Intranasal immunization with peptide-based immunogenic complex enhances BCG vaccine efficacy in a murine model of tuberculosis

Prime-boost immunization strategies are required to control the global tuberculosis (TB) pandemic, which claims approximately 3 lives every minute. Here, we have generated an immunogenic complex against Mycobacterium tuberculosis (M.tb), consisting of promiscuous T cell epitopes (M.tb peptides) and TLR ligands assembled in liposomes. Interestingly, this complex (peptide–TLR agonist–liposomes; PTL) induced significant activation of CD4(+) T cells and IFN-γ production in the PBMCs derived from PPD(+) healthy individuals as compared with PPD(–) controls. Furthermore, intranasal delivery of PTL significantly reduced the bacterial burden in the infected mice by inducing M.tb-specific polyfunctional (IFN-γ(+)IL-17(+)TNF-α(+)IL-2(+)) immune responses and long-lasting central memory responses, thereby reducing the risk of TB recurrence in DOTS-treated infected animals. The transcriptome analysis of peptide-stimulated immune cells unveiled the molecular basis of enhanced protection. Furthermore, PTL immunization significantly boosted the Bacillus Calmette-Guerin–primed (BCG-primed) immune responses against TB. The greatly enhanced efficacy of the BCG-PTL vaccine model in controlling pulmonary TB projects PTL as an adjunct vaccine against TB.