STEP study shows HIV vaccine from Merck does not protect against HIV infection

November 12, 2008

The failure of the latest HIV vaccine from Merck is analysed in two Articles and a Comment published early Online and in an upcoming edition of The Lancet. The vaccine failed to give any protection from HIV infection, and the usefulness of non-human models for HIV vaccine development have been called into question.

In the first Article, Dr Susan Buchbinder, HIV Research Section, San Francisco Department of Public Health, USA, directly assessed the efficacy of this cell-mediated* vaccine, (name: MRKAd5 HIV-1 gag/pol/nef), namely its ability to protect against HIV-1 infection or change in early plasma HIV-1 levels. The results showed that the vaccine failed to achieve either objective, and in fact people given the vaccine had a higher rate of HIV infection (4.6%) compared with controls (3.1%), although this result had borderline statistical significance. However, this increased risk of HIV infection among the vaccine group was only seen in men who were uncircumcised and men who had pre-existing antibodies to the virus adenovirus 5 -- that was used as the backbone of this vaccine. Male vaccine recipients who were circumcised and men who did not have pre-existing antibodies to adenovirus 5 had no increased risk of HIV infection. The reasons for this increase in risk are currently being explored. The vaccine itself cannot cause HIV infection. The authors say: "High levels of protocol adherence provide further confidence in this study's conclusions about the vaccine's absence of protective efficacy... We noted no indication that early plasma viral concentrations were reduced in vaccine recipients compared with placebo recipients in this study."

They add: "The Step Study has also deepened our understanding of the potential, and potential pitfalls, of present non-human primate challenge models**", adding that results from this trial suggest that the particular type of non-human primate challenge model is not a useful predictor of the use of T-cell-based vaccines in human beings.

In the second Article, Dr M Juliana McElrath, Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, USA, and colleagues assessed vaccine-induced immunity and its potential contributions to infection risk. They found that the potency of HIV-specific CD8+ T cells in vaccinated cases was similar to that in matched non-cases. The authors say: "These findings suggest two possible explanations for the disappointing trial results: first, the characteristics of T-cell immunity that might afford HIV-1 protection has to be more broadly reactive or qualitatively different than those elicited by this vaccine; or second, immune responses mounted by T-cell-based vaccines alone will not be sufficient to protect against HIV infection or disease. We view that, before concluding the second hypothesis, we have to exclude the possibility of the first as feasible both in the Step Study and future HIV preclinical and clinical trials."

They conclude: "Obviously, an efficacious HIV vaccine must afford protection against heterologous virus, and the enormous variability of HIV-1 creates a major hurdle in design of a vaccine that can induce a sufficiently broad response to allow recognition. This barrier could be one that ultimately compromises the effectiveness of T-cell-based vaccines... Faced with an epidemic that will be best halted by an effective vaccine, there is no better time to channel knowledge from data, not hindsight or opinion, into careful planning for the next steps in the search for a preventive HIV vaccine.

In an accompanying Comment, Dr Merlin Robb, US Military HIV Research Program, Rockville, MD, USA, says***: "The Step Results have profoundly affected the HIV-vaccine development field. The predictive value of the non-human SHIV-challenge model** is not supported by this experience...The failure of Step has not closed the door on the T-cell vaccine concept. However, the reflection it has caused might be a crucial step towards a HIV-vaccine."
Notes to editors: *as cell-mediated immunity vaccines act by killing HIV infected cells, they would probably have their biggest effect in control of viral replication, rather than prevention of infection.

**non-human simian-HIV (SHIV) challenge model = an animal model for HIV vaccines, which evaluates the ability of a given vaccine regimen to protect macaques against infection or disease following administration of a mixed virus (chimera) of mostly SIV (simian immunodeficiency virus) and some components of HIV. (Alternatively, the challenge virus can be SIV, rather than the SHIV chimera.)

***The opinions or assertions of the Comment author contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the US Army or the US Department of Defense.

Dr Susan Buchbinder, HIV Research Section, San Francisco Department of Public Health, USA T) +1 415 554-9070 E)

Dr M Juliana McElrath, Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, USA T) +1 206-667-6704 E)

For Dr Merlin Robb, US Military HIV Research Program, Rockville, MD, USA please contact Lisa Reilly T) +1 301-251-5070 / +1 301-339-3566 E) /

For full Articles and Comment, please see:


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