Abstract

Bacillus Calmette-Guerin (BCG) remains the only clinically approved tuberculosis (TB) vaccine despite limited efficacy. Preclinical studies of next generation TB vaccines have typically used a murine aerosol challenge model that employs a high supraphysiologic challenge dose. Here we show that the protective efficacy of a live attenuated Mycobacterium tuberculosis (Mtb) vaccine candidate {Delta}LprG markedly exceeds that of BCG in a low dose murine aerosol challenge model. BCG vaccination reduced bacterial loads but failed to prevent establishment or dissemination of infection in this model. In contrast, {Delta}LprG prevented detectable infection in 61% of mice and resulted in striking anatomic containment of 100% breakthrough infections to a single lung. Protection was partially abrogated in a repeated low dose challenge model, which revealed serum IL-17A, IL-6, CXCL2, CCL2, IFN-{gamma}, and CXCL1 as correlates of protection. These data demonstrate that {Delta}LprG provides strikingly increased protection compared to BCG, including reduced detectable infection and anatomic containment, in a low dose murine challenge model.