Researchers have gained important clues about immune system responses that could play a role in protecting people from HIV infection in follow-up studies from the world's largest HIV vaccine trial to date. Results from laboratory studies based on the trial were published in the New England Journal of Medicine.
The HIV vaccine trial in Thailand, called RV144, showed that the group receiving the vaccine regimen was estimated to be 31.2 percent less likely to be infected than those who didn't get the vaccine, and researchers set out to learn why.
Researchers analyzed samples from RV144 trial participants to look at immune responses in the vaccine recipients. The researchers found that different types of antibody responses were associated with a higher or lower rate of HIV infection.
"By studying those who became infected compared to those who did not, we believe we have found very important clues for how the RV144 trial might have worked," said Barton F. Haynes, MD, who led the study and is the Frederic M. Hanes Professor of Medicine and Immunology at Duke.
"The hypothesis is that protection in the trial was primarily mediated by antibodies. All of the antibody types studied have been isolated from RV144 vaccinees, and the antibodies' protective effect will be tested to see if they prevent acquisition of infection in non-human primate studies."
The RV144 trial provided the first evidence in humans that a safe and effective preventive HIV vaccine is possible, and it provided an opportunity to look for vaccine-induced immune responses that correlated with the rate of infection.
The current results are based on intensive laboratory studies of the patient specimens collected in the Thai trial. These studies are the result of nearly two years of work by more than 100 researchers at 25 institutions, who collaborated to understand how the RV144 vaccine regimen prevented HIV infection in some vaccine recipients.
The first finding is that antibodies specific to a particular region of the HIV envelope (outside coat) protein, called V1V2, correlated with lower infection rates among those who were vaccinated. Antibodies are proteins that the body produces to defend against harmful agents such as viruses or bacteria.
The hypothesis is that when these IgG antibodies bind to the V1V2 region of the outer coat of the virus, they might help prevent infection.
A second finding indicates that vaccine recipients with the highest blood levels of a different type of envelope protein binding antibody, known as IgA, had less protection from HIV than those with low levels. When compared with the placebo group, there was no difference in the rate of infection among the vaccinated group with high IgA antibodies and volunteers who received placebo, so the scientists believe that these IgA antibodies may have interfered with other vaccine-induced protective responses.
These findings, and the laboratory tests used in the studies, may help to explain the efficacy seen in RV144, and they will be tested in future studies to assess their importance to the protective effect of the vaccine.
Results from RV144, which involved more than 16,000 adult volunteers in Thailand, were published in the New England Journal of Medicine in October 2009. The results showed that the prime-boost combination of ALVAC® HIV and AIDSVAX® B/E was safe and lowered the rate of HIV infection by an estimated 31.2 percent compared with placebo (p=0.04) in a community-based population in Thailand. The vaccine combination was based on HIV strains that commonly circulate in Thailand.
"These studies reinforce and extend the results seen in the RV144 trial and provide new insights that may lead to a better and longer-lasting HIV vaccine," noted Col. Jerome Kim of the U.S. Military HIV Research Program (MHRP), senior author of the study.
These new laboratory studies inform new testable hypotheses that, if validated, may help scientists prioritize vaccine candidates for future clinical trials, potentially accelerating the development of a more effective vaccine.
Researchers noted that these results are unique to the RV144 regimen, and that different vaccines may protect against HIV in different ways. More research is needed to fully understand these results, and to determine if they can be generalized to other types of HIV vaccines or similar vaccines tested against other regional types of HIV.
These studies were conducted by a large international collaboration led by the Center for HIV/AIDS Vaccine Immunology (CHAVI), which Dr. Haynes directs and which is funded by the National Institutes of Health (NIH), the National Institute of Allergy and Infectious Diseases (NIAID) and by the Collaboration for AIDS Vaccine Discovery, which is funded by the Bill & Melinda Gates Foundation.
The research was initiated and coordinated by the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research, which receives funding from the U.S. Army Medical Research and Materiel Command and the Division of AIDS, NIAID, NIH. The statistical design and analyses were conducted by the Statistical Center for HIV/AIDS Research and Prevention (SCHARP) at the Fred Hutchinson Cancer Research Center.
- Barton F. Haynes, Peter B. Gilbert, M. Juliana McElrath, Susan Zolla-Pazner, Georgia D. Tomaras, S. Munir Alam, David T. Evans, David C. Montefiori, Chitraporn Karnasuta, Ruengpueng Sutthent, Hua-Xin Liao, Anthony L. DeVico, George K. Lewis, Constance Williams, Abraham Pinter, Youyi Fong, Holly Janes, Allan DeCamp, Yunda Huang, Mangala Rao, Erik Billings, Nicos Karasavvas, Merlin L. Robb, Viseth Ngauy, Mark S. de Souza, Robert Paris, Guido Ferrari, Robert T. Bailer, Kelly A. Soderberg, Charla Andrews, Phillip W. Berman, Nicole Frahm, Stephen C. De Rosa, Michael D. Alpert, Nicole L. Yates, Xiaoying Shen, Richard A. Koup, Punnee Pitisuttithum, Jaranit Kaewkungwal, Sorachai Nitayaphan, Supachai Rerks-Ngarm, Nelson L. Michael, Jerome H. Kim. Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial. New England Journal of Medicine, 2012; 366 (14): 1275 DOI: 10.1056/NEJMoa1113425
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