Spatiotemporal-multimodal integration reveals BCG-induced skin-blood crosstalk

Tuberculosis (TB) remains the leading cause of infectious death. The Bacille Calmette-Guérin (BCG) vaccine has been the only licensed vaccine available for TB prevention. Despite BCG being administered intradermally for over a century to >100 million individuals annually, the molecular events in the skin following BCG administration have not been investigated; as a result, measurable correlates of protection that could predict vaccine effectiveness already early after vaccination are lacking. Here we show that BCG immediately (within one day after vaccination) induces dynamic molecular waves that drive the acute human host response across space (layers of the skin and systemically in blood) and time (days). Integration of this data across space and time identified robust networks of interactive modules related to immune surveillance (e.g. Langerhans cells), cell trafficking (e.g. endothelial cells, ITGB5 ), and trained immunity (e.g. neutrophils, macrophages, γδ-T cell). Importantly, not only were we able to identify BCG-activated pathways associated with ‘trained immunity’ such as mTOR signaling and glycolysis/gluconeogenesis, we were able to pinpoint the time-point and precise location (skin layer) of the initial activation of theses pathways. Combining tissue biopsies of human skin (spatial genomics) with ‘liquid biopsies’ (cell-free blood plasma RNASeq) following BCG vaccination our data both confirmed known evidence (e.g. prominent γδ-T cell induction at the site of BCG administration; negative correlation of blood vs tissue myeloid-derived suppressor cells), but also generated promising new leads such as baseline levels of B cells, platelets and nuocytes in the skin prior to BCG administration predict eventual outcome, and that these predictive differences in baseline cellular composition can be captured non-invasively using high resolution images of the site of injection (dermatoscopy). Given this data represents the first holistic view of the acute molecular response to BCG in the skin in a human population at medium to high TB risk, we anticipate our findings of the immediate/early events following BCG vaccination, including non-invasive predictive assessment will support acceleration of vaccine development in the fight against TB.