Results from an AIDS vaccine trial known as RV144 involving more than 16,000 participants from Thailand show that a prime-boost regimen of two genetically engineered vaccine candidates demonstrated marginal but statistically significant protection against acquisition of HIV -- the first time an AIDS vaccine candidate has shown any efficacy in preventing transmission of the virus, prompting excitement among many researchers. The trial tested Sanofi Pasteur's canarypox vector-based candidate ALVAC HIV (vCP1521) in combination with AIDSVAX B/E, a genetically engineered version of HIV's gp120 surface protein that was previously tested alone in two efficacy trials but showed no effect.
Among the 8,198 volunteers who received placebo, there were 74 HIV infections during the three-year study, compared to 51 infections among the other half of the volunteers who received six shots of the two vaccine candidates (four of ALVAC HIV and two of AIDSVAX B/E) over a six-month period. This equates to a vaccine efficacy of 31.2%, according to trial investigators. "To be clear, the 31.2% level of efficacy demonstrated by this vaccine is a modest one. However, it is the first time that we have ever seen a positive signal of efficacy in a human trial of any HIV vaccine -- a welcome and exciting result in a field that has been characterized by many disappointments for more than two decades," said Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID). His agency paid for the bulk of the US$105 million trial, the largest AIDS vaccine trial to ever be conducted. "This study represents a major scientific achievement and is the result of an outstanding international and inter-agency collaboration involving many partners from the Thai and US governments, private companies, non-profit organizations, and Thai volunteers," said Eric Schoomaker, surgeon general of the US Army, which sponsored the study and funded a quarter of the trial costs.
The prime-boost regimen had no impact on set point viral load -- a major predictor of disease progression -- in volunteers who became infected despite vaccination. Individuals who became HIV infected during the trial are being followed in a companion study, RV152, which will continue collecting information from these volunteers at six-month intervals. "We had power to detect a very small viral load difference," said Nelson Michael, the director of the US Military HIV Research Program (MHRP), but the viral load set points were "spot on the same between the two groups," he added, at least through the first year following infection. This contradicted what scientists would have expected from the canarypox vaccine candidate that elicits primarily cellular mediated immunity (CMI), which is thought to be associated with control of viral load. "The absence of an effect on viral load suggests this [protective effect] wasn't due to CMI," said Stanley Plotkin, a veteran vaccinologist and consultant with Sanofi Pasteur, the company that developed ALVAC.
Plotkin, among others, suggests instead that the protection afforded by the prime-boost combination was more likely mediated by antibodies. "Most people are pinning this efficacy to antibodies since we did see some sterilizing immunity," said Michael. In 1995, NIAID refused to fund a large-scale vaccine trial of an earlier version of AIDSVAX after experiments showed that the antibodies triggered by the vaccine, while effective in neutralizing cell-line adapted HIV strains in the laboratory, could not neutralize strains in circulation at that time. "The speculation I would make is that it was somehow the combination," said Plotkin. "It suggests the antibody response was improved by canarypox." This has led to consideration of other antibody functions, including the role of non-neutralizing antibodies, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular viral inhibition.
Another puzzling question is why this prime-boost regimen that overall induced less impressive cellular immune responses compared to other vaccine candidates showed any efficacy while others have failed. "The issue is why did the vaccine work when adenovirus failed," said Plotkin, referring to Merck's adenovirus vector-based vaccine candidate that failed to provide any effect against either HIV acquisition or viral load set point in a Phase IIb test-of-concept study known as the STEP trial. "No one at this point can answer that question," added Plotkin. Analyzing the data from RV144 to try to answer this question will now become the major focus among researchers at MHRP and NIAID, as well as multiple consortia of other experts in the field that have already been set up by the trial investigators. "I find it amusing on a human level that although many people looked down their noses at the ALVAC vector it is giving us the first immunological evidence of protection against HIV," said Plotkin.
