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How do you respond to a smallpox outbreak in the AIDS era? Very carefully.

In 1987, a young Army recruit underwent a series of standard vaccinations designed to prepare him for the possible dangers of military life. Included among them was a dose of the vaccine against smallpox, which is made with a closely related virus called vaccinia (cowpox) that is generally harmless in humans.

The recruit proved to be an unfortunate exception. He developed a rare complication in which the cowpox overtook his body, giving him a disease very much like smallpox. It turned out that he also was HIV-infected and his immune system was severely suppressed, allowing the cowpox virus to reproduce out of control. He survived the vaccinia but died 20 months later of AIDS.

Four years later, French immunologist Dr. Daniel Zagury was conducting studies of possible treatments for HIV disease in France. One experiment involved giving people with HIV a therapeutic vaccine designed with the use of a vaccinia vector. Because of its large size and general harmlessness, vaccinia was for many years widely used by scientists as a way of introducing other, possibly beneficial, proteins into cells.

But in this instance, the use of vaccinia as a vector proved fatal. Three of Zagury’s patients developed vaccinia necrosum, which killed them. In layman’s terms, the cowpox virus had eaten through the skin from the site at which the patients were vaccinated and into the muscle of these individuals with severe immune suppression. The virus then spread a layer of gangrenous sores over their bodies. Their deaths caused an international scientific scandal and nearly derailed Zagury’s career.

Because of the possibility of such reactions, the Centers for Disease Control and Prevention (CDC) in Atlanta recommends that people with HIV not routinely be given the smallpox vaccine, which is now being discussed as a potential preventive measure against bioterrorism. Other people with altered immunity, such as those with cancer or who have received organ transplants, should also avoid the vaccine, according to the CDC. So should pregnant women and people with a history of eczema or other chronic skin conditions.

All of this raises a troubling question: How should an AIDS-era public-health agency design a response to a possible bioterrorist incident involving smallpox and also minimize the risk to people with HIV or other forms of immune suppression?

The CDC and major city health departments are trying to figure that out, and there are no definitive answers yet. “Certainly when the [smallpox] vaccine was given routinely, there was no HIV, so we have very little experience,” says Dr. Carol Tacket of the Center for Vaccine Development at the University of Maryland, Baltimore, who is conducting a study of diluted smallpox vaccine.

“Everyone is very reluctant to vaccinate people with HIV,” says Tacket. “These are tremendous concerns.”

Already, one thing has become abundantly clear to those concerned with fighting bioterrorism: This issue will be of particular concern in Washington, D.C., where AIDS experts estimate that one in 20 adults is HIV-infected and where the most extensive bioterrorist attack of the war on terrorism took place just last month.

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The classic public-health response to a smallpox outbreak is to find all possible contacts that an infected person may have had in the three weeks before the disease struck and to vaccinate them. Studies in Africa during the World Health Organization’s Global Smallpox Eradication Campaign found that rapidly vaccinating people who’ve been exposed to smallpox—even if they are already infected—can prevent them from getting the disease or mitigate its severity if they do get it.

When the Center for Strategic and International Studies, the Johns Hopkins Center for Civilian Biodefense Studies, and other organizations hosted the “Dark Winter” bioterrorism war game last June, the experts raised the specter of “suicide-bomber” bioterrorism, in which an infected terrorist would come to the United States to spread disease in his wake. But because people who have been vaccinated against smallpox decades ago (the United States stopped requiring universal vaccination in 1972; other countries gradually followed suit) can retain residual immunity, a bioterrorist would not necessarily have to die to start an outbreak. Around 70 percent of victims survive smallpox. And people with waning vaccine immunity can contract a less severe form of the disease, but nonetheless spread the virus to others.

A 1973 smallpox outbreak occurred in exactly this fashion: The infection of 40 people was traced to a man who had only one smallpox lesion on his wrist. The last outbreak on U.S. soil, however, spread from a more severe case. The man who started the 1947 outbreak in New York City had contracted hemorrhagic smallpox, the most fatal form of the disease, while in Mexico. The disease spread to 12 people, four of whom died, before it was contained. The New York City Department of Health responded to the infection by gearing up its own vaccine-production facilities and then vaccinating the entire city of New York—at that time, 6.35 million people—against smallpox within a month after the first case was identified.

Today, however, such a comprehensive vaccination campaign could potentially sicken or kill thousands of people with HIV.

Federal authorities have made only scant progress in resolving questions of how to protect those who cannot be vaccinated. “I know this issue has been discussed at least informally,” says Curtis Allen, a spokesperson for the CDC in Atlanta. “There is an operational plan that has been put together on this, but I’m not sure if those issues are addressed specifically.”

The risks of vaccination must be weighed against the risk of smallpox, notes Dr. Lisa Rotz of the CDC’s Bioterrorism Response Program. “If an exposure to smallpox has occurred, there are no contraindications. All persons with a high-risk exposure to smallpox virus should be vaccinated, as their risk for serious disease outweighs their risk of potential adverse events from the vaccine.”

