Historical BCG vaccination combined with drug treatment enhances inhibition of mycobacterial growth ex vivo in human peripheral blood cells

Satria A Prabowo,Andrea Zelmer,Helen A Fletcher,Steven G Smith,Lisa Stockdale,Karin Seifert,Utkarsh Ojha

doi:10.1038/s41598-019-41008-4

Satria A Prabowo, Andrea Zelmer + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-41008-4

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Abstract

Tuberculosis (TB) is a leading infectious cause of death globally. Drug treatment and vaccination, in particular with Bacillus Calmette-Guérin (BCG), remain the main strategies to control TB. With the emergence of drug resistance, it has been proposed that a combination of TB vaccination with pharmacological treatment may provide a greater therapeutic value. We implemented an ex vivo mycobacterial growth inhibition assay (MGIA) to discriminate vaccine responses in historically BCG-vaccinated human volunteers and to assess the contribution of vaccine-mediated immune response towards the killing effect of mycobacteria in the presence of the antibiotics isoniazid (INH) and rifampicin (RIF), in an attempt to develop the assay as a screening tool for therapeutic TB vaccines. BCG vaccination significantly enhanced the ability of INH to control mycobacterial growth ex vivo. The BCG-vaccinated group displayed a higher production of IFN-γ and IP-10 when peripheral blood mononuclear cells (PBMC) were co-cultured with INH, with a similar trend during co-culture with RIF. A higher frequency of IFN-γ+ and TNF-α+ CD3− CD4− CD8− cells was observed, suggesting the contribution of Natural Killer (NK) cells in the combined effect between BCG vaccination and INH. Taken together, our data indicate the efficacy of INH can be augmented following historical BCG vaccination, which support findings from previous observational and animal studies.

Highlights

Tuberculosis (TB) is a leading infectious cause of death worldwide
Fifty participants were enrolled in the main cohort of this study; 21 vaccine-naïve volunteers with no history of Bacille Calmette-Guérin (BCG) vaccination and 29 volunteers previously vaccinated with BCG
An Interferon-γ (IFN-γ) Enzyme-Linked ImmunoSpot (ELISpot) assay was performed to measure the magnitude of mycobacteria-specific response from historically BCG-vaccinated and BCG-naïve participants

Summary

Introduction

Tuberculosis (TB) is a leading infectious cause of death worldwide. Over the past 200 years, the disease has killed one billion people, surpassing any other infectious disease[1]. ELISA assays were performed using the MGIA supernatant to investigate cytokine productions (IFN-γ, IP-10, IL-10, TNF-α, IL-12p40, GM-CSF, IL-6 and IL-17) which may be associated with ex vivo growth inhibition at all drug concentrations.

Results

Conclusion