An experimental vaccine tested in more than 16,000 Thai volunteers has prevented some new infections of HIV—the first time a clinical trial has shown even a minor protective effect against the virus that causes AIDS.
The results of the RV144 trial, announced Sept. 24 by U.S. and Thai researchers, comes after years of high-profile failures that had left AIDS researchers increasingly glum about the prospect of a true HIV vaccine.
“Although the level of protection is modest at 31 percent efficacy, the study represents a major scientific achievement,” said Lieutenant General Eric Schoomaker, U.S. Army Surgeon General, at a press briefing. The U.S. Army sponsored the trial.
“These results have instilled new hope in the HIV vaccine research field and promise that a safe and highly effective HIV vaccine may become available for populations throughout the world,” added the World Health Organization and UNAIDS, the Joint United Nations Programme on HIV/AIDS, in a combined statement.
But researchers also warned that this was only a “proof of concept” study and that more analysis and testing is needed to fully understand the results and incorporate them into the design of future trials.
HIV has proven a notoriously difficult virus to combat, in part because the proteins on its outer coat mutate too quickly for the human immune system to keep up with. Researchers have tried a number of vaccine strategies to get around this—including inducing antibody attacks against relatively static portions of the virus—with little success.
So when the RV144 trial—the largest AIDS vaccine trial conducted so far—began in 2003, it met with a healthy amount of skepticism, since it involved a combination of two previous failed products. Neither ALVAC HIV vCP1521, developed by Sanofi Pasteur, or AIDSVAX, developed by VaxGen and now licensed to Global Solutions for Infectious Diseases, proved effective against HIV infection when tested singly.
Researchers hypothesized, however, that a “prime-boost” approach of combining vaccines might give an edge to RV144, which was funded by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and the U.S. Army Medical Research and Materiel Command. “The idea is to use one vaccine to get the immune system going and one to amplify it,” says Ralph Steinman, a professor and senior physician at the Rockefeller University and a Dana Foundation advisor.
ALVAC, the priming vaccine, uses the bird virus canarypox to ferry three HIV genes into the body. AIDSVAX, the booster, consists of a modified version of an HIV surface protein. Since neither uses any whole HIV, becoming infected due to the vaccine is impossible, and an independent survey of the trial found no safety issues.
Without a booster, the body’s immune system is likely to become sensitized over time to the bird part of ALVAC instead of the HIV portion, rendering it useless, Steinman says. The second type of vaccine might circumvent this problem.
In total, 16,395 HIV-negative men and women between the age of 18 and 30 took part in the trial, receiving either a vaccine regimen of four ALVAC and two AIDSWAX doses or placebos. Of those taking the placebo, 74 contracted HIV; only 51 of the vaccine-takers became infected. The results were statistically significant and equate to a 31.2 percent reduction in infection rates.
But many questions need to be answered before this vaccine might be ready for wider use, according to the researchers, including how the vaccine works exactly, how long the protection might last, whether booster shots would be necessary and whether the results would apply to other groups of people and other locations.
“We’d like to emphasize that this vaccine was tested in Thailand, against the types of HIV that circulate in Thailand: subtypes B and E,” said Col. Jerome Kim, who helped lead the study, at the press briefing. “Whether this will work in different parts of the world with different subtypes of HIV or in populations at different risk of HIV infection is not known.”
Thailand was chosen at the site of the study because of a long working relationship between the U.S. Army and the Thai government.
Another puzzle is why the vaccine did not reduce the amount of virus circulating in the blood of the people who received it who later became infected. One aim of the trial was to test whether the vaccine would reduce viral loads in this group, since the researchers had expected that the same kinds of immune responses that would prevent infection in the first place would also attack the virus after infection.
“One of the most intriguing and important findings of the Thai trial is that the vaccine regimen prevented HIV acquisition among a modest proportion of vaccinated participants, yet failed to affect viral load in vaccine recipients who later became infected,” said Anthony Fauci, director of NIAID. “This clearly begs the question of whether protective immune responses that prevent infection are related to those that control viral load.”
Most commercially produced vaccines are 60 percent to 90 percent effective, adds Tom Hassell, vice president for vaccine development at the International AIDS Vaccine Initiative, a non-for-profit organization not involved in the Thai trial. Given that, it’s unlikely that RV144 would ever be released publicly in its current form, but rather it will serve as the inspiration for better trials in the future. “It’s terrifically exciting after many years if setbacks and failures,” he says. “But although we’re excited, we’re excited about what can be done going forward.”
Hassell adds that scientists will scrutinize more-detailed scientific information from the trial that is to be presented at the Oct. 19-22 AIDS Vaccine Conference in Paris. For instance, blood test results may shed some light on which parts of the immune system were most vital to fending off HIV. “One would guess both arms of the immune system would be activated,” he says, referring to both white blood cells that directly attack foreign invaders and antibodies. “Which one was dominant in this trial will be very, very closely studied.”
“Everyone’s very excited,” Steinman says. “One, because we saw a little bit of efficacy, and two, we saw vast room for improvement.
“This shows there’s no substitute for doing studies in humans,” he adds. “Everyone predicted it wasn’t going to work at all. It shows we still don’t have the criteria to predict results without actually doing the trials.”