In the STEP study, one of two phase II trials of investigational HIV vaccine ( V520 ), the vaccine was not 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 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.
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.
STEP was a multi-center, randomized, 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 behavioral practices.
Approximately 38 percent of study participants were women and 62 percent were men.
The first volunteer enrolled in the study in December 2004, and enrollment was completed in March 2007. More than 2,500 participants ( 2,675 ) had received all three doses of vaccine or placebo.
STEP was initially designed to include only volunteers with low levels of Ad5 immunity ( Ad5 antibody level less than or equal to 200 units ), because these volunteers were expected to have the best response to the vaccine. Subsequently, volunteers with higher levels of immunity to Ad5 were also enrolled in the trial because new data became available indicating that the vaccine was immunogenic in individuals with high Ad5 immunity ( Ad5 antibody levels more than 200 units ).
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 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.
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.
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:
a) In volunteers who could be considered as having no pre-existing immunity to Ad5 at enrollment ( baseline Ad5 titer less than 18 units ), 20 cases of HIV infection were seen in the 382 volunteers in the vaccine group and 20 cases were seen in the 394 volunteers in the placebo group.
b) In volunteers with immunity to Ad5 between 18 to 200 units, eight HIV infections were observed in the 140 volunteers in the vaccine group compared to four infections in the 142 volunteers in the placebo group.
c) In volunteers with immunity to Ad5 between 200 to 1000 units, 14 cases were seen in the 229 volunteers in the vaccine group and seven cases were seen in the 229 volunteers in the placebo group.
In volunteers with very high levels of immunity to Ad5, defined as greater than 1000 units, seven cases of HIV infection were observed in the 163 volunteers in the vaccine group and two cases were observed among the 157 in the placebo group.
Viral load levels were also evaluated across the total population, and there was no obvious correlation between levels of Ad5 immunity and viral load.
In a post-hoc analysis of those male volunteers with high levels of immunity to Ad5 who developed HIV infection, the geometric means of HIV RNA levels were observed to be approximately 19,000 copies/mL in the vaccine group ( based on 21 infections ) and 90,000 copies/mL in the placebo group ( based on nine infections observed ).
In the total study population, including male volunteers with both low and high levels of immunity to Ad5, the geometric means of HIV RNA levels were approximately 29,000 copies/mL for the vaccine group ( based on 46 infections ) and approximately 38,000 copies/mL in the placebo group ( based on 30 infections ).
There are a number of confounding factors that make it difficult to draw conclusions about why those who received the vaccine with higher levels of immunity to Ad5 developed more infections than those who received placebo. For example, on some measures, HIV infected volunteers in the vaccine group and the placebo group reported engaging in risk practices more frequently than uninfected volunteers in both groups, although these data are still being collected and analyzed. Also, fewer men in the study with higher levels of pre-existing immunity to Ad5 were circumcised than were men with lower levels of pre-existing immunity to Ad5. There were also geographic differences in the two study populations. More than 70 percent of the participants with lower levels of pre-existing immunity to Ad5 were from the United States, while approximately 41 percent of participants with higher levels of pre-existing immunity to Ad5 were from the U.S.
Demographic characteristics, such as age and race, of the volunteers who received vaccine were similar to those who received placebo at each of the study sites, and there is no evidence to suggest that differences in demographics explain the differences in the number of infections in the vaccine and placebo groups.
Source: Merck, 2007