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
Affiliations
Samuel J. Vidal
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Daniel Sellers
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Jingyou Yu
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Shoko Wakabayashi
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Jaimie Sixsmith
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Malika Aid
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Julia Barrett
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Sage F. Stevens
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Xiaowen Liu
Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
Wenjun Li
Department of Public Health, University of Massachusetts Lowell, Lowell, MA, USA
Courtney R. Plumlee
Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA
Kevin B. Urdahl
Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Department of Immunology, University of Washington, Seattle, WA, USA
Amanda J. Martinot
Department of Infectious Diseases and Global Health, Tufts University Cummings School of Veterinary Medicine, North Grafton, MA, USA
Dan H. Barouch
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Corresponding author
Summary: 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.
