Advancing Innovative Next_generation Heterologous Vaccines Against Tuberculosis - PROJECT SUMMARY/ABSTRACT Throughout modern history, tuberculosis (TB) has killed more people than any other infectious disease to date (estimated > 2 billion people over the past 350 years) and TB continues to kill 4,000 patients each day. In 2019 alone, the World Health Organization estimated that ~1.4 million people died of TB and 8-9 million patients were newly diagnosed. The only approved vaccine, M. bovis Bacille Calmette-Guerin (BCG) has had many successes but its protection is variable and BCG-vaccinated TB patients still transmit M.tb. Across the globe, an equilibrium of transmission and disease exists such that one new case of pulmonary TB arises from each existing TB patient; thus, efforts must be reinvigorated to drive TB rates lower. New strategies are needed to combat TB including discovery and advancement of new vaccines to control the pathogen Mycobacterium tuberculosis (M.tb). With that end goal in mind, we answer the call for RFA AI-21-007: Innovation for Tuberculosis Vaccine Discovery (ITVD), forming partnerships between PIs with vaccine development expertise, and expertise using animal models of TB. We propose three novel means to advance TB vaccines. In the R61 phase, we develop and identify the best performing new vaccine candidates. Specifically, we (i) combine the ID93 protein antigen with new adjuvants designed to maximize mucosal immune responses and durability; (ii) capitalize on novel RNA platform to create vaccines expressing ID93 and related M.tb antigens to induce rapid and durable immunity; (iii) optimize heterologous protein/RNA prime-boost candidates for strong and durable mucosal, humoral, and cellular anti-M.tb immunity, and select the final candidates to move into challenge studies. To maximize early-stage development, rigor, and reproducibility, we perform immunogenicity studies in a selected panel of Collaborative Cross (CC) inbred strains, representing known differential susceptibility to M.tb infection. In the R33 phase, i.e., M.tb challenge studies, we exploit the Diversity Outbred (DO) mouse population for its outstanding representation of genotypic and phenotypic diversity equivalent to humans, a major hurdle in TB vaccine development efforts to date. We will also test the final vaccine candidates in guinea pigs, the classic preclinical model for TB vaccines to ensure success in 2 animal models.
