before continuing: "By the second wave, their contacts will be scattered all over the country. With air travel what it is today, this is a global catastrophe. And if it happens in Brazil, or Mexico, or wherever, it's our problem, too."

How likely, then, is a smallpox attack?

Jonathan Tucker, director of the Chemical and Biological Weapons Nonproliferation Program at the Monterey Institute of International Studies, and author of Scourge: The Once and Future Threat of Smallpox, estimates that the risk is minuscule -- even in light of September 11.

"The number of groups that could use smallpox is very, very small," he says. "They need a motive to cause widespread destruction" that could eventually wash over them and their backers as well. And, he said, "they have to be able to cloak their activities." That is small comfort given what happened at the World Trade Center and Pentagon.

But to use smallpox, they would also need the highly technical expertise for culturing the virus, transporting it either as a powder or suspended in liquid, and then dispersing it into the air for intended victims to breathe. Anti-terrorism experts, and Alibek and Henderson, believe that expertise is available on the international market in the form of out-of-work Russian biologists.

"In bioweapons, the most sensitive product is knowledge," says Alibek. Several dozen of his former colleagues from Vector and other Soviet bioweapons labs remain unaccounted for. In the 1990s, Iranian officials recruited former Biopreparat biologists and engineers, offering as much as $5,000 a month -- a huge sum for Soviet scientists at the time -- to bring their skills to Iran. It's unknown how many, if any, scientists took the offer.

Most would-be terrorists, says Bill Patrick, a former bioweaponeer who worked at Fort Detrick, Md., before the American offensive biological weapons program was dismantled in 1969, are incompetent when it comes to biology.

The Japanese cult Aum Shinrikyo, for example, failed at repeated attempts to release anthrax before finally managing in 1995 to poison several thousand commuters and kill 12 in the Tokyo subway system with the nerve agent sarin.

Only a state-sponsored group or terrorists with a lot of money and connections would be able, in Patrick's opinion, to acquire the smallpox virus and the means for wielding it as a weapon.

No one is certain whether that would include Osama bin Laden, leader of the al Qaeda terrorist group that American officials say organized the September 11 attacks.

But if those hurdles were surmounted, it would be quick work for a decent virologist to produce enough virus for a limited assault.

Bioweaponeers in the US program, says Patrick, had begun weaponizing smallpox before the US biological weapons offensive effort was halted. "We made a beautiful powder for smallpox," he says. "We used chemicals to protect it during dissemination and aerosolization," which is the only effective way to spread it.

How much powdered virus would be needed to infect 100 people with smallpox? Patrick thinks for a moment and then replies: "A gram." That's about the equivalent of a quarter of a teaspoon of baking powder.

When I relate Patrick's recipe for disaster to Jonathan Tucker, he pauses for a moment before responding. "The probability of a smallpox attack is extremely low. But it is not zero. The potential consequences of a deliberate release of the virus are so horrible, it's prudent to take some precautionary measures."

The US government came to the same conclusion in the mid-1990s, when it decided to begin rebuilding the nation's supply of smallpox vaccine. The entire US vaccine stockpile currently consists of 15 million doses of vaccine manufactured 30 years ago by Wyeth-Ayerst Laboratories, though as few as 8 million are thought to be usable. It is stored in an undisclosed, highly secure location, ready to be shipped at a moment's notice.

The method used by Wyeth-Ayerst for making its vaccine was virtually unchanged since the late 1700s, when an English country doctor, Edward Jenner, discovered vaccination. Jenner named his discovery after the Latin word vacca, for cow, because his vaccine was made not from smallpox virus, but from cowpox, a closely related virus that causes a similar disease in cows.

As Jenner refined the vaccine, the virus somehow transformed into a new organism, called vaccinia, whose lineage remains uncertain to this day. Vaccinia might be a crippled form of smallpox virus, or a hybrid between the viruses that cause cowpox and smallpox.

The vaccine sitting in Wyeth-Ayerst's freezers was made by first scratching the bellies of calves and then rubbing some vaccinia virus into the skin. The virus was allowed to thoroughly infect the calves' skin for several days. The animals were then slaughtered, the pustules on their bellies were scraped with a knife, and those scrapings were freeze-dried.

The resulting vaccine, called Dryvax, is basically freeze-dried, live vaccinia virus, mixed with calf pus and a few stray calf hairs.

Dryvax was a great vaccine for its time -- easily transported, stable even in hot climates -- but it would never pass muster today with the Food and Drug Administration. Modern vaccines must be manufactured in cell culture, or cells that live in petri dishes inside the pristine environment of a laboratory, and they are difficult to produce.

Nobody has ever made smallpox vaccine in cell culture, at least not in large quantities.

