The Vaccinia Dilemma
Smallpox shot poses modest danger, uncertain benefit

Ben Harder

Consider two troubling scenarios. First, imagine that the government's current smallpox vaccination campaign peters out before even a million people are vaccinated. Then, a month or perhaps a decade from now, terrorists cause simultaneous smallpox outbreaks in several cities. Within days, cases of the once-eradicated disease pop up across the country and around the world. The epidemic burns for months and leaves many thousands dead before it's extinguished.

Here's a second possibility: Government workers vaccinate some 10 million healthcare workers, emergency responders, and citizens. A dozen of those vaccinated die of side effects, and hundreds more suffer serious life-threatening complications. Moreover, even without receiving the shot, scores of people at high risk for the vaccine's side effects become fatally infected with its live virus accidentally imparted by vaccinated friends or family members. A decade later, no smallpox epidemic has appeared, but the country is peppered with memorials to these victims of a terrorism event that never occurred.

Someday, with the luxury of hindsight, the current wrenching debate over smallpox vaccination may appear to have had an unambiguous answer. But for policy makers, health-care professionals, and other individuals who must make decisions today, the fog of alternative scenarios lies thick.

At the heart of the controversy is the uncertain likelihood that smallpox, which vanished a quarter-century ago, will reappear. "The key factor is the one factor that no one knows," says infectious-disease physician Kent A. Sepkowitz of Memorial Sloan-Kettering Cancer Center in New York.

The risk of a smallpox strike isn't the only important unknown. Others include how much mortality and illness will come with widespread public vaccination and whether, in the event of an outbreak, the protection afforded by vaccination will save more lives that the campaign itself destroys.

In spite of those uncertainties, a phalanx of researchers is developing scientifically informed recommendations on who should and shouldn't be vaccinated and when immunization should take place. The scientists' tools include hard-won knowledge from combating smallpox in the 1960s and 1970s, data from current vaccination campaigns, and mathematical models. Different approaches are yielding conflicting results. With so much potentially at stake, this politically charged issue is fanning a fiercely emotional debate.

Population at risk

British surgeon Edward Jenner launched the practice of vaccination in 1796 by using live, transmissible vaccinia or cowpox virus to protect his patients from closely related smallpox. Immunization has since become one of the safest public-health strategies. Yet because it uses a live virus, the smallpox shot is among the vaccines with the most severe side effects.

When vaccinia was widely used in the past, it caused 1 or 2 deaths and several dozen serious side effects per 1 million recipients. Those risks pale in comparison to the 20 to 40 percent of victims that smallpox infections killed.

The few deaths from the vaccine weren't evenly spread throughout the population. Vaccine-related deaths in healthy adults were "virtually unheard of," says William J. Bicknell of Boston University, a former Massachusetts state health commissioner.

However, large segments of today's population may be highly vulnerable to the worst effects vaccinia can dish out. Individuals at elevated risk include those with certain skin conditions, such as eczema, and those with suppressed immune systems, which today include people with HIV and recipients of cancer therapies or transplanted organs. People in these risk categories were few in the 1960s and 1970s during the last major smallpox vaccination campaigns. Because vaccinia can spread from one person to the next, even unvaccinated people face a small risk of infection and side effects.

To understand how dangerous vaccinia might be in today's population, J. Michael Lane, formerly of the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga., reviewed studies of post-vaccination transmission of vaccinia before 1970. In the October 16, 2002 Journal of the American Medical Association, he, John M. Neff of Children's Hospital and Regional Medical Center in Seattle, and their colleagues report that 20 to 60 cases of accidental infection occurred in the United States for every million people vaccinated. However, they predict today that the frequency would be higher, primarily because of HIV and increased incidence of eczema.

At least 125 deaths would result from vaccinating everyone in the United States, Lane and his colleague Joel Goldstein of the Children's Clinic in Morrow, Ga., estimate in the March 18 Annals of Internal Medicine.

Current experiences with the vaccine are consistent with a low incidence of side effects and accidental infection. The Bush administration in late January launched an effort to vaccinate initially 500,000 and as many as 10 million people. So far, the U.S. government has given vaccinia inoculations to more than 200,000 members of the armed forces and some 25,000 civilian health care workers. Ongoing monitoring indicates only a few dozen serious reactions among vaccinees and a handful of cases of secondary vaccinia infections among nonvaccinees. However, some vaccine recipients appear to have developed heart disease as a result of the shot, raising the possibility of previously unknown side effects.

