Increased vaccine efficacy against tuberculosis with a recombinant BCG overexpressing the STING agonist cyclic di-AMP

Tuberculosis (TB) remains the leading cause of death due to infection globally. Bacillus Calmette Guérin (BCG), a live attenuated bacterial strain, is the only available TB vaccine, but it has poor efficacy in preventing pulmonary TB in adults. There are advantages associated with the BCG platform however, including a remarkable safely profile, billions of administered doses and a public health ecosystem associated with its production, administration and care. A recombinant/modified BCG (rBCG/modBCG) anti-TB vaccine candidate would be able to leverage these advantages while improving on efficacy. BCG-STING is a recombinant BCG strain which overexpresses the mycobacterial diadenylate cyclase disA gene leading to the release of ∼15-fold greater levels of the endogenous small molecule STING agonist cyclic di-AMP. We evaluated vaccination with BCG-STING compared to its parental BCG-WT strain in rhesus macaques challenged with virulent Mycobacterium tuberculosis (Mtb). BCG-STING given intradermally was well-tolerated, and during life serial BAL samples showed that BCG-STING vaccinated animals had lower Mtb CFU counts than those receiving BCG-WT. At necropsy, BCG-STING vaccinated animals had significantly lower Mtb lung CFU counts, and a higher percentage of sterile lobes and granuloma lesions than the BCG-WT recipients. The enhanced protection observed in BCG-STING vaccinated animals was associated with significant elevations of antigen-specific CD4 ⁺ and CD8 ⁺ T cells. Modifying BCG to overexpress a small molecule recognized by the innate immune system significantly improves protection and cell-mediated immune responses against TB the non-human primate (NHP) model.