Ten years ago President Bill Clinton set a national goal to develop an AIDS vaccine within a decade. At that time, the human immunodeficiency virus (HIV) that causes AIDS had infected some 25 million people worldwide. Clinton established a research center at the National Institutes of Health and pledged to enlist other nations in the effort.

“There are no guarantees,” he said in a speech delivered at Morgan State University announcing the initiative. “It will take energy and focus and demand great effort from our greatest minds. But with the strides of recent years, it is no longer a question of whether we can develop an AIDS vaccine, it is simply a question of when.”

Infectious disease experts cautioned that the goal was overly optimistic. They were right. Today there is still no vaccine, despite an increasingly organized global effort and the quadrupling of funds committed to it. “We have learned in that period of time how formidable an adversary HIV is,” says Wayne Koff, senior vice president for research and development at the International AIDS Vaccine Initiative (IAVI).

The vaccine search suffered its latest disappointment in September, when investigators called an early stop to a clinical trial of a much anticipated new type of HIV vaccine. Like many other candidates now in testing, it was designed to coax the immune system's disease-killing T cells into attacking the virus more aggressively. Experts say that such a vaccine is unlikely to prevent HIV infection. But they hope at least one candidate will weaken the virus enough to delay the complications of AIDS and to reduce the need for expensive antiretroviral drugs.

Increased funding and more sophisticated organization have played a key role in getting the project this far. “By the early to mid-1990s the AIDS vaccine effort was relatively moribund,” says IAVI president Seth Berkley, who founded the group in 1996. “It's 100 percent a scientific problem; however, without an enabling environment, you can’t solve the science.”

Global spending for HIV vaccine research increased from $186 million in 1997 to $759 million in 2005, according to the Joint United Nations Program on HIV/AIDS. The IAVI helped to move the field forward by establishing research consortia so that investigators could more easily coordinate and exchange information. The group partnered with governments and vaccine makers to conduct trials outside the U.S., which account for nearly half of the 30-plus trials currently in progress. The NIH formed its own HIV vaccine trial network in 2000 to oversee clinical research sites in the U.S., Africa, Asia, the Caribbean and South America.

The scale of the effort reflects the scientific challenges. In the early 1980s, after identifying the HIV virus as the cause of AIDS, researchers were at first confident that they could come up with a vaccine against it within a few years, Koff says. Vaccines work by exposing the body to a disease-causing agent or a fragment of it. That exposure primes the immune system to produce a flood of antibodies that stick to the infecting organism and block it from entering cells. Researchers identified a protein on the surface of HIV, dubbed gp120, that enables the virus to infect and then slowly destroy so-called helper T cells, which regulate immune responses. The gp120 protein seemed like a good candidate for an HIV vaccine.

And early tests of a gp120 vaccine looked promising. But optimism faded by the early 1990s as researchers learned the vaccine worked only against strains of HIV that had adapted to conditions in the laboratory. In 2003 results finally came in from a phase III clinical effectiveness trial of a gp120 vaccine manufactured by VaxGen: it failed to prevent infections or reduce the number of virus particles circulating in the blood. (A related vaccine, VaxSyn, based on the gp160 protein [see illustration at left], never progressed to late-stage clinical testing.)

By then, HIV researchers had turned to a different idea for a vaccine. They inserted segments of HIV genes into the DNA of partially disabled non-HIV viruses. The resulting viruses could deliver the HIV genes into cells without causing a lethal infection. Infected cells would produce and display HIV proteins, however—thereby energizing the immune system's T cells to attack those proteins wherever they might appear.

Merck, along with the federally funded HIV Vaccine Trials Network (HVTN), initiated a phase II clinical proof-of-concept trial in late 2004 to quickly study the effectiveness of its adenovirus-based vaccine containing three HIV genes. In September a peek at the data revealed that participants injected with the vaccine had contracted HIV no less often than had those receiving a sham. Investigators halted the study, which had enrolled 3,000 people in the Americas and Australia, as well as a second trial begun in 2006 in South Africa. In the coming months, researchers hope to figure out why the vaccine failed and how to improve the remaining crop.

Next up for rapid testing is a broader-spectrum vaccine developed by the NIH's Vaccine Research Center (VRC). Sanofi-Aventis is conducting a phase III clinical trial in Thailand of its product, which combines a canarypox virus vaccine with VaxGen's gp120 vaccine. Results are due as early as 2008.

“The immune response and the safety so far have put these out there further than the other candidates we have,” says disease specialist Scott Hammer of Columbia University, part of the team designing the VRC vaccine trial.

Studies in monkeys seem to support the concept, says immunologist David Watkins of the University of Wisconsin–Madison. Watkins and his colleagues reported in 2006 that rhesus monkeys injected with four genes from the simian immunodeficiency virus—which causes an AIDS-like disease in monkeys and apes—were no less susceptible to infection by the identical strain of the simian virus than were unvaccinated monkeys, but they did maintain lower levels of virus in their blood for up to a year after infection. Another group reported that vaccinated monkeys were more likely to survive three years after infection than unvaccinated animals were. “That was pretty encouraging,” Watkins says. But he cautions against putting too much weight on the early results.

The ability of HIV to mutate rapidly remains one of the biggest obstacles to a successful vaccine. Its genetic material is prone to errors during duplication and replicating HIV molecules frequently exchange pieces of genes. Because of this instability and the potentially rapid life cycle of the virus, the genetic sequences of HIV particles in a single person can be as diverse as those of all the influenza viruses in the world. A vaccine that produces an immune response against one HIV sequence may have no effect on other strains.

To address this problem, the VRC vaccine contains three variants of the HIV envelope gene—the gene that most readily mutates to resist treatment. The HVTN began a second trial of Merck's vaccine last February in South Africa, where the circulating virus differs from the one on which the vaccine is based.

T cell–stimulating vaccines may help destroy cells infected with HIV, preventing them from reproducing. But experts say they probably would not trigger the immune system to make antibodies and would therefore be only partially effective. “You’re trying to control replication, not prevent infection,” Watkins says. “Although, who knows? Maybe a T cell vaccine could do that.”

Merck and the HVTN called their test “STEP,” because a successful T cell vaccine would be only a step toward full protection—but it could be a highly significant one. The IAVI estimates that even a 30 percent effective vaccine given to just 20 percent of those at risk would avert 5.5 million infections worldwide between 2015 and 2030—or 11 percent of all estimated new infections for that period. A 70 percent effective vaccine administered to twice as many patients could avert 28 million infections.

Still, there are no guarantees. “We should never assume that what we have is going to work,” says Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition in New York City. “We’ve got some very good candidates,” the IAVI's Berkley adds, “and if they work it's going to be about access” for developing countries. “We have to make sure there's going to be the political and financial commitment to drive this effort forward, no matter the results of these trials.”

In the future, researchers hope to find new candidates for antibody vaccines. A few people, when infected with HIV, spontaneously generate antibodies that can fend off the virus for decades. Researchers are studying the structure of these natural molecules. The IAVI established its neutralizing antibody consortium in 2002 to speed the discovery of triggers that would prod the immune system to generate more of them.

After 10 years of research, experts are in a better position to judge their expectations for the future. The consensus: a fully effective AIDS vaccine is a long way off. “There are people who will tell you we will never have a vaccine—I can’t say those people are wrong,” Hammer says. But he adds that “you shouldn’t be in this business if you don’t have some degree of optimism based on the science. The world needs an AIDS vaccine. To give up now is selling the science short.”