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• MTBVAC construction and characterization has abided by Pasteur principles, similar to BCG. • BCG has served as gold standard for safety and efficacy in MTBVAC development. • MTBVAC shows superior efficacy in mice, guinea pigs, NHP, and similar safety to BCG. • MTBVAC is safe and immunogenic in clinical trials in adults and newborns. • MTBVAC is ready to initiate efficacy trials 100 years after BCG. At 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. [ABSTRACT FROM AUTHOR]

Summary Development of novel more efficient preventive vaccines against tuberculosis (TB) is crucial to achieve TB eradication by 2050, one of the Millennium Development Goals (MDG) for the current century. MTBVAC is the first and only live attenuated vaccine based on a human isolate of Mycobacterium tuberculosis developed as BCG-replacement strategy in newborns that has entered first-in-human adult clinical trials. In this work, we characterize the safety, immunogenicity and protective efficacy of MTBVAC in a model of newborn C57/BL6 mice. Our data clearly indicate that MTBVAC is safe for newborn mice, and does not affect animal growth or organ development. In addition, MTBVAC-vaccinated mice at birth showed enhanced immunogenicity and better protection against M. tuberculosis challenge in comparison with BCG. [ABSTRACT FROM AUTHOR]

Highlights: [•] Construction, characterization and preclinical studies of MTBVAC, an attenuated Mycobacterium tuberculosis. [•] MTBVAC vaccine candidate is genetically engineered to fulfil the Geneva consensus (Vaccine Kamath et al., 2005). [•] MTBVAC is the first live attenuated M. tuberculosis vaccine to enter clinical evaluation. [•] MTBVAC Clinical trials started in January 2013 (Swissmedic reference MTBVAC 2012GT1002). [ABSTRACT FROM AUTHOR]