title: Enhanced and durable protective immune responses induced by a cocktail of recombinant BCG strains expressing antigens of multistage of Mycobacterium tuberculosis.
abstract: Although Bacillus Calmette-Guérin (BCG) vaccine confers protection from Mycobacterium tuberculosis infection in children, its immune protection gradually wanes over time, and consequently leads to an inability to prevent the reactivation of latent infection of M. tuberculosis. Therefore, improving BCG for better control of tuberculosis (TB) is urgently needed. We thus hypothesized that recombinant BCG overexpressing immunodominant antigens expressed at different growth stages of M. tuberculosis could provide a more comprehensive protection against primary and latent M. tuberculosis infection. Here, a novel cocktail of recombinant BCG (rBCG) strains, namely ABX, was produced by combining rBCG::85A, rBCG::85B, and rBCG::X, which overexpressed respective multistage antigens Ag85A, Ag85B, and HspX of M. tuberculosis. Our results showed that ABX was able to induce a stronger immune protection than individual rBCGs or BCG against primary TB infection in C57BL/6 mice. Mechanistically, the immune protection was attributed to stronger antigen-specific CD4(+) Th1 responses, higher numbers of IFN-γ(+) CD4(+) TEM and IL-2(+) CD8(+) TCM cells elicited by ABX. These findings thus provide a novel strategy for the improvement of BCG efficacy and potentially a promising prophylactic TB vaccine candidate, warranting further investigation.
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science & Technology, Wuhan 430030, PR China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science & Technology, Wuhan 430030, PR China.
authors.forename: Xindong
authors.initials: X
authors.lastname: Teng
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science & Technology, Wuhan 430030, PR China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science & Technology, Wuhan 430030, PR China.
authors.forename: Chunwei
authors.initials: C
authors.lastname: Shi
authors.affiliation: Beijing Pushikang Pharmaceutical Co., Ltd., Beijing 100020, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yue
authors.affiliation: Beijing Pushikang Pharmaceutical Co., Ltd., Beijing 100020, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science & Technology, Wuhan 430030, PR China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science & Technology, Wuhan 430030, PR China. Electronic address: xlfan@hust.edu.cn.
authors.forename: Xionglin
authors.initials: X
authors.lastname: Fan
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis / Q000097:blood; D017951:Antigen Presentation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014611:Vaccination
chemical_list: D000907:Antibodies, Bacterial; D016056:Immunodominant Epitopes; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma
keywords: Ag85 complex; HspX; Mycobacterium tuberculosis; Recombinant BCG; Tuberculosis; Vaccine