Bottai Daria, Frigui Wafa, Clark Simon, Rayner Emma, Zelmer Andrea, Andreu Nuria, de Jonge Marien I, Bancroft Gregory J, Williams Ann, Brodin Priscille, Brosch Roland
Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France; Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, University of Pisa, Pisa, Italy.
Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
Vaccine. 2015 May 28;33(23):2710-8. doi: 10.1016/j.vaccine.2015.03.083. Epub 2015 Apr 11.
Mycobacterium bovis BCG is presently the only available anti-tuberculosis vaccine used, worldwide. While BCG protects against miliary tuberculosis (TB) and tuberculoid meningitis in children, it often fails to protect against adult pulmonary TB. It is thus imperative that new improved anti-TB vaccines are developed. The integration of the ESX-1 secretion system, absent from BCG due to the deletion of region of difference 1 (RD1), into the genome of BCG has been shown to confer to BCG::ESX-1 enhanced protection against TB as compared to BCG.
In the present study, to counterbalance the increase in virulence resulting from the integration of the RD1 region into BCG, we have constructed and evaluated several BCG::ESX-1 variants that carry selected amino-acid changes in the ESX-1-secreted antigen ESAT-6. In order to find the candidate that combines low virulence with high protective efficacy, these novel recombinant BCG::ESX-1 strains were tested for their virulence properties and their protective efficacy against Mycobacterium tuberculosis in two different animal models (mouse and guinea-pig).
Among several candidates tested, the BCG::ESAT-L28A/L29S strain, carrying modifications at residues Leu(28)-Leu(29) of the ESAT molecule, showed strong attenuation in mice and high protective efficiency both in mouse and guinea-pig vaccination-infection models.
This strain thus represents a promising candidate that merits further investigations and development. Our research also provides the proof of concept that selected ESX-1-complemented BCG strains may show low virulence and increased protective potential over parental strains.
牛分枝杆菌卡介苗（BCG）是目前全球唯一可用的抗结核疫苗。虽然BCG可预防儿童粟粒性结核病（TB）和结核样脑膜炎，但它往往无法预防成人肺结核。因此，开发新的改良抗结核疫苗势在必行。已证明，由于差异区域1（RD1）的缺失，BCG中不存在ESX-1分泌系统，将其整合到BCG基因组中可使BCG::ESX-1对TB的保护作用增强。
在本研究中，为了平衡RD1区域整合到BCG中导致的毒力增加，我们构建并评估了几种在ESX-1分泌抗原ESAT-6中携带选定氨基酸变化的BCG::ESX-1变体。为了找到低毒力与高保护效力相结合的候选菌株，在两种不同的动物模型（小鼠和豚鼠）中测试了这些新型重组BCG::ESX-1菌株的毒力特性及其对结核分枝杆菌的保护效力。
在测试的几种候选菌株中，在ESAT分子的Leu(28)-Leu(29)残基处有修饰的BCG::ESAT-L28A/L29S菌株在小鼠中表现出强烈的减毒作用，并且在小鼠和豚鼠疫苗接种-感染模型中均具有高保护效率。
因此，该菌株是一个有前景的候选菌株，值得进一步研究和开发。我们的研究还提供了概念证明，即选定的ESX-1补充型BCG菌株可能比亲本菌株表现出更低的毒力和更高的保护潜力。
