Cross-species blood transcriptional correlates of BCG-mediated protection against tuberculosis include innate and adaptive immune processes

The Bacillus Calmette-Guerin (BCG) vaccine is the only licensed vaccine against tuberculosis (TB), yet the immune mechanisms that it induces, and the subset that mediate protection, remain incompletely understood. Verifying vaccine-induced protection in humans is difficult, and while studies in animal models such as mice and nonhuman primates (NHPs) have advanced knowledge, differences in the relevance of biological pathways across species limit the direct translation of these insights to humans. To address this challenge, we applied a systems modeling framework, Translatable Components Regression (TransCompR), to integrate transcriptional data from humans with outcomes of Mycobacterium tuberculosis (Mtb) challenge studies in BCG-vaccinated NHPs. Using this approach, we identified human blood transcriptional signatures whose variability predicted protection in NHPs. The pathways associated with protection included innate and adaptive immune activation, Type I interferon signaling, and T helper cell cytokine responses with known anti-mycobacterial activity. We further explored the relevance of these pathways in humans by partially validating the associations using publicly available microarray data from BCG-vaccinated infants, some of whom developed TB during two years of follow-up while others remained healthy. The findings supported the role of the identified immune pathways in mediating protection after BCG vaccination. Overall, the work demonstrates how species-translation modeling can leverage animal studies to generate mechanistic hypotheses about human responses to infection and vaccination. Such integrative approaches provide a way to gain insights into protective immunity that are otherwise difficult to uncover from human data alone.