Live attenuated TB vaccines representing the three modern Mycobacterium tuberculosis lineages reveal that the Euro–American genetic background confers optimal vaccine potential
Irene Pérez,
Santiago Uranga,
Fadel Sayes,
Wafa Frigui,
Sofía Samper,
Ainhoa Arbués,
Nacho Aguiló,
Roland Brosch,
Carlos Martín,
Jesús Gonzalo-Asensio
Affiliations
Irene Pérez
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
Santiago Uranga
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
Fadel Sayes
Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris, France
Wafa Frigui
Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris, France
Sofía Samper
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; Unidad de Investigación Translacional, Instituto Aragonés de Ciencias de la Salud, Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain
Ainhoa Arbués
Present adress: Medical Parasitology & Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland
Nacho Aguiló
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
Roland Brosch
Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris, France
Carlos Martín
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; Servicio de Microbiología Hospital Universitario Miguel Servet, Zaragoza, Spain
Jesús Gonzalo-Asensio
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; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), Zaragoza, Spain; Corresponding author.
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).
