The Thai Phase III HIV vaccine clinical trial, also known as RV144, was the largest HIV vaccine study ever conducted and involved more than 16,000 volunteers in Thailand. This U.S. Army-sponsored study showed that an investigational HIV vaccine regimen was safe and modestly effective at reducing the rate of HIV infection; study participants who received the vaccine were 31.2% less likely to have become HIV-infected were placebo recipients.
In addition to demonstrating modest protection, RV144 also provided the first opportunity for a detailed comparison of immune responses in vaccine recipients who remained uninfected to those who were not protected from becoming infected. This may help improve our understanding of what immune responses are needed for protection against HIV. Since the results of RV144 were reported in 2009, the U.S. Military HIV Research Program (MHRP) and the RV144 collaborators, including NIAID, have been working with international experts to better understand and build on these results quickly and effectively. The extensive laboratory analyses were published in the New England Journal of Medicine in April 2012 and provided important clues about what types of immune responses may be required for a preventive HIV vaccine to work. Specifically, scientists found that among the adults who received the experimental HIV vaccine used in RV144, those who produced relatively high levels of a specific antibody after vaccination were less likely to get infected with HIV than those who did not. This particular antibody attaches to a part of the outer coat of the virus called the first and second variable regions, or V1V2 and it belongs to a family of antibodies called immunoglobulin G (IgG).
Other vaccinated participants who had relatively high levels of a different type of HIV binding antibody appeared to have less protection from the virus than vaccinated participants who had low levels of this protein. This antibody attaches to a different part of HIV’s outer coat known as the first constant region or C1 and belongs to a family called immunoglobulin A (IgA). The researchers believe that the C1 IgA was either associated with less benefit from HIV vaccination or that it directly reduces the benefit of vaccination.
The researchers now plan to investigate whether high levels of V1V2 antibodies directly caused the modest protective effect seen in the study or were simply linked to other, still unidentified factors.
In addition, follow-up studies are attempting to determine if protection can be extended in duration with additional vaccine doses (boosters) because higher levels of efficacy (60%) were seen at 12 months in the RV144 trial. A small immunogenicity study is underway (RV305) to evaluate an extended boosting regimen using the same vaccine components that were used in RV144. Another study to evaluate multiple boosting strategies (RV306) is also being planned.
It is also important to note that different vaccine candidates may protect against HIV in different ways. Therefore, more research is needed to understand whether these new findings will be relevant to other types of HIV vaccines or to similar vaccines tested against HIV strains from other regions or against different routes of exposure to the virus, according to the authors.
The Pox Protein Public-Private Partnership or P5 was established in 2010 to build on the results of RV144. The partnership, which is comprised of the NIAID, The Bill and Melinda Gates Foundation, the HIV Vaccine Trials Network, the U.S. Military HIV Research Program, Sanofi Pasteur and Novartis Vaccines, seeks to advance and ultimately license HIV pox-protein vaccine candidates that have the potential to achieve a broad public health impact.
Clinical studies are being planned for Thailand and South Africa to determine the effect of an improved RV144 regimen in other populations with different risk factors and levels of HIV incidence, and in regions where other strains of HIV circulate (namely clade C in South Africa). While these studies will take much longer to plan and execute, they will provide important clinical data and may accelerate the development of a safe, effective and durable vaccine that could be used globally.
The P5 is also planning to test other pox-protein HIV vaccine candidates in South Africa in “discovery” trials to gather information about other potential vaccine candidates. The purpose of these trials, which would have a flexible trial design to help accelerate progress, would be to identify other potential prime-boost combinations.
In this study, scientists report that several Simian Immunodeficiency Virus (SIV) prime-boost vaccine regimens have demonstrated partial protection against acquisition of infection by a virulent, tough-to-neutralize SIV strain that is different from the strain used to make the vaccine—a scenario analogous to what people might encounter if an HIV vaccine were available. The experimental vaccine regimens reduced the monkeys’ likelihood of becoming infected per exposure to SIV by 80 to 83 percent compared to a placebo vaccine regimen. Further, in those monkeys that did become infected, the experimental vaccine regimens substantially reduced the amount of virus in the blood compared to controls. Now plans are underway for early-stage clinical trials of a human-adapted version of one of the study’s prime-boost vaccine combinations.
The best predictor of protection from SIV in the vaccinated monkeys was the presence of antibodies that latched onto the virus surface protein. This finding reinforces what scientists have learned so far about why the first modestly effective HIV vaccine worked in humans and indicates that the HIV surface protein Env is a critical vaccine ingredient. The new research also provides strong evidence that the immune system’s mechanism for preventing infection is significantly different from its mechanism for controlling viral replication.
The NIAID-supported HIV Vaccine Trials Network (HVTN), known as HVTN 505, expanded its primary goals to include an examination of whether or not the experimental vaccine regimen prevents infection. The primary goal of the study had been to determine if the vaccine regimen decreases the amount of virus in the blood of vaccine recipients who later become infected with HIV. Preventing HIV infection was originally a secondary goal. However, promising data from the RV144 study and from a series of non-human primate studies suggest that this vaccine regimen might be more protective than scientists had anticipated. The study, which opened in 2009, is examining a combination of two investigational HIV vaccines to 1) test whether the vaccine regimen can reduce viral load (the amount of HIV in the blood) of vaccinated people who later become infected with HIV, and 2) provide additional information about the existing good safety record of the vaccine regimen.
In order to address the study goals in a timely manner, the HVTN 505 also expanded its enrollment from 1,350 to 2,200 participants. The study is enrolling only circumcised men who have sex with men and who have no detectable previous exposure to a particular common cold virus (adenovirus Type 5, or Ad5). The number of study sites also expanded from the 13 original sites to a total of 21 sites in order to meet these enrollment figures and expedite study enrollment.
HVTN 505 is designed to answer important scientific questions that could lead to the discovery and development of new and improved HIV vaccines in the future. These new measures will assist the study investigators in reaching their goals.
For more information about HVTN 505, visit the NIAID’s Q&A about the study, as well as its official Web site, Hope Takes Action.
HIV Vaccine Awareness Day, May 2012
Vaccine Protection against Acquisition of Neutralization-Resistant SIV Challenge, D. H. Barouch, January 2012
HIV vaccine development--improving on natural immunity, A.S, Fauci, M.I. Johnston, NEJM, September 2011
Consortia for AIDS Vaccine Research in Nonhuman Primates, August 2011
HVTN 505 HIV Vaccine Study To Expand Scope, August 2011
HIV Vaccine Awareness Day, May 2011
HIV Vaccines and Adaptive Trial Designs, L. Corey, G.L. Nabel, C. Dieffenbach, et.al., April 2011
Last Updated August 27, 2012
Last Reviewed August 27, 2012