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

Abstract

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 <i>in vitro</i> 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 <i>Mycobacterium tuberculosis</i> (Mtb). BAdv^85C5 protected mice against tuberculosis both as a booster after BCG vaccine (>1.4-log₁₀ reduction in Mtb lung burden) and as a single intranasal dose (>0.5-log₁₀ 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.