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Summary BCG vaccination can strengthen protection against pathogens through the induction of epigenetic and metabolic reprogramming of innate immune cells, a process called trained immunity. We and others recently demonstrated that mucosal or intravenous BCG better protects rhesus macaques from Mycobacterium tuberculosis infection and TB disease than standard intradermal vaccination, correlating with local adaptive immune signatures. In line with prior mouse data, here, we show in rhesus macaques that intravenous BCG enhances innate cytokine production associated with changes in H3K27 acetylation typical of trained immunity. Alternative delivery of BCG does not alter the cytokine production of unfractionated bronchial lavage cells. However, mucosal but not intradermal vaccination, either with BCG or the M. tuberculosis-derived candidate MTBVAC, enhances innate cytokine production by blood- and bone marrow-derived monocytes associated with metabolic rewiring, typical of trained immunity. These results provide support to strategies for improving TB vaccination and, more broadly, modulating innate immunity via mucosal surfaces., Graphical Abstract, Highlights Nonhuman primates recapitulate trained immunity upon live attenuated TB vaccination Intravenous BCG induces changes in H3K27 acetylation and enhances cytokine production Mucosal BCG improves induction of trained immunity of monocytes over intradermal BCG The M. tuberculosis-derived candidate vaccine MTBVAC appears equally potent as BCG, Vierboom et al. demonstrate the induction of trained immunity in blood and bone marrow monocytes after vaccination with live attenuated TB vaccines in nonhuman primates. Mucosal respiratory delivery of BCG or MTBVAC induces trained immunity more efficiently compared to standard intradermal vaccination.

Summary To fight tuberculosis, better vaccination strategies are needed. Live attenuated Mycobacterium tuberculosis-derived vaccine, MTBVAC, is a promising candidate in the pipeline, proven to be safe and immunogenic in humans so far. Independent studies have shown that pulmonary mucosal delivery of Bacillus Calmette-Guérin (BCG), the only tuberculosis (TB) vaccine available today, confers superior protection over standard intradermal immunization. Here we demonstrate that mucosal MTBVAC is well tolerated, eliciting polyfunctional T helper type 17 cells, interleukin-10, and immunoglobulins in the airway and yielding a broader antigenic profile than BCG in rhesus macaques. Beyond our previous work, we show that local immunoglobulins, induced by MTBVAC and BCG, bind to M. tuberculosis and enhance pathogen uptake. Furthermore, after pulmonary vaccination, but not M. tuberculosis infection, local T cells expressed high levels of mucosal homing and tissue residency markers. Our data show that pulmonary MTBVAC administration has the potential to enhance its efficacy and justifies further exploration of mucosal vaccination strategies in preclinical efficacy studies., Graphical Abstract, Highlights Pulmonary MTBVAC delivery confers immune signature correlating with TB protection This signature spreads through the lung without a recall response in the skin Vaccine-induced T cells have increased mucosal homing and tissue residency markers Vaccine-induced antibodies enhance phagocytosis of M. tuberculosis, Dijkman et al. show that pulmonary immunization with the M. tuberculosis-derived vaccine candidate MTBVAC confers a local mucosal antigen-specific signature—polyfunctional Th1/Th17 cells exhibiting increased homing and tissue residency marker expression, IL-10, and phagocytosis-promoting immunoglobulins—that has been associated previously with protection from TB infection and disease in rhesus macaques.