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Treating Vaccine Reactions: Two Lifelines, But No Guarantees

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Science  20 Dec 2002:
Vol. 298, Issue 5602, pp. 2313
DOI: 10.1126/science.298.5602.2313

The pictures are almost too gruesome to look at. Dozens of them, displayed in neat rows on an educational Web page* by the U.S. Centers for Disease Control and Prevention (CDC), remind viewers of the horrific side effects of the smallpox vaccine in a small minority of cases. Unfortunately, doctors will have only limited means to help such patients when the United States resumes vaccination. Although two treatments are recommended for vaccine complications, little hard evidence supports the efficacy of either one.

Like smallpox itself, complications from the vaccine—a live, replicating virus called vaccinia—were fading from memory until the terrorism threat brought them back. Most of the researchers who have witnessed these rare cases have retired or died, and most papers describing their work are more than 35 years old. Back then, expertise with the vaccine's side effects was concentrated at the University of Colorado Medical Center in Denver. There, a renowned pediatrician named Henry Kempe led a national reference center where patients—most of them children—were brought to be treated.

Kempe died in 1984, but his younger co-worker Vincent Fulginiti, now retired and living in Arizona, vividly remembers some of the children—especially those with progressive vaccinia, an uncontrollable and usually fatal infection, triggered by a malfunctioning immune system, that spread from the vaccination site. “The virus literally ate up their entire bodies,” Fulginiti recalls.

In the 1950s, Kempe pioneered what is still the first line of defense for vaccine-induced disease: vaccinia immune globulin (VIG), a product made from the blood plasma of recently vaccinated people, which is high in antibodies against vaccinia. The United States has about 600 to 700 doses left from the 1960s, enough to treat the side effects expected when 4 million to 6 million people are vaccinated. But that cache is rapidly being supplemented with new VIG, produced by Cangene, a company inWinnipeg, Canada, and Dynport, a military contractor in Frederick, Maryland.

That's less reassuring than it sounds, because VIG is no wonder drug. Kempe became convinced early on of VIG's efficacy in treating some side effects, says Michael Lane, a former director of CDC's smallpox eradication unit, so he never carried out a controlled clinical trial. “He was a great clinician and a wonderful humanitarian but not a man of science,” says Lane. In fairness to Kempe, Lane adds, there might not have been enough patients available for a rigorous trial. Instead, Kempe compared the fate of VIG-treated patients with historic data.

Bad reaction.

Severe vaccinia side effects are rare but can be devastating, as in this 22-month-old boy.

SOURCE: CDC

Those and other studies suggested that VIG worked well and reduced the death rate from eczema vaccinatum, an occasionally fatal complication in eczema patients, by as much as 70%. It also seemed beneficial in severe cases of generalized vaccinia, a pocklike rash that covers the body. But it rarely helped in progressive vaccinia, says Fulginiti, and it was useless against encephalitis. Anecdotal as they may be, such early experiences form the basis for today's treatment guidelines (see table).

View this table:

Today's proposed dosing regimen is based on similarly soft data. In the 1960s, Fulginiti recalls, “we more or less went by the seat of our pants,” starting out with 0.6 milliliters of VIG per kilogram of body weight and—absent improvement—ratcheting up to as much as 10 milliliters per kilogram.

In the past, VIG also has been used to prevent, rather than treat, side effects. In the Netherlands, for instance, adults routinely received a shot of VIG when they were vaccinated, after a 1962 trial suggested that this could cut the encephalitis rate by as much as 77%. (To mass-produce VIG, recalls former director Hans Cohen of the Dutch National Institute for Public Health, vaccinated military recruits were asked to donate plasma in return for “an afternoon off and a pancake.”) But the Dutch had an unusually high encephalitis rate to begin with—perhaps because they used a more virulent vaccine strain—and little is known about VIG's ability to prevent other side effects. The United States has no plans to try a similar strategy today.

If VIG doesn't work, CDC recommends an experimental antiviral drug called cidofovir. Cidofovir is already approved to treat cytomegalovirus infections of the retina in AIDS patients, so many hospitals have the drug on hand and doctors have some experience with it. In lab studies, cidofovir halts vaccinia's replication in the test tube and can save mice from otherwise lethal vaccinia infections.

But whether the mouse data are applicable to humans remains to be seen, because vaccinia gives mice a very severe pneumonia instead of the side effects seen in humans, says John Huggins of the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland. Good animal models for side effects such as progressive vaccinia and eczema vaccinatum don't exist and would be hard to develop, says Huggins. Cidofovir can also have severe side effects.

The bottom line, says Lane, is that sick vaccinees have two potential lifelines, but neither one offers any guarantees. That makes it all the more important to ensure that those with known risk factors, such as eczema or compromised immune systems, don't get the vaccine. Even with those precautions, as vaccination rates rise, so does the likelihood that Kempe's work will have a 21st century follow-up—and nobody's looking forward to it.

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