With the full results of the Thai HIV vaccine trial released this morning (October 20) at a conference in Paris, the HIV/AIDS research community can breathe a sigh of relief: The vaccine candidate does appear to offer a real, albeit modest, level of protection against HIV infection.

Human Immunodeficiency Virus Image: Wikimedia commons, NIAID

"What we saw today was a more complete presentation of different types of analyses that were done, [and] the scientific conclusions are as they were described earlier," said virologist Gary Nabel, director of the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., who did not participate in the research. "This really is a landmark study for HIV vaccine research."

After the preliminary results were released late last month, many raised concerns about whether the 31% decrease in HIV infection risk shown by the vaccine candidate was genuine or a statistical anomaly. The doubts were in part fueled by hints of additional analyses that yielded weaker and non-significant effects.

The full data, presented at the meeting and published today in the New England Journal of Medicine (NEJM), alleviated some of those uncertainties by showing the same trend in three different analyses -- the intent to treat (ITT), which included all 16,402 subjects; the modified intent to treat (MITT), which excluded seven individuals who were infected with HIV before the trial even began (and was the only analysis made public last month); and the per protocol analysis, which excluded any subject who did not receive all six doses of the vaccine within the correct time periods (about 25% of subjects) as well as any individuals who became infected over the course of the study (about 31% of subjects).

Although the MITT analysis was the only one that reached statistical significance, it "was the most appropriate," and "all three analyses are qualitatively similar," said infectious disease epidemiologist Seth Berkley, CEO of the International AIDS Vaccine Initiative (IAVI), who was not involved in the study. "It's unfortunate that the controversy occurred, [but] now with all the data in front of us, [we can see that] there is a signal there."

What's important now, researchers agree, is learning as much as possible from the results of this trial. Two "intriguing" trends in particular that emerged during today's meeting deserve a closer look, Berkley said. First, the vaccine seemed to provide a higher level of protection early that waned over time, and second, that protection appeared to be stronger for low and moderate risk groups, as opposed to the high risk group.

"All those things make sense if you think about the pathogenesis of HIV," said viral immunologist Barney Graham of the VRC, who was not involved in the research. "Typically in an HIV infection you're only infected with one virus. [These results suggest] we may be right on the threshold of being able to control a single virion, but we may not be close to controlling a group of virions -- for example, in IV drug users, or people with genital ulcers."

Another area that warrants further investigation is the mechanism behind the vaccine's effectiveness. The vaccine is a combination of two HIV vaccine candidates -- one that showed no effect and another that was never tested in an efficacy trial. "The combination of the two worked," Berkley said, "and so the question is why? What's the mechanism?"

"I think this has inspired the field and given hope that it is possible to give protection in human," Berkley said. "If a poor vaccine and a weakly immunogenic vaccine together can provide protection, then [developing an effective vaccine] may be easier than we originally thought."

In addition, the trial revealed no difference in viral load or CD4 counts of infected individuals, suggesting that "those immune responses that might be able to initially prevent HIV infection and those that modulate [the virus] once you have become infected might be quite different," Colonel Nelson Michael of the Walter Reed Army Institute of Research and the US Military HIV Research Program (MHRP) said during a press conference this morning.

The trial's collaborators are assembling four advisory committees "to interpret the results and plan future [vaccine trials]," said Michael, who is a coauthor on the NEJM paper. "We're looking forward to the rich discussion [about the results] that has already begun."