In a new paper just published online by the Journal of Virology, researchers from Merck present the first direct comparisons of the functional profiles of T cell responses induced by a DNA priming immunization followed by an Ad5 vector boost and an Ad5 prime/Ad5 boost regimen (as was used in the STEP trial). Merck’s original plan was to develop the DNA/Ad5 approach, but they subsequently decided to pursue Ad5 alone because the immunogenicity of the two strategies – when measured by interferon gamma ELISpot – appeared similar.
The data in the J. Virology paper indicate that the DNA/Ad5 regimen induced CD4 T cell responses in a significantly greater proportion of recipients and the CD4 and CD8 T cells induced by this approach displayed more functions, particularly in terms of IL-2 production, when compared to Ad5/Ad5. Although it might be a stretch to criticize Merck’s decision to drop the DNA prime based on the functional measures (which were not well characterized at the time), the issue of the proportion of recipients developing CD4 T cell responses does raise questions about the company's transparency during the development process. At no point can I recall Merck acknowledging clearly that there was a significant difference in the proportion of CD4 T cell responders between the DNA/Ad5 and Ad5/Ad5 approaches, and data presentations at meetings and conferences focused almost exclusively on CD8 T cell responses. The potential importance of CD4 T cell help was well appreciated at the time the DNA prime was discontinued.
Correction: embarrassingly, I realized that I recently posted a 2005 CROI abstract to the blog in which Danny Casimiro from Merck reported that only ~30% of Ad5 recipients developed HIV-specific CD4 responses; my original statement above regarding Merck not disclosing this data is erroneous. It would be more accurate to say that I don't recall seeing the CD4 data presented before the STEP trial began.
JVI Accepts, published online ahead of print on 4 June 2008
J. Virol. doi:10.1128/JVI.00620-08
DNAgag/Ad5gag and Ad5gag/Ad5gag Vaccines Induce Distinct T cell Response Profiles
Kara S. Cox, James H. Clair, Michael T. Prokop, Kara J. Sykes, Sheri A. Dubey, John W. Shiver, Michael N. Robertson, and Danilo R. Casimiro
Department of Vaccine Basic Research, Merck Research Laboratories, West Point, PA USA; Biostatistics and Research Decision Sciences, Merck Research Laboratories, West Point, PA USA; Infectious Disease Vaccines Clinical Research, Merck Research Laboratories, Upper Gwynedd, PA USA
Abstract
Results from Merck's phase II Ad5-gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against HIV infection in a high-risk population. Among the many questions to be explored following this outcome are whether or not 1) the Ad5 vaccine induced the quality of T cell responses necessary for efficacy and 2) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV-1 specific T cell responses. Here we present a comprehensive evaluation of the T cell response profiles from cohorts of clinical trial subjects who received the HIV CAM-1 gag insert delivered by either a DNA priming followed by Ad5 boosting regimen (N=50) or homologous Ad5/Ad5 prime/boost regimen (N=70). The samples were tested using a statistically qualified 9-color intracellular cytokine staining assay measuring IL-2, TNF, MIP1, and IFN-N production and expression of CD107a. Both vaccine regimens induced CD4+ and CD8+ HIV gag-specific T cell responses which variably expressed several intracellular markers. Several trends were observed in which the frequencies of HIV-1 specific CD4+ T cells and IL-2 production from antigen-specific CD8+ T cells in the DNA/Ad5 cohort were more pronounced than in the Ad5/Ad5 cohort. Implications of these results in future vaccine development will be discussed.
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