000089668 001__ 89668 000089668 005__ 20230330095434.0 000089668 0247_ $$2doi$$a10.1016/j.ebiom.2020.102761 000089668 0248_ $$2sideral$$a117772 000089668 037__ $$aART-2020-117772 000089668 041__ $$aeng 000089668 100__ $$0(orcid)0000-0001-5407-7271$$aPérez, Irene$$uUniversidad de Zaragoza 000089668 245__ $$aLive attenuated TB vaccines representing the three modern Mycobacterium tuberculosis lineages reveal that the Euro–American genetic background confers optimal vaccine potential 000089668 260__ $$c2020 000089668 5060_ $$aAccess copy available to the general public$$fUnrestricted 000089668 5203_ $$aBackground: 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. 000089668 536__ $$9info:eu-repo/grantAgreement/EC/H2020/643381/EU/TBVAC2020; Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development/TBVAC2020$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 643381-TBVAC2020$$9info:eu-repo/grantAgreement/ES/ISCIII/PI18-0336$$9info:eu-repo/grantAgreement/ES/MICINN/RTI2018-097625-B-100$$9info:eu-repo/grantAgreement/ES/UZ-IBERCAJA-CAI/CM3-18 000089668 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/ 000089668 590__ $$a8.143$$b2020 000089668 591__ $$aMEDICINE, RESEARCH & EXPERIMENTAL$$b17 / 140 = 0.121$$c2020$$dQ1$$eT1 000089668 592__ $$a2.596$$b2020 000089668 593__ $$aMedicine (miscellaneous)$$c2020$$dQ1 000089668 593__ $$aBiochemistry, Genetics and Molecular Biology (miscellaneous)$$c2020$$dQ1 000089668 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000089668 700__ $$0(orcid)0000-0001-7866-2803$$aUranga, Santiago$$uUniversidad de Zaragoza 000089668 700__ $$aSayes, Fadel 000089668 700__ $$aFrigui, Wafa 000089668 700__ $$0(orcid)0000-0002-3011-2519$$aSamper, Sofía$$uUniversidad de Zaragoza 000089668 700__ $$0(orcid)0000-0002-3377-4171$$aArbués, Ainhoa 000089668 700__ $$0(orcid)0000-0001-7897-9173$$aAguiló, Nacho$$uUniversidad de Zaragoza 000089668 700__ $$aBrosch, Roland 000089668 700__ $$0(orcid)0000-0003-2993-5478$$aMartín, Carlos$$uUniversidad de Zaragoza 000089668 700__ $$0(orcid)0000-0001-8841-6593$$aGonzalo-Asensio, Jesús$$uUniversidad de Zaragoza 000089668 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología 000089668 7102_ $$11011$$2X$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cProy. investigación HQA 000089668 773__ $$g55 (2020), 102761 1-10$$pEBioMedicine$$tEBioMedicine$$x2352-3964 000089668 8564_ $$s1335532$$uhttps://zaguan.unizar.es/record/89668/files/texto_completo.pdf$$yVersión publicada 000089668 8564_ $$s49904$$uhttps://zaguan.unizar.es/record/89668/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000089668 909CO $$ooai:zaguan.unizar.es:89668$$particulos$$pdriver 000089668 951__ $$a2023-03-30-09:42:12 000089668 980__ $$aARTICLE