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311 Enhanced Potency RNA Optimized HIV-1 Plasmid Vaccines Encoding Engineered B7 Costimulatory Molecules or IL-15
J. Boyer1, S. Kudchodkar1, M. Agadjanian7, J. Im-Sin1, D. Zhang1, J. Kim2, J. Eldridge4, Z. Israel4, G. Pavlakis5, R. Sekaly6, and D. B. Weiner*1
1Univ. of Pennsylvania, Philadelphia, USA; 2Viral Genomix, Philadelphia, PA, USA; 3St. Christopher’s Hosp. for Children, Philadelphia, PA, USA; 4Wyeth Vaccines, Pearl River, NY, USA; 5NCI-FCRF, Frederick, MD, USA; 6Univ. of Montreal, Quebec, Canada; and 7IMM, Los Angeles, CA, USA
Background: We studied the effects of plasmid vaccines in 167 individuals using first generation HIV-1 plasmid vaccines. The vaccines were well very tolerated and immunogenic. The vaccines induced helper T-cell responses in most vaccine recipients. However, the CTL responses were below a 20% response rate. In primate studies the same plasmid vaccine design protected primates from CD4 T-cell loss and controlled viral load following pathogenic SIV challenge. These studies support that this vaccine approach, with enhancement is likely to be of benefit as a component of an HIV-1 vaccine.
Results: One enhancement is the use of second generation plasmid vaccines that are RNA optimized to function in a rev independent fashion. These vaccines express 20- to 100-fold better than first generation plasmid vectors. These constructs drive improved immune responses in particular improved CD8 effector cell function has been clearly observed. However, our results support that additional enhancements are needed to further boost the immune response. We have observed that we can enhance CD8 effector cell response of RNA optimized constructs dramatically by including an engineered B7 costimulatory molecule as a plasmid vaccine adjuvant. This molecule removes the C domain of B7.1 or 2 and results in dramatically enhanced CTL responses in vivo. Further we have extensively studied the effects of cytokine cDNAs as part of the plasmid vaccines. In particular, IL-15 was even more potent at driving CD8 IFNg in ICC assays, enhancing CTLs, and expanding CD8 effector T cells. In a murine challenge model IL-15 dramatically enhanced survival. Importantly treatment of HIV+ PBMCs with IL-15 expanded anti-HIV CD8 T-cell effector function suggesting an important role for this adjuvant in immune therapy.
Conclusions: We have observed that we can dramatically improve CD8 effector T-cell responses induced by RNA optimized vectors by engineering as part of the plasmid vaccines either novel costimulatory molecules or IL-15. IL-15 appears to have particular immune stimulatory activity on HIV-infected samples. These results have important implications for the design of plasmid vaccines for HIV-1 for prophylaxis and Therapy. It is our goal to move this approach now to clinical evaluation.
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