Recombinant BCG::Rv2645 elicits enhanced protective immunity compared to BCG in vivo with induced ISGylation-related genes and Th1 and Th17 responses.

Vaccine

State Key Laboratory of Virology and Department of Immunology, College of Basic Medical Sciences, Medical Research Institute and Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Hubei Province, Wuhan 430071, China. Electronic address:

Published: May 2018

There is a need to develop protective vaccines against tuberculosis (TB). Recently, we identified an immunodominant T-cell antigen, Rv2645, from the region of deletion 13 (RD13) of M. tuberculosis (M. tb) H37Rv, which is absent in Bacille Calmette-Guérin (BCG). Here, a recombinant BCG expressing Rv2645, namely, BCG::Rv2645, was constructed. Compared to BCG, we found that BCG::Rv2645 improved the antigen presentation capacity of dendritic cells (DCs) and elicited much stronger Th1 and Th17 responses, higher CD44CD62 effector memory CD4 T cells (T), and fewer T regulated cells (Treg) and regulatory B10 in mice. Importantly, BCG::Rv2645 exhibited enhanced protective efficacy against virulent M. tb H37Rv challenge in both mice and rhesus monkeys, showing less severe pathology and reduced pathogens. Further, transcriptomic analysis and reverse transcription-quantitative real time PCR revealed that the mRNA levels of ISGylation (Isg)-related genes such as interferon-stimulated gene 15 (Isg15), and Th1- and Th17-related genes such as interferon-γ (IFN-γ) and interleukin-17A (IL-17A) were significantly up-regulated in splenocytes and macrophages after stimulation with Rv2645. This study shows that BCG::Rv2645 is a promising TB vaccine candidate with enhanced protective immunity. The enhanced Th1/Th17 immune responses and up-regulation of ISGylation-related genes induced by Rv2645 may be major factors contributing to the protective immunity of BCG::Rv2645.

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Source
http://dx.doi.org/10.1016/j.vaccine.2018.04.025DOI Listing

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