Image: Courtesy of the CDC
US citizens will not be lining up for smallpox vaccinations anytime soon, despite months of news reports on the stockpiling of enough vaccine for every man, woman, and child. On June 20, the US Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP), after evaluating information provided at public forums in New York City, San Francisco, St. Louis, and San Antonio, recommended to Tommy Thompson, secretary of Health and Human Services (HHS), not to vaccinate the entire population.1
"There was no compelling evidence that it would be appropriate to recommend it, given what we know about the threat level and the fact that there has been no disease since 1977," says David A. Neumann, director of the Alexandria, Va.-based National Partnership for Immunization, who served as a liaison representative to the committee.
Anthony Fauci, director of the National Institute of Allergy and Infectious Disease,2 William Bicknell, professor of international health at the Boston University School of Medicine and former health commissioner of Massachusetts,3 and others had requested the forums to debate whether vaccination practices to contain natural outbreaks of smallpox would translate into a setting of deliberate infection: bioterrorism. But leaders of the World Health Organization's (WHO) Global Smallpox Eradication Campaign, who worked in the trenches from 1966 to 1977, were unanimous that the strategies used then could work now, preventing deaths and illness from the live vaccine.
According to the recommendations, teams of specified first responders and medical personnel will be vaccinated ahead of time, "probably somewhere between ten and twenty thousand individuals," said John Modlin, chairman of ACIP on June 20. State or local governments will organize the teams. If an outbreak of smallpox occurs, the teams will implement "surveillance and containment through selective vaccination of contacts," new lingo for "ring vaccination," says Neumann. In the smallpox eradication effort, ring vaccination successfully identified and immunized contacts of cases, and the contacts of the contacts, ringing the outbreaks. This is possible because vaccinating within four days of ex-posure prevents symptoms. Recalls Don Francis, president of VaxGen in Brisbane California, "I was in the last outbreak in Europe, in Yugoslavia. We had to immunize the whole country, even outside the secondary and tertiary contacts. There was tremendous social concern, but it worked."
LOOKING BACK--AND AHEAD "Smallpox is dead!" declared the front page of the WHO's flagship magazine in May 1980, heralding an unprecedented medical success story.4 Anticipating the end of the disease, most nations had ceased vaccination programs years earlier. "In 1970 and 1971, people were concerned about suspending the vaccination program, but they were shouted down. One death per million from vaccine seemed easy to skip when the threat of smallpox globally had been reduced to nil," says Matthew Davis, assistant professor of pediatrics and internal medicine at the University of Michigan Health System in Ann Arbor, Mich.
Ceasing vaccination created young, immunologically naïve populations, which was not deemed dangerous, despite strong suspicions of the existence of weaponized smallpox. Then in October 2001, anthrax spores delivered with the US mail catapulted bioterrorism from theoretical doomsday scenario to possible reality. With smallpox heading the new hit parade of fears, talk of vaccination resurfaced. Said HHS Secretary Thompson on Nov. 28, 2001, "While the probability of an intentional release of the smallpox virus is low, the risk does exist and we must be prepared."
In the wake of the Sept. 11 terrorist attacks, some nations rushed to thaw, dilute, and reinvent smallpox vaccines, as researchers simulated and extrapolated attack scenarios. The big question: does it make more sense to vaccinate everyone beforehand, or wait for disaster to "ring" the danger?
For now, CDC has opted against population-wide vaccination because traditional smallpox vaccine is quite crude by modern standards. The live vaccinia vaccine is a cowpox relative, grown in calf serum or more recently in tissue culture. The vaccine is administered by scratching it into the arm using a bifurcated needle. According to the last year (1968) for which vaccine data were available in the United States, nine deaths occurred among 14.2 million vaccinated individuals. Extrapolation to the present US population yields 180 deaths from vaccination. But those were the days before AIDS, increased cancer survival, and the rise of organ transplantation. Given these changes, says Francis, "Vaccine use in the US population would kill 250 to 1,000 people. If someone has HIV and doesn't know it, God knows what would happen."
Photo: Courtesy of Vaxgen Inc.
In immunosuppressed patients, smallpox vaccine can cause such complications as encephalitis or a nasty skin ulceration called vaccinia necrosum. It can also be lethal. The public would not tolerate the risk, says Francis. "We can talk about universal vaccination, but people would be very happy until the first person with HIV or the first kid with eczema is vaccinated. I can just imagine a TV camera zooming in on a face with a big ugly hole from vaccinia necrosum. Then it would all stop, nobody would take it." But people would accept vaccination under other circumstances. "I don't think anyone wouldn't take the risk of being vaccinated if there is a definite exposure or a person is in the second ring of contacts," Francis adds.
The flipside of vaccine risk is the specter of widespread smallpox. "As bad as a mass smallpox vaccination program could be, an attack could be much worse," says Davis. He reported his group's study using the historical US data of one vaccine-related death per million population at the Pediatric Academic Societies' meeting on May 7 in Baltimore. "Consider a smallpox attack that initially exposes 100 people in an urban center. We found that in the first year after the attack, we'd expect 2,160 deaths from smallpox. In contrast, if we vaccinated 50% of all 1- to 29-year-olds before an attack, [and] then implemented ring vaccination after, we'd get 358 deaths, of which 58 would be due to the vaccine, and 300 to smallpox. That's a saving of 1,800 lives over the first year," he says.
