Extremely grim news for the HIV vaccine field: The phase IIb efficacy trial of Merck's adenovirus-based HIV vaccine candidate (MRKAd5, also recently referred to as V520) has been stopped after an interim analysis by the trial's Data Safety Monitoring Board (DSMB) found no differences between the placebo and vaccine groups for either of the trial's primary endpoints: acquisition of HIV infection or post-infection viral load levels (in this case, the geometric means of two viral load measurements taken 8 and 12 weeks after infection).
The details are contained in Merck's press release:
"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 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 did not reduce the amount of virus in the bloodstream of those who became infected; HIV RNA levels approximately 8 to 12 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."
Like Merck's vaccine, most HIV vaccines in the developmental pipeline are designed to induce memory T cell responses, because these immune responses have consistently offered some degree of enhanced post-infection control of viral load in animal models. The apparent failure of the HIV-specific memory T cell responses induced by Merck's Ad5 vaccine to offer any benefits could therefore have devastating implications for the overall field. However, there are issues that still need to be explored, such as:
- Any longer term differences in outcome between vaccinees and placebo recipients that became infected (e.g. in terms of viral load levels, CD4 T cell counts and immune activation levels)
- Correlations (if any) between the functional properties of the HIV-specific CD4 and CD8 T cell responses induced by the vaccine and the outcomes in the trial
- The genetics of the infecting viral strains
- The timing of the infections (there is some basic immunology data which might suggest that there is a period immediately after immunization when activation of CD4 T cells could enhance susceptibility to HIV infection, before their differentiation into memory CD4 T cells is completed)
- The finding that the difference between vaccine and placebo recipients in terms of acquisition of infection seemed to widen after two immunizations (19 vaccinees vs. 11 placebo recipients) but skewed the other way in people that received only one immunization (5 vaccinees vs. 10 placebo recipients)
A second efficacy study of the same Merck vaccine construct that was slated to start in South Africa has been placed on hold until a more detailed review of these data can take place.
The results of this trial are likely to consume much of the conversation at the upcoming Keystone Meeting on Challenges of Global Vaccine Development, which takes place in Cape Town from October 8-13.