doi:10.1016/j.vaccine.2021.06.049engMartín, C.Marinova, D.Aguiló, N.Gonzalo-Asensio, J.MTBVAC, a live TB vaccine poised to initiate efficacy trials 100 years after BCGART-2021-126758At its 100th birthday of its first administration to a newborn, BCG has been (and continues being) an inspiration for the construction and development of hundreds of new TB vaccine candidates in the last two and a half decades. Today, 14 candidates are in clinical development inside the global TB vaccine pipeline. MTBVAC is one of these candidates. Based on a live-attenuated Mycobacterium tuberculosis clinical isolate, MTBVAC''s 25 years of vaccine discovery, construction and characterisation have followed Pasteur principles, and in the process, BCG has served as a reference gold standard for establishing the safety and protective efficacy of new TB vaccine candidates. MTBVAC, which contains the antigen repertoire of M. tuberculosis, is now poised to initiate Phase 3 efficacy trials in newborns in TB-endemic countries. BCG''s efficacy extends beyond that against TB, shown to confer heterologous non-specific immunity to other diseases and reduce all-cause mortality in the first months of life. Today, WHO recognises the importance that any new TB vaccine designed for administration at birth, should show similar non-specific benefits as BCG vía mechanisms of trained immunity and/or cross-reactivity of adaptive immune responses to other pathogens. Key recent studies provide strong support for MTBVAC''s ability of inducing trained immunity and conferring non-specific heterologous protection similar to BCG. Research on alternative delivery routes of MTBVAC, such as a clinically feasible aerosol route, could facilitate vaccine administration for long-term TB eradication programmes in the future. © 2021 The Author(s)2021http://zaguan.unizar.es/record/11721610.1016/j.vaccine.2021.06.049http://zaguan.unizar.es/record/117216oai:zaguan.unizar.es:117216info:eu-repo/grantAgreement/EC/H2020/643381/EU/TBVAC2020; Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development/TBVAC2020This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 643381-TBVAC2020info:eu-repo/grantAgreement/ES/MICINN/RTC-2017-6379-1VACCINE 39, 50 (2021), 7277-7285by-ndhttp://creativecommons.org/licenses/by-nd/3.0/es/info:eu-repo/semantics/openAccess