Having accepted the possibility that samples of the highly contagious and deadly smallpox virus have gotten into the wrong hands, the U.S. government is racing to obtain millions of doses of new vaccine before the end of this year - more than 100 million doses by Sept. 11. But how that vaccine will be used remains a hot-button issue.

A scientific advisory panel concluded June 20 that vaccine should be stockpiled. Only perhaps 15,000 public health workers need vaccination before an outbreak, the panel said, and immunization could be limited to fairly small numbers in seriously exposed areas.

But many physicians, medical organizations and political leaders are clamoring to have vaccines now.

"I believe the threat of a smallpox attack outweighs the risks of providing smallpox vaccinations to a well-informed public," Sen. Bill Frist (R-Tenn.), a physician, said this week in a New York Times article. " . . . every American should be given this option."

A Harvard University poll released June 5 found 59 percent of Americans would get vaccinations immediately if they were available. If smallpox surfaced somewhere in the country, 81 percent of those surveyed said, they would want to be vaccinated immediately.

Less than three months ago, scientific experts thought they had closed the book on the issue. Two factors seem to be key to the new debate. First, consensus is building among national security experts that some groups have, indeed, obtained the smallpox virus. Second, there is disagreement about how best to control a smallpox epidemic in a totally nonimmune population - a problem not faced for more than a century.

"While the threat of a smallpox attack is believed to be low, it is indeed possible, and unfortunately, we now live in a world where we need to be prepared ... " Health and Human Services Secretary Tommy Thompson said June 20. "As part of that preparedness, we expect to have in stock by the end of this year enough smallpox vaccine for every American should it ever be needed."

Unlike the tetanus or measles vaccines, which are quite safe, smallpox inoculation can be risky. This spring, the National Institutes of Health administered the vaccine to 680 healthy adults born after all U.S. vaccine programs ceased in 1972. Nine percent of those vaccinated suffered fevers, 21 percent had muscle aches and pains, 6 percent developed skin rashes. Twelve of the subjects suffered reactions severe enough to warrant hospitalization.

No one knows for sure how much immunity people vaccinated before 1972 retain, but historical evidence indicates all immunity wanes within 20 years.

Another recent NIH study showed that the key immune response elicited by the vaccine involves so-called T cells - the kind that are depleted in people who are infected with HIV, are undergoing cancer chemotherapy or are elderly.

In Senate testimony May 2, Thompson estimated that "about 18 individuals out of a million would have serious repercussions from taking the vaccine ... about two to four would die" because high-risk groups that were not targeted for vaccination in the 1960s would be today.

Furthermore, the new smallpox vaccines are being made through novel processes - not in the way used in the 1960s, when the vaccinia virus was inoculated into cows, which in turn produced the vaccine.

"There is a risk, and everybody realizes it's possible, that the vaccine will turn out differently from what we want," Dr. James LeDuc of the Centers for Disease Control and Prevention in Atlanta said in an interview. LeDuc is heading up efforts to guarantee the safety and efficacy of the new stockpile.

If smallpox surfaced anywhere in the world, LeDuc's team would rush a sample to the CDC's BioSafety Level-4, top security laboratory, for analysis. Working with counterparts at VECTOR, the old bioweapons lab in Siberia, the CDC has determined the genetic sequences of several known strains of smallpox.

"This will give us a variable database to trace the origin of smallpox, should it ever reappear - the pedigree," LeDuc said. "It will also help us to rapidly identify if the genome has been manipulated," to give the virus special powers of transmissibility or virulence.

LeDuc's task would be relatively easy. The really tough task would fall on pediatrician Harold Margolis, also of the CDC. He would have to decide, in the face of immense uncertainties, who should be vaccinated first, second and further down the road.

The historical record shows that fatality rates in smallpox epidemics were generally "around 30 percent, but could be as high as 80 percent," Margolis explained in an interview. "But those studies were done long ago. We have much better supporting care today, so would people who died then, live today?"

In 1972, Drs. Alfred Sommer and Stanley Foster led efforts to control a raging smallpox epidemic in Bangladesh. In that epidemic, about 60 percent of unvaccinated people came down with smallpox, and as many as half of those individuals died.

Nevertheless, Sommer, who is now dean of the Bloomberg School of Public Health at Johns Hopkins University, and Foster, who is on the faculty of Emory University in Atlanta, stopped the epidemic. They did so by a method called ring vaccination, in which infected individuals are identified and quarantined, and every person residing or working within a ringed distance of that person is vaccinated.

They discovered there was no need to immunize health care workers in advance, as the vaccine was so powerful that they were protected even if they didn't get the vaccine before handling a dying patient.

Three recent computer models offer conflicting conclusions about the likelihood the Sommer/Foster strategy would work in the United States today. A Los Alamos National Laboratory study says the epidemic would move so slowly that authorities would have ample time to respond. LeDuc and colleagues found that the ring strategy would work, but that 4,200 people would develop smallpox with a 30 percent mortality rate, and 40 million Americans would have to be vaccinated. Finally, a Yale School of Public Health group calculated that the ring strategy would leave 110,000 people dead, whereas mass vaccination would result in only 560 lost lives.

In the end, Margolis said, "let's just hope we don't ever have to find out the truth."