President Bill Clinton gave AIDS vaccine research a shot in the arm on May 19, 1997, when he called for scientists to develop a vaccine for the disease within ten years--and invoked the spirit of John F. Kennedy's 1961 declaration that the U.S. would set a man on the moon within ten years. Although activists criticized Clinton for not promising new money to support the initiative, having a vaccine as a presidential goal is likely to help boost funding for vaccine research in future federal budgets. In the meantime, the Administration says it plans to propose extending federal Medicaid coverage to buy costly and potent drugs for infected low-income people who have not yet developed the symptoms of full-blown AIDS. Medicaid recipients are now excluded from early access to these drugs.
Although some researchers are concerned about the demoralizing consequences if Clinton's timetable proves impossible, many are optimistic that the campaign might spur drug companies to step up their efforts to protect against HIV. Manufacturers have tested dozens of potential vaccines in small groups of people. These small trials are aimed at establishing that the preparations are safe and that they stimulate the immune system. But the results so far have not persuaded pharmaceutical companies to organize large "phase 3" trials involving thousands of volunteers--the kinds of tests which will be necessary to prove that a vaccine is safe for widespread use and effective and preventing infection.
Researchers do not yet understand what aspects of the immune response are necessary to confer protection against HIV; some even worry that no highly effective vaccine is possible. And development efforts have slowed since 1994, when the National Institutes of Health decided that small tests had produced insufficient evidence to justify large-scale U.S. trials of two candidate vaccines based on an HIV protein called gp-120.
AIDS vaccines have largely fallen out of the spotlight since then, but very recent findings suggest possible ways to overcome some of the widely-recognized obstacles to developing an effective vaccine. One of the big problems bedeviling such efforts is that there are multiple strains of HIV, and different ones predominate in different regions. As a result, a vaccine that works acceptably in one part of the world might be useless elsewhere. Recently, however, Kent Weinhold of Duke University Medical Center demonstrated that several vaccine candidates in development could actually elicit immune responses to a variety of HIV strains. In the tests, immune-system cells known as cytotoxic T lymphocytes, taken from a group of volunteers, were exposed to cells harboring various strains of HIV. Having thus been "trained" to recognize the characteristic proteins of HIV, the lymphocytes often were then able to kill HIV-infected cells.
The vaccines that Weinhold investigated were based on a modified canarypox virus (a virus that causes disease in canaries but not in humans) that had been genetically engineered to contain a gene from HIV. These vaccines are more sophisticated than the gp-120 vaccines that NIH declined to test in 1994. In the newer tests, vaccinated volunteers were injected first with the canarypox preparation, and subsequently given a booster shot consisting of just HIV's gp-120 protein, a protein that HIV uses as a gateway to enter the human cells. Consequently, the body's immune cells were exposed to HIV proteins from two different sources--both the ones manufactured by the canarypox virus, and the gp-120 protein that was injected directly--to assist the cells in identifying and destroying the invading AIDS virus.
The encouraging results from laboratory tests do not yet prove the vaccines will work in people. "The only way to establish protection is to do a phase 3 trial," notes Carole A. Heilman, associate director of the division of AIDS at the National Institutes of Health. But the latest finding show that the new candidates have potential. "There seems to be more activity going on in AIDS vaccines in general," Heilman comments.
David B. Weiner the University of Pennsylvania recently announced another encouraging discovery. He and his colleagues were able to make two chimpanzees resistant to HIV infection (like humans, chimps are susceptible to the virus) by vaccinating them with a preparation based on "naked" DNA encoding HIV genes. Conventional vaccines employ killed or modified pathogens, or proteins made by them, rather than DNA. In contrast, a DNA vaccine like the one used by Weiner works by allowing the body's cells to make viral proteins in a harmless, non-infectious form; the immune system then gets sensitized to them, which helps prevent subsequent infection by the actual virus. Weiner's result provides evidence that a naked DNA vaccine might work in people, although there are substantial differences between chimpanzees and humans: most notably, chimps usually do not become sick with AIDS when infected with HIV.
Scientists have also learned a lot in recent years about the molecular-level interactions between HIV and the receptors on cells of the body, which provide the virus with its foothold for entering the cells. "We can work to find the best immunogens," Heilman declares. Moreover, researchers have acquired new tools in the form of genetically-engineered small animals, such as rabbits, that are susceptible to infection with HIV. (Non-primates are normally immune to infection with HIV and its close viral relatives.) These animals will speed the testing of anti-AIDS therapies and vaccines.
Plans are moving ahead to test various types of HIV vaccine in humans in intermediate and large-scale trials; studies are now being planned in Uganda, Thailand and the U.S. And despite the past gloom in the field, Heilman says there is no reason to believe that President Clinton's goal is out of reach. Most successful vaccines are the end result of trail and error modifications, she notes. But HIV researchers have a more sophisticated understanding of their quarry than did previous generations of immunologists. "This is not very different from how vaccines generally are developed," she points out: "Everything is consistent with our enthusiasm."