The US government is about to start. Six years ago, the Department of Defense gave responsibility for producing a vaccine for troops to a Pentagon office known as JVAP, for Joint Vaccine Acquisition Program. JVAP, in turn, contracted with a company called DynPort. Over the next 10 years, DynPort is scheduled to produce for the Pentagon 17 vaccines and antidotes against potential bioweapons, with smallpox being the first in line.

The contract calls for the company to deliver 300,000 doses of smallpox vaccine around 2005, at a cost of more than $900,000.

The Pentagon's smallpox vaccine program is described by many outside observers in less than glowing terms. For one thing, JVAP provided DynPort with a strain of vaccinia that traces its lineage to a vaccine never tested in an actual epidemic.

For another, there are 2.4 million people in the armed forces, not counting their dependents. Three hundred thousand doses of smallpox vaccine won't be nearly enough to protect them, says Peter Jahrling, chief scientific adviser at the US Army Medical Research Institute of Infectious Diseases, at Fort Detrick.

"I don't think anybody was thinking about the fact that this is a contagious disease. They were thinking about projecting forces into hostile areas. The fact that those people might contract the disease and bring it home, that wasn't really factored in."

The Pentagon has not commented on the reasoning behind the decision. But DynPort officials say they can make several billion doses if called upon, at a rate of 700,000 a month. The company is now poised to produce its first test batch of vaccine. The first pilot doses will be ready for testing on humans by March.

Just off I-270, near Rockville, the 60,000-square-foot facility where the vaccine will be produced sparkles with modernity. The working parts of the plant are sealed off from the hallway where outsiders are permitted. Through a large plate-glass window, a visitor can see inside a room where a VW Bug-size stainless steel and glass box sits.

That's where vials will one day be filled with vaccine. There are yellow glove-lined holes in the sides of the box, for workers to reach their hands in and manipulate vials of vaccine. Accordion-pleated hoses, six inches in diameter, hang from the ceiling. The entire place is squeaky clean. Even a fly couldn't get in, since the air flows outward at each door to the building's exterior.

Within a year, DynPort plans to recruit several thousand people, mostly firefighters and Peace Corps volunteers, for a large-scale clinical trial to test its vaccine's effectiveness. The Army has already conducted a small safety trial, inoculating 80 healthy volunteers in Baltimore. Nobody got sick, and everybody developed a painful pustule at the site of the inoculation, just as people who got Dryvax did 30 years ago, suggesting the new vaccine may be as good as the old one.

But there's no way to be absolutely sure, short of an outbreak. The best DynPort will be able to do is compare its version against the old vaccine. The company will inoculate one group of volunteers with the old vaccine and another group with the new. Then it will compare the two, looking for antibodies and immune cells in the blood, and the rates at which the two groups develop pustules.

The government's effort to produce a new vaccine stockpile for American civilians has gotten off to a slower start. It began in 1998, shortly after a public health doctor named Peggy Hamburg arrived in Washington, fresh from doing battle with an epidemic of drug-resistant tuberculosis in New York.

As commissioner of health for New York City, Hamburg had already begun preparing for the possibility of a bioterrorism attack. When she took her new post as assistant secretary for planning and evaluation at the Department of Health and Human Services, Hamburg was concerned that a similar public health effort did not appear to be underway at the federal level.

"When I got to Washington, I called a higher-up at HHS," Hamburg says. "I asked what kinds of special, high-alert activities are we responsible for in the threat of bioterrorism. He was stunned that the department would even need to be involved in such a situation. The department didn't view the issue as theirs."

Soon after, then-HHS Secretary Donna Shalala gave Hamburg responsibility for reviewing the agency's role in protecting the nation from bioterrorism, and coming up with a road map. Hamburg began talking to other agencies, and to security experts from the National Security Council, the CIA and the Pentagon.

She found that few Washington officials had grasped that a biological attack would most resemble an infectious disease epidemic and would require a massive public health effort. Some thought of a biological attack as a version of a bombing.

"Somebody in the FBI told me firemen were going to go in and defuse the pathogen," says Hamburg. Other experts in the intelligence community were mired in a kind of nuke-think, the misconception that preparing for a biological threat is no different from combating nuclear weapons.

A significant turning point came when President Bill Clinton requested that HHS seek emergency funding from Congress to combat bioterrorism. One of the first tasks Hamburg set for herself was rebuilding the civilian smallpox vaccine stockpile.

Initially, she hoped to piggyback on the Pentagon's effort, and that DynPort could simply ramp up production to make an additional 40 million doses for civilian use. "It seemed like a no-brainer," she says. But representatives from HHS, the Pentagon and DynPort found themselves, at a series of meetings, stumbling over one reason after another not to collaborate.

"DynPort wanted to charge us an unbelievable amount of money if we piggybacked," Hamburg recalls. "They claimed they would have to revamp their whole production methodology to make millions of doses."