Despite this grim forecast, ACIP nixed population vaccination because the bioterrorism scenario is not likely to happen. But they could not be pinned down on the risk estimates, which are apparently based on classified information. Explained Modlin on June 20 to a reporter's question about the lack of risk quantification, "The committee has been told that the risk is low but not zero. We obviously can't put a number on that, but we are assuming that it's low. The decision that we made balanced that low or very low risk with the risk from the vaccine." Because of the uncertainty, the recommendations are flexible. "If additional circumstances warrant more widespread use of vaccine in an area or a community, then those steps, of course, would be taken," said Julie Gerberding, acting deputy director of CDC.
Another factor arguing against population vaccination is the conviction that ring vaccination can work. Francis evokes a scenario of 10 exposures in New York City's Grand Central Station that paints a different portrait than Davis' simulation. "There would be a major effort to identify the people exposed. Finding and vaccinating 100 percent of them will stop the epidemic more than vaccinating everyone in Manhattan." Plus, smallpox is not easily spread. "You can't infect people with smallpox unless you're clinically ill. The idea of introducing a suicide smallpox bomber doesn't work. He or she would have pus all over the face," Francis adds. And today's improved communications would help find the contacts in ways not possible in the eradication days. "At the meeting in Atlanta June 20, someone said that once the contacts are identified, CNN [TV] would run them on ribbons on the bottom of the TV screen," says Neumann.
VACCINE SOURCES Despite the recommendation for limited vaccination, the US government is continuing to stockpile enough vaccine for everyone, as well as continuing efforts to improve the safety profile. "Manufacture of smallpox vaccine stopped worldwide with the announcement of eradication in 1980," said Donald A. Henderson at a conference at the University of Rochester on May 10, 2002. Henderson headed the WHO's eradication campaign. "Not having enough vaccine is really scary. If this baby got loose with no vaccine, we'd be back to the days of quarantine," says Francis.
That was nearly the case on Sept. 11, when the US government had only 15.4 million doses of stored Dryvax vaccine from Wyeth Laboratories of Marietta, Pa. Since then, the government has been scrambling to acquire the 286 million doses needed to protect the entire population. Diluting stored vaccine, making more, and developing new sources will help in reaching the goal as early as 2003.
Building smallpox vaccine stores was already in progress before Sept. 11. In 2000, the US government ordered 54 million doses from Acambis in Cambridge, UK, increasing it to 155 million doses after Sept. 11. Aventis Pasteur, of Swiftwater, Pa., has offered 75 to 90 million doses frozen in Lyon, France, since the 1950s. Aventis will have a cell-culture-based vaccine ready for Europe by the end of 2002 and is working on a highly attenuated vaccine.
Meanwhile, in November 2001, a multicenter team began testing reconstituted Dryvax at fivefold and tenfold dilutions. Each of 680 individuals who had never been vaccinated against smallpox received undiluted vaccine or either of the two dilutions.3 "We thought the 1:10 dilution would work because there are hundreds of thousands of particles in the standard vaccine, and a tenth of that should be adequate. And that's exactly what we found. There were no significant differences in 'take' rates among the three strengths," which were near 100 percent, explains John Treanor, director of the Vaccine Treatment Evaluation Unit at the University of Rochester Medical Center. He calls the few side effects "annoying, but not serious," including fever, headache, myalgia, chills, nausea, fatigue, and rash. "Still, this is much higher than [with] new vaccines being tested today. We'd reject it if it was new today," he adds. Treanor estimates that the 15.4 million doses of Dryvax can be expanded by dilution to 77 million doses.
Other nations are building their smallpox vaccine stores too. On April 12, 2002, the Department for Health in the United Kingdom revealed a stockpile sufficient for half its population, some 30 million doses, and has ordered more from PowderJect Pharmaceuticals in Oxford. Health Canada, the national health agency, reports 365,000 stored doses, which it plans to dilute to at least 3 million.
Even if the vaccine is never used, and the doom-and-gloom scenarios never come to pass, the resurgence in interest in smallpox could have hidden benefits. "We will be learning new things about disease in general," points out Treanor. Henderson concurs. "If there is suddenly dengue in south Florida or a new flu, we'll be better equipped to deal with it."
One thing is certain in this era of great uncertainty: Researchers are reevaluating the very idea of eradication of an infectious disease. Sums up Davis, "Before 9/11, my supervisor asked me to consider aspects of bioterrorism in my work on vaccines. I scoffed at it. But since 9/11, everything else I do became inconsequential. It is an entirely new era in trying to protect our public against a variety of health problems. In the past it was us against nature. Now it is us versus other human beings. That's a lot more unpredictable and requires a different set of calculations, ones we're not sure of at this time."
Ricki Lewis (firstname.lastname@example.org) is a contributing editor.
1. CDC Office of Communications Telebriefing Transcript, June 20, 2002, available online at: www.cdc.gov/od/oc/media/transcripts/t020620.htm.
2. A. Fauci, "Smallpox vaccination policy--the need for dialogue," New England Journal of Medicine (NEJM), 346:1319-20, April 25, 2002.
3. W. Bicknell, "The case for voluntary smallpox vaccination," NEJM, 346:1323-24, April 25, 2002.
4. World Health Organization, "Smallpox and its eradication," 1988, available online at: www.who.int/emc/diseases/smallpox/Smallpoxeradication.html.
5. S.E. Frey et al., "Clinical responses to undiluted and diluted smallpox vaccine," NEJM, 346:1265-74, April 25, 2002.