Route of BCG administration determines success.

Tuberculosis (TB) is the single most deadly human pathogen and has been for centuries. BCG, a vaccine designed to protect from TB, is the most frequently administered vaccine in human history. Despite BCG's many shortcomings, which include suboptimal protection from TB, BCG has for over 100 y remained the only available vaccine in the fight against TB. Recent evidence from animal models indicates that BCG administered intravenously provides superior protection compared to cutaneous routes, such as intradermal or subcutaneous. Therefore, the route to improve success for BCG in the fight against TB and other illnesses, such as bladder cancer and neonatal sepsis, may simply relate to changing the route of its administration. We here trace the trajectory regarding the centrality of route of administration for BCG from its roots all the way to the most recent scientific breakthroughs, and with that illuminate a potential path ahead toward deploying BCG most optimally.