Attenuated <i>Mycobacterium tuberculosis</i> Vaccine Protection in a Low Dose Murine Challenge Model

Abstract Bacillus Calmette–Guérin (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 ΔLprG 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, ΔLprG 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-γ, and CXCL1 as correlates of protection. These data demonstrate that ΔLprG provides strikingly increased protection compared to BCG, including reduced detectable infection and anatomic containment, in a low dose murine challenge model.