A former military scientist involved in the negotiations says it was JVAP that balked, because the military did not want its effort to be delayed by joining forces with HHS. A spokesman for the Pentagon says that its vaccine "remains a viable candidate for use in the civilian stockpile" if there are problems with a civilian vaccine.

A DynPort official says the company did not want to bid on the civilian vaccine contract because HHS would not accept liability for civilians who would suffer side effects from the vaccine. For every thousand people vaccinated for smallpox, several will be hit with side effects ranging in severity from giant, spreading pustules to gangrene. In the past, one or two per million died from the vaccination.

After months of wrangling, Hamburg and HHS abandoned the effort to collaborate with the military. Last year, HHS signed a $343 million contract with a different company, OraVax, a small biotech company based in Cambridge, Mass., to produce 40 million doses of smallpox vaccine for civilian use -- an amount that medical scientists believe would be enough to stop an epidemic in the United States.

OraVax, which has since merged with Acambis, is already making pilot-scale lots of vaccine. Originally, it expected to produce its first 10 million doses by 2003, with the final 30 million doses available two years later. Now, that schedule has been speeded up, and by the second half of 2002 a new stockpile of smallpox vaccine will be building up.

Sometime next year, if things go according to the current plan, the last official stocks of the smallpox virus, the contents of the frozen vials in Atlanta and Novosibirsk, will be destroyed. Half an hour at 250 degrees in a sterilizing device called an autoclave ought to do it.

Similar deadlines have come and gone before. For all the dread that smallpox inspires, and the terrifying possibility of its reemergence as a terrorist weapon, scientists, anti-terrorism experts and doctors remain deeply divided over whether it would now be a colossal error to eliminate those vials.

Peter Jahrling believes strongly that the smallpox virus must be preserved to allow scientists to test AIDS-era antiviral drugs against the virus for their potential to treat victims in the event of an outbreak. Since 1995, Jahrling has led a team of scientists from Fort Detrick to spend several months a year in the biocontainment laboratory at the CDC in Atlanta, for such testing.

They now have a handful of candidate drugs that can kill the smallpox virus effectively, at least in a test tube. Jahrling also has recently succeeded in infecting cynomolgus monkeys with variola, producing a disease resembling human smallpox and providing an animal model for testing both antiviral drugs and new generations of vaccine.

The need to test drugs on the actual virus has been a persuasive argument against destruction in the past. The virus was given its most recent stay of execution by the WHO in 1999 in part to give Jahrling's teams more time.

DA Henderson objected vehemently to that delay. "You have to stretch your imagination and your pocketbook to even think an antiviral will work," he says. He argues that developing antiviral drugs for use with smallpox victims will be expensive, time-consuming and ultimately pointless, since there is no way to actually test the drug in humans before an outbreak. In his view, the vaccine vanquished smallpox before; it will do it again.

But Jahrling argues the ring method Henderson used in the past won't work now. Back then, most of the population was already immunized, so it was possible to surround a victim with people who would not get smallpox. That is not the case now. And these days, people are much more mobile. But the most important reason to search for antiviral drugs, Jahrling says, is the emergence of AIDS.

People infected with the AIDS virus have compromised immune systems and will almost certainly resist being vaccinated for smallpox, since the vaccine is a live virus that could kill them. They also will be acutely vulnerable to the smallpox virus itself, which reproduces explosively in the body when its immune system is weakened.

In past epidemics, smallpox patients whose immune systems were already debilitated by another illness became human hot zones. Far more infectious than the average smallpox patient, they sent millions upon millions of viral particles into the air with every breath.

"With a family living in a thatched hut in Africa exposed to one guy shedding smallpox virus, it may be that you can successfully intervene with vaccine four days later," says Jahrling. "But that may not be true in an air-conditioned condo with recirculating air where the exposed person also has HIV and is putting out a hundred times as much virus. We just don't know."

Such uncertainties do not sway Henderson, who wants more than anything to see the official stocks of smallpox virus destroyed. He acknowledges that other countries now have clandestine stocks of virus.

But the World Trade Center and Pentagon attacks have only strengthened his belief that a ceremonial destruction of the official stocks would serve as a moral deterrent to rogue nations that might consider using variola as a weapon.

It is hard to believe that moral suasion alone can stop terrorists. Yet Henderson's wish is understandable. His greatest accomplishment, indeed, one of the great achievements of medical science, could be subverted by a few vials of a tiny organism that were spirited out of Soviet bioweapons laboratories and are now being kept alive in some unknown freezer.

Henderson looks out the window of his office, at a vast, dense cityscape of Baltimore. He turns back toward the room and then says, "I thought both countries could be trusted to keep it under lock and key."

Washington Post October 28, 2001; Page W08