Prevention of tuberculosis in macaques after intravenous BCG immunization

Patricia A. Darrah, Joseph J. Zeppa, Pauline Maiello, Joshua A. Hackney, Marc H. Wadsworth, Travis K. Hughes, Supriya Pokkali, Phillip A. Swanson, Nicole L. Grant, Mark A. Rodgers, Megha Kamath, Chelsea M. Causgrove, Dominick J. Laddy, Aurelio Bonavia, Danilo Casimiro, Philana Ling Lin, Edwin Klein, Alexander G. White, Charles A. Scanga, Alex K. Shalek, Mario Roederer, JoAnne L. Flynn and Robert A. Seder ()
Additional contact information
Patricia A. Darrah: National Institutes of Health (NIH)
Joseph J. Zeppa: University of Pittsburgh School of Medicine
Pauline Maiello: University of Pittsburgh School of Medicine
Joshua A. Hackney: National Institutes of Health (NIH)
Marc H. Wadsworth: Ragon Institute of MGH, Harvard, and MIT
Travis K. Hughes: Ragon Institute of MGH, Harvard, and MIT
Supriya Pokkali: National Institutes of Health (NIH)
Phillip A. Swanson: National Institutes of Health (NIH)
Nicole L. Grant: University of Pittsburgh School of Public Health
Mark A. Rodgers: University of Pittsburgh School of Medicine
Megha Kamath: National Institutes of Health (NIH)
Chelsea M. Causgrove: University of Pittsburgh School of Medicine
Dominick J. Laddy: Aeras
Aurelio Bonavia: Aeras
Danilo Casimiro: Aeras
Philana Ling Lin: Children’s Hospital of the University of Pittsburgh of UPMC
Edwin Klein: University of Pittsburgh School of Medicine
Alexander G. White: University of Pittsburgh School of Medicine
Charles A. Scanga: University of Pittsburgh School of Medicine
Alex K. Shalek: Ragon Institute of MGH, Harvard, and MIT
Mario Roederer: National Institutes of Health (NIH)
JoAnne L. Flynn: University of Pittsburgh School of Medicine
Robert A. Seder: National Institutes of Health (NIH)

Nature, 2020, vol. 577, issue 7788, 95-102

Abstract: Abstract Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide1. The only available vaccine, BCG (Bacillus Calmette–Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission1,2. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography–computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis.

Date: 2020
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DOI: 10.1038/s41586-019-1817-8

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