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Merck has been testing a candidate HIV vaccine in two large phase II clinical trials; the STEP study in North and South America, the Caribbean and Australia, and a parallel study called Phambili in South Africa.
STEP was a multi-center, randomized, double-blind, placebo-controlled phase II test-of-concept clinical trial. Started in December 2004, enrollment in the study was completed by March 2007 and more than 2,500 participants had received all three doses of vaccine or placebo. STEP was evaluating two primary efficacy endpoints:
- Whether the vaccine prevented HIV infection in subjects who were HIV negative at the beginning of the study.
- Whether the vaccine lowered the amount of virus in subjects who became HIV infected during the course of the study.
However, last month the drug trial was halted because the vaccine appeared to be increasing the risk of HIV infection among study participants. The South African study Phambili, which began in 2007 using the same vaccine has been halted .
Merck reported earlier this week that neither efficacy endpoint was met with STEP . Results from tests on the 3,000 participants identified 49 cases of HIV infection among 914 male volunteers in the vaccine group (5.36%) compared to 33 cases among 922 male volunteers in the placebo group (3.58%).
Earlier test results of the vaccine appeared to show promise. In vitro (meaning in a test tube), blood cells injected with the vaccine attacked HIV-infected cells, suggesting that the vaccine would simulate an immune response in humans . However, this did not happen. In fact, more people that received the vaccine got infected with HIV than those that received the placebo. There are a number of confusing factors that make it difficult to draw many conclusions. All but one infection was in men, principally homosexual men who reported being sexually active during the trial, so little information is available regarding the effects of the vaccine in women or heterosexual men. Analyses of the STEP data are ongoing, but it will likely take some time to fully understand the results.
According to Merck :
The vaccine cannot cause HIV infection. The vaccine was created using a mixture of three components, each made with a replication-defective version of one of the common cold viruses, adenovirus type 5 (Ad5), which served as a carrier, or delivery vector, for three synthetically produced HIV genes.
Indeed, current STEP results suggest that those study participants who had higher levels of pre-existing immunity to Ad5 may have an increased susceptibility to acquiring HIV . Using replication-defective Ad5 as a delivery vector has a number of advantages, including targeted, efficient gene delivery and high potency.
STEP was initially designed to only include volunteers with low levels of Ad5 immunity, since these participants were expected to have the best response to the vaccine . However, new data indicated that the vaccine would produce an immune response in people with high Ad5 immunity, so volunteers with higher levels of immunity to Ad5 were also enrolled.
Most vaccines work by exposing a weakened or killed virus to the immune system, prompting an immune response so that your body develops antibodies necessary to fight viral infection (see the flu vaccine). If the virus presents itself after vaccination, the antibodies signal immune system cells to destroy the invader. However, experimental HIV vaccines have never been able to prompt the immune system to produce antibodies powerful enough to fight HIV infection. Merck’s HIV vaccine used a different approach termed cell-mediated immunity, which involves the activation of specific immune system cells, including macrophages, natural killer cells and antigen-specific cytotoxic T-lymphocytes. Using a cold virus, adenovirus type 5 (Ad5), as a delivery vector (meaning a carrier), three HIV genes — Gag, Pol and Nef — were introduced to the immune system. The intention was for immune system cells to engulf the virus and then display the gene markers. This would teach the immune system cells to recognize and destroy HIV-infected cells.
According to Dr. Seth Berkley, president and CEO of the International AIDS Vaccine Initiative (IAVI) :
It is also important to recognize that the failure of the Merck product to prevent HIV infection is not unexpected. Merck’s candidate, like nearly all vaccine candidates now in the pipeline, was designed to activate the T-cell arm of the immune system. T-cells work like commando units, traveling through the body, seeking out pathogen-infected cells, which they then kill. Because T-cells only attack cells that are already infected, many scientists, including those at IAVI, think T-cell vaccines are unlikely to protect individuals from becoming infected. It’s more likely T-cell vaccines will reduce the amount of virus in people who, once vaccinated, become infected.
We’ve discussed previously how many therapies that were promising in vitro and in animal models may not work in humans. The results of the STEP study are an example of this and demonstrate how challenging it can be to translate positive experimental results to favorable responses in human clinical trials.
- Phambili HIV Vaccine Trial Stopped. International AIDS Vaccine Initiative. 2007 Oct 23.
- Data from STEP Study Presented at Open Scientific Session Confirm Merck’s Investigational HIV Vaccine was not Effective. Research & Development News, Merck & Co., Inc. Press Release. 2007 Nov 7.
- S. Africa troubled by problems with AIDS vaccine. All Things Considered, National Public Radio. 2007 Nov 9.
- New Analysis Confirms Conclusion that Discarded Merck Vaccine Candidate is Ineffective. International AIDS Vaccine Initiative. 2007 Nov 7.