Local AIDS agencies have held informal talks with the D.C. Department of Health about bioterrorism, says a spokesman for the Whitman-Walker Clinic, the District’s largest service agency for the HIV-infected. This week, Jack Pannell, a spokesperson for the Department of Health, expressed surprise that there might be a problem vaccinating people with HIV against smallpox. “This is the first time I’ve heard of this,” he said. “I’m not sure if there are any plans. As you know, we are working very avidly to plan for bioterrorist attacks.”

Ronald Lewis, who heads the HIV/AIDS Administration at the Department of Health, adds, “As we’ve learned with anthrax, the protocol could shift day to day based on the experience you have….We would clearly be discouraging people with HIV from getting any kind of vaccination against smallpox, but that’s the advice for all populations at this point.”

Other localities at high risk for a terrorist attack have begun to address the problem formally. New York State’s Department of Health, led by former U.S. Surgeon General Antonia Novello, already has undertaken a series of high-level discussions to plan for the protection of special populations, such as people with HIV, in the event of a smallpox outbreak.

“Our health commissioner has certainly been aware that HIV-infected individuals have issues that might be more problematic, and we have been looking at ways to address that,” says a source at the New York State health agency, adding that the state’s AIDS Institute has been brought into the bioterrorism-planning process. “This is a plan that we don’t want everyone to have specific details about, so they can’t counter our plan or our strategy. I hope that whoever is doing this doesn’t figure out that there are people who are even more vulnerable and attack them….[But] we do have plans in place to be prepared in the event of the unthinkable.”

Meanwhile, local AIDS groups are trying to plan for the unthinkable without unnecessarily scaring their clients or themselves. “We have been making phone calls to CDC so we can be prepared to serve our clients in case there is an outbreak of smallpox or botulism, or other bioterrorism attacks. Unfortunately, we haven’t received any very good advice yet,” says Michael Cover, the press agent for the Whitman-Walker Clinic.

“We have to be careful about what the clinic is communicating to people who are HIV-positive,” adds Cover. “We don’t want to instill panic in people.”

The options that health departments and people with HIV are struggling to evaluate range from the unpleasant to the unfeasible. Thousands of people in D.C. unwittingly carry HIV infection, despite almost universal recommendations that people at high risk should get themselves tested. This situation requires that any plan address both those who know they have HIV and those who don’t.

The Food and Drug Administration has approved a relatively fast HIV test, called OraSure, which can provide accurate results from a saliva sample within three days, but no more rapid test is available. Such a test could, conceivably, be used to screen high-risk individuals during the course of a smallpox outbreak prior to vaccination and to identify and avoid vaccinating those who are HIV-infected. The logistics of such a campaign would be daunting, however, and the consequences of large numbers of people learning that they carry HIV in the midst of a smallpox outbreak are unknowable.

“We are still looking into rapid HIV testing,” says Lewis. “We do not have that capacity yet.”

Craig Hooper, an epidemiologist now with the CDC in Atlanta, wrote a letter to the editor of the New England Journal of Medicine in 1998 examining several of these issues and the thorny dilemma they pose to public-health planners. He was not optimistic about the feasibility of widespread HIV testing during a smallpox outbreak. “It would…be impossible to exclude HIV-positive persons from being vaccinated,” he wrote. “Outbreak control requires widespread vaccination, so even if a quick method of screening for HIV were available, control of the outbreak would take precedence.”

Additionally, current guidelines for people with HIV recommend that neither they nor their housemates and relatives get vaccinated, because the relatives could infect them with cowpox by close contact. “[F]ollowing these guidelines will fail to protect public health during a smallpox emergency in areas with a large number of HIV-infected persons,” Hooper noted.

Of course, people with HIV may also be at increased risk of catching, transmitting, and dying from smallpox. If those newly diagnosed with HIV infection were brought into contact with infectious individuals at a mass-vaccination clinic, those individuals could potentially catch smallpox. Once back in their communities, they would act as vectors of infection. Because so many people with HIV live in communities with other people with HIV, these unvaccinated, exposed individuals could then infect and sicken precisely the vulnerable population public health officials were trying to protect by not vaccinating them.

It is also quite possible that not all people with HIV are equally at risk from vaccination. Those with relatively normal immune systems or who are taking antiretroviral medications may have responses similar to those of the non-HIV-infected. And some anti-viral medications that people with AIDS use are actually believed to fight the smallpox virus. Cidofovir, which is currently used almost exclusively by people with HIV to treat the opportunistic infection cytomegalovirus, has shown promise in laboratory studies as a possible treatment for smallpox, according to a National Institutes of Health study.

Another option would be to vaccinate HIV-positive people and also treat them with vaccinia immunoglobulin (VIG), a serum of antibodies to cowpox isolated from the blood of people recently vaccinated against smallpox. The national stock of VIG, however, is so depleted that the CDC recommends that it only be used to treat severe vaccine complications, not to prevent them.

Perhaps the single course of action most likely to minimize harm to people with HIV in the event of a smallpox outbreak would be broad-scale, voluntary HIV testing by at-risk people beforehand.

“We strongly believe that people should learn their HIV status,” says Terje Anderson, executive director of the Washington-based National Association of People with AIDS. “We encourage people to seek out voluntary testing because this information is real power over your life. Because if they suddenly launch a national smallpox-vaccination program, we don’t want people to die from the vaccination.” CP