Mycobacterium tuberculosis (Mtb) is the leading cause of death from
infection worldwide1. The only available
vaccine, BCG (Bacillus Calmette-Guérin), is given intradermally and has variable efficacy against
pulmonary tuberculosis, the major cause of mortality and disease transmission1,2. Here we show that
intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or
aerosol delivery, intravenous immunization induced substantially more
antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of
antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of
infection, as determined by positron emission tomography-computed tomography imaging, mycobacterial growth, pathology and
granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb
infection in highly susceptible rhesus macaques has important implications for
vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of
vaccine-elicited protection against
tuberculosis.