BCG overexpressing a small molecule STING agonist as a vaccine for TB

Abstract Tuberculosis (TB) remains the topmost killer among infectious diseases globally, and is one of the world’s most significant medical challenges. Approximately one quarter of the world population has been infected with Mycobacterium tuberculosis (M.tb), the majority being latent cases that could give rise to active disease. Ten million incident cases associated with 1.4 million deaths were reported in 2019. In the last 90+ years, Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, has been the only available vaccine against TB. The vaccine has been effective in preventing life-threatening extra-pulmonary TB in children, but has variable efficacy in preventing pulmonary TB in adults, and is associated with side effects. With escalating population movement around the globe, the need for improved TB vaccines that can prevent infection has become critical. Yet, despite significant interest, vaccine development has been limited by insufficient funding, as well as a lack of clear understanding of the nature of both innate and acquired immunity in the lung, and their role in the protective immune response against M.tb. In order to address the need for improved versions of BCG that provide better efficacy and safety compared to traditional BCG, OncoSTING is developing OS-101 and OS- 151, recombinant versions of BCG engineered to overexpress the potent STING agonist c-di-AMP for a two- pronged mechanism of action: (i) induction of anti-TB immunity by the same mechanisms known to be elicited by traditional BCG (BCG-WT ) and (ii) stimulation of the STING pathway leading to upregulation of a several pro- inflammatory responses and enhanced “Trained Immunity” (TI) in macrophages. OncoSTING is the only company developing STING agonist delivery by a live bacterial vaccine—BCG. As supported by preliminary data, these improved versions of BCG offer potential both for greater protective efficacy that lasts into adulthood, and an improved safety profile. A significant database has been compiled for OS-101, which is resistant to the antibiotic kanamycin. However, the FDA does not allow advanced human clinical trials with BCG strains harboring antibiotic resistance. OncoSTING has therefore generated OS-151, an antibiotic resistance-free version of OS-101. In Phase I of this Fast-Track proposal bridging mouse immunogenicity and efficacy studies will be conducted to support the use of data generated with the OS-101 strain in regulatory filings for OS-151. In Phase II, OS-151 drug product formulation and manufacturing approach will be established, and pivotal GLP toxicology studies will be conducted to position for an IND application and clinical trial initiation. A toxicology study in guinea pig to characterize post vaccination toxicity and identify potential for vaccination site inflammatory response, systemic toxicity, and long-term persistence of any adverse findings will establish that OS-151 is safe to initiate a clinical trial. The results from this proposal will position OncoSTING to submit an IND and conduct a U.S. Phase 1 first time in human trial (FTIH); with the ultimate goal of demonstrating superiority of OS-151 versus BCG as a vaccine against TB.