Clear and Present Danger

We thought we'd wiped out smallpox, a highly contagious disease that has killed countless millions. Could an ancient scourge, in enemy hands, come back to haunt us?

By Shannon Brownlee

Sunday, October 28, 2001; Page W08

Ken Alibek hardly seems like the sort of fellow to have overseen the development of the world's most terrifying biological weapon. A short, stout, moon-faced man in his early fifties, Alibek has a shock of black hair cut straight across his brow, like a schoolboy, and a whispery voice clotted with the round vowels and rolling R's of his native Kazakhstan. He scurries along a hallway of George Mason University, where he is a research biologist, trying to procure a cup of coffee for a visitor. "I have a very important question," he says to a colleague. "Do you know where I can get a clean cup?"

A little more than a decade ago, Alibek was still Kanatjan Alibekov, creator of the world's most potent strain of anthrax bacteria, and second in command of Biopreparat, the Soviet Union's vast biological weapons program. The U.S. intelligence community knew nothing of Biopreparat until 1989, when a mid-level Soviet biologist under Alibek named Vladimir Pasechnik defected to Britain. Pasechnik detailed for British intelligence officers the existence of clandestine laboratories, scattered around the Soviet Union, devoted to developing such potential biological weapons as anthrax, Marburg virus, tularemia, Q fever, plague, Ebola and, most appalling of all, smallpox.

After British agents passed along Pasechnik's report, the American and British ambassadors in Moscow accused the Soviet Union of violating the 1972 Biological Weapons Treaty, which banned the production and use of biological weapons. The treaty had been signed by 143 nations, including the United States and the Soviet Union. After some tense negotiations and phone calls among British Prime Minister Margaret Thatcher, President George H.W. Bush and Soviet leader Mikhail Gorbachev, a team of American and British biologists flew to Moscow in January 1991 for the first of several mutual inspections. They found hints of biowarfare research at a number of Soviet laboratories.

Ken Alibek: "When I was talking, people would say, this is Ken's sheer fantasy." D.A. Peterson - The Post But the full scope of the Soviet violation was not known until the fall of 1992. A year earlier, as part of the mutual inspections, Alibek and 12 other Soviet scientists and military officials came to the United States to inspect sites their reconnaissance experts had told them were American biowarfare facilities. The Soviet contingent found abandoned warehouses, with grass growing at the entrances, and military labs devoted to defensive research, such as finding new vaccines for biological agents. Alibek realized that Soviet intelligence was either incompetent or lying, and that his American hosts were telling the truth: The United States had long ago abandoned offensive bioweapons research. He and his family defected shortly thereafter, in October 1992.

In a building off I-66, in Virginia, intelligence officers and officials from the departments of State, Agriculture and Defense quizzed Alibek for nearly a year. At first, his American handlers found his reports almost too incredible to be believed. "When I was talking, people would say, this is Ken's sheer fantasy," says Alibek. Biopreparat, he told them, could mix up batches of deadly viruses in 95-gallon bioreactors, tanks big enough for a microbrewery. Soviet biologists, he said, had modified pathogens to survive delivery by warheads. Engineers had devised a platform that could release canisters of liquid or dry pathogens, smallpox among them, as a missile moved over successive targets.

Slowly, the Americans began to understand the gravity of the security risk Alibek was describing. Smallpox, a savage disease that had killed countless millions throughout history before being eradicated more than two decades ago, once again loomed as a potential threat.

Bioterrorism experts now believe the smallpox virus exists in clandestine biowarfare laboratories in at least three, and possibly more, countries. The U.S. government has a list of nations that it suspects are harboring secret stocks of the virus, or have tried to buy or steal some. That list is classified, but several public health doctors and virologists who have been briefed say that, along with Russia, it includes Iraq and North Korea. Civilian bioterrorism experts and the press have speculated that China, Libya, South Africa, Israel and Pakistan may also be on the list.

Some of these nations are also suspected of harboring and aiding terrorist groups, including those believed to be involved in attacks on Americans abroad, and now at home. Indeed, when the World Trade Center buildings were destroyed last month, officials feared that the terrorists also might have unleashed biological or chemical agents into the smoking ruins. It turned out not to be the case, but the risk of bioterrorism was no longer merely academic. What would we do -- could we do -- if smallpox were the terrorists' next weapon of choice?

