RO1 abstract Effective CD8+ T cell responses are important for the control and clearance of many viruses and other intracellular pathogens. Although several vaccine approaches involving peptide immunization or cross- presentation of soluble proteins are under investigation, attenuated live vaccines are often the most successful at generating strong CD8+ T cell memory. In these studies, we present unpublished new data demonstrating a novel approach to vaccine development in which we inactivate intact virus particles using hydrogen peroxide (H202). This approach preserves the antigenic structure of virus particles/proteins better than other commonly used inactivation techniques such as heat, formaldehyde, or UV cross-linking. To determine if hydrogen peroxide vaccines might be capable of inducing CD8+ T cell memory, we have used LCMV (lymphocytic choriomeningitis virus) as a rigorous model system for characterizing vaccine-induced CD8+ T cell responses. We show that MHC Class I-restricted LCMV NP118-specific CD8+ T cells are induced by a single dose of an H202-inactivated LCMV vaccine (without adjuvant) and achieve LCMV-specific CD8+ T cell numbers similar in magnitude to that induced by live recombinant vaccinia virus expressing the LCMV nucleoprotein antigen. H202-inactivated vaccines represent an entirely new approach to vaccine technology and has the potential for eliciting highly effective CD8+ T cell responses. In the proposed studies, we plan to test the effectiveness of clinically feasible adjuvants that augment antiviral immune responses through known interactions with specific Toll-Like Receptors (TLR) to determine the best approach for developing effective T cell vaccines.
The Specific Aims of this application include: I). Determine the inactivated vaccine regimen that elicits the best virus-specific T cell responses II). Determine the kinetics, phenotype, and immunodominance of vaccine-induced CD8+ T cells III). Determine the antiviral functions of vaccine-induced CD8+ T cells
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