Intravenous BCG Vaccination of Diversity Outbred Mice Results in Moderately Enhanced Protection against Challenge with Mycobacterium tuberculosis Compared to Intradermal Vaccination.

Tuberculosis is still the leading cause of death globally from any infectious disease, despite the widespread use of the live attenuated vaccine Bacille Calmette Guerin (BCG). While BCG has some efficacy against disseminated TB disease in children, protection wanes into adulthood resulting in over 1.8 million TB deaths per year. This has led to efforts to develop novel vaccine candidates that either replace or boost BCG, as well as to test novel delivery mechanisms to enhance BCG's efficacy. Traditional BCG vaccination is performed as an intradermal (ID) injection but delivering BCG by an alternate route may enhance the depth and breadth of protection. Previously, we demonstrated that phenotypically and genotypically disparate Diversity Outbred (DO) mice have heterogenous responses to M. tuberculosis challenge following intradermal BCG vaccination. Here, we utilize DO mice to examine BCG-induced protection when BCG is delivered systemically via intravenous (IV) administration. We find that DO mice vaccinated with IV BCG had a greater distribution of BCG throughout their organs compared to ID-vaccinated animals. However, compared to ID-vaccinated mice, M. tuberculosis burdens in lungs and spleens were not significantly reduced in animals vaccinated with BCG IV, nor was lung inflammation significantly altered. Nonetheless, DO mice that received BCG IV had increased survival over those vaccinated by the traditional ID route. Thus, our results suggest that delivering BCG by the alternate IV route enhances protection as detected in this diverse small animal model.