A lipidated bi-epitope vaccine comprising of MHC-I and MHC-II binder peptides elicits protective CD4 T cell and CD8 T cell immunity against Mycobacterium tuberculosis

Abstract

BackgroundThe clinical trials conducted at Chingleput India suggest that BCG fails to protect against tuberculosis (TB) in TB-endemic population. Recent studies advocate that non-tuberculous mycobacteria and latent Mycobacterium tuberculosis (Mtb) infection interferes in the antigen processing and presentation of BCG in inducing protective immunity against Mtb. Thereby, indicating that any vaccine that require extensive antigen processing may not be efficacious in TB-endemic zones. Recently, we have demonstrated that the vaccine candidate L91, which is composed of lipidated promiscuous MHC-II binder epitope, derived from latency associated Acr1 antigen of Mtb is immunogenic in the murine and Guinea pig models of TB and conferred better protection than BCG against Mtb.MethodsIn this study, we have used a multi-stage based bi-epitope vaccine, namely L4.8, comprising of MHC-I and MHC-II binding peptides of active (TB10.4) and latent (Acr1) stages of Mtb antigens, respectively. These peptides were conjugated to the TLR-2 agonist Pam2Cys.ResultsL4.8 significantly elicited both CD8 T cells and CD4 T cells immunity, as evidenced by increase in the enduring polyfunctional CD8 T cells and CD4 T cells. L4.8 efficiently declined Mtb-burden and protected animals better than BCG and L91, even at the late stage of Mtb infection.ConclusionsThe BCG-L4.8 prime boost strategy imparts a better protection against TB than the BCG alone. This study emphatically denotes that L4.8 can be a promising future vaccine candidate for controlling active and latent TB.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1653-x) contains supplementary material, which is available to authorized users.

A multiple T cell epitope comprising DNA vaccine boosts the protective efficacy of Bacillus Calmette–Guérin (BCG) against Mycobacterium tuberculosis

“…Cumbersome therapeutic strategies, drug-resistant strains, and failures of the common BCG vaccine all further the necessity of efficacious vaccine development. Subunit vaccines have provided a benefit over whole cell-based vaccines [ 8 , 9 , 71 ]. Overall, our studies indicate that a multi T cell epitope-based DNA vaccine substantially enhances the immunity and protection of BCG against Mtb .…”

“…Spleen, lymph nodes (LNs), and lung cells were prepared by crushing of tissues followed by RBC lysis. Lymphocytes (2 × 10 5 /well) isolated from spleens/LNs or lungs were cultured in 96-well U bottom plates and stimulated with PPD (25 μg/ml) and 5 C6 peptides (5 μg/ml each) as Rv0476 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) was unable to synthesize. For DCs and macrophages activation status studies, cells were stimulated with LPS (1 μg/ml) for 24 h.…”

“…Recently, we developed a lipidated promiscuous peptide vaccine comprising of the immunodominant CD4 and CD8 T cell epitopes of Acr1 and TB10.4 proteins of Mtb conjugated to TLR-2 ligand Pam2Cys [8,9]. These constructs elicited enduring memory T cells response and showed better protection than BCG in mouse and Guinea pig TB models.…”

Analysis of Putative Epitope Candidates of Mycobacterium tuberculosis Against Pakistani Human Leukocyte Antigen Background: An Immunoinformatic Study for the Development of Future Vaccine

“…L4.8 significantly elicited CD8 + and CD4 + T cells and was claimed for better protection against Mtb infection than BCG. It is, however, not approved clinically and needs validation on model organisms (Rai et al 2018). In 2019, an immunoinformatics based study from Elhag Mustafa et al reported four immunogenic peptides, from the conserved regions of the PPE65 family protein of Mycobacterium tuberculosis, along with the population coverage of these epitopes.…”

Recent Advances in the Development of Protein- and Peptide-Based Subunit Vaccines against Tuberculosis

“…A recently published study highlighted that peptide nanofiber vaccines in combination with BCG reduce bacterial load in the lungs of Mtb -infected mice and thus may be an effective strategy for boosting BCG-primed individuals [ 79 ]. Moreover, some studies have suggested that developing subunit vaccines that include classical T-cell epitopes derived from proteins that are expressed by the active and latent form of the causative agent may represent a new frontier in tuberculosis vaccine research [ 80 , 81 ]. In this context, several supportive tools are used to predict the most suitable epitopes to involve in the vaccine design, including immunoinformatic, genomic, and proteomic approaches [ 39 , 82 , 83 , 84 ].…”