Immunogenicity and protective potential of a mucosal protein-only vaccine candidate for tuberculosis

Despite the widespread use of the BCG vaccine, tuberculosis remains a leading global health threat. The primary limitation of BCG lies in its failure to prevent pulmonary TB in adults, largely due to its systemic administration route which fails to induce robust mucosal immunity at the site of primary infection. This study evaluates a novel mucosal vaccine platform, TB-PCF, incorporating Mycobacterium tuberculosis antigens ESAT6 and CFP10 fused with Cholera Toxin B subunit (CTB) and an IgG-Fc domain to enhance polymerisation and antigen uptake by antigen-presenting cells. Following systemic priming and mucosal boosting in mice, TB-PCF vaccine elicited significant antigen-specific antibody responses in serum and bronchoalveolar lavage fluid, as well as polyfunctional systemic Th1 and Th17 responses, characterised by elevated IFN-γ and IL-17. Notably, splenocytes from vaccinated mice exhibited significant bacterial killing in a modified mycobacterial growth inhibition assay (MGIA), trending higher than BCG. However, in the subsequent in vivo challenge test, only the BCG-vaccinated group achieved a statistically significant reduction in lung bacterial burden. While the failure to translate in vitro bacterial killing into in vivo protection suggests that the ESAT6-CFP10 antigen duo may lack the necessary antigenic breadth for full protection, we propose that the TB-PCF platform is a promising, new tool for future screening of diverse antigen combinations to overcome current roadblocks in mucosal TB vaccination.