As physical specimens, the Baylor University students were fit and healthy, the "creme de la creme," in the words of researcher Kathy Edwards. Yet when she inoculated them with smallpox vaccine, arms swelled, temperatures spiked and panic spread.
It was the same at clinics in Iowa, Tennessee and California. Of 200 young adults who received the vaccine as part of a recent government study, one-third missed at least one day of work or school, 75 had high fevers, and several were put on antibiotics because physicians worried that their blisters signaled a bacterial infection.
Even for experts such as Edwards, the Vanderbilt University physician overseeing the study, the side effects were startling. "I can read all day about it, but seeing it is quite impressive," she said. "The reactions we saw were really quite remarkable."
President Bush is poised to announce plans, perhaps as early as this week, to resume vaccinating Americans against smallpox as part of a massive push to protect the nation from a biological assault. As he weighs the decision, researchers are becoming reacquainted with the unpleasant -- often severe -- complications of the vaccine.
The experiences in a half-dozen clinical trials offer an early look at what military personnel, hospital workers and other emergency workers will likely encounter if Bush adopts the recommendations of his top health advisers to vaccinate as many as 11 million people in the coming months. What is disconcerting, say the people participating in the clinical trials, is that when it comes to smallpox vaccination, what had once been considered ordinary is rather extraordinary by today's standards.
"I just wanted to go to bed for a day or two there," said Alison Francis, a New York University graduate student who received the vaccine. Francis, 24, said she felt tired and achy after getting her shot. Her arm was heavy, warm to the touch and terribly itchy. "I thought, 'Can you just chop off my arm?' "
Participating in the study was part patriotism and part selfishness, she said. "Now I'm protected."
Once among the deadliest scourges on earth, smallpox was declared eradicated worldwide in 1981. But growing hostilities with Iraqi President Saddam Hussein, Osama bin Laden and others have renewed fears that the virus could be used as a potent, stealthy weapon. Vaccination is surefire protection against the disease, but it is risky. For every 1 million vaccinated, between 15 and 52 people will suffer life-threatening consequences such as brain inflammation, and one or two will die, according to historical data. Pregnant women, babies, people with eczema or weakened immune systems should not receive the vaccine.
Federal health officials have proposed resuming vaccination in stages, beginning with as many as 500,000 hospital workers most likely to see an initial case. Later, as many as 10 million police, fire and medical personnel would be offered the vaccine. The Pentagon hopes to vaccinate 500,000 soldiers.
Over the past year, federal researchers have been testing the 40-year-old vaccine for its safety and potency. None of the 1,500 volunteers has died or been seriously injured by the vaccine. But even the most mundane cases can be disturbing to doctors and patients unaccustomed to the live virus used in the vaccine and its side effects.
Unlike most modern vaccines, the smallpox vaccine is administered by 15 quick pricks that "establish an infection in your skin," said Julie Gerberding, director of the Centers for Disease Control and Prevention in Atlanta. "There is the immediate discomfort of getting poked in the arm and a range of annoying reactions."
Within three to four days, a red itchy bump develops, followed by a larger blister filled with pus. In the second week, the blister dries and turns into a scab that usually falls off in the third week. During the three weeks, many people experience flu-like symptoms -- aches, fever, lethargy -- and terrible itchiness.
"You can't scratch it; it's all bandaged up; all I could do was smack it," said Meg Gifford, a University of Maryland junior who participated in one study. For a weekend, she was "pretty miserable," suffering from a slight fever, an arm that was hot to the touch and swollen lymph nodes in her armpit.
At the University of Rochester Medical Center, researcher John Treanor saw a wide range of reactions, from a small rash to swelling the size of a grapefruit. About 5 percent of the 170 participants had rashes that spread to other parts of the body. It took time and experience, he said, for the team to get comfortable with the natural course of the vaccine.
"The reactions we are seeing are totally out of line with today's vaccine experience and absolutely in line with historical experience," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "In the 30 years since we had routine vaccination, the public's tolerance level has gone way down."
Maryland researchers have begun a second trial revaccinating older adults to see how much immunity stays in the system. Early indications are that people who have been previously inoculated do not suffer as many severe side effects. "I had a small red mark and that was about it," said Edward Dudley, 33.
Very few of today's physicians have administered the vaccine or treated its side effects. Even at the CDC, where health experts work with an array of germs, smallpox vaccinations were briefly halted when 10 people had serious enough reactions to begin antibiotics, said Walter Orenstein, director of the CDC's National Immunization Program.
"The clinic physician couldn't decide if this was a normal, primary exuberant take or a bacterial infection," he said. He added that, in fact, the swollen, itchy, red arms were routine.
As a first-year medical student 33 years ago, Orenstein was so alarmed by the fever, swollen glands and red streak up his arm after he was vaccinated that he went to the emergency room for antibiotics. "I respect this vaccine," he said.
If Bush moves forward with vaccination, Edwards warns doctors to expect the array of unsightly, unfamiliar complications that will come.
"You are going to have to be prepared to see these individuals and to see really bad takes," she told state health officers. "You'll wonder if they are bacterial infections; in some cases the rash will move up the arm and onto the chest. The vaccinee requires a lot of TLC."