Blood Transcriptional Correlates of BCG-Induced Protection Against Tuberculosis in Rhesus Macaques

Blood-based correlates of vaccine-induced protection against tuberculosis (TB) are urgently needed. We analyzed the blood transcriptome of rhesus macaques immunized with varying doses of intravenous (IV) BCG followed by Mycobacterium tuberculosis (Mtb) challenge. We used high-dose IV BCG recipients for "discovery" and validated our findings in low-dose recipients and in an independent cohort of macaques receiving BCG via different routes. We identified seven vaccine-induced gene modules, including an innate module (module 1) enriched for type 1 interferon and RIG-I-like receptor signaling pathways. Module 1 on day 2 post-vaccination was highly correlated with lung antigen-responsive CD4 T cells at week 8 and with Mtb and granuloma burden following challenge. Parsimonious signatures within module 1 at day 2 post-vaccination predicted protection following challenge with AUROCs [≥] 0.91. Together these results indicate that the early innate transcriptional response to IV BCG in peripheral blood may provide a robust correlate of protection against TB.