Elucidating the mechanism and correlates of protection elicited by CDN adjuvanted vaccines for M. tuberculosis.

Project Summary Mycobacterium tuberculosis (Mtb) is leading cause of death worldwide by a single infectious agent. In 2023, approximately 10.8 million people fell ill with tuberculosis (TB) and 1.25 million people died.1 The only licensed vaccine available, Mycobacterium bovis Bacillus Calmette-Guerin (BCG), has limited efficacy that wanes over time and fails to protect against adult pulmonary TB or impede TB transmission.3 Efforts to develop new and effective TB vaccines have remain unsuccessful primarily due to our lack of understanding of the immune responses that mediate TB protection. The persistence of the TB pandemic and the absence of an efficacious vaccine for preventing TB disease emphasize the urgent need to further understand mechanisms and immune correlates of protection to TB that can help guide the design of novel vaccines. The use of experimental vaccines that elicit protection against Mtb challenge in animal models could lead to insights into adaptive immune mechanisms that are important for protection against Mtb infection. We recently demonstrated that intranasal (i.n.) vaccination with the experimental vaccine H1/CDN provides remarkable protective efficacy against infection with Mtb in the mouse model. This protein subunit vaccine consists of H1 Ag, a fusion of two highly immunodominant Mtb protein antigens (Ag85b and ESAT-6), and the STING activating adjuvant cyclic-di-nucleotide (CDN) ML-RR-cGAMP (H1/CDN). While we have shown that IL- 17 and IFN-γ producing CD4 T cells are required for CDN adjuvanted vaccine efficacy, the precise phenotypes and localization of Th1 and Th17 cells required for protection are still unclear. In addition, the specific cell types that respond to IL-17 during vaccination and Mtb challenge and the role of IL17 in their activation and recruitment remain unknown. Furthermore, the mechanism by which STING activation leads to increased protection also remains elusive. In this project, our goal is to investigate the mechanisms and correlates of protection elicited by CDN adjuvanted vaccines for tuberculosis. In Aim 1, we will determine how spatial localization and trafficking of Th1 and Th17 cells impacts vaccine efficacy. In Aim 2, we will determine the role of IL-17 in the recruitment, spatial localization, and phenotypes of both epithelial and innate and adaptive immune cells necessary to confer vaccine-elicited protection. Finally in Aim 3, we will determine whether STING mediated autophagy contributes to CDN adjuvanted vaccine efficacy. Together these results will provide a better understanding of the mechanisms underlying CDN vaccine protection and inform the development of more effective vaccines against Mtb.