Induction of trained immunity by a novel Bovine adenovirus vectored tuberculosis vaccine that upregulates Dectin signaling and control of tuberculosis in mice 3049

Abstract Description Mycobacterium tuberculosis (Mtb) causes tuberculosis, killing a million people each year. Because the BCG vaccine has a partial efficacy against tuberculosis, many booster vaccines have been investigated to improve its efficacy. We developed novel, replication deficient bovine adenovirus (BAdv)- based TB vaccines that encode secreted mycobacterial Ag85B, ESAT6 and CFP10. Because a first generation BAdv-TB vaccine protected C57BL/6 mice against tuberculosis, we examined the hypothesis that it may also upregulate innate immunity pathways increasing efficacy. Human macrophages were treated with vaccines or vector control followed by an overlay for CD4 T cell hybridoma specific for an epitope of Ag85B; IL-2 in the supernatants was measured for antigen presentation. Prior to vaccine addition, autophagy was downregulated using siRNA against ATG-5/7 and Cathepsins (CTSB, CTSD, CTSS and CTSL) were blockaded using drugs. At 48 hr. post infection, macrophages were analyzed using an RT2-PCR array that had genes of innate regulation, autophagy and trained immunity. Ag85B containing BAdv-TB vaccines induced robust peptide presentation ex vivo, which was decreased after autophagy and Cathepsin blockade. Unexpectedly, multiple genes of C-type lectin receptors (aka. dectin) were upregulated by BADv-vaccines but not BADV vector. In mice, BAdv-TB induces T cell responses. Ex vivo data suggest that BAdv-TB vaccines can also engender trained immunity in mice and protect against tuberculosis. Funding Sources Supported by AI161015 NIAID, NIH Topic Categories Vaccines and Immunotherapy (VAC)