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

Abstract

AbstractTuberculosis, caused byMycobacterium tuberculosis(Mtb), 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 againstMtbpulmonary 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 ofMtblacking the ability to synthesize leucine and pantothenate are safe and sterilized in immunocompromised mice and SIV-infected Rhesus macaques. We examined how immunization with aMtbtriple auxotrophic strain, mc27902, which cannot synthesize leucine, pantothenate, and arginine, protects immunocompetent mice from a virulentMtbinfection. The route of immunization was a crucial factor for protection with mc27902 with intravenous immunization being 100 times more effective in protecting immunocompetent mice fromMtbchallenge 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 mc27902. When tested by prime-boost immunization of immunocompetent mice followed by aerosol challenge with virulentMtb, mc27902 Δesx1provided similar protection to mc27902. This robust protection againstMtbinfection conferred by mc27902 and mc27902 Δesx1in a mouse model paves the way for new TB vaccine development using highly attenuated, auxotrophicMtbstrains.