Before vaccination was invented, in 1796, smallpox epidemics could change the course of history, killing as many as half their victims and crippling entire civilizations. The Aztecs, for instance, were defeated in the 16th century not so much by Hernando Cortes's comparatively puny army as by the smallpox the Spaniards inadvertently brought with them. In the 20th century, smallpox killed 300 million people, far more than all of the century's wars combined.

The disease is caused by a virus known as variola, from Latin for "speckled." The first signs of illness come 10 days or so after infection, with a splitting headache, backache, vomiting and raging fever. Just as the fever wanes and the patient starts to feel better, the first red spots appear on the face and extremities. The rash spreads rapidly as the spots turn to lumps, called pustules, which fill with an opalescent fluid that seeps from capillaries, making them feel hard, or "shotty," as doctors describe them, like BBs embedded just under the skin.

Smallpox causes unspeakable misery. Layers of skin separate as fluid fills the spaces between them. Pustules line the nose, mouth and throat, making swallowing exquisitely painful. Sometimes the lesions are so numerous, the body takes on the texture of a pebbled walkway, and sheets of skin may slough away at the slightest touch -- a blanket, or a nurse's fingers taking a pulse. In fatal cases, death comes within 10 to 16 days, from organ failure, or maybe pneumonia, or possibly an overreaction of the immune system. Nobody really knows precisely how variola kills.

The planet has not seen a case of smallpox since 1977, two years before the disease was declared eradicated after an intensive 11-year vaccination campaign by the World Health Organization. Within a decade, scientists around the world had turned over their remaining stocks of the variola virus to two designated facilities for safekeeping. One of these sites is the Centers for Disease Control and Prevention, in Atlanta. Variola's other official resting place is inside a freezer in a Russian laboratory known as Vector, outside Novosibirsk, Siberia.

Several times over the years, WHO officials have scheduled and then called off the destruction of the two legitimate stocks of the virus as scientists debated the wisdom of intentionally destroying a species and doctors argued for eliminating it. Alibek's revelations, along with the 1991 collapse of the Soviet Union and end of its tight system of political control, have made such lofty debates irrelevant. There is no longer any question that clandestine stocks of the smallpox virus exist; the only unknown is who has them and whether they'd be cruel enough to use them.

A biological attack with smallpox virus -- though perhaps not as unlikely as it was just weeks ago -- is still a "low-probability, high-impact" event, in the parlance of security experts. That means it probably won't happen. But if it did -- through, say, infected carriers on suicide missions or release into a building ventilation system or, quite unlikely, from a crop-duster -- the result could be a catastrophe. Variola kills between 10 and 40 percent of its victims. There is no treatment for the disease, and routine vaccination ceased around the world after the disease was declared eradicated. Americans born before 1972 can probably run their fingers over a dime-sized scar on their arms or legs, where they were immunized as children. That vaccination's ability to protect began to wane within a decade after it was given.

Just how vulnerable Americans may be was brought home in a two-day simulation exercise held at Andrews Air Force Base in June. It showed quite clearly that federal and state officials would be ill-prepared for a rogue attack using smallpox. The exercise began with 24 simulated cases. It ended two imaginary weeks later, with the nation's stockpile of vaccine exhausted, 15,000 people infected and 1,000 dead, and the expectation that every two weeks after that would see a tenfold increase in cases.

Jeff Koplan in Bangladesh in 1973 during the campaign to eradicate smallpox. Courtesy Centers for Disease Control and Prevention Other models starting with just 100 smallpox cases in an American city predict the disease would become a worldwide conflagration in as little as a year, unless a massive immunization campaign were mounted to stop it. There is not enough vaccine on hand for such an effort. About 60 million doses of vaccine exist worldwide, only a fraction of them in the United States; experts estimate that blocking the spread of smallpox released in a single bioterrorism event in a single American city would require a minimum of 30 to 40 million doses. Which means that unless something is done, a lot of Americans -- and others -- would be vulnerable.

