Merck HIV vaccine trial halted by DSMB for lack of efficacy

2 October 2007. Related: Vaccines and microbicides.

Richard Jefferys, TAG

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 immune system genetics of trial participants, particularly HLA types which are an important genetic determinant of the ability to mount a T cell response against a given pathogen.
• 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.

A press release form the Treatment Action Group expanded on the implications of these disappointing results:

HIV vaccine researchers have long sought a vaccine candidate that can reliably induce a type of immune defense called a killer CD8 T cell response, because CD8 T cells have been consistently associated with control of viral replication in animal models. Merck’s vaccine represented a breakthrough because it was able to induce HIV-specific CD8 T cell responses (and the supportive HIV-specific CD4 T cells that are needed to sustain them) in the majority of people who received it. Hence there were sound reasons to hope that the vaccine might reduce viral load and slow disease progression to a significant degree.

The interim STEP study results show that this hope has not been borne out, raising critical and difficult questions for the HIV vaccine field as a whole. It will be crucial to analyse the outcomes in the STEP study in detail and assess how they might impact other HIV vaccine candidates in development. [ …. ]

While the failure of Merck’s HIV vaccine represents extremely discouraging news for T cell-based HIV vaccines, it would be premature at this juncture to conclude that all such approaches are doomed to failure. Due to the difficulty of inducing effective neutralising antibodies against HIV, most HIV vaccines currently in the pipeline aim to induce T cell responses.

The next planned HIV vaccine efficacy trial involves two constructs developed by the Vaccine Research Center (VRC) at the National Institutes of Health. Like Merck’s vaccine, it includes an adenovirus component, but there are several differences in the approach that could potentially be important, including a ‘priming’ immunization using a different DNA-based vaccine, plus several additional proteins (the envelope proteins derived from three different subtypes or clades of HIV).

These differences highlight some of the near-term options for HIV vaccine researchers in the light of Merck’s results: exploring whether the quality – in other words, the functionality – of the T cell response induced by a vaccine is an important factor (i.e. DNA priming may lead to a qualitatively different T cell response) and also whether the parts of HIV included in the vaccine influence the outcome. Merck’s vaccine included the HIV proteins Gag, Pol and Nef because these proteins are most frequently targeted by T cells in infected people. Strategies targeting additional structural and regulatory proteins from HIV also need to be evaluated.

Sources:

Richard Jefferys Vaccine Prevention Blog
http://tagbasicscienceproject.typepad.com

Merck press release: Vaccination and Enrollment Are Discontinued in Phase II Trials of Merck’s Investigational HIV Vaccine Candidate (21.09.07)
http://www.merck.com/newsroom/press_releases/research_and_development/2007_0921.html

Treatment Action Group (TAG) press release
http://www.treatmentactiongroup.org