Last Updated

13 Nov 2002

Source: Science 296 (5573), May 31, 2002, p. 1594.

BIOTERRORISM:

In Search of a Kinder, Gentler Vaccine

by Martin Enserink

James Koopman saw the last 16 cases of smallpox in the Indian district of Azhagar in the early 1970s, but by now they blur together. Crystal clear, however, is the memory of a child, about 1 year old, who suffered from an uncontrollable infection called progressive vaccinia after receiving a smallpox vaccination in 1973. "It completely destroyed her arm, right down to the bone," says Koopman, now a researcher at the University of Michigan, Ann Arbor.

To Koopman, that girl is a grim reminder that the traditional smallpox vaccine, a virus called vaccinia that's harvested from the pustules on the skin of infected calves, is very effective -- and also quite dangerous. So current talk of vaccinating thousands or millions makes him rather nervous. But it's not yet clear what the alternatives are.

Vaccinia -- known in the United States as a Wyeth product called Dryvax -- works by producing a local infection on the arm, a so-called take, which normally heals in 2 to 3 weeks. But in progressive vaccinia, it grows out of control. Other serious side effects include eczema vaccinatum, a localized or systemic infection in people with a history of eczema, and encephalitis, a brain inflammation. During the smallpox eradication era, about 1250 in every million vaccinees -- many of them children under 2 years of age--suffered one of these side effects, and about one in a million died. Researchers expect that those numbers would be significantly higher today, as millions of people have compromised immune systems as a result of HIV or immunosuppressive drugs. Eczema rates have also shot up, for unknown reasons.

A huge new batch of vaccine scheduled for delivery to the government before the end of the year is not expected to be much safer. Produced by a company called Acambis and its subcontractor Baxter, the vaccine is a single, clonal strain of vaccinia, rather than the melange in Dryvax, and it's produced by cleaner techniques. But it was chosen to resemble the old vaccine as closely as possible, says Thomas Monath, chief scientific officer at Acambis, because that's known to work. Animal tests suggest that the new version has a slightly lower risk of causing encephalitis, but other side effects will probably be the same, Monath says. Clinical trials are under way.

The National Institutes of Health is pushing both academic and commercial researchers to develop a safer alternative. Such a vaccine could be used in the more than 20% of Americans who either belong to one of various risk groups or are in close contact with those in them -- and perhaps in the long run, the general population. Prime candidates are vaccinia strains that are much more weakened, so that they're powerless to set up an infection but still elicit an immune response.

Such highly attenuated vaccinia viruses are already used as backbones for several other vaccines. Aventis Pasteur, for instance, is developing an HIV vaccine based on a highly weakened vaccinia strain called NYVAC; now, it plans to test whether NYVAC by itself might make a smallpox vaccine.

But the candidate with the best prospects, experts say -- simply because it has the longest track record -- is a vaccine called modified vaccinia Ankara (MVA). Produced by passaging vaccinia 574 times in chicken embryo fibroblasts, MVA was given to more than 150,000 Germans in the 1970s, most of them at high risk of side effects. The vaccine was used as a primer to establish a baseline immunity, thus preparing the body for the traditional smallpox shot given several months later. MVA was shown to be safe, and it helped people tolerate the real vaccine. One of the two companies developing it, Copenhagen-based Bavarian Nordic, has recently given its version of MVA to small groups of healthy and immunocompromised volunteers; they, too, didn't suffer serious side effects, the company recently reported.

But does the combination of MVA and a traditional vaccine work? Unlike Dryvax and other old-style vaccines, it has not proven its mettle in endemic areas, and there was no smallpox around in Germany when it was used. It doesn't produce the telltale take -- and the subsequent scar -- that researchers have always relied on to indicate protection.

Because it's unethical to do tests in which human vaccinees are exposed to smallpox, the Food and Drug Administration will have to rely on animal tests, as well as measurements of the immune response it generates in humans. Researchers at the Centers for Disease Control and Prevention and the U.S. Army Medical Research Institute of Infectious Diseases have developed a monkey model of smallpox, which they hope to perfect this year; MVA is one of the first products they plan to test.

Because MVA protects against several other members of the orthopoxvirus family, Bavarian Nordic president Peter Wulff is confident that it will pass those remaining tests. He predicts that the combination will eventually replace Dryvax and other traditional vaccines -- not just for high-risk groups but for the general population as well. The objection that it doesn't produce a take, Wulff adds, "is a little beside the point from a scientific viewpoint. What counts is the immune response."

But others are not so sure. Donald A. Henderson, former head of the World Health Organization's eradication effort and now a top bioterrorism adviser to the Department of Health and Human Services, for instance, says he'd be leery of relying on anything less than the tried and true to protect the population. "I don't know how you could ever be completely sure of [MVA's] efficacy," Henderson says.

The dilemma seems certain to crop up more frequently as scientists shore up the world's defenses against bioterrorist threats. Most of the diseases that would appeal to terrorists are extremely rare in nature, so doing efficacy tests of new drugs and vaccines in humans will usually be impossible -- unless, of course, the worst scenario materializes.