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

Abstract

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.

Peptide-Based Vaccines for Tuberculosis

“…Previous studies on TB subunit vaccines have provided a large number of vaccine candidate antigens for peptide-based vaccines development, such as Ag85A (Rv3804c) ( 241 ), Ag85B (Rv1886c) ( 116 , 202 , 239 , 240 ), 6-kDa early secretory antigenic target (ESAT-6, Rv3875) ( 222 , 223 , 238 , 239 ), heat shock protein HspX (also known as Hsp16.3, Acr, and 14 kDa antigen, Rv2031c) ( 115 , 146 , 202 , 210 , 211 , 242 ), TB10.4 (Rv0288) ( 2 , 115 , 211 , 240 ), Rv0476 ( 211 ), Hsp65 ( 202 ), 19-kDa lipoprotein (Rv3763) ( 202 ), Rv1733c ( 202 , 203 ), PE/PPE proteins ( 2 , 243 , 244 , 248 ), MPT64 (Rv1980c) ( 246 , 247 ), Mtb8.4 ( 2 ), and resuscitation-promoting factors (Rpfs) ( 2 , 228 ). These antigens have been reported to be attractive vaccine candidates for preventing and controlling TB.…”

“…Previous studies have shown that Ag85A and Ag85B proteins are rich in epitope resources, giving them a distinct advantage in constructing peptide-based vaccines (257,265). Kumar S et al generated a vaccine mixture (peptide-TLR agonist-liposomes, abbreviation for PTL), consisting of three Ag85B peptides, four ESAT-6 peptides, TLR2 agonist Pam3Cys-SK-4, and TLR9 agonist CpG ODN (Table 3) (239). Interestingly, the BCG-PTL coimmunization enhanced the proportion of vaccineinduced Tcm cells and polyfunctional cytokine responses and increased the defensive efficiency against TB compared with BCG vaccination (239).…”

Tuberculosis: The success tale of less explored dormant Mycobacterium tuberculosis

“…It is well-known that only available vaccine against TB is BCG that fails to induce long term memory and thereby insufficient to prevent resuscitation ( Negi et al., 2022 ). Therefore, a potential adjunct complex, termed as peptide-TLR agonist-liposome (PTL) when administered with BCG enhances the long-term memory and reduces the rate of reactivation, thereby reduction in bacterial burden in the lungs of mice ( Kumar et al., 2021 ).…”

In vivo fate and intracellular trafficking of vaccine delivery systems

“…Nasal and pulmonary routes aim to enhance the induction of secretary IgA antibody in nasal passages and lung mucosal sites [59] . Indeed, nasal and pulmonary routes were shown to be effective to provide immune responses against influenza [60] , [61] and tuberculosis [62] , [63] , respectively. Subcutaneous route can allow the migration of vaccine antigens to lymph nodes, the primary organs of adaptive immune response [64] .…”