Five sets of locked doors and an eighth of a mile of hallways lie between the main entrance to the Centers for Disease Control and Prevention and the biocontainment laboratories where variola major lives in suspended animation inside a locked stainless steel freezer. The freezer contains some 400 different strains of the virus, taken from patients afflicted with smallpox during the last century. Each sample of virus is trapped inside a bullet-shaped lump of cloudy, frozen fluid. Together, the vials take up a space no bigger than an oven, but their contents could infect every human being alive.

The reality of what that means is not lost on Jeff Koplan, who has served as the CDC's director since 1998. A tall, balding, wiry man in his fifties, Koplan bears a strong resemblance to Dick Cavett, and has a voice to match. In 1973, when he still sported a wild mane of strawberry-blond hair and a beard, Koplan was sent by the CDC to Bangladesh, to test a drug that some thought might be effective against smallpox. By that time, Europe and the United States had already eliminated it. The only remaining pockets of disease were in Africa, South America and on the Indian subcontinent. To find enough patients for his experiments, Koplan headed for Dhaka, Bangladesh, where he was given an empty ward in one of the city's hospitals.

"When I say empty ward, it was empty, it was a concrete shell," he recalls. "I hired an ex-sergeant from the Pakistan army, with a curled mustache and military demeanor, as my right-hand man. We cajoled and borrowed and found some beds, found a place with running water to use as a lab, moved the beds in." City officials and international health workers steered patients to Koplan's ward, where he gave half the patients the experimental drug, and half standard care, which consisted of trying to keep them comfortable and providing IV fluids and antibiotics for secondary bacterial infections.

The drug was a flop, but Koplan learned to read his patients' futures in the rashes that appeared on their skin. The chances of dying from variola major, the most common form of the virus, depend upon how big a dose of virus a victim receives, and how vigorous a defense his or her immune system mounts. Most of the patients Koplan saw developed the form of the disease doctors call "discrete" -- the pustules were separated from one another by unaffected skin. Patients usually survived, though they were scarred for life.

In more severe cases, called "confluent" pox, the pustules were so numerous they ran together on the skin, and the patients puffed up horribly with fluid. "I have pictures of people who on admission are recognizable, with a rash," Koplan says. "Then five days later they're unrecognizable -- they look like they have been burned. They couldn't take anything by mouth. They were comatose. They were extremely uncomfortable." Many of those patients died, usually after suffering for 10 days to two weeks.

Koplan saw two other types of smallpox that were considerably less common, but which killed patients far more efficiently. "Flat" pox, a form of the disease in which the pustules never raise above the skin, kills 75 percent of patients afflicted with it.

"Hemorrhagic" smallpox, or black pox, is mercifully the rarest form of all. Invariably fatal within days after the fever begins, black pox causes blood vessels throughout the body to leak blood, which seeps into the mouth and gut and under the skin, where it leaves dark, bruise-like blotches. Even the whites of the eyes darken with blood. Unable to move or speak, patients with hemorrhagic pox often are aware of what is happening to them almost to the point of death.

"I had one patient in our study group who was hemorrhagic," Koplan recalls. "When I did an exam on him, I remember, it was 5 or 6 in the evening, and I could talk to him. He didn't have much in the way of skin lesions. I came in the next morning, and he was turned to the side and there was a pool of blood next to his pillow. He bled out into his bed. One day he was sick, febrile, and not well . . . and he was dead the next morning."

The man who best knows the anatomy of a smallpox epidemic is Donald Ainslie Henderson. Known as D.A. to his colleagues, Henderson is a doctor and the director of the Center for Civilian Biodefense Studies, a think tank run by Johns Hopkins University. From 1966 to 1977, he ran the WHO smallpox eradication program, one of the greatest medical achievements of the 20th century. When he began his effort, 10 to 15 million people a year were still being infected by smallpox, and between 2 and 3 million were dying, mostly in Africa, Asia and South America. In a little more than a decade, Henderson and his team had bottled up the virus and confined it to vials in laboratories.

