A Human Lung Challenge Model to Evaluate the Safety and Immunogenicity of PPD and Live Bacillus Calmette-Guerin

被引:31
作者
Davids, Malika [1 ,2 ]
Pooran, Anil [1 ,2 ]
Hermann, Clemens [3 ]
Mottay, Lynelle [1 ,2 ]
Thompson, Fawziyah [1 ,2 ]
Cardenas, Jacob [4 ]
Gu, Jinghua [4 ]
Koeuth, Thearith [4 ]
Meldau, Richard [1 ,2 ]
Limberis, Jason [1 ,2 ]
Gina, Phindile [1 ,2 ]
Srivastava, Shashikant [4 ]
Calder, Bridget [3 ]
Esmail, Aliasgar [1 ,2 ]
Tomasicchio, Michele [1 ,2 ]
Blackburn, Jonathan [3 ]
Gumbo, Tawanda [4 ]
Dheda, Keertan [1 ,2 ,5 ]
机构
[1] Univ Cape Town, Ctr Lung Infect & Immun, Lung Inst, Cape Town, South Africa
[2] Univ Cape Town, South African Med Res Council, Ctr Study Antimicrobial Resistance, Cape Town, South Africa
[3] Univ Cape Town, Inst Infect Dis & Mol Med, Dept Integrat Biomed Sci, Cape Town, South Africa
[4] Baylor Inst Immunol Res, Dallas, TX USA
[5] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Immunol & Infect, London, England
基金
比尔及梅琳达.盖茨基金会; 英国医学研究理事会;
关键词
tuberculosis; BCG; immunology; vaccine; MYCOBACTERIUM-BOVIS BCG; TUBERCULOSIS VACCINES; PULMONARY; CELLS; PROTECTION; RESPONSES; IMPACT;
D O I
10.1164/rccm.201908-1580OC
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Rationale: A human model to better understand tuberculosis immunopathogenesis and facilitate vaccine development is urgently needed. Objectives: We evaluated the feasibility, safety, and immunogenicity of live bacillus Calmette-Guerin (BCG) in a lung-oriented controlled human infection model. Methods: We recruited 106 healthy South African participants with varying degrees of tuberculosis susceptibility. Live BCG, sterile PPD, and saline were bronchoscopically instilled into separate lung segments (n = 65). A control group (n = 34) underwent a single bronchoscopy without challenge. The primary outcome was safety. Cellular and antibody immune signatures were identified in BAL before and 3 days after challenge using flow cytometry, ELISA, RNA sequencing, and mass spectrometry. Measurements and Main Results: The frequency of adverse events was low (9.4%; n = 10), similar in the challenge versus control groups (P =0.8), and all adverse events were mild and managed conservatively in an outpatient setting. The optimal PPD and BCG dose was 0.5 TU and 10(4) cfu, respectively, based on changes in BAL cellular profiles (P = 0.02) and antibody responses (P = 0.01) at incremental doses before versus after challenge. At 10(4) versus 10(3) cfu BCG, there was a significant increase in number of differentially expressed genes (367 vs. 3; P <0.001) and dysregulated proteins (64 vs. 0; P < 0.001). Immune responses were highly setting specific (in vitro vs. in vivo) and compartment specific (BAL vs. blood) and localized to the challenged lung segments. Conclusions: A lung-oriented mycobacterial controlled human infection model using live BCG and PPD is feasible and safe. These data inform the study of tuberculosis immunopathogenesis and strategies for evaluation and development of tuberculosis vaccine candidates.
引用
收藏
页码:1277 / 1291
页数:15
相关论文
共 32 条
[31]  
Zhang Y, 2013, PLOS ONE, V8, DOI [10.1371/journal.pone.0071243, 10.1371/journal.pone.0064601, 10.1371/journal.pone.0067564]
[32]   Potential public health impact of new tuberculosis vaccines [J].
Ziv, E ;
Daley, CL ;
Blower, S .
EMERGING INFECTIOUS DISEASES, 2004, 10 (09) :1529-1535