Attenuated Mycobacterium tuberculosis vaccine protection in a low-dose murine challenge model

Samuel J Vidal; Daniel Sellers; Jingyou Yu; Shoko Wakabayashi; Jaimie Sixsmith; Malika Aid; Julia Barrett; Sage F Stevens; Xiaowen Liu; Wenjun Li; Courtney R Plumlee; Kevin B Urdahl; Amanda J Martinot; Dan H Barouch

doi:10.1016/j.isci.2023.106963

Attenuated Mycobacterium tuberculosis vaccine protection in a low-dose murine challenge model

iScience. 2023 May 28;26(6):106963. doi: 10.1016/j.isci.2023.106963. eCollection 2023 Jun 16.

Authors

Samuel J Vidal^{1

2}, Daniel Sellers¹, Jingyou Yu¹, Shoko Wakabayashi³, Jaimie Sixsmith³, Malika Aid¹, Julia Barrett¹, Sage F Stevens¹, Xiaowen Liu⁴, Wenjun Li⁵, Courtney R Plumlee⁶, Kevin B Urdahl^{6

7

8}, Amanda J Martinot⁹, Dan H Barouch^{1

10}

Affiliations

¹ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
² Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁵ Department of Public Health, University of Massachusetts Lowell, Lowell, MA, USA.
⁶ Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA.
⁷ Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁸ Department of Immunology, University of Washington, Seattle, WA, USA.
⁹ Department of Infectious Diseases and Global Health, Tufts University Cummings School of Veterinary Medicine, North Grafton, MA, USA.
¹⁰ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.

Abstract

Bacillus Calmette-Guérin (BCG) remains the only approved tuberculosis (TB) vaccine despite limited efficacy. Preclinical studies of next-generation TB vaccines typically use a murine aerosol model with a supraphysiologic challenge dose. Here, we show that the protective efficacy of a live attenuated Mycobacterium tuberculosis (Mtb) vaccine ΔLprG markedly exceeds that of BCG in a low-dose murine aerosol challenge model. BCG reduced bacterial loads but did not prevent establishment or dissemination of infection in this model. In contrast, ΔLprG prevented detectable infection in 61% of mice and resulted in anatomic containment of 100% breakthrough infections to a single lung. Protection was partially abrogated in a repeated low-dose challenge model, which showed serum IL-17A, IL-6, CXCL2, CCL2, IFN-γ, and CXCL1 as correlates of protection. These data demonstrate that ΔLprG provides increased protection compared to BCG, including reduced detectable infection and anatomic containment, in a low-dose murine challenge model.

Keywords: Immunology; Medical microbiology.

Grants and funding

T32 AI007387/AI/NIAID NIH HHS/United States