Attenuated Mycobacterium tuberculosis Vaccine Protection in a Low Dose Murine Challenge Model
Vidal, S. J.; Sellers, D.; Yu, J.; Wakabayashi, S.; Sixsmith, J.; Aid, M.; Barrett, J.; Stevens, S. F.; Liu, X.; Li, W.; Plumlee, C. R.; Urdahl, K. B.; Martinot, A. J.; Barouch, D. H.
Show 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.
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