## 5 TB Vaccine Candidates in Clinical Trials
### Whole-Cell Vaccine Candidates  
#### 5.1.1 Live Attenuated Vaccines  
Attenuated live vaccines based in _Mtb_ in humans is expected to stimulate specific host-immune responses mimicking natural TB infection without causing disease (similar to with latent TB infection (LTBI)). In support of this rationale, prospective cohort studies with individuals exposed to patients with active TB indicate that those persons LTBI could be close to 80% more protected against secondary _Mtb_ infection than individuals naive to _Mtb_ infection [52]. MTBVAC is based on the Pasteurian approach of vaccinology, to attenuate the pathogen from a human clinical isolate. The rational attenuation of MTBVAC is due to deletions in the major virulence genes _phoP_ and _fadD26_. Following the Geneva consensus for attenuated TB vaccines [30], antibiotic markers were eliminated in MTBVAC [53]. As an attenuated derivative from the human pathogen, MTBVAC contains all antigens present in _Mtb_[54], including those contained in the RD1 region, which is deleted in BCG and responsible for increasing the protection in animal models [55] (Figure 3). The primary target population of MTBVAC are neonates; the secondary target population includes adolescents and adults (as a booster vaccine). A Phase Ia trial in adults showed that MTBVAC is safe and immunogenic [56] and a second Phase Ib in neonates in an endemic country showed that MTBVAC is as safe as BCG and more immunogenic [57]. Dose-defining Phase IIa trials in both target populations started in 2019 with funding support from US NIH in collaboration with IAVI in adults (ClinicalTrials.gov NCT02933281) and the EDCTP in collaboration with TBVI in neonates (ClinicalTrials.gov NCT03536117) (Figure 2). MTBVAC development is included in TBVI pipeline. MTBVAC was discovered and constructed at the University of Zaragoza (Spain) in collaboration with Pasteur Institute (France). Recently it was demonstrated that similarly to BCG, MTBVAC is able to induce trained immunity through the induction of glycolysis and glutaminolysis, accumulation of histone methylation marks at the promoters of pro-inflammatory genes, facilitating an enhanced response after secondary challenge. Importantly, these findings in human primary myeloid cells are complemented by a strong MTBVAC induced heterologous protection against a lethal challenge _with Streptococcus pneumoniae_ in an experimental murine model of pneumonia ([PERSON] et al. in press PLOS Pathogens 2020). The Spanish Biopharmaceutical company Biofabri is vaccine manufacturer of MTBVAC responsible for industrial and clinical development of the vaccine under the umbrella of TBVI. BCG/BCG revaccination strategy showed a positive signal in prevention studies of _Mtb_ infection [51] and has been included for application in adolescents and adults vaccinated with BCG at birth (Figure 2). BCG revaccination in adults reduced the rate of upper respiratory tract infections as compared to a subunit vaccine or placebo groups (2.1%, 9.4% and 7.9%, respectively; P\(<\)0.001 for both comparisons) [51] suggesting that BCG revaccination could prevent respiratory diseases including AMR forms of these diseases. The POI trial tested the ability of BCG revaccination to prevent _Mtb_ infection using IGRA conversion QuantiFERON test in healthy South African adolescents [51]. However, considering the difficulty of understanding what IGRA conversion and reversion means in terms of developing TB disease, POD trials should be performed in order to obtain the authorization by the regulatory agencies for licensure of new TB vaccines. BCG/BCG revaccination strategy is included in the pipe line of the Bill and Melinda Gates Foundation. VPM1002 is a recombinant _M. bovis_ BCG, which is developed by the Max Planck Institute in Berlin to express Listeriolysin from _Listeria monocytogenes_ and with a deletion of the gene coding for urease C [58] (Figure 3). VPM1002 is in clinical development led by Vakzine Projekt Management and in collaboration with Serum Institute of India and is included in TBVI pipeline.