One factor that may have contributed to the observed protection is the population in which the vaccine candidates were evaluated. Rather than enrolling volunteers at high risk of HIV infection, volunteers in RV144 were recruited from the general population. "This includes people at higher risk and people at very low or no risk," said Jerome Kim, deputy director of science at MHRP. This could impact the route of exposure and the amount of virus people were exposed to. While some men who have sex with men and injection-drug users were enrolled, the majority of volunteers were heterosexual men and women. "One of the reasons people have postulated that this trial may have succeeded is that the intensity of [HIV] exposure in this trial might have been lower," added Kim. "We know from work on other vaccines that even if you have a highly effective vaccine, you can overcome that vaccine immune response with a sufficiently high-dose challenge." The two previously conducted Phase III trials of AIDSVAX involved at-risk populations. One involved 5,000 volunteers who were primarily men who have sex with men from North America and the Netherlands, and the second involved 2,500 injection-drug users from Thailand. Global Solutions for Infectious Diseases, headed up by Don Francis, now holds the intellectual property rights to AIDSVAX.
Results of the trial, which was conducted by the Thailand Ministry of Public Health, were announced on Thursday in Thailand and videocast to the Rayong and Chon Buri provinces where the clinical research centers were located. The news that this experimental regimen, which many prominent AIDS vaccine researchers considered not worth evaluating in such a large trial, had managed to prevent HIV infection caught some of the study's investigators by surprise. "I was stunned," said Michael.
Others were more circumspect in their reaction to the results and await more immunological data. John Moore, an immunologist at Weill Cornell Medical College, who was a vocal skeptic of the trial from its start, said it is too soon to tell whether the results will hold up. "[The raw numbers] turned out to be highly deceptive when trying to understand the STEP trial. My sense is that the same dynamics might evolve over the RV144 trial results once they are fully analyzed and digested," said Moore.
The findings are currently being reviewed for publication in a major medical journal. "We do have immunogenicity data," said Michael, although none has been released yet to the public. "What we can say based on this data is the kinds of immune responses are the same as in the Phase I and II trials," he added. Data from RV144 will also be presented at the AIDS Vaccine Conference in Paris next month. This will likely stimulate even more discussion about how these results may impact the future direction of AIDS vaccine research. "Nothing is going to change the field like a positive signal," said Seth Berkley, president and chief executive officer of IAVI. "This validates the importance of clinical research."
However, interpreting the trial results will take time and researchers agree there is much work to be done. "This is by no means our final destination," said Fauci. "Now we have a foundation upon which to explore potential correlates of immunity and to pursue further study to improve on these findings."
If researchers could determine from the small number of vaccinated volunteers who were protected precisely what the immune correlates were, they could capitalize on this to develop improved candidates. "Extracting correlates from this study will be essential," said Plotkin. However, researchers have limited cell samples from vaccinated volunteers to work with. "We have about 20 million cells," said Michael, who noted that many cells are necessary to run the more sophisticated assays researchers have planned, such as polychromatic flow cytometry and viral inhibition assays. Investigators also plan to study plasma and serum samples to fully evaluate antibody responses among volunteers. "We do not know whether our current measures of the human immune response are even relevant to the protection that we see in this trial," warned Fauci.
Sponsors of the trial stressed that the study was not intended as the final hurdle before seeking licensure for the vaccine candidates. While the official title of RV144 declared it was a Phase III efficacy trial, Michael said that the trial was actually a Phase IIb test-of-concept trial, based on the number of HIV infection endpoints investigators anticipated due to the significantly reduced HIV incidence in Thailand when the trial began. Also, the potential efficacy of this regimen outside of HIV clades B and E, which are the predominantly circulating subtypes in Thailand, is unknown. The ALVAC vaccine had been genetically engineered to express HIV subtype B gag and pro and subtype E env, and the gp120 proteins in AIDSVAX were also from subtypes B and E. "The vaccines were designed for use in Thailand," said Kim.
All of these issues will be discussed and debated over the coming weeks as immunology data is shared and plans are hatched to further evaluate the RV144 results. "We need to bring the best minds together and map the way forward," said Fauci. "Today I have a renewed sense of cautious optimism that the possibility of improving on these encouraging results and ultimately developing a highly effective vaccine to protect against HIV infection is within our reach." Plotkin agrees. "This should make everyone more hopeful."
Andreas von Bubnoff contributed reporting to this article.