DS-TB [17, 18]. A US National Institutes of Health-funded phase 2b therapeutic trial of ID93/ GLA-SE is planned, which will vaccinate 1500 DS-TB patients at progressively earlier time points during TB treatment to evaluate safety, immunogenicity and efficacy against TB-related unfavourable treatment outcomes. ID93/GLA-SE is also being co-developed in South-East Asia as QTP101, which has completed dose-defining trials of safety and immunogenicity in BCG-vaccinated adolescents (ClinicalTrials.gov identifier NCT03806699) and healthcare workers (ClinicalTrials.gov identifier NCT03806686). A phase 2b efficacy trial of QTP101 for prevention of TB disease in BCG-vaccinated adults is planned to start in 2023. M72/AS01E M72/AS01E is a recombinant fusion protein derived from the antigens Mtb32A and Mtb39A, combined with the AS01E adjuvant. M72/AS01E appeared safe and immunogenic in phase 1–2a studies in adolescent and adult populations [19, 20], including M. tuberculosis-sensitised and -unsensitised individuals [20], but a trial of M72/AS01E among adult TB patients receiving treatment was previously discontinued due to unacceptable reactogenicity events [50]. The results of a phase 2b study of M72/AS01E reported the first positive efficacy signal for an adjuvanted protein-subunit TB vaccine and showed that M. tuberculosis-sensitised individuals were protected against progression to TB disease by vaccination [21]. The trial enrolled 3573 healthy, IGRA-positive, HIV-negative adults aged 18–50 years of age in South Africa, Kenya and Zambia, who were followed for symptomatic, microbiologically confirmed TB disease. Vaccine efficacy over 3 years of follow-up was 49.7% (95% CI 2.1–74.2%) [22]. A phase 3 licensure trial is now planned to confirm these exciting findings in a larger, more geographically diverse population, with a wider age range, to test efficacy against TB disease in IGRA-positive individuals. M72/AS01E vaccination of IGRA-negative adolescents and adults results in lower T-cell responses compared with IGRA-positive individuals [19, 20]. The planned phase 3 trial will include a subset of IGRA-negative individuals and will be powered to test efficacy against sustained IGRA conversion, but not against TB disease, in this group. The planned phase 3 trial will enrol an anticipated 26 000 adolescents and adults aged 15–44 years in multiple countries, selected in part on the basis of an ongoing epidemiological study of IGRA-positive prevalence at the different sites. PLHIV will be included, based on the results of a recently completed study of safety and immunogenicity of M72/AS01E vaccination in PLHIV who have been established on ART (ClinicalTrials.gov identifier NCT04556981). GamTBvac GamTBvac is a recombinant vaccine containing three M. tuberculosis antigens, Ag85A and an ESAT-6–CFP-10 (10 kDa culture filtrate protein) fusion protein, with a diethylaminoethyl- dextran and CpG-based adjuvant. A first-in-human trial in 60 IGRA-negative, previously BCG-vaccinated volunteers showed that GamTBvac had an acceptable safety profile and was well tolerated [23]. A subsequent phase 2a trial in 180 IGRA-negative, previously BCG- vaccinated Russian adults showed that GamTBvac induced antigen-specific humoral and cellular immune responses [24]. An ongoing phase 3 trial is recruiting 7180 previously BCG-vaccinated, IGRA- and TST-negative participants aged 18–45 years to receive placebo or two doses of GamTBvac (ClinicalTrials.gov identifier NCT04975737). The primary end-point is TB disease not associated with HIV. Given the low TB incidence expected in an IGRA-negative population, it remains to be seen whether the trial is adequately powered to estimate vaccine efficacy in a study of this size. AEC/BC02 AEC/BC02 is a recombinant vaccine containing Ag85B and an ESAT-6–CFP-10 fusion protein, combined with a proprietary adjuvant, BC02A [25]. A phase 1b study evaluating the safety and 168 https://doi.org/10.1183/2312508X.10024922 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY