title: A live attenuated BCG vaccine overexpressing multistage antigens Ag85B and HspX provides superior protection against Mycobacterium tuberculosis infection.
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.
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Xindong
authors.initials: X
authors.lastname: Teng
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Yukai
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Jilei
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Maopeng
authors.initials: M
authors.lastname: Tian
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Beijing Pushikang Pharmaceutical Co., Ltd., Beijing, 100020, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Beijing Pushikang Pharmaceutical Co., Ltd., Beijing, 100020, People's Republic of China.
authors.forename: Ruibo
authors.initials: R
authors.lastname: Wang
authors.affiliation: Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan, 430030, People's Republic of China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Wang
authors.affiliation: Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan, 430030, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China. xlfan@hust.edu.cn.
authors.forename: Xionglin
authors.initials: X
authors.lastname: Fan
mesh_terms: D000217:Acyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000235:genetics / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; C118127:HspX protein, Mycobacterium tuberculosis; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis
keywords: Ag85B; HspX; Overexpresssion; Recombinant BCG; Tuberculosis; Vaccine