Search for a safer smallpox vaccine

URBANA, ILLINOIS — It's a tough decision, but someone has to make it. On Thursday 20 June, 15 scientific advisors will recommend to Tommy Thompson, the top US health official, who would get vaccinated should terrorists unleash the smallpox virus on US civilians. For 77% of Americans surveyed in a recent Gallup poll, the question was a no-brainer: everyone should. But that's not the current policy, and for good reason. The current smallpox vaccine is one of the most hazardous vaccines around. Because of that, and the terrorist threat, a handful of companies is trying to come up with a safer vaccine for a disease once thought dead and buried.During the smallpox eradication campaign, health officials vaccinated people in endemic areas with live vaccinia virus, a weaker cousin of variola virus, which causes smallpox. The vaccine strain protected almost everyone from the disease. For most people, the side effects were moderate but worth it: a blister that turns into a scab after two weeks; a fever of greater than 100°F; an occasional rash, followed by complete recovery. But 1 in 100,000 develop life-threatening brain infections, and about one in a million (usually immune-compromised patients), die from the encephalitis. In other immune-compromised patients, such as patients with AIDS, organ transplants, and even eczema, vaccinia can occasionally multiply out of control, causing difficult-to-treat skin infections that can be fatal. "If there's [ever] a need for a vaccine, then it would be ideal to have a vaccine that is much safer then the one we have," says Sharon Frey, an associate professor at St Louis University in St Louis, Missouri, and an investigator in a division of National Institute of Allergy and Infectious Diseases (NIAID) that tests vaccines for the government. After September 11 and the subsequent anthrax attacks raised fears of an intentional smallpox release, however, the US government's most visible efforts went toward increasing the supply of conventional smallpox vaccine. The only vaccine at the time was Wyeth's Dryvax, a traditional live vaccinia vaccine that the company no longer makes but had stored frozen since health officials stopped routine vaccination two decades ago. When supplies of Dryvax were found too scarce to vaccinate all Americans, the NIH and Centers for Disease Control contracted with Acambis, a vaccine maker in Cambridge, UK, to produce a total of 155 million doses of a similar vaccine by the end of 2002. But Acambis's vaccine isn't really much of an alternative, says Paul Offit, Chief of Infectious Diseases at Children's Hospital of Philadelphia, and one of the 15 members of the Advisory Committee on Immunization Practices (ACIP) that's advising Thompson. That's because both Dryvax and Acambis's vaccine use the same strain of vaccinia, called New York City Board of Health (NYCBOH), which proved its mettle as a vaccine during the global eradication campaign. Dryvax was produced by inoculating the vaccinia virus under the skin of calves and harvesting it from pus in the resulting blisters — a procedure that could expose vaccine recipients to infectious agents from cows. Acambis's vaccine is grown instead in cell culture. But most of the side effects are due to the strain itself, not vaccine contaminants. "I doubt if there would be a significant difference," he says.Nevertheless, it's worth developing an alternative to the current vaccine, Offit says. The risk is still high as vaccines go, and modern medicine has allowed more immunocompromised patients to survive than ever before. What's more, "when you give a [traditional] smallpox vaccine to someone, they are contagious with vaccinia virus. That could be dangerous to immunocompromised people." It means that simply not vaccinating immunocompromised people may not be enough to protect them.While the Acambis contract grabbed the headlines last fall, others continued working behind the scenes to develop safer vaccines. "There's a lot of effort being put into figuring out alternatives," says Carole Heilman, who directs microbiology and infectious-disease research at the National Institute of Allergy and Infectious Diseases (NIAID). Some five or six companies are working with NIH to develop safer vaccines, Heilman says, although she declined to specify which companies, citing confidentiality agreements. One top vaccine candidate consists of a weakened vaccinia strain called modified vaccinia Ankara (MVA), which is being tested as a vaccine by Bavarian Nordic of Copenhagen. Developed in the last years of the smallpox epidemic by a German research institute, MVA was grown in cultured chicken cells. In the 1970s, more than 120,000 Germans received MVA, and none developed serious side effects. MVA was used then as a so-called primer — a vaccine given a few months before the standard smallpox vaccine that boosted immunity enough to hold off side effects from the standard vaccine strain. And Bavarian Nordic has touted the vaccine not just as a primer, but as a replacement for the traditional vaccinia strains. But MVA has yet to prove itself in the clinic. "There's certainly reason for optimism, but whether that vaccine induces enough immunity to protect is still a question," Offit says. Several of the companies working with NIAID are testing live but crippled vaccinia strains developed as vehicles to create AIDS vaccines, Heilman says. Instead of inserting HIV antigens, the companies are testing whether the vectors themselves might work as smallpox vaccines, either alone or as part of a prime–boost strategy. And researchers at a company that's collaborating with NIAID are also looking seriously at an inactivated vaccinia vaccine, which would be given together with an adjuvant designed to boost antibody production, Heilman says. "What's really needed is a vaccine that is perhaps a killed virus or part of a virus," Frey says.No matter what new vaccine is developed, testing will be far from straightforward, Heilman says. NIAID has begun helping companies test prospective vaccines to see whether they protect a series of animal models. If they protect mice from an orthopox infection called ectromelia, next up would be rhesus monkeys exposed to monkey pox. Finally, rhesus monkeys could be tested for protection against smallpox itself at CDC's BSL 4 facilities in Atlanta, Heilman says. What's more, researchers will compare the antibodies and cytokines produced in people immunized with new vaccines and traditional vaccines. That would give a pretty good idea of how similarly the vaccines act, Heilman says. But "Could you ever be absolutely sure that [the new vaccine] would prevent smallpox? No, you couldn't," she admits.So how to ensure their protection for millions of people in the event of a smallpox outbreak? On Thursday, the ACIP will recommend to Thompson whether to continue current government policy of immunizing people with healthy immune systems who have come in contact with an infected person. Safer smallpox vaccines, if they are ever developed, could help protect the rest of the population. But until then, the decisions won't be getting any easier.

Search for a safer smallpox vaccine

As US officials decide who should get the smallpox vaccine, there's new emphasis on developing a safer vaccine.

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