# Tuberculosis Vaccines: An Update of Recent and Ongoing Clinical Trials
## 3 TB Novel Vaccines
### Attenuated Live Vaccines
#### MTBVAC  
MTBVAC is a live attenuated mycobacterial vaccine. It is based on a rationally attenuated _M. tuberculosis_ clinical isolate belonging to modern lineage 4 (one of the most widespread lineages among humans), that conserves most of the T cell epitopes described for TB, including the antigens ESAT6 and CFP10 of the RD1, while incorporating two independent stable genetic deletions of the _phoP_ and _fadD26_ genes [31]. It is hoped that this vaccine may replace the BCG vaccine in newborns and also be utilised as a preventative vaccine in adolescents and adults. The preclinical studies highlighted that MTBVAC induced immunity to ESAT6 and CFP10 and demonstrates improved efficacy in comparison to BCG [31]. As a result, a randomized controlled double-blinded dose escalation trial in adults and neonates was conducted (ClinicalTrials.gov: NCT02729571). In this trial, eighteen adults were enrolled and randomly assigned, nine each, to the BCG and MTBVAC groups [32]. In addition, thirty-six infants were enrolled and randomly assigned: eight to the BCG group; nine to the 2.5 \(\times\) 10\({}^{3}\) CFU MTBVAC group; nine to the 2.5 \(\times\) 10\({}^{4}\) CFU group; and ten to the 2.5 \(\times\) 10\({}^{5}\) CFU group [32]. Safety and immunogenicity analyses were completed in those receiving a dose of vaccine. Mild injection-site reactions occurred only in infants in the BCG and the 2.5 \(\times\) 10\({}^{5}\) CFU MTBVAC groups [32]. Systemic AESs were evenly distributed across BCG and MTBVAC dose groups and were mostly mild in severity [32]. Moreover, eight SAEs were reported in seven vaccine recipients (one adult MTBVAC recipient, one infant BCG recipient, one infant in the 2.5 \(\times\) 10\({}^{3}\) CFU MTBVAC group, two in the 2.5 \(\times\) 10\({}^{4}\) CFU MTBVAC group, and two in the 2.5 \(\times\) 10\({}^{5}\) CFU MTBVAC group), and one infant died as a result of possible viral pneumonia [32]. Vaccination with all MTBVAC doses induced durable antigen-specific Th1 cytokine-expressing CD4 cell responses in infants, peaking 70 days postvaccination, and detectable 360 days after vaccination [32]. For the highest MTBVAC dose, the response exceeded responses induced by an equivalent dose of the BCG vaccine up to 360 days postvaccination [32]. Dose-related IGRA conversion was noted in 38% of infants in the 2.5 \(\times\) 10\({}^{3}\) CFU MTBVAC group, in 75% of infants in the 2.5 \(\times\) 10\({}^{4}\) CFU MTBVAC group, and in 78% of infants in the 2.5 \(\times\) 10\({}^{5}\) CFU MTBVAC group, at day 180, compared with 0% in the BCG group [32]. By day 360, IGRA reversion had occurred in all infants in the 2.5 \(\times\) 10\({}^{3}\) CFU MTBVAC group, in 67% of infants in the 2.5 \(\times\) 10\({}^{4}\) CFU MTBVAC group, and in 43% of infants in the 2.5 \(\times\) 10\({}^{5}\) CFU MTBVAC group [32]. In the adult groups, only secondary outcomes, including local injection-site, systemic reactions, and haematology and biochemistry, at days 7 and 28 were measured [32]. A phase II clinical trial to assess the dose-defining safety and immunogenicity of MTBVAC in neonates (ClinicalTrials.gov: NCT03536117), and a further phase II clinical trial assessing the same parameters in adults with and without latent TB, had been recruiting, however, the current status is unknown (ClinicalTrials.gov: NCT02933281). Not yet recruiting is a phase III clinical trial in which the safety, immunogenicity, and efficacy of the MTBVAC vaccine will be evaluated in HIV-uninfected infantsborn to HIV-infected, and HIV-uninfected, mothers, as compared to the standard BCG vaccination regime (Clinicaltrials.gov: NCT04975178).