IL-10 Receptor Blockade Delivered Simultaneously with Bacillus Calmette–Guérin Vaccination Sustains Long-Term Protection against Mycobacterium tuberculosis Infection in Mice

Key Points A single dose of BCG/anti–IL-10R1 generates long-term BCG-specific memory immunity. A single dose of BCG/anti–IL-10R1 reverses waning protective efficacy of BCG. Mycobacterium bovis bacillus Calmette–Guérin (BCG) immunization still remains the best vaccination strategy available to control the development of active tuberculosis. Protection afforded by BCG vaccination gradually wanes over time and although booster strategies have promise, they remain under development. An alternative approach is to improve BCG efficacy through host-directed therapy. Building upon prior knowledge that blockade of IL-10R1 during early Mycobacterium tuberculosis infection improves and extends control of M. tuberculosis infection in mice, we employed a combined anti–IL-10R1/BCG vaccine strategy. An s.c. single vaccination of BCG/anti–IL10-R1 increased the numbers of CD4+ and CD8+ central memory T cells and reduced Th1 and Th17 cytokine levels in the lung for up to 7 wk postvaccination. Subsequent M. tuberculosis challenge in mice showed both an early (4 wk) and sustained long-term (47 wk) control of infection, which was associated with increased survival. In contrast, protection of BCG/saline-vaccinated mice waned 8 wk after M. tuberculosis infection. Our findings demonstrate that a single and simultaneous vaccination with BCG/anti–IL10-R1 sustains long-term protection, identifying a promising approach to enhance and extend the current BCG-mediated protection against TB.