Secondary transmission of vaccinia—and its health consequences—could be a considerably more serious problem in hospitals than in the general population, says Sepkowitz, who has reviewed past reports of vaccinia's spread in medical centers. In 12 outbreaks in which a total of 85 cases occurred, secondary vaccinia proved fatal in 9 instances, Sepkowitz reports in the Jan. 30 New England Journal of Medicine.

Lane attributes the success of the vaccination campaign so far to careful pre-vaccination screening to identify and exclude people at risk for complications. He also credits the education of vaccine recipients about how they can reduce the likelihood of transmitting vaccinia, a condition referred to as contact vaccinia. If the campaign accelerates or if it broadens to include volunteers from the general public, however, that assiduous screening and education might lapse, he suggests.

"If you vaccinate many more people faster, … you're going to have more contact vaccinia," predicts Neff. "The more measured pace that we're taking now is highly appropriate."

That pace isn't slow entirely by design. Hospital workers have expressed concerns that they could transmit vaccinia to patients, many of whom have risk factors for complications from the virus. Some health providers also worry about diverting resources from fighting active public health threats, such as influenza. For those and other reasons, many health care workers have refused President Bush's request that they get vaccinated, and the administration is still far short of achieving its initial goal of vaccinating 500,000 such health-care providers.

What if?

In lieu of data from actual smallpox attacks, several recently devised mathematical models simulate how vaccination and other public health measures could shape the course of hypothetical epidemics. A model by Martin I. Meltzer and his colleagues at CDC suggests that isolating people diagnosed with smallpox and vaccinating family members and others who had had extended contact with them—a tactic called contact tracing—would be sufficient to control an outbreak.

A related but more aggressive tactic, known as ring vaccination, calls for vaccination of everyone who might have had contact with an individual during his or her infectious period. For example, an entire town might be vaccinated in response to a single case.

A combination of isolation, contract tracing, and ring vaccination is widely credited with halting the spread of smallpox worldwide by 1977. In many parts of the world, universal vaccination was never implemented.

According to Meltzer's model, a future outbreak would grind to a halt if infectious people were promptly isolated, even if no vaccine was used.

Epidemiologist Edward H. Kaplan of Yale University and his colleagues present a more alarming scenario. They hold that without vaccination, a smallpox outbreak would expand indefinitely. Even selective vaccination would prove insufficient, they argued in the Aug. 6, 2002 Proceedings of the National Academy of Sciences (SN: 7/13/02, p. 21: Available to subscribers at http://www.sciencenews.org/articles/20020713/fob6.asp). In one instance, they calculate that after an initial attack that infects 1,000 people, launching mass vaccination as soon as smallpox is identified would save at least 4,000 lives as compared with contact tracing for the first month.

If an attack does come, Kaplan says, everyone in the affected city and its vicinity should be vaccinated. Also, because any attack indicates significant possibility of attacks elsewhere, a single case in New York City might well merit complete preemptive vaccination throughout the country, Kaplan reasons.

In any case, public clamor for inoculations might require a liberal vaccination program after an outbreak.

"Smallpox vaccine is a precious commodity," Neff says. The U.S. stockpile of smallpox vaccine should be used conservatively in case it's needed to help control a global outbreak.

Interrupting transmission

Many of the contradictions among outbreak scenarios stem from conflicting perceptions of how smallpox spreads. Transmission occurs mostly via airborne droplets of saliva or other bodily fluids. Before a person shows symptoms or becomes contagious, the smallpox virus incubates within an infected individual for 1 to 2 weeks. At that point, the person develops a high fever that lasts 2 to 4 days, then the fever drops and the patient may feel somewhat better. In the throat, however, virus-filled pustules develop. A characteristic rash soon appears over the face, extremities, and trunk and keeps the patient bedridden for the 2-to-3-week balance of the illness.

Scientists disagree about whether an infected person is likely to pass on the virus before the external rash appears. Kaplan's model assumes that transmission occurs in this brief period between the infection's first nonspecific symptoms and the onset of the disease's distinctive rash.

Linking infectivity with this period of relative relief is a fiction, other researchers claim. They see the most infectious period as coming after the rash develops. At this time, the bedridden patients release many viral particles and are likely to infect their caretakers. "Almost all smallpox is contracted at the bedside," says Thomas Mack of University of Southern California in Los Angeles.

