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

"There are no guarantees," he said in a speech delivered at Morgan State University in Baltimore 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. A decade later, 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 immunologist Wayne Koff, senior vice president for research and development at the International AIDS Vaccine Initiative (IAVI).

The next two years will reveal whether researchers are on the right track for at least a partially effective vaccine. Three clinical trials are underway to test the effectiveness of coaxing the immune system's disease-killing T cells into attacking the virus more aggressively. Experts say that such a vaccine is unlikely to prevent the HIV infection. But they hope it will weaken the virus enough to delay the complications of AIDS and reduce the need for expensive antiretroviral drugs.

Increased funding and more sophisticated organization have played a key role in getting 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 move the field forward by establishing research consortia so investigators can more easily coordinate and exchange information. The group partnered with governments and vaccine makers to conduct trials outside of the U.S., which now account for nearly half of the 30-plus trials currently underway. 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 confident they could come up with a vaccine against it within a few years, says Koff. Vaccines work by exposing the body to the disease-causing agent or a fragment of it, which primes the immune system to produce a flood of antibodies that stick to the infecting organism and block it from entering cells.

HIV infects so-called helper T cells, which regulate the immune response, and slowly destroys them. Researchers rapidly identified the molecule that grants HIV entry into those cells—a surface protein called gp120, which inserts itself into CD4 receptor molecules on the helper cells.

Early tests of a gp120 vaccine looked promising, but optimism faded by the early 1990s as researchers learned the vaccine only worked against strains of HIV that had adapted to conditions in the laboratory. In 2003 results finally came in from a phase III clinical trial of a gp120 vaccine manufactured by VaxGen: It failed to prevent infections or reduce the number of virus particles circulating in the blood.

By then, HIV researchers had turned to the idea of energizing killer T cells by injecting DNA-encoding genes from circulating strains of the virus. This approach entails using a partially disabled, non-HIV virus to infect and deliver the HIV DNA to the cells that the delivery virus would normally infect. This stimulates the cells to produce the corresponding HIV proteins and display them on their surfaces to attract helper and killer T cells.

Drugmakers Merck and sanofi-aventis have each made versions of a T cell–stimulating vaccine by inserting HIV genes into a viral vector, or gene delivery system. Sanofi-aventis is conducting a phase III clinical trial in Thailand of its canarypox vector mixed with gp120. The results are due in 2009.

Merck has initiated a proof-of-concept phase IIb clinical trial to study the effectiveness of its adenovirus-based vaccine, along with subjects' resistance to infection by the relatively common adenovirus—a potential drawback to the vaccine. Results are expected as early as next year. The NIH's Vaccine Research Center (VRC) has developed a similar vaccine that is in earlier-stage testing.

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

Studies in monkeys seem to support the concept, but immunologist David Watkins of the University of Wisconsin–Madison, cautions against putting too much weight on the early results. Watkins and colleagues reported last year that rhesus monkeys injected with four genes from simian immunodeficiency virus—the ape version of HIV—had low levels of virus in their blood up to a year after infection but did not develop full-blown AIDS. "That was pretty encouraging," he says. But he notes that other monkey vaccines had provoked immune responses but did not ultimately control infections.

The ability of HIV to mutate rapidly remains one of the biggest obstacles to a successful vaccine. The DNA 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.

Hammer says the VRC vaccine tries to solve this problem by including three variants of the HIV envelope gene—the one that most readily mutates to resist treatment. Merck began a second trial of its vaccine in February in South Africa, where the circulating virus differs from the one the vaccine is based on.

T cell–stimulating vaccines may lead to the destruction of cells infected with HIV, preventing them from reproducing. But experts say it probably would not trigger the immune system to make antibodies, and would, therefore, only be partially effective. "You're trying to control replication, not prevent infection," says Watkins, "although, who knows? Maybe a T cell vaccine could do that."

A successful T cell vaccine would be a step along the way (Merck calls its trial the "step" trial) but it could be a significant step. The IAVI estimates that even a 30 percent effective vaccine given to 20 percent of those at risk would avert 5.5 million infections worldwide between 2015 and 2030—or 11 percent of estimated new infections—compared with 28 million infections averted during that same period by a 70 percent effective vaccine administered to twice as many patients.

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," adds the IAVI's Berkley, "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 by building on the success of the T cell approach or to replace it if it fails. Some people infected with HIV generate antibodies that fend off the virus successfully for decades. Researchers have isolated and are studying the structure of several of these natural molecules. The IAVI established its neutralizing antibody consortium in 2002 to speed the discovery of substances that prod the immune system to generate the HIV-fighting antibodies.

After 10 years of research, experts are in a better position to judge 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," says Columbia's Hammer. But "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."