Merck & Co., Inc said that in the STEP study, one of two phase II trials of its investigational HIV vaccine (V520), showed it wasn't effective at either preventing infection in volunteers not previously infected with HIV or at reducing viral loads in those study volunteers who became infected with HIV during the trial.

Analyses presented indicate that in those volunteers with pre-existing immunity to the cold virus used as a carrier for synthetic HIV genes in the vaccine, there were more infections in those volunteers who received the vaccine than in those who received placebo. Most of these analyses are considered exploratory in nature, and the reasons for this result are still being studied.

Data from the first, planned interim analysis of STEP in one study population were first reported on Sept. 21, 2007 by the three trial sponsors. New analyses of the data from the entire study population were presented at a special open scientific meeting of the HVTN.

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.

The current STEP results suggest that those who received the vaccine might have an increased susceptibility to acquiring HIV infection, particularly those volunteers who had higher levels of pre-existing immunity to Ad5 because of prior natural exposure to Ad5. However, there are a number of confounding factors that make it very difficult to draw conclusions about this finding.

All but one infection was in men, primarily in men who reported having sex with other men, so little information is available about the effects of the vaccine in women or in heterosexual men.

Study volunteers are being counseled about the possibility that those who received the vaccine may be more susceptible to developing HIV infection when exposed to HIV.

"The data from this trial are remarkably complex. We are analyzing the data to try to determine if the results are due to immune responses induced by the vaccine, differences in study populations, or some other biological phenomenon we don't yet understand, or simply due to chance," said Keith Gottesdiener, M.D., vice president, Vaccine and Infectious Disease Clinical Research, Merck Research Laboratories. "It will take some time before we understand why the vaccine did not work and why there was a trend toward more cases of infection in volunteers who received the vaccine. We recognize that understanding STEP is important for the study volunteers, investigators and for the entire field of HIV vaccine research, and we remain committed to continuing to thoroughly analyse the data and share it as broadly and as quickly as possible."

"We are enormously grateful to the investigators and volunteers who have dedicated so much of their time and their energy to these trials," said Larry Corey, M.D., principal investigator, HVTN. "We know the STEP study results are of great importance to our volunteers and to our network of investigators around the world. We may not be able to fully understand the results of STEP until more research is conducted. We are optimistic that this work will provide insight into how to advance the search for an effective HIV vaccine."

Further analyses are being conducted. The trial partners will share the data as it becomes available with the broader scientific community at subsequent scientific meetings and in publications over the next several months. A presentation is scheduled at the Conference on Retroviruses and Opportunistic Infections in Boston in February, 2008.

The study was co-sponsored by Merck & Co., Inc.; the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health; and the HIV Vaccine Trials Network (HVTN), which is funded by NIAID.

The Merck vaccine candidate was being studied in two phase IIb clinical trials, STEP and Phambili. In both studies, half the study participants received three doses of the vaccine over six months, while the other half were given three doses of a placebo. All volunteers were counselled on ways to reduce their risk of exposure to HIV at all study visits throughout the trial.

STEP (HVTN 502, Merck V520 Protocol 023) was a multi-centre, randomised, double-blind, placebo-controlled phase II test-of-concept clinical trial. The 3,000 HIV-negative volunteers in this trial were between 18 and 45 years of age, from diverse backgrounds, and at risk of HIV infection based on behavioural practices. 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. Approximately 38 percent of study participants were women and 62 percent were men. The first volunteer enrolled in the study in December 2004, and enrolment was completed in March 2007. More than 2,500 participants (2,675) had received all three doses of vaccine or placebo.

The second phase II trial of this vaccine candidate, Phambili (HVTN 503, Merck V520 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 and many other parts of the world with the highest rates of new HIV infections. Because this study just started this year, only 801 volunteers had been enrolled and 58 volunteers had received three doses of the vaccine or placebo.

Primary efficacy analyses of STEP study volunteers with low Ad5 immunity
STEP evaluated two primary efficacy endpoints: whether the vaccine prevented HIV infection in those who were HIV negative at the start of the study, and whether the vaccine reduced the amount of virus in those who became HIV infected during the course of the study. These primary efficacy analyses were based on volunteers who had low levels of pre-existing immunity to Ad5.

In the pre-specified analysis [conducted for the STEP trial Data and Safety Monitoring Board (DSMB) review on September 18] of volunteers who had received at least one dose of vaccine or placebo and were HIV negative at the start of the trial, called the "modified intent to treat" study population, 24 cases of HIV infection were observed in the 741 volunteers with low pre-existing Ad5 immunity who received vaccine and 21 cases of HIV infection were observed in the 762 participants in the placebo group. In the analysis of a subgroup of this study population, those who had received at least two vaccinations and who were HIV negative for at least the first 12 weeks of the trial, 19 cases of HIV infection were observed in the 672 volunteers who received vaccine and 11 cases were observed in the 691 volunteers who received placebo. (Most cases not included in this more stringent study population analysis but included in the "modified intent to treat" population were volunteers diagnosed as having acquired HIV at or before week 12.)

In addition, the vaccine was not effective based on the analysis of the second primary endpoint, viral load levels in study volunteers who became HIV infected. HIV RNA levels approximately eight to 12 weeks after diagnosis of infection were generally similar in the vaccine and the placebo arms in the modified intention to treat population. 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 24 volunteers in the vaccine group who developed HIV infection and approximately 26,000 copies/mL in the 21 volunteers in the placebo group who developed infection.

Post-hoc analyses included all cases of HIV infection observed in the overall STEP study population through Oct. 17, 2007, including eight additional cases that have been observed since the initial interim analysis was reviewed by the STEP DSMB on September 18. Because all of the cases of infection except one were in males, the extensive post-hoc analyses on the "modified intent to treat" population were conducted only on males.

In a post-hoc analysis of the overall study population, a total of 49 cases of HIV infection were seen among the 914 male volunteers in the vaccine group compared to 33 cases of HIV infection among the 922 male volunteers in the placebo group. Although the study was not designed to assess whether study volunteers with high Ad5 immunity who received vaccine were more likely to acquire HIV infection, the difference in the number of cases of HIV infection between the vaccine and placebo groups was more pronounced among volunteers with high Ad5 immunity. Among the 778 male volunteers who had high levels of pre-existing immunity to Ad5 (greater than 200 units), 21 cases of HIV infection were observed in those who had received vaccine and nine cases of HIV infection were observed in the volunteers who had received placebo.

To better understand this finding, additional post-hoc analyses were conducted based on levels of pre-existing immunity to Ad5:

Vaccination and enrolment have been discontinued in both studies As announced on Sept. 21, 2007 after study sites had been informed, vaccination was discontinued in trials of this vaccine candidate after the STEP DSMB reviewed an interim analysis of STEP data on Sept. 18, 2007. This pre-specified analysis of data from the low Ad5 population (the group expected to have the best response and the furthest along in the study) was designed to provide insight as soon as possible into