The results of the Merck HIV vaccine efficacy trial (the STEP study), which have been covered extensively on the blog since they were announced in September of 2007, have now been published in the advance online section The Lancet. The papers offer a detailed and thoughtful analysis of the data, but the mystery of the apparent enhancement effect among uncircumcised gay men with pre-existing immunity to Ad5 remains unresolved and, although analyses continue, may never be resolved. As the authors note, the study outcome offers a sobering lesson on the need to better understand vaccine vector biology (a lesson that applies to vaccine research broadly, not just HIV). In terms of the immunological analyses, one of the most striking findings is that less than a third of vaccine recipients developed both CD4 and CD8 T cell responses to the encoded antigens; given the dependence of CD8 T cell responses on CD4 T cell help, these data suggest that the success of the vector in inducing CD8 T cell responses in the majority of recipients may have been somewhat pyrrhic.
The Lancet, Early Online Publication, 13 November 2008doi:10.1016/S0140-6736(08)61591-3
Susan P Buchbinder, Devan V Mehrotra, Ann Duerr, Daniel W Fitzgerald, Robin Mogg, David Li, Peter B Gilbert, Javier R Lama, Michael Marmor, Carlos del Rio, M Juliana McElrath, Danilo R Casimiro, Keith M Gottesdiener, Jeffrey A Chodakewitz, Lawrence Corey, Michael N Robertson, the Step Study Protocol Team
Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels.
We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576.
In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1·2 [95% CI 0·6—2·2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4·61 vs 4·41 log10 copies per mL, one tailed p value for potential benefit 0·66). The vaccine elicited interferon-γ ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2·3 [95% CI 1·2—4·3]) and uncircumcised men (3·8 [1·5—9·3]), but was not increased in Ad5 seronegative (1·0 [0·5—1·9]) or circumcised (1·0 [0·6—1·7]) men.
This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.
The Lancet, Early Online Publication, 13 November 2008doi:10.1016/S0140-6736(08)61592-5
M Juliana McElrath, Stephen C De Rosa, Zoe Moodie, Sheri Dubey, Lisa Kierstead, Holly Janes, Olivier D Defawe, Donald K Carter, John Hural, Rama Akondy, Susan P Buchbinder, Michael N Robertson, Devan V Mehrotra, Steven G Self, Lawrence Corey, John W Shiver, Danilo R Casimiro, the Step Study Protocol Team
In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk.
To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-γ ELISPOT and intracellular cytokine staining assays, using a case—cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2lo) CD4+ T cells expressing CCR5.
We detected interferon-γ-secreting HIV-specific T cells (range 163/106 to 686/106 peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon γ or tumor necrosis factor α (TNFα), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0·4—1·0%) in 117 of 160 (73%) participants, expressing predominantly either interferon γ alone or with TNFα. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2lo/CCR5+CD4+ T cells did not differ between cases and non-cases.
Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.
The Lancet, Early Online Publication, 13 November 2008doi:10.1016/S0140-6736(08)61593-7
Merlin L Robb
An HIV vaccine remains the primary goal for a comprehensive strategy to curb the global HIV epidemic. Yet the path to success is unknown and, on the basis of two reports from the Step Study in today's Lancet,1,2 seems to have become more complicated.