Trials of the most promising HIV vaccine to date have been halted following news that the vaccine did not protect against HIV infection, according to a press release issued on Friday by developer Merck.
According to a Merck press release, released late Friday:
Vaccination in a phase II clinical trial of Merck & Co., Inc.'s investigational HIV vaccine (V520) is being discontinued because the vaccine was not effective. The announcement was made today by the co-sponsors of this clinical trial, Merck & Co., Inc., and the HIV Vaccine Trials Network (HVTN), which is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health.
The trial, called STEP, was an international phase II “test of concept” trial in uninfected volunteers at high risk for acquiring HIV infection. The independent Data Safety Monitoring Board (DSMB) for STEP reviewed safety data and results of an interim efficacy analysis of the study, and recommended that vaccination be discontinued because the STEP trial will not meet its efficacy endpoints.
Study investigators have been instructed to discontinue vaccinating volunteers in this study and to monitor them in accordance with the study protocol. Enrolment and vaccination in a second Phase II trial of this vaccine being conducted by the HVTN in South Africa called Phambili, and two additional Phase I trials, have been discontinued. The DSMB for the Phambili trial will evaluate the available data.
The Merck vaccine candidate is a mixture of three components, each made with a weakened version of a common virus (adenovirus type 5), that serves as a carrier, or delivery vector, along with three synthetically produced HIV genes known as gag, pol and nef.
The STEP study (HVTN 502, Merck V520 Protocol 023) was a multicenter, randomised, double-blind, placebo-controlled phase II test-of-concept clinical trial. The trial enrolled 3,000 HIV-negative volunteers from diverse backgrounds between 18 and 45 years of age at high risk of HIV infection.
The study evaluated two primary efficacy endpoints: whether the vaccine prevented HIV infection and whether the vaccine reduced the amount of virus in those who developed infection. As planned, an interim efficacy analysis was conducted in the approximately 1,500 volunteers expected to have the best response to the vaccine because they had low levels of pre-existing immunity to adenovirus 5.
The vaccine did not prevent infection: in volunteers who received at least one dose of the three-dose vaccine series, 24 cases of HIV infection were observed in the 741 volunteers who received vaccine and 21 cases of HIV infection were observed in the 762 participants in the placebo group.
In the subgroup who had received at least two vaccinations and who were HIV-negative for at least the first twelve weeks of the trial, 19 cases of HIV infection were observed in the 672 volunteers who received vaccine and eleven cases were observed in the 691 volunteers who received placebo.
In addition, the vaccine did not reduce the amount of virus in the bloodstream of those who became infected; HIV RNA levels approximately eight to twelve weeks after diagnosis of infection were similar in the vaccine and the placebo arms. The geometric means of the HIV RNA levels in the blood of infected individuals, the standard measure of ongoing HIV replication, were approximately 40,000 copies/ml in the vaccine group and approximately 37,000 copies/ml in the placebo group. Additional analyses will be conducted on the entire study population and will be shared with the scientific community.
Study volunteers were followed for approximately thirteen months. Overall adverse event rates were generally similar among the two groups, except for a higher rate of local injection-site related reactions in the vaccine group.
"This trial was the first test of concept trial that provided us information on this vaccine more quickly and efficiently than with a traditional Phase III design. While we are very disappointed that this vaccine candidate did not demonstrate protection, the data from this trial will provide critical insights into this disease and future vaccine development," said Larry Corey, M.D., principal investigator of the HVTN.
"This is a huge disappointment for all of us who have been involved in the search for an HIV vaccine," said Glenda Gray, M.D., principal investigator of the HVTN sponsored Phambili trial. "HIV is ravaging our communities, and all the scientists, participants and communities involved in HIV vaccine studies have been affected by this epidemic. The scientific community must continue the race to find a vaccine to help secure an HIV free generation for the future."
The Merck adenovirus-based vaccine used a cell-mediated immune response approach; it was hypothesised that the HIV genes in the vaccine would stimulate the body to generate an HIV-specific immune response through the body’s own CD8 T-cells, which become programmed to recognize and kill HIV-infected cells.
Adenoviruses are among the causes of common cold; the type 5 adenovirus used in this investigational vaccine had been modified so that it was unable to replicate and could not cause a cold. Also, because the vaccine did not contain live HIV and contained only three HIV genes, volunteers could not become infected with HIV from the vaccination. This vaccine had previously been tested in several smaller clinical trials and was found to be generally well tolerated and capable of inducing significant levels of HIV-specific cell-mediated immune responses.
STEP included multiple clinical trial sites in North and South America, the Caribbean and Australia, where HIV subtype B, the subtype of HIV from which the HIV genes included in the vaccine, is predominant. Half the study participants received three doses of the vaccine over six months, while the other half were given three doses of a placebo. The first volunteer enrolled in the study in December 2004, and enrolment was completed in March 2007.
The second phase II trial of this vaccine candidate, the Phambili trial, (HVTN 503, Merck V 520 Protocol 026) was begun in 2007 in South Africa by the HVTN to explore whether Merck's vaccine would be effective at preventing infection, reducing viral levels, or both, from HIV subtype C, which is more common in southern Africa.