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.

doi:10.1101/2023.03.17.533226

bioRxiv · 10.1101/2023.03.17.533226

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.

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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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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.. 2023-03-18. Attenuated Mycobacterium tuberculosis Vaccine Protection in a Low Dose Murine Challenge Model. https://doi.org/10.1101/2023.03.17.533226

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