Journal
VACCINE
Volume 34, Issue 50, Pages 6301-6308Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.vaccine.2016.10.069
Keywords
Recombinant BCG; Tuberculosis; Vaccine
Categories
Funding
- Japan Agency for Medical Research and Development, AMED
- Ministry of Health, Labour, and Welfare of Japan [H25-Shinko-Ippan-005, H24-Shinko-Ippan-009]
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Enhancement of the T cell-stimulating ability of Mycobacterium bovis BCG (BCG) is necessary to develop an effective tuberculosis vaccine. For this purpose, we introduced the PEST-HSP70-major membrane protein-II (MMPII)-PEST fusion gene into ureC-gene depleted recombinant (r) BCG to produce BCG-PEST. The PEST sequence is involved in the proteasomal processing of antigens. BCG-PEST secreted the PEST-HSP70-MMPII-PEST fusion protein and more efficiently activated human monocyte-derived dendritic cells (DCs) in terms of phenotypic changes and cytokine productions than an empty-vector introduced BCG or HSP7O-MMPII gene-introduced ureC gene-depleted BCG (BCG-DHTM). Autologous human naive CD8(+) T cells and naive CD4(+) T cells were effectively activated by BCG-PEST and produced IFN-gamma in an antigen-specific manner through DCs. These T cell activations were closely associated with phagosomal maturation and intraproteasomal protein degradation in antigen-presenting cells. Furthermore, BCG-PEST produced long-lasting memory-type T cells in C57BL/6 mice more efficiently than control rBCGs. Moreover, a single subcutaneous injection of BCG-PEST more effectively reduced the multiplication of subsequent aerosol-challenged Mycobacterium tuberculosis of the standard H37Rv strain and clinically isolated Beijing strain in the lungs than control rBCGs. The vaccination effect of BCG-PEST lasted for at least 6 months. These results indicate that BCG-PEST may be able to efficiently control the spread of tuberculosis in human. (C) 2016 Elsevier Ltd. All rights reserved.
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