STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection

There are a limited number of adjuvants that elicit effective cell-based immunity required for protection against intracellular bacterial pathogens. Here, we report that STING-activating cyclic dinucleotides (CDNs) formulated in a protein subunit vaccine elicit long-lasting protective immunity to Mycobacterium tuberculosis in the mouse model. Subcutaneous administration of this vaccine provides equivalent protection to that of the live attenuated vaccine strain Bacille Calmette-Guérin (BCG). Protection is STING dependent but type I IFN independent and correlates with an increased frequency of a recently described subset of CXCR3-expressing T cells that localize to the lung parenchyma. Intranasal delivery results in superior protection compared with BCG, significantly boosts BCG-based immunity, and elicits both Th1 and Th17 immune responses, the latter of which correlates with enhanced protection. Thus, a CDN-adjuvanted protein subunit vaccine has the capability of eliciting a multi-faceted immune response that results in protection from infection by an intracellular pathogen. [Display omitted] •Vaccines containing STING-activating adjuvants protect against TB infection•Subcutaneous immunization elicits antigen-specific Th1 T cells•Protection requires STING but not type I IFN signaling•Mucosal immunization elicits Th17 T cells and enhances protective efficacy Van Dis et al. demonstrate that STING-activating cyclic dinucleotides provide significant protection when used as adjuvants in a protein subunit vaccine against Mycobacterium tuberculosis and show that mucosal administration of this vaccine elicits a Th17 immune response that correlates with enhanced protection.