A recombinant bovine adenoviral mucosal vaccine expressing mycobacterial antigen-85B generates robust protection against tuberculosis in mice

Although the BCG vaccine offers partial protection, tuberculosis remains a leading cause of infectious disease death, killing ∼1.5 million people annually. We developed mucosal vaccines expressing the autophagy-inducing peptide C5 and mycobacterial Ag85B-p25 epitope using replication-defective human adenovirus (HAdv 85C5 ) and bovine adenovirus (BAdv 85C5 ) vectors. BAdv 85C5 -infected dendritic cells (DCs) expressed a robust transcriptome of genes regulating antigen processing compared to HAdv 85C5 -infected DCs. BAdv 85C5 -infected DCs showed enhanced galectin-3/8 and autophagy-dependent in vitro Ag85B-p25 epitope presentation to CD4 T cells. BCG-vaccinated mice were intranasally boosted using HAdv 85C5 or BAdv 85C5 followed by infection using aerosolized Mycobacterium tuberculosis (Mtb). BAdv 85C5 protected mice against tuberculosis both as a booster after BCG vaccine (>1.4-log 10 reduction in Mtb lung burden) and as a single intranasal dose (>0.5-log 10 reduction). Protection was associated with robust CD4 and CD8 effector (T EM ), central memory (T CM ), and CD103 + /CD69 + lung-resident memory (T RM ) T cell expansion, revealing BAdv 85C5 as a promising mucosal vaccine for tuberculosis.