Identifying mediators of STING-dependent TB vaccine immunity

Abstract Tuberculosis (TB) is the top infectious killer in the world. The only current licensed vaccine for TB, Mycobacterium bovis Bacille Calmette-Guérin (BCG), has not proven reliably effective against adult pulmonary TB in all studies. It furthermore cannot be administered safely to immunocompromised individuals as it is a live attenuated vaccine. Protein subunit vaccines offer increased safety over live attenuated vaccines. Many recently developed protein subunit TB vaccines use toll-like receptor-stimulating adjuvants that induce potent inflammatory responses, but it is uncertain whether they can induce long-lasting memory protection against an intracellular bacterium such as TB. Cyclic-di-nucleotides are an alternative adjuvant that target the cytosolic immunosurveillance pathway mediated by STING. Recently, a STING-activating cyclic-di-nucleotide (CDN)-adjuvanted TB protein subunit vaccine was shown to elicit an effective memory T cell response against TB challenge in mice. Intriguingly, intranasal delivery of the vaccine provided superior protection compared to subcutaneous administration of the CDN-adjuvanted vaccine or BCG. Protection induced by mucosal administration correlates with a potent Th17 response rather than the Th1-dominated CD4+ T cell response induced by subcutaneous vaccination. Protection is partially dependent on IL-17 and type I interferon, while the transcription factor STAT6 is dispensable. The Th17 response and protection both precedes Th1 influx into the lungs and also persists after the Th1 response wanes. We are currently determining whether the transcription factor IRF3 and cytokine IFNγ are also mediators of Th17 memory induction and protection against TB infection.