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.