Intranasal immunization with peptide-based immunogenic complex enhances BCG vaccine efficacy in a murine model of tuberculosis
Santosh Kumar, Ashima Bhaskar, Gautam Patnaik, Chetan Sharma, Dhiraj Kumar Singh, Sandeep Rai Kaushik, Shivam Chaturvedi, Gobardhan Das, Ved Prakash Dwivedi
Santosh Kumar, Ashima Bhaskar, Gautam Patnaik, Chetan Sharma, Dhiraj Kumar Singh, Sandeep Rai Kaushik, Shivam Chaturvedi, Gobardhan Das, Ved Prakash Dwivedi
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Research Article Immunology Infectious disease

Intranasal immunization with peptide-based immunogenic complex enhances BCG vaccine efficacy in a 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.

Authors

Santosh Kumar, Ashima Bhaskar, Gautam Patnaik, Chetan Sharma, Dhiraj Kumar Singh, Sandeep Rai Kaushik, Shivam Chaturvedi, Gobardhan Das, Ved Prakash Dwivedi

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Figure 8

T cells from BCG-PTL–coimmunized mice confer improved protection against TB.

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T cells from BCG-PTL–coimmunized mice confer improved protection against...
(A) T lymphocytes isolated from BCG, PTL, or BCG-PTL immunized and M.tb-infected animals (50 days after infection) were subjected to surface staining with anti-CD3, anti-CD4, and anti-CD8 followed by sorting by FACSAria into 2 distinct populations: CD4+ and CD8+ T cells. Sorted CD4+ and CD8+ T cells were cultured overnight and transferred into irradiated recipient Thy1.1 mice. Seven days after adoptive transfer, all mice were challenged with M.tb H37Rv through the aerosol route. At 25 days after infection, the mice were euthanized for CFU enumeration and immune profiling. (B and C) CFU in the lungs of mice receiving CD4+ (B) and CD8+ (C) T cells. (D–G) Dot plots representing the percentage of INF-γ– and IL-17–producing CD4+ and CD8+ T cells in the spleens of infected mice. Two-tailed Student’s t test was performed for statistical analysis in B and C. One-way ANOVA, followed by multiple Tukey tests, was performed for statistical analysis for D–G. Data are representative of 2 independent experiments (n = 5 mice/group). *P < 0.05, **P < 0.005, ***P < 0.0005.