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Looking for Vaccines That Pack a Wallop Without the Side Effects

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Science  20 Dec 2002:
Vol. 298, Issue 5602, pp. 2314
DOI: 10.1126/science.298.5602.2314

Like many pox researchers, Bert Jacobs of Arizona State University in Tempe believes it is “premature” to distribute the smallpox vaccine widely. The threat of an outbreak is uncertain, he points out, and dangerous side effects from the existing vaccine, which contains vaccinia virus, are all too real. Why not wait, he wonders, given that “we have the potential for alternatives, at least in advanced research, in the next couple of years.”

Since the 11 September terrorist attacks, the quest for a safer smallpox vaccine has taken on a new urgency, drawing in a number of leading labs. (These efforts are in addition to the vaccinia already in production at Acambis, a U.S.-U.K. biotech company in both Cambridge, Massachusetts, and Cambridge, U.K. Scheduled to reach the market by 2004, the Acambis vaccine is not expected to be much safer than the existing one is.) Some researchers have dusted off experimental vaccines from the 1970s; others have turned to cutting-edge genetic approaches. “There are really exciting new ways to possibly immunize against smallpox,” says Alfred Prince, head of virology at New York City's New York Blood Center, who collaborates with Jacobs. Among the new approaches:

Modified vaccinia Ankara. MVA is a weakened strain of vaccinia developed 40 years ago by Anton Mayr and colleagues at Munich University in Germany. The German researchers reported that by 1978, 120,000 people had received it without any serious side effects. Unlike garden-variety vaccinia, MVA cannot replicate in human cells, but this key safety feature means it may not generate a protective immune response. And MVA never received a real-world test in an actual smallpox outbreak. Researchers have a myriad of tests planned on monkeys and humans over the next several months. In one study, researchers will vaccinate monkeys and then “challenge” them with monkeypox, a simian virus akin to smallpox. A human study will compare vaccinia and MVA head to head, challenging with vaccinia and carefully assessing immune responses.

If the vaccine looks promising, the U.S. National Institute of Allergy and Infectious Diseases may contract for 30 million doses. Even if MVA does not produce an impressive immune response by itself, the earlier German studies suggest it might work as a prevaccine to blunt vaccinia's side effects. Bavarian Nordic, a German-Danish company headquartered in Copenhagen, has begun manufacturing the vaccine; it recently announced that it sold 1 million doses to the German army for that purpose.

Weak in review.

Can an old attenuated vaccinia called MVA safely protect against smallpox?

CREDIT: BAVARIAN NORDIC

LC16m8. This is another weakened vaccinia strain but, unlike MVA, it replicates in human cells. Developed at the Chiba Research Institute in Japan, LC16m8 caused few side effects when tested in 50,000 children in the 1970s. But some leading poxvirus researchers have serious reservations about LC16m8 because it doesn't go through the stage in the viral life cycle called extracellular enveloped virus, which produces the main protective antibody response in vaccinia.

“We're pushing a rapid research agenda into LC16 very hard,” says Donald A. Henderson, a key biodefense adviser to the U.S. Department of Health and Human Services. With his help, VaxGen of Brisbane, California, recently struck a deal with Japan's Kaketsuken to start clinical trials of the vaccine.

Vaccinia-tetracycline combo. Paula Traktman, a poxvirus researcher at the Medical College of Wisconsin in Milwaukee, and her co-workers have genetically engineered vaccinia, stitching in a repressor that shuts down specific viral genes unless the antibiotic tetracycline is present. In theory, a person could take tetracycline and the vaccine simultaneously. If an adverse reaction occurred, stopping the drug immediately would shut down the vaccine virus. Traktman, in collaboration with Prince, is considering testing the idea in humans.

Engineered vaccinia mutants. Like Traktman, Jacobs genetically engineers various versions of vaccinia to study it. By mutating specific genes that control vaccinia's virulence, Jacobs and co-workers have created mutants that replicate well but, when injected into the brains of mice, seem much less likely to cause neurological damage. Clinical trials are a long way off, but a similar vaccine in humans might avoid the brain swelling caused by vaccinia, one of its most devastating side effects.

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