89668 20230330095434.0 doi 10.1016/j.ebiom.2020.102761 sideral 117772 ART-2020-117772 eng Pérez, Irene Universidad de Zaragoza (orcid)0000-0001-5407-7271 Live attenuated TB vaccines representing the three modern Mycobacterium tuberculosis lineages reveal that the Euro–American genetic background confers optimal vaccine potential 2020 Access copy available to the general public Unrestricted 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. 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 This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 643381-TBVAC2020 info:eu-repo/grantAgreement/ES/ISCIII/PI18-0336 info:eu-repo/grantAgreement/ES/MICINN/RTI2018-097625-B-100 info:eu-repo/grantAgreement/ES/UZ-IBERCAJA-CAI/CM3-18 info:eu-repo/semantics/openAccess by-nc-nd http://creativecommons.org/licenses/by-nc-nd/3.0/es/ 8.143 2020 MEDICINE, RESEARCH & EXPERIMENTAL 17 / 140 = 0.121 2020 Q1 T1 2.596 2020 Medicine (miscellaneous) 2020 Q1 Biochemistry, Genetics and Molecular Biology (miscellaneous) 2020 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Uranga, Santiago Universidad de Zaragoza (orcid)0000-0001-7866-2803 Sayes, Fadel Frigui, Wafa Samper, Sofía Universidad de Zaragoza (orcid)0000-0002-3011-2519 Arbués, Ainhoa (orcid)0000-0002-3377-4171 Aguiló, Nacho Universidad de Zaragoza (orcid)0000-0001-7897-9173 Brosch, Roland Martín, Carlos Universidad de Zaragoza (orcid)0000-0003-2993-5478 Gonzalo-Asensio, Jesús Universidad de Zaragoza (orcid)0000-0001-8841-6593 1011 630 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Microbiología 1011 X Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Proy. investigación HQA 55 (2020), 102761 1-10 EBioMedicine EBioMedicine 2352-3964 1335532 http://zaguan.unizar.es/record/89668/files/texto_completo.pdf Versión publicada 49904 http://zaguan.unizar.es/record/89668/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:89668 articulos driver 2023-03-30-09:42:12 ARTICLE