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.