immunogenicity of AEC/BC02 versus placebo in 30 IGRA- and TST-negative adult volunteers was completed recently (ClinicalTrials.gov identifier NCT04239313). A six-dose schedule of low and high doses of AEC/BC02 and adjuvant alone is currently being tested for safety, tolerability and immunogenicity in a phase 2 study in 200 skin test-positive adults (ClinicalTrials.gov identifier NCT05284812). Inactivated mycobacterial vaccines Three inactivated mycobacterial candidates are in phase 2b–3 trials. Mycobacterium indicus pranii or Immuvac Immuvac is a preparation that contains heat-killed M. indicus pranii, a nonpathogenic, nontuberculous mycobacterium closely related to Mycobacterium avium that was originally developed as an adjunctive leprosy treatment, but has been tested as an immunomodulator in TB patients [51]. Immuvac showed a small but statistically significant improvement in sputum culture conversion during treatment for PTB, compared with treatment alone, which was not associated with differences in rates of cure or relapse [26]. In a large therapeutic trial for TB pericarditis, a five-dose M. indicus pranii regimen had no significant benefit on the composite primary outcome of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis [27]. M. indicus pranii immunotherapy also did not significantly modulate frequencies of mycobacteria-specific T-cell responses in the blood [28]. A large phase 3 trial is currently under way that will compare the safety and efficacy of Immuvac or VPM1002 (see later) versus placebo for prevention of TB disease in children, adolescents and adults who are household contacts of recently diagnosed TB patients in India (Clinical Trials Registry India identifier CTRI/2019/01/017026). RUTI RUTI is comprised of purified fragments of M. tuberculosis bacilli that were cultured under stress conditions, delivered in liposomes, and was originally developed as an adjunctive immune modulator to shorten the duration of TB treatment [52]. RUTI was well tolerated, with dose-dependent local adverse reactions, and induced elevated IFN-γ-expressing T-cell responses to purified tuberculin protein in healthy volunteers [29]. A phase 2a trial in IGRA-positive and TST-positive individuals with and without HIV who were receiving isoniazid preventive therapy showed an acceptable safety profile, although nodules and abscesses were observed at the injection site [30]. RUTI administration also induced increases in purified tuberculin protein-specific IFN-γ-expressing cells in this trial. A study of the early bactericidal activity of RUTI in 44 DS-TB patients is ongoing (ClinicalTrials.gov identifier NCT05455112), as is a phase 2b trial of the therapeutic efficacy of RUTI, given as a single dose within 1 month of starting TB treatment, in 140 DS- or DR-TB patients (ClinicalTrials.gov identifier NCT04919239). DAR-901 DAR-901 is a broth-grown, heat-inactivated, whole-cell mycobacterial vaccine made from Mycobacterium obuense. The agar-grown precursor of DAR-901, SRL172, although not scalable, is notable for providing the only positive efficacy signal of any TB vaccine among PLHIV [31]. In the DAR-DAR trial, a five-dose regimen of SRL172 did not offer statistically significant protection against the primary end-point, disseminated TB however, the rate of culture-confirmed TB was reduced by 39% (hazard ratio 0.61, 95% CI 0.39–0.96). DAR-901 appeared to be safe and moderately immunogenic in a subsequent phase 1 trial in adults with and without HIV infection [32], and although it was safe and immunogenic in a phase 2b trial among M. tuberculosis-unsensitised adolescents (ClinicalTrials.gov identifier NCT02712424), https://doi.org/10.1183/2312508X.10024922 169 RECENT ADVANCES IN VACCINES |A.K.K. LUABEYA ET AL.