Intravenous Immunization with Triple Auxotrophs of : A novel vaccine strategy against tuberculosis.

Tuberculosis, caused by ( ), remains a leading infectious cause of mortality worldwide despite widespread use of the BCG vaccine and the availability of sterilizing pharmacopoeia. Recent research indicates that the intravenous administration of BCG confers sterilizing immunity against pulmonary challenge in non-human primates. However, while BCG is relatively safe, complications such as disseminated BCGosis have been observed in immunocompromised individuals. Double auxotrophic mutants of lacking the ability to synthesize leucine and pantothenate are safe and sterilized in immunocompromised mice and SIV-infected Rhesus macaques. We examined how immunization with a triple auxotrophic strain, mc 7902, which cannot synthesize leucine, pantothenate, and arginine, protects immunocompetent mice from a virulent infection. The route of immunization was a crucial factor for protection with mc 7902 with intravenous immunization being 100 times more effective in protecting immunocompetent mice from challenge when compared to conventional subcutaneous vaccination with BCG. To further increase the safety of the attenuated auxotroph for vaccine purposes, the type VII secretion system Esx1 responsible for BCG attenuation was deleted in mc 7902. When tested by prime-boost immunization of immunocompetent mice followed by aerosol challenge with virulent , mc 7902 Δ provided similar protection to mc 7902. This robust protection against infection conferred by mc 7902 and mc 7902 Δ in a mouse model paves the way for new TB vaccine development using highly attenuated, auxotrophic strains.