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Live attenuated TB vaccines representing the three modern Mycobacterium tuberculosis lineages reveal that the Euro–American genetic background confers optimal vaccine potential
- Source :
- EBioMedicine, EBioMedicine, 2020, 55, pp.102761. ⟨10.1016/j.ebiom.2020.102761⟩, Zaguán. Repositorio Digital de la Universidad de Zaragoza, instname, EBioMedicine, Vol 55, Iss, Pp-(2020), EBioMedicine, Elsevier, 2020, 55, pp.102761. ⟨10.1016/j.ebiom.2020.102761⟩, Zaguán: Repositorio Digital de la Universidad de Zaragoza, Universidad de Zaragoza
- Publication Year :
- 2020
-
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).<br />Graphical abstract Image, graphical abstract
- Subjects :
- 0301 basic medicine
Research paper
CFP-10
Epidemiology
Lineage (evolution)
[SDV]Life Sciences [q-bio]
Live vaccines
lcsh:Medicine
Gene Expression
Mice, SCID
Ligases
Mice
0302 clinical medicine
Immunogenicity, Vaccine
ESAT-6
PDIM
Tuberculosis Vaccines
lcsh:R5-920
Attenuated vaccine
biology
Virulence
Vaccination
General Medicine
3. Good health
Mycobacterium tuberculosis complex
030220 oncology & carcinogenesis
BCG Vaccine
Female
Patient Safety
lcsh:Medicine (General)
Genetic Background
Tuberculosis
Vaccines, Attenuated
Pathogen evolution
General Biochemistry, Genetics and Molecular Biology
White People
Mycobacterium tuberculosis
03 medical and health sciences
Bacterial Proteins
medicine
Animals
Humans
Tuberculosis, Pulmonary
lcsh:R
biology.organism_classification
medicine.disease
Virology
Survival Analysis
030104 developmental biology
BCG vaccine
Gene Deletion
Subjects
Details
- Language :
- English
- ISSN :
- 23523964
- Database :
- OpenAIRE
- Journal :
- EBioMedicine, EBioMedicine, 2020, 55, pp.102761. ⟨10.1016/j.ebiom.2020.102761⟩, Zaguán. Repositorio Digital de la Universidad de Zaragoza, instname, EBioMedicine, Vol 55, Iss, Pp-(2020), EBioMedicine, Elsevier, 2020, 55, pp.102761. ⟨10.1016/j.ebiom.2020.102761⟩, Zaguán: Repositorio Digital de la Universidad de Zaragoza, Universidad de Zaragoza
- Accession number :
- edsair.doi.dedup.....16c075a783ed3f8b9de3d6bcfd303cd7