The level of immunogenicity and efficacy of multi epitope DNA vaccines can be influenced by several factors. One critical factor is efficient in vivo delivery that allows for subsequent high-level expression of the encoded epitopes. We have designed a project that will allow for the systematic evaluation of several DNA vaccine delivery systems in rhesus macaques. using SIV CTL and HTL epitopes. This non-human primate model for HIV-1 was selected for use because of our current level of knowledge on the rhesus macaque MHC (Mamu) and the availability of characterized SIV-derived Mamu-restricted CTL and HTL epitopes. The program is organized into three phases: (1) design and in vitro optimization of multi- epitope DNA vaccines encoding the SIV-derived CTL and HTL epitopes (2) immunogenicity testing of a selected number of optimized vaccines formulated with up to four different DNA vaccine delivery systems in non-infected macaques, and (3) evaluation of one or two formulations in SIV-infected macaques that are concomitantly being treated with an anti- retroviral drug (PMPA). The immune responses of vaccinated macaques will be thoroughly characterized using multiple assays to allow for the measurement of CTL activity, numbers of circulating of epitope-specific CD8+ T cells and epitope-specific cytokine production. The levels of SIV will be followed in animals throughout the program to determine which vaccine formulation induces the most efficacious immune responses. The goal of the project is to identify a prototype DNA vaccine formulation that can be used as a model to design a comparable formulation to be testing in a clinical trial with a multi-epitope DNA vaccines based on HIV-1 derived epitopes. To increase the potential for a successful conclusion of the project, only delivery systems that have been used successfully in either vaccine or gene therapy clinical trials will be evaluated. Thus, the data obtained will support the design of clinical trial portion of the IPCP program.
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