Project Summary CD8 T cell mediated immunity is instrumental in the clearance of numerous viruses and protection from secondary infections. With the advent of cancer vaccines and a better appreciation for the central role of cell mediated immunity, T cell responses are at the forefront of modern vaccinology. Synthetic Long Peptide (SLP) vaccination has proved effective in cervical cancer trials and we have shown that SLPs can be used to focus T cell responses in infectious disease. Despite their advantages and preclinical efficacy, SLPs must be formulated with sometimes toxic and expensive experimental adjuvants to induce immune responses. Furthermore, the immunogenicity of SLPs is hampered by the relatively poor delivery of soluble peptides to dendritic cells (DCs) and the suboptimal processing of SLPs by the ubiquitin-proteasome system (UPS) into short peptides that are then presented to CD8 T cells. Here, we propose to test an SLP-based vaccine composed of nanoparticles loaded with epitope specific SLPs modified with a proteolysis targeting molecule (ProTM) that recruits E3 ubiquitin ligase, thus optimizing SLP degradation via the UPS and subsequent presentation of SLP epitopes to T cells. We plan to synthesize, optimize, and test an SLP vaccine that utilizes biodegradable nanoparticles loaded with either a T cell-activating adjuvant or SLPs modified with an endosomal escaped domain (EED) and ProTM. We anticipate that our vaccine will elicit robust T cell responses by targeting both adjuvants and modified SLPs to DCs. Once internalized, SLP's will be released from the biodegradable particles, gain access to the cytosol, and be trafficked to the UPS for degradation, thus enhancing peptide presentation via MHCI to CD8 T cells. Our proposal describes a vaccine platform that can be easily tailored to treat malignancies or prophylactically to generate protective T cell responses against infectious disease. It is the first vaccine platform that utilizes ProTMs to enhance antigen presentation to T cells.