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A potent vaccine against tuberculosis, one of the world's deadliest diseases, is needed to enhance the immunity of people worldwide, most of whom have been vaccinated with the partially effectiveMycobacterium bovis BCG vaccine. Here we investigate novel live attenuated recombinantListeria monocytogenes (rLm) vaccines expressing theMycobacterium tuberculosis 30-kDa major secretory protein (r30/antigen 85B [Ag85B]) (rLm30) as heterologous booster vaccines in animals primed with BCG. Using three attenuatedL. monocytogenes vectors,L. monocytogenes ΔactA (LmI),L. monocytogenes ΔactA ΔinlB (LmII), andL. monocytogenes ΔactA ΔinlB prfA * (LmIII), we constructed five rLm30 vaccine candidates expressing r30 linked in frame to theL. monocytogenes listeriolysin O signal sequence and driven by thehly promoter (h30) or linked in frame to the ActA N-terminal 100 amino acids and driven by theactA promoter (a30). All five rLm30 vaccines secreted r30 in broth and macrophages; while rLm30 expressing r30 via a constitutively activeprfA * regulon (rLmIII/a30) expressed the largest amount of r30 in broth culture, all five rLm30 vaccines expressed equivalent amounts of r30 in infected macrophages. In comparative studies, boosting of BCG-immunized mice with rLmIII/a30 induced the strongest antigen-specific T-cell responses, including splenic and lung polyfunctional CD4+ T cells expressing the three cytokines interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) (P &lt; 0.001) and splenic and lung CD8+ T cells expressing IFN-γ (P &lt; 0.0001). In mice and guinea pigs, the rLmIII/a30 and rLmI/h30 vaccines were generally more potent booster vaccines than r30 with an adjuvant and a recombinant adenovirus vaccine expressing r30. In a setting in which BCG alone was highly immunoprotective, boosting of mice with rLmIII/a30, the most potent of the vaccines, significantly enhanced protection against aerosolizedM. tuberculosis (P &lt; 0.01).

infection and immunity

Listeria-Vectored Vaccine Expressing the Mycobacterium tuberculosis 30-Kilodalton Major Secretory Protein via the Constitutively Active <i>prfA</i> * Regulon Boosts Mycobacterium bovis BCG Efficacy against Tuberculosis

Listeria-Vectored Vaccine Expressing the Mycobacterium tuberculosis 30-Kilodalton Major Secretory Protein via the Constitutively Active prfA * Regulon Boosts Mycobacterium bovis BCG Efficacy against Tuberculosis