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 7

PTL induces superior antigen-specific T cell memory responses in the lungs and the spleens of infected mice.

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PTL induces superior antigen-specific T cell memory responses in the lun...
T lymphocytes isolated from the lungs and the spleens of the indicated groups of experimental mice at 50 days after infection were surface stained with anti-CD3, anti-CD4, anti-CD8, anti-CCR7, anti-CD44, anti-CD62L, and anti–PD-1 antibodies and fixed prior to acquisition by flow cytometry. (A) Gating strategy employed to quantify the memory T cell responses. (B and C) Percentage of central memory (Tcm; CCR7hiCD62LhiCD44hi) (B) and effector memory (Tem; CCR7loCD62LloCD44hi) (C) CD4+ T cells on lymphocytes isolated from the lungs of infected animals. (D and E) Frequency of PD-1 expression on central memory (D) and effector memory (E) CD4+ T cell subset. (F and G) Percentage of Tcm (CCR7hiCD62LhiCD44hi) (F) and Tem (CCR7loCD62LloCD44hi) (G) CD8+ T cells on lymphocytes isolated from the lungs of infected animals. (H and I) Frequency of PD-1 expression on these cell subsets. (J–Q) Frequency of central memory, effector memory, and PD-1 expression on these cell subsets on the lymphocytes isolated from the spleens of infected mice. 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.