The key to eradicating smallpox was a system for choking off outbreaks. Rather than inoculate every last person on Earth, an impractical if not impossible task, Henderson and his team decided instead to track every case they could find, and encircle the virus with people who had been vaccinated. Past experience had shown that a person who has been exposed to, and even infected with variola, can still be protected by the vaccine, provided it is delivered within five days of exposure. Unlike some viruses, Ebola for instance, smallpox is not carried by animals. Its only host is human beings. The most common route of infection is through inhaling virus-laden droplets during face-to-face contact with a smallpox victim, although the virus can survive for hours in the air, or for days in the bedding of infected persons. Under normal circumstances, smallpox is not as easily passed from person to person as, say, the flu or measles, which can rip through a classroom in a single morning. But it is far more contagious than HIV, the virus that would cause the AIDS epidemic a decade later.

D.A. Henderson: "if it happens in Brazil, or Mexico, or wherever, it's our problem, too." D.A. Peterson - The Post Henderson's team reasoned that if they could draw the noose tight enough around a smallpox outbreak, they could cut off the virus's path to its next human host. They called their method surveillance and ring vaccination.

The WHO enlisted thousands of local volunteers who, together with doctors from developed nations, scoured villages and cities for active smallpox cases. Doctors identified cases and ordered them quarantined in their homes or in hospitals. Volunteers stood guard, enforcing the quarantines, and tracked down every last one of a victim's face-to-face contacts. Doctors and volunteers alike could vaccinate; all it took was a vial of vaccine and a special bifurcated, or two-pronged, needle. In October 1975, a WHO team cornered the last naturally occurring case of variola major: in a 3-year-old girl named Rahima Banu, from Bhola Island, Bangladesh. In 1977, Ali Maow Maalin, a Somali cook, became the ultimate victim of a less virulent form of the disease, known as variola minor. Both survived. (The WHO has since lost track of them.)

At 73, Henderson still strikes an imposing figure. He is well over 6 feet tall, barrel-chested, with a craggy face and prominent nose, and a diamond ring on one pinkie. To him, a smallpox epidemic is a terrifying prospect, whether it occurs naturally or as a result of bioterrorism. A full-blown epidemic comes in waves, rings of infection that spread outward, like ripples on a pond, from each index case. Two weeks after the first round of infected people fall ill, a new wave of cases appears, only to remain steady for another two weeks, when the number of victims escalates yet again. With each wave, the number of victims increases exponentially. Graphed on paper, the cases rise in little foothills at first, until the number shoots upward, like a viral Mount Vesuvius.

Epidemiologists think of this topography of infection as a road map to disaster. The only hope of containing an outbreak is when it's still in the foothill stage, when the number of infections is low and ring vaccination can be used to choke off the virus. Failing to catch an outbreak early allows it to erupt. Henderson recalls the smallpox conflagration that was sparked in Bangladesh in 1971 by the savage civil war that led to the country's independence from Pakistan. By then, smallpox had been all but eradicated from Bangladesh. Henderson was at WHO headquarters in Geneva when fighting broke out.

"Refugees were fleeing across the border into India," he says. "I got a call from the U.S., a guy from the CDC, who had seen pictures of people in an Indian refugee camp. He said it looked like smallpox. I took a plane to the camp and there was smallpox everywhere." When independence was declared, the refugees began flooding home. "One hundred thousand people poured across the border," says Henderson. "Smallpox exploded across Bangladesh." More than 200,000 people were infected and 40,000 died over the four years it took the WHO team to encircle the disease again.

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 U.S. 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 Rus-sian 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.

http://www.washingtonpost.com/ac2/wp-dyn/A42547-2001Oct23?language=printer

-- Martin Thompson (mthom1927@aol.com), October 28, 2001

Answers

Fair use for educational/research purposes only

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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 U.S. program, says Patrick, had begun weaponizing smallpox before the U.S. 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 U.S. 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 U.S. 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.

A lab at Dynport, which will produce smallpox vaccine for the U.S. military. (D.A. Peterson - The Post) 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 U.S. 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 U.S. 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.

Ali Maow Maalin, the last smallpox vicim. (Terence Spencer - TimePix) "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.

A child with smallpox in the Congo in 1960. (J. Wickett - Pan American Health Organization; World Health Organization) 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.

D.A. 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."

http://www.washingtonpost.com/wp-dyn/articles/A56411-2001Oct26.html

-- Martin Thompson (mthom1927@aol.com), October 28, 2001.