# Tuberculosis Vaccines: An Update of Recent and Ongoing Clinical Trials
## 3 TB Novel Vaccines
### TB Subunit Vaccines
#### 3.1.1 M72/As01E  
This vaccine is a recombinant fusion protein derivative of the _M. tuberculosis_ antigens, Mtb3A and Mtb39A, in combination with the AS01E adjuvant system [11; 12]. In 2010, a phase II clinical trial in infants assessed the safety and immunogenicity of M72/AS0113. An acceptable safety profile was demonstrated, with no safety concerns identified, and adverse events (AEs) and serious adverse events (SAEs) being equal to those in similar vaccine studies [13]. Further noted was the M72-specific CD4+ T cell responses that were significantly higher after two M72/AS01 doses, even up to one-year post vaccination [13]. Similar assessments were made in a phase II clinical trial, completed in 2015, assessing the safety and immunogenicity of M72/AS01E in HIV-positive (HIV+) adults, aged 18-59 years, living in a TB-endemic region (ClinicalTrials.gov: NCT01262976). In this double-blind trial, 240 participants were enrolled in three cohorts each, with a placebo comparator: HIV+ adults on highly active antiretroviral therapy (HAART); HIV+ adults not on HAART; and HIV-negative (HIV-) adults. Depending on the study group, two doses of M72/AS01E, or placebo (saline), were administered at day 0 and day 30. Across doses in the total study population, a headache preventing normal activity (3.75%) was the most reported solicited AE, followed by malaise (1.25%), mylagia (0.83%), and gastrointestinal symptoms (0.4%). SAEs (medical occurrences resulting in death, considered life-threatening, requiring hospitalization or prolongation of hospitalization, or resulting in disability/incapacity) were reported in 1.25% of the total study population. The antimycobacterium tuberculosis fusion protein (M72)-specific antibody concentrations were assessed in all groups at days 0, 30, 60, 210, and at years 1, 2, and 3, as measured by the enzyme-linked immunosorbent assay (ELISA), and given in ELISA units per millilitre (EU/mL). At day 0, all groups were found with antibody concentrations between 1.4 and 1.5 EU/mL. However, all intervention groups were found with increased antibody concentrations on the subsequent days, peaking at day 60 (range 249.4-754.5 EU/mL), and declining until year 3, where antibody concentrations within the intervention groups were found to range from 4.9-24.3 EU/mL. Within these intervention groups, the percentages of seroconverted subjects for M72-specific antibodies ranged from 66.7-97.3%. These findings were substantiated with the phase IIb clinical trial, where adults (18-50 years old) with _M. tuberculosis_ infection (defined by positive results on an IFN-\(\gamma\) release assay), without evidence of active TB disease, were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered one month apart (ClinicalTrials.gov: NCT0175598). The results of the three-year final analysis of the efficacy, safety, and immunogenicity demonstrated that the efficacy at month 36 was 49.7% (90% confidence interval (CI), 12.1 to 71.2; 95% CI, 2.1 to 74.2) in the M72/AS01E group, whereas the concentrations of M72-specific antibodies, and the frequencies of M72-specific CD4+ T cells, increased after the first dose, and were sustained throughout the follow-up period [11]. Pyrexia, as an SAE, was recorded in the intervention group, with no deaths determined to be related to the trial regimen [11]. Potential immune-mediated diseases were reported in the intervention group [11]. Currently recruiting is a phase II clinical trial to assess the safety and immunogenicity of the M72/AS01E vaccine in virally supressed antiretroviral-treated participants with HIV (ClinicalTrials.gov: NCT04556981).