Intranasal immunization with peptide-based immunogenic complex enhances BCG vaccine efficacy in a murine model of tuberculosis
Santosh Kumar, … , Gobardhan Das, Ved Prakash Dwivedi
Santosh Kumar, … , Gobardhan Das, Ved Prakash Dwivedi
Published January 14, 2021
Citation Information: JCI Insight. 2021;6(4):e145228. https://doi.org/10.1172/jci.insight.145228.
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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 1

Mycobacterial antigens induce activation of protective T cell responses.

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Mycobacterial antigens induce activation of protective T cell responses....
T cells isolated from the spleens of mice infected with H37Rv and treated with DOTS were stimulated with DCs preloaded with the peptides for 48 hours, followed by surface staining with anti-CD3, anti-CD4, anti-CD8, and anti-CD69 and staining for intracellular cytokines with anti–IFN-γ and anti–IL-17 antibodies. (A–C) Bar graphs depicting the percentage of CD4+CD69+ and CD8+CD69+ T cells (A), CD4+IFN-γ+ and CD8+IFN-γ+ T cells (B), and CD4+IL-17+ and CD8+IL-17+ T cells (C). (D) Activation of CD4+ and CD8+ T cells cocultured with unstimulated DCs (Cnt), DCs pulsed with CSA, or DCs pulsed with the peptide combo. (E and F) CD4+ and CD8+ T cells expressing IFN-γ (E) and ΙL-17 (F) after stimulation with the combo. Each experiment was performed at least three times in triplicate. Two-tailed Student’s t test was performed for statistical analysis. Data represent mean ± SD (n = 3). *P < 0.05.