BCG-triggered skin-to-blood signals reveal early vaccine responses

Tuberculosis (TB) remains the world’s leading infectious killer, and the Bacille Calmette-Guérin (BCG) vaccine is the only licensed vaccine for prevention. BCG has been given intradermally for more than a century to over 100 million people each year, yet until now the molecular events that unfold in the skin after vaccination had not been mapped in humans. That gap has made it hard to find early, measurable signals that predict whether vaccination will trigger protective immune responses. In new work led by Nelly Amenyogbe, researchers took a close, time-sensitive look at the immediate response to BCG in the human skin and in blood. They sampled the site of injection and circulating blood over the first days after vaccination and integrated those data to follow how signals moved across layers of the skin and into the bloodstream. By tracing these spatiotemporal patterns, the team set out to identify the cellular players and molecular pathways that appear first, and to discover whether non-invasive tests might reveal which people mount the most promising responses to BCG.

To capture both local and systemic responses the team combined tissue biopsies of human skin using spatial genomics with ‘liquid biopsies’ analyzed by cell-free blood plasma RNASeq. They also used high-resolution images of the injection site with dermatoscopy to relate visible features to molecular findings. Within one day of vaccination they observed dynamic molecular waves that changed over skin layers and over the following days in blood. Integrated analysis revealed interacting networks tied to immune surveillance (Langerhans cells), cell trafficking (endothelial cells, ITGB5), and hallmarks of trained immunity including neutrophils, macrophages and γδ-T cell responses. The study identified activation of pathways previously linked to trained immunity, such as mTOR signaling and glycolysis/gluconeogenesis, and uniquely mapped the precise skin layer and timing when these pathways first turn on. Their data confirmed known observations like prominent γδ-T cell induction at the BCG site and a negative correlation between blood and tissue myeloid-derived suppressor cells, while pointing to new leads: baseline levels of B cells, platelets and nuocytes in the skin predicted later outcomes and these baseline differences could be seen non-invasively by dermatoscopy.

This work provides the first holistic picture of the very early molecular response to BCG in human skin among people at medium to high TB risk, and it does so by linking tissue-level changes to signals detectable in blood. Pinpointing when and where trained-immunity pathways such as mTOR signaling and glycolysis/gluconeogenesis are activated gives investigators concrete molecular events to test as early correlates of protection in future trials. The finding that baseline cellular composition in the skin — including B cells, platelets and nuocytes — predicts later responses, and that dermatoscopy can capture these predictive differences non-invasively, opens practical ways to screen individuals or compare vaccine candidates without needing large numbers of invasive biopsies. Overall, by mapping skin-to-blood crosstalk after BCG, the study offers new biomarkers and timepoints that could accelerate evaluation and design of better TB vaccines.