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 6

BCG-PTL coimmunization induces the antigen-specific polyfunctional cytokine responses in the lungs and the spleens of infected animals.

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BCG-PTL coimmunization induces the antigen-specific polyfunctional cytok...
(A) Lymphocytes isolated from the lungs of infected animals were stained with anti-CD3, anti-CD4, anti-CD8, anti–IFN-γ, anti-TNF-α, anti–IL-17, and anti–IL-2 to assess polyfunctional cytokine responses. (B and C) Pie charts depicting the percentage of CD4+ (B) and CD8+ (C) T cells expressing 4, 3, 2, 1, and 0 cytokines (IFN-γ, TNF-α, IL-17, and IL-2) in the lungs of the mice. (D and E) The pie charts representing the average percentage of cytokine-producing CD4+ (D) and CD8+ (E) T cells producing 5 combinations (0+, 1+, 2+, 3+, and 4+) of the 4 cytokines analyzed in the spleens of infected animals. (F and G) Fifteen possible cytokine combinations are shown for CD4+ (F) and CD8+ (G) T cells from the lungs of infected animals. (H and I) Box and whisker plots depict 15 combinations of responses for the 4 cytokines analyzed on the x axis with the percentage of CD4+ (H) and CD8+ (I) responding splenic T cells on the y axis. One-way ANOVA, followed by multiple Tukey tests, was performed for statistical analysis. Data are representative of 2 independent experiments (n = 5 mice/group). *P < 0.05, **P < 0.005, ***P < 0.0005.