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A live attenuated BCG vaccine overexpressing multistage antigens Ag85B and HspX provides superior protection against Mycobacterium tuberculosis infection

  • Applied genetics and molecular biotechnology
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Abstract

Tuberculosis (TB) remains one of the most menacing infectious diseases, although attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine has been widely used to protect children against primary TB. There are increasing evidences that rapid growing and dormant Mycobacterium tuberculosis (M. tuberculosis) coexist in vivo after infection. However, BCG vaccine only elicits cell-mediated immune responses to secretory antigens expressed by rapid growing pathogen. BCG vaccine is thus unable to thwart the reactivation of latent tuberculosis infection (LTBI), and its protection wanes over age after neonatal immunization. In order to extend its ability for a durable protection, a novel recombinant BCG (rBCG) strain, named rBCG::XB, was constructed by overexpressing immunodominant multistage antigens of Ag85B and HspX, which are expressed by both rapid replicating and dormant M. tuberculosis. Long-term protective effect and immunogenicity of rBCG::XB were compared with the parental BCG in vaccinated C57BL/6 mice. Our results demonstrated that rBCG::XB provided the stronger and long-lasting protection against M. tuberculosis H37Rv intranasal infection than BCG. The rBCG::XB not only elicited the more durable multistage antigen-specific CD4+Th1-biased immune responses and specific polyfunctional CD4+T cells but also augmented the CD8+ CTL effects against Ag85B in vivo. In particular, higher levels of CD4+ TEM and CD8+ TCM cells, dominated by IL2+ CD4+ and CD8+ TCM cells, were obtained in the spleen of rBCG::XB vaccinated mice. Therefore, our findings indicate that rBCG::XB is a promising candidate to improve the efficacy of BCG.

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Acknowledgments

This study was funded by grants of the National High Technology Research and Development of China (863 program; No.2012AA02A401) and the National Mega-projects of Science Research for the 12th Five-year Plan of China (2012ZX10003008-005).

Ethical statement

Tongji Medical School Committee on Biosafety and the Committee on the Ethics of Animal Experiments of Tongji Medical College (Wuhan, China) approved the research protocol. Animal experiments were performed in accordance with the guidelines of Chinese Council on Animal Care.

Conflict of interest

The authors declare that they have no conflict of interest.

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    Authors and Affiliations

    1. Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

      Xuefeng Yuan, Xindong Teng, Yukai Jing, Jilei Ma, Maopeng Tian, Qi Yu & Xionglin Fan

    2. Beijing Pushikang Pharmaceutical Co., Ltd., Beijing, 100020, People’s Republic of China

      Lei Zhou & Ruibo Wang

    3. Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan, 430030, People’s Republic of China

      Weihua Wang & Li Li

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    1. Xuefeng Yuan
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    Correspondence to Xionglin Fan.

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    Xuefeng Yuan, Xindong Teng and Yukai Jing contributed equally to this work.

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    Yuan, X., Teng, X., Jing, Y. et al. A live attenuated BCG vaccine overexpressing multistage antigens Ag85B and HspX provides superior protection against Mycobacterium tuberculosis infection. Appl Microbiol Biotechnol 99, 10587–10595 (2015). https://doi.org/10.1007/s00253-015-6962-x

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    • DOI: https://doi.org/10.1007/s00253-015-6962-x

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