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

Abstract

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.

Type I interferon responses contribute to immune protection against mycobacterial infection

“…In support of a protective role for type I interferons, adjunctive interferon alpha therapy in addition to conventional anti-tuberculous antibiotic treatment led to symptomatic and radiological improvement, with a reduction in bacterial burden in respiratory tract samples, in small-scale human studies (38)(39)(40). In keeping with this, an early peripheral blood type I interferon-inducible gene signature predicts successful BCG-induced protection of macaques from subsequent Mtb challenge (41). Type I interferon mediated restriction of mycobacterial growth in in vitro granulomas comprising collagen impregnated microspheres containing Mtb infected human peripheral blood mononuclear cells (PBMC) (42) also suggests that type I interferon responses benefit the host.…”

CD4 T cells and CD8α+ lymphocytes are necessary for intravenous BCG-induced protection against tuberculosis in macaques

“…Correlates analyses of macaques immunized with a wide dose range of IV BCG revealed a highly integrated and coordinated immune response in the airway, some features of which could be predicted by early (day 2) innate signatures in whole blood ( 19, 20 ). Antigen-specific cytokine- producing CD4 T cells (IL-2, TNF, IFNψ, IL-17) and natural killer (NK) cell numbers in the airway were among features most strongly correlated with protection.…”

Intravenous BCG induces a more potent airway and lung immune response than intradermal BCG in SIV-infected macaques1

“…Understanding vaccine-elicited immune responses that correlate with TB protection is critical for rational vaccine development. Several features have been associated with TB protection in IV BCGvaccinated, SIV-naive macaques, including an influx of mycobacterial-specific T cells into the airways and expansion of TRM cells in lung tissue (16,20), elevation of mycobacterial-specific antibodies in circulation and in airway (21), and distinct transcriptional profiles in circulating PBMC (22). In a correlates analysis across a dose range of IV BCG, CD4 T cells expressing different combinations of IFNγ, TNF and/or IL-17 as well as the number of NK cells in airways were correlates of protection independent of BCG dose (20).…”