Prophylactic and post-exposure efficacy of a Pichinde virus vector-based tuberculosis vaccine.

Mycobacterium tuberculosis (Mtb) remains the leading cause of death from a single infectious agent, despite the availability of the Bacillus Calmette-Guérin (BCG) vaccine and antibiotic therapies. New tuberculosis (TB) vaccines are urgently needed to effectively protect adults against pulmonary Mtb infections, whether used alone, as a BCG booster, or as a therapeutic strategy. We developed TBpV1, a multivalent TB vaccine, using recombinant Pichinde virus (rPICV) vector rP18tri. TBpV1 comprises three rP18tri-vectored components that collectively deliver 13 known and novel antigens targeting both the latent and active stages of the Mtb infection cycle. In mice, the pooled TBpV1 vaccine elicited robust antigen-specific CD4+ and CD8+ T cell responses, including polyfunctional Th1 and IL-17-producing cells, at levels equivalent to individual rP18tri-vectored vaccines. As a standalone vaccine, TBpV1 significantly reduced bacterial burden following an Mtb Erdman aerosol challenge, achieving protection comparable to BCG. TBpV1 also enhanced protection when administered as a BCG booster, reducing lung inflammation and bacterial loads. Lastly, TBpV1 reduced splenic bacterial burden in a post-exposure setting. These results demonstrate that pooling multi-stage antigens via the rP18tri vector maintains immunogenicity while improving protective efficacy. TBpV1 is a promising candidate for both TB prevention and therapeutic intervention, supporting further evaluation in preclinical models.