I-Corps: A disease-agnostic platform for enhanced vaccine immunogenicity using live microbial vectors

The broader impact/commercial potential of this I-Corps project is the development of a disease agnostic platform for the creation of prophylactic and therapeutic vaccines. For diseases ranging from cancer to pathogenic bacteria, weak immunogenicity or tolerance of antigens limits their practical targeting in vaccines. Using the proposed live bacterial vaccine platform and nitrated antigen technology, it may be possible to unlock these antigens as targets. The proposed platform may be used for developing vaccines against diseases lacking current vaccines or diseases with immunotherapeutic solutions with limited efficacy. If successful, it may be possible to create commercial products that will save lives and reduce patient and health care burden. This I-Corps project is based on the development of a technology to enable the vaccination of antigens with weak natural immunity. Several diseases may benefit from immunotherapies or vaccines that can target weakly immunogenic but highly conserved antigens. Bacterial vectors have been developed that autonomously produce proteins with selective introduction of nitro functionalization at desired sites by using metabolic engineering, chemical engineering, and protein engineering. Studies have demonstrated that protein nitration may result in an amplification of CD4+ T cell immune response with enhancement for both bacterial and cancer-associated antigens. This strategy uses non-standard amino acid (nsAA)-based technology. To date, commercial endeavors involving nsAAs focused on using bio-orthogonal functional groups for purposes of reactivity or stability. Here nsAA technology is used in an alternative direction, the improved immunogenic response in vaccines. In addition, the proposed technology combines metabolic synthesis of nsAAs and incorporation into protein antigens, which may circumvent limitations toward nitrated protein synthesis (namely, transport given the intracellular synthesis) and delivery (given bacterial synthesis). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.