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) and bovine adenovirus (BAdv) vectors. BAdv-infected dendritic cells (DCs) expressed a robust transcriptome of genes regulating antigen processing compared to HAdv-infected DCs. BAdv-infected DCs showed enhanced galectin-3/8 and autophagy-dependent Ag85B-p25 epitope presentation to CD4 T cells. BCG-vaccinated mice were intranasally boosted using HAdv or BAdv followed by infection using aerosolized (Mtb). BAdv protected mice against tuberculosis both as a booster after BCG vaccine (>1.4-log reduction in Mtb lung burden) and as a single intranasal dose (>0.5-log reduction). Protection was associated with robust CD4 and CD8 effector (T), central memory (T), and CD103/CD69 lung-resident memory (T) T cell expansion, revealing BAdv as a promising mucosal vaccine for tuberculosis.