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

Pérez, Irene (Universidad de Zaragoza) ; Uranga, Santiago (Universidad de Zaragoza) ; Sayes, Fadel ; Frigui, Wafa ; Samper, Sofía (Universidad de Zaragoza) ; Arbués, Ainhoa ; Aguiló, Nacho (Universidad de Zaragoza) ; Brosch, Roland ; Martín, Carlos (Universidad de Zaragoza) ; Gonzalo-Asensio, Jesús (Universidad de Zaragoza)

Resumen: 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.

Idioma: Inglés

DOI: 10.1016/j.ebiom.2020.102761

Año: 2020

Publicado en: EBioMedicine 55 (2020), 102761 1-10
ISSN: 2352-3964

Factor impacto JCR: 8.143 (2020)

Categ. JCR: MEDICINE, RESEARCH & EXPERIMENTAL rank: 17 / 140 = 0.121 (2020) - Q1 - T1

Factor impacto SCIMAGO: 2.596 - Medicine (miscellaneous) (Q1) - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/EC/H2020/643381/EU/TBVAC2020; Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development/TBVAC2020
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI18-0336
Financiación: info:eu-repo/grantAgreement/ES/MICINN/RTI2018-097625-B-100
Financiación: info:eu-repo/grantAgreement/ES/UZ-IBERCAJA-CAI/CM3-18

Tipo y forma: Article (Published version)

Área (Departamento): Área Microbiología (Dpto. Microb.Ped.Radio.Sal.Pú.)
Área (Departamento): Proy. investigación HQA (Dpto. Microb.Ped.Radio.Sal.Pú.)