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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.

Intranasal Immunization with Peptide-based Immunogenic Complex Enhances BCG Vaccine Efficacy in murine model of Tuberculosis