Another discrepancy among the models is how easily smallpox jumps from one person to the next and, therefore, how explosive an outbreak could be. With no immunity in the population and no control measures, a typical smallpox victim spreads the disease to between 1 and 6 new victims. In Kaplan's outbreak model, a transmission rate of 5 new cases per victim results in many deaths, unless large-scale vaccination is implemented promptly. In other models, a similar transmission rate leads to less disastrous outbreaks.

However, some individuals transmit the virus on a much larger scale through casual or indirect contact, and the various models weigh that factor differently. Kaplan argues that officials should plan for the worst possible scenarios. In 1902, a single victim reportedly infected more than 100 people on a train car. In 1972, a Yugoslavian man hospitalized with undiagnosed smallpox spread the disease to 38 people, most of them hospital staff and other patients.

The 1972 Yugoslav outbreak, despite its "smallpox-spreading champion", was halted rapidly after the disease was recognized and patients were quarantined, notes Lane. The effectiveness of quarantine means a smallpox attack "would be more like a grenade than a dirty bomb," says Mack. It would have an immediate, localized effect, not one that ripples out insidiously. Thus, control measures less drastic than massive, nationwide vaccination would be enough even if an outbreak occurred, Mack, Lane, and others argue.

Planning ahead

Differences of opinion over the proper response to a smallpox outbreak have led to disagreements over what needs to be done to prepare for that possibility.

The top priority, Kaplan says, is to create a pool of first-responders who could administer vaccine to others in the event of an outbreak. He envisions preemptively vaccinating between 1.25 and 2.5 million potential first-responders in the United States. Next, he says, clinics should be prepared to rapidly roll out a full-scale campaign that could vaccinate everyone in the country within 10 days. In an outbreak, "everyone should know where they report," he says.

Bicknell advocates immediately vaccinating more people—8 to 10 million emergency workers, hospital workers, and others who could administer vaccine in the case of an outbreak. "When that's done, we're well protected," he says. He also favors encouraging widespread voluntary vaccination among the entire civilian population, a step that makes his recommendations even more aggressive than the Bush administration's current goals.

Other researchers suggest that only thousands of health workers need to be vaccinated to set the stage for immunizing the 300 or so million U.S. residents, if that was deemed necessary, in response to an outbreak. Epidemiologist Samuel A. Bozzette of RAND Health Care in Santa Monica, Calif., says that he has considered several bioterrorism scenarios using both pessimistic and optimistic assumptions about the course a smallpox outbreak would take.

In all cases, vaccination of health care workers and first-responders is justified, he says. Unless an attack is imminent, however, general vaccination shouldn't occur "because the certainty of harm outweighs the small chance of a net benefit," Bozzette and his colleagues conclude in the Jan. 30 New England Journal of Medicine.

Old lessons, new world

Until and unless the threat of smallpox permanently subsides, any vaccination campaign would need to continue indefinitely, says CDC's Meltzer. "You can't just vaccinate everybody, step back, and dust your hands," he says. Staff turnover at hospitals would necessitate ongoing vaccination. Also, as immunity of past vaccines wanes over decades, revaccinations would be needed. Therefore, the cumulative health toll of staying on guard against smallpox would steadily climb. Even if safer forms of smallpox vaccine were developed, the financial cost would mount.

In some ways, the world may be lucky that the threat of smallpox has resurfaced now, rather than several decades hence. Many leaders in public health who participated in the disease's eradication are still alive. "All 70 years old and sharp as a tack" is how Sepkowitz describes his senior colleagues.

They remember aspects of disease control that weren't well documented. For example, they report anecdotal evidence that vaccination soon after exposure to the disease can prevent infection.

Still, there may be danger in relying too heavily upon past lessons. A genetically engineered smallpox virus, for example, could cast out the most basic of assumptions. And "if it turned out that the vaccine didn't work, we'd all be in trouble," says Kaplan.

More optimistically, immunizing a population might stave off an attack by reducing the virus' strategic value for terrorists, he posits.

With fundamental aspects about the contemporary threat of smallpox unknown, the hard question about whether and how to vaccinate remains just that—a question.

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Letters:

Why has so much focus been placed on protecting us against the threat of a smallpox outbreak when a terrorist could choose to release a different infectious disease? Wouldn't it be wiser to discuss ways to respond to and contain any unknown disease? More public awareness of this possibility would prevent the false sense of security the smallpox vaccinations may create. That it took 3 weeks to add SARS to the list of diseases warranting quarantine is evidence that we may not be as prepared as we imagine ourselves to be.

