it did not protect against initial or sustained IGRA conversion [33]. DAR-901 is no longer being developed as a TB vaccine (C.F. von Reyn, personal communication), but remains in clinical development as a candidate vaccine against nontuberculous mycobacterial disease. Live-attenuated mycobacterial vaccines Three live mycobacterial vaccines are in phase 2b–3 trials. MTBVAC MTBVAC is a live-attenuated mycobacterial vaccine derived from a clinical isolate of M. tuberculosis lineage 4, which was rendered nonvirulent by the deletion of two independent genes, encoding PhoP and FadD26 [53, 54]. PhoP is a transcription factor that regulates expression of 2% of M. tuberculosis genes, most of which are implicated in virulence. FadD26 is required for the biosynthesis and export of phthiocerol dimycocerosates, a major virulence-associated cell-wall lipid of M. tuberculosis. MTBVAC contains the genes present in the M. bovis BCG vaccine, except for phoP and fadD26, plus the RD1 (region of difference 1) genes originally deleted from M. bovis [53]. MTBVAC was safe in animal models, including SCID (severe combined immunodeficient) mice, and was more immunogenic, with improved protection against TB, than BCG [54]. Phase 1–2 trials of MTBVAC in newborn infants and adults have shown acceptable safety and immunogenicity [34, 35], and larger dose-defining trials have recently been completed (ClinicalTrials.gov identifiers NCT02933281 and NCT03536117). A large, multicentre phase 3 trial of MTBVAC, in approximately 7000 newborns (HIV unexposed, and HIV exposed and uninfected) recently started in Madagascar, Senegal and South Africa (ClinicalTrials.gov identifier NCT04975178). Participants will be followed for TB disease for up to 72 months. An efficacy trial of MTBVAC is also planned for adolescents and adults. As MTBVAC is a live vaccine like BCG with potential to cause disease in immunocompromised individuals, a study of the safety of MTBVAC in PLHIV on ART will be required to establish whether this population at increased risk for TB can be included in a future licensure trial. VPM1002 VPM1002 is a recombinant, urease C-deficient, listeriolysin-expressing BCG vaccine derived from the BCG Prague strain, thus lacking both RD1 and RD2 regions. Completed phase 1 and 2 trials have demonstrated the safety and immunogenicity of VPM1002 in infants and adults [36, 37]. VPM1002 appeared less reactogenic, with lower rates of injection site ulceration, abscess and scarring, but was also less immunogenic than BCG in a recent phase 2 trial among infants [38]. Three efficacy trials of VPM1002 are currently being conducted in parallel, in different populations. First, a phase 3 infant trial has now fully enrolled 6940 newborns (HIV unexposed, and HIV exposed and uninfected) in Gabon, Kenya, South Africa, Tanzania and Uganda, to assess the safety and efficacy of VPM1002 in comparison with BCG in the prevention of TBI, defined by IGRA-positive conversion (ClinicalTrials.gov identifier NCT04351685) secondary end-points include TB disease, occurring through at least 36 months of follow-up. Second, a prevention of disease trial among close contacts of TB patients in India has enrolled 12 721 HIV-uninfected household contacts 6 years of age, and will test the efficacy and safety of VPM1002 or M. indicus pranii/Immuvac versus placebo for prevention of incident TB disease over 3 years of follow-up (Clinical Trials Registry India identifier CTRI/2019/01/017026). Third, a phase 2b trial in India to assess the efficacy of VPM1002 for prevention of recurrent TB in 2000 HIV-uninfected, adult TB patients who have been successfully treated and cured of active TB is expected to complete in 2023 (ClinicalTrials.gov identifier NCT03152903). A phase 1–2 trial is planned to evaluate the safety and immunogenicity of VPM1002 and BCG revaccination in pre-adolescents with and without HIV, and with and without M. tuberculosis sensitisation, who have previously received the BCG vaccine at birth (ClinicalTrials.gov identifier NCT05539989). 170 https://doi.org/10.1183/2312508X.10024922 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY