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Journal of Virology, August 2008, p. 8161-8171, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00620-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

DNA gag/Adenovirus Type 5 (Ad5) gag and Ad5 gag/Ad5 gag Vaccines Induce Distinct T-Cell Response Profiles{triangledown}

Kara S. Cox,1* James H. Clair,2 Michael T. Prokop,1 Kara J. Sykes,1 Sheri A. Dubey,1 John W. Shiver,1 Michael N. Robertson,3 and Danilo R. Casimiro1

Department of Vaccine Basic Research, Merck Research Laboratories, West Point, Pennsylvania,1 Biostatistics and Research Decision Sciences, Merck Research Laboratories, West Point, Pennsylvania,2 Infectious Disease Vaccines Clinical Research, Merck Research Laboratories, Upper Gwynedd, Pennsylvania3

Received 19 March 2008/ Accepted 28 May 2008

Results from Merck's phase II adenovirus type 5 (Ad5) gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against human immunodeficiency virus (HIV) infection in a high-risk population. Among the many questions to be explored following this outcome are whether (i) the Ad5 vaccine induced the quality of T-cell responses necessary for efficacy and (ii) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV type 1 (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 regimen with DNA priming followed by Ad5 boosting (n = 50) or a homologous Ad5/Ad5 prime-boost regimen (n = 70). The samples were tested using a statistically qualified nine-color intracellular cytokine staining assay measuring interleukin-2 (IL-2), tumor necrosis factor alpha, macrophage inflammatory protein 1β, and gamma interferon 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 for future vaccine development will be discussed.

* Corresponding author. Mailing address: Merck & Co., Inc., P.O. Box 4, WP26A-4000, West Point, PA 19486-0004. Phone: (215) 652-8029. Fax: (215) 652-2439. E-mail: Kara_cox{at}merck.com

{triangledown} Published ahead of print on 4 June 2008.

Journal of Virology, August 2008, p. 8161-8171, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00620-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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