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三种现代结核分枝杆菌谱系的减毒活结核疫苗表明，欧洲-美洲遗传背景赋予了最佳的疫苗潜力。

Live attenuated TB vaccines representing the three modern Mycobacterium tuberculosis lineages reveal that the Euro-American genetic background confers optimal vaccine potential.

机构信息

Grupo de Genética de Micobacterias, Departamento de Microbiología y Medicina Preventiva, Facultad de Medicina, Universidad de Zaragoza, IIS Aragón, Zaragoza, Spain; CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.

Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris, France.

出版信息

EBioMedicine. 2020 May;55:102761. doi: 10.1016/j.ebiom.2020.102761. Epub 2020 Apr 28.

DOI:10.1016/j.ebiom.2020.102761
PMID:32361249
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7195525/
Abstract

BACKGROUND

Human tuberculosis (TB) is caused by a plethora of Mycobacterium tuberculosis complex (MTBC) strains belonging to seven phylogenetic branches. Lineages 2, 3 and 4 are considered "modern" branches of the MTBC responsible for the majority of worldwide TB. Since the current BCG vaccine confers variable protection against pulmonary TB, new candidates are investigated. MTBVAC is the unique live attenuated vaccine based on M. tuberculosis in human clinical trials.

METHODS

MTBVAC was originally constructed by unmarked phoP and fadD26 deletions in a clinical isolate belonging to L4. Here we construct new vaccines based on isogenic gene deletions in clinical isolates of the L2 and L3 modern lineages. These three vaccine candidates were characterized at molecular level and also in animal experiments of protection and safety.

FINDINGS

Safety studies in immunocompromised mice showed that MTBVAC-L2 was less attenuated than BCG Pasteur, while the original MTBVAC was found even more attenuated than BCG and MTBVAC-L3 showed an intermediate phenotype. The three MTBVAC candidates showed similar or superior protection compared to BCG in immunocompetent mice vaccinated with each MTBVAC candidate and challenged with three representative strains of the modern lineages.

INTERPRETATION

MTBVAC vaccines, based on double phoP and fadD26 deletions, protect against TB independently of the phylogenetic linage used as template strain for their construction. Nevertheless, lineage L4 confers the best safety profile.

FUNDING

European Commission (TBVAC2020, H2020-PHC-643381), Spanish Ministry of Science (RTI2018-097625-B-I00), Instituto de Salud Carlos III (PI18/0336), Gobierno de Aragón/Fondo Social Europeo and the French National Research Council (ANR-10-LABX-62-IBEID, ANR-16-CE35-0009, ANR-16-CE15-0003).

摘要

背景

人类结核病（TB）是由属于七个系统发育分支的大量结核分枝杆菌复合群（MTBC）菌株引起的。分支 2、3 和 4 被认为是 MTBC 的“现代”分支，负责全球大多数结核病。由于目前的卡介苗（BCG）疫苗对肺结核的保护作用各不相同，因此正在研究新的候选疫苗。MTBVAC 是唯一一种在人体临床试验中基于结核分枝杆菌的减毒活疫苗。

方法

MTBVAC 最初是通过对属于 L4 的临床分离株进行无标记 phoP 和 fadD26 缺失构建的。在这里，我们基于现代谱系 L2 和 L3 的临床分离株的同源基因缺失构建了新的疫苗。这三种候选疫苗在分子水平和动物保护和安全性实验中进行了表征。

结果

在免疫功能低下的小鼠中进行的安全性研究表明，MTBVAC-L2 的减毒程度不如卡介苗（BCG） Pasteur，而原始的 MTBVAC 则比 BCG 更具减毒作用，MTBVAC-L3 则表现出中等表型。与用每种 MTBVAC 候选物免疫接种后用三种现代谱系代表菌株进行挑战的免疫功能正常的小鼠相比，三种 MTBVAC 候选物的保护作用与 BCG 相似或更优。

解释

基于双 phoP 和 fadD26 缺失的 MTBVAC 疫苗可独立于构建其模板菌株的系统发育谱系预防结核病。然而，L4 谱系提供了最佳的安全性。

资金

欧洲委员会（TBVAC2020，H2020-PHC-643381）、西班牙科学部（RTI2018-097625-B-I00）、西班牙卡洛斯三世健康研究所（PI18/0336）、阿拉贡政府/欧洲社会基金和法国国家研究委员会（ANR-10-LABX-62-IBEID、ANR-16-CE35-0009、ANR-16-CE15-0003）。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/19a985576a2b/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/f81c0da06f28/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/94e6e8dfb577/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/5573f9ebd338/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/d211a71fd28e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/19a985576a2b/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/f81c0da06f28/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/94e6e8dfb577/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/5573f9ebd338/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/d211a71fd28e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2da/7195525/19a985576a2b/gr4.jpg

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