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All vaccines accomplish the same thing: like a self-defense instructor who impersonates a mugger, a vaccine teaches the immune system what to do in an emergency. When a real thug appears, the lesson is recalled and a swift immune response immediately overpowers the attacker. Traditional vaccines are made from disease-producing organisms that have been weakened or killed. Albert Sabin's polio vaccine, for example, consisted of a live attenuated virus too weak to cause disease, while Jonas Salk made one from killed polio virus. Either protected against sickness, paralysis, or death.
Donald P. Francis, of VaxGen, is directing the first large-scale human clinical trial of prospective AIDS vaccine. |
Although traditional vaccines have eradicated smallpox, driven polio to the brink of extinction, and held dozens of other infectious scourges in check, most scientists don't believe they can defeat HIV. A live attenuated approach pioneered by Ronald C. Desrosiers, professor of microbiology and molecular genetics at Harvard Medical School and director of the New England Regional Primate Research Center, will probably not be used in humans, because a parallel vaccine tested in rhesus monkeys kept some of them safe from simian AIDS but made others sick. Salk, in the last years of his life, developed a killed HIV vaccine that eventually failed in clinical trials.
AIDS has driven scientists to reinvent vaccinology, and vaccine designers now use molecular tools to snip genes out of HIV and stick them into various systems for making or delivering vaccines. Protein subunit vaccines, for example, are made by inserting an HIV gene into a cell line that thrives in the laboratory, where it generates lots of protein that can be purified for injection. These immunizations stimulate an antibody response, just like an old-fashioned vaccine, and they are extremely safe. Last June, a subunit vaccine made by VaxGen, a biotechnology company based in Brisbane, California, entered the first clinical trials large enough to discover whether a vaccine can prevent AIDS. This effort is spearheaded by microbiologist Donald P. Francis, S.D. '79, M.D., VaxGen's cofounder and president, who studied virology in Myron Essex's lab at the Harvard School of Public Health in the 1970s. Although few expect VaxGen's product to protect more than a modest proportion of immunized volunteers, its efficacy won't be known until results are available three years from now.
A second promising approach, so-called live vector vaccines, involves putting HIV genes into viruses or bacteria that penetrate human cells but don't cause disease. The HIV genes direct production of viral proteins that are displayed on the cell surface--where in theory they will program the host's T cells to kill HIV that they subsequently encounter. Naked DNA vaccines work the same way, but in this case HIV genes are packaged not in whole viruses or bacteria but in plasmids--tiny circles of DNA that bacteria use to swap genetic material among themselves. Several DNA and live vector vaccines are currently being studied in small clinical trials, but none has yet entered a large field study.
Ronald C. Desrosiers has been working on a simian AIDS vaccine.
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During the past 12 years, 27 experimental HIV vaccines have been approved for human testing in the United States. Most have not been good enough to merit testing in more than a few hundred volunteers. The National Institutes of Health currently sponsors about one dozen small trials; VaxGen is paying for its own large studies, with some laboratory assistance from the government.
So far, no vaccine has been specifically designed to combat the HIV-1C epidemic that is raging through Africa. Although a few experiments indicate that some vaccines developed for the United States and Asia can also stimulate immune responses to African viruses, there are sound scientific and political reasons for developing subtype-C vaccines. A vaccine that matches its challengers is not only more likely to protect, but also less likely to arouse concern that African volunteers are being used as guinea pigs for products that will mainly benefit affluent Americans.
Two vaccines against African subtypes are now being developed with support from the International AIDS Vaccine Initiative, a New York-based organization that received a $25-million boost from the William H. Gates Foundation in May. One aims to protect against HIV-1C, the other against subtype A. Other companies say they are working on vaccines for Africa, despite a shortage of financial incentives. Congress is considering a tax credit for companies engaged in vaccine research, and further motivation could come from creation of an international fund that would purchase vaccines for developing nations.
The new vaccinology driven by AIDS could have panoramic effects, leading to new preventive vaccines for hepatitis C, malaria, and other epidemics that are emerging as this century ends. Lessons learned from the search for an HIV vaccine will help protect us against the first great epidemic of the twenty-first century--whatever that turns out to be.