Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination

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.

Automated summary

BCG vaccination can enhance protection against pathogens by inducing epigenetic and metabolic reprogramming of innate immune cells, known as trained immunity. In rhesus macaques, intravenous BCG was shown to better protect against Mycobacterium tuberculosis infection and TB disease compared to standard intradermal vaccination, correlating with local adaptive immune signatures. Additionally, mucosal vaccination, either with BCG or the MTBVAC candidate, was found to enhance innate cytokine production by monocytes derived from blood and bone marrow, showing metabolic rewiring typical of trained immunity.