Benjamin Karas
Cleveland, OH

Your article twice refers to vaccinia as "cowpox virus." The two are actually two separate viruses. It is unclear exactly where vaccinia comes from, as it isn't a naturally occurring virus. It is thought that the strain of cowpox used for vaccinations has, over the years, mutated into a new, genetically distinct virus.

Paul Matz
Philadelphia, PA

References:

Bicknell, W., and K. James. 2003. The new cell culture smallpox vaccine should be offered to the general population. Reviews in Medical Virology 13(January–February):5–15. Abstract available at http://dx.doi.org/10.1002/rmv.382.

Bozzette, S.A., et al. 2003. A model for a smallpox-vaccination policy. New England Journal of Medicine 348(Jan. 30):416–425. Available at http://content.nejm.org/cgi/content/full/348/5/416.

Kaplan, E.H., D.L. Craft, and L.M. Wein. 2002. Emergency response to a smallpox attack: The case for mass vaccination. Proceedings of the National Academy of Sciences 99(Aug. 6):10935–10940. Available at http://dx.doi.org/10.1073/pnas.162282799.

Lane, J.M., and J. Golstein. 2003. Evaluation of 21st-Century risks of smallpox vaccination and policy options. Annals of Internal Medicine 138(March 18):488–493. Available at http://www.annals.org/cgi/content/full/138/6/488 (html) or http://www.annals.org/cgi/reprint/138/6/488.pdf (pdf).

Mack, T. 2003. A different view of smallpox and vaccination. New England Journal of Medicine 348(Jan. 30):460–463. Available at http://content.nejm.org/cgi/content/full/348/5/460.

Meltzer, M.I., et al. 2001. Modeling potential responses to smallpox as a bioterrorist weapon. Emerging Infectious Diseases 7(November-December):959–969. Available at http://www.cdc.gov/ncidod/eid/vol7no6/meltzer.htm.

Neff, J.M., J.M. Lane, et al. 2002. Contact vaccinia—Transmission of vaccinia from smallpox vaccination. Journal of the American Medical Association 288(Oct. 16):1901–1905. Available at http://dx.doi.org/10.1001/jama.288.15.1901.

Sepkowitz, K.A. 2003. How contagious is vaccinia? New England Journal of Medicine 348(Jan. 30):439–446. Available at http://content.nejm.org/cgi/content/full/348/5/439.

Further Readings:

Seppa, N. 2002. Vaccine for all? Math model supports mass smallpox inoculation. Science News 162(July 13):21. Available to subscribers at http://www.sciencenews.org/articles/20020713/fob6.asp.

Osterholm, M.T. 2003. The case for smallpox vaccinations. Minneapolis Star Tribune (Feb. 23). Available at http://www.startribune.com/stories/1519/3665257.html.

For CDC's smallpox page, go to http://www.bt.cdc.gov/agent/smallpox/.

Sources:

William J. Bicknell
Department of International Health
School of Public Health
715 Albany Street, T
Boston University
Boston, MA 02118

Samuel A. Bozzette
RAND Center for Domestic and International Health Security
1700 Main Street
Santa Monica, CA 90407-2138

William Foege
Rollins School of Public Health
Emory University
1518 Clifton Road, NE
Atlanta, GA 30322

Edward H. Kaplan
Yale University School of Management and Department of Epidemiology and Public Health
Yale School of Medicine
New Haven, CT 06520-8200

Jeffrey Koplan
Rollins School of Public Health
Emory University
1518 Clifton Road, NE
Atlanta, GA 30322

J. Michael Lane
869 Clifton Road, NE
Atlanta, GA 30307-1223

Thomas Mack
Keck School of Medicine
University of Southern California
Los Angeles, CA 90089

Martin I. Meltzer
Centers for Disease Control
Mailstop D-59
1600 Clifton Road
Atlanta, GA 30333

John M. Neff
Center for Children with Special Needs
Children's Hospital and Regional Medical Center
P.O. Box 50020, Mailstop S-219
6901 San Point Way NE
Seattle, WA 98145-5020

Kent A. Sepkowotz
Infectious Disease Service
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, NY 10021

From Science News, Volume 163, No. 14, April 5, 2003, p. 218.