## 5 TB Vaccine Candidates in Clinical Trials
### Subunit Vaccines
#### 5.2.2 Adjuvant Subunit Vaccines  
D93 + GLA-SE vaccine was developed by the Infectious Disease Research Institute (IDRI) in the United States. ID93+GLA-SE comprises four _Mtb_ antigens, of which three are associated with virulence (Rv2608, Rv3619 and Rv3620) and one (Rv1813), with latency) formulated with the adjuvant GLA-SE for delivery [67] (Figure 3). It has been evaluated Phase IIa trial in South Africa among HIV-negative TB patients who have recently completed TB treatment for active pulmonary disease [68] (Figure 2). This is in preparation for Phase II safety and immunogenicity trials among adults undergoing active TB therapy. A POI Phase IIa trial in BCG-vaccinated healthy health care workers is also underway [2].  
H56:IC31 is a fusion protein of three _Mtb_ antigens (Ag85B, ESAT-6 and Rv2660c) and delivered in the adjuvant IC31(c) (Valneva Austria GmBH, Vienna, Austria) (Figure 3). H56:IC31 was discovered and developed by the Statem Serum Institut (SSI) of Copenhagen. It has been tested in three Phase I or I/IIa trials for safety and immunogenicity in BCG-vaccinated adults (Figure 2) showing acceptable safety and immunogenicity. It has completed a Phase Ib safety and immunogenicity trial in adolescents. A POR Phase IIb trial funded by EDCTP and coordinated by IAVI is underway in South Africa and the United Republic of Tanzania [2].  
M72/AS01E is also a subunit candidate vaccine comprising two _Mtb_ antigens (32A and 39A) formulated in the AS01 adjuvant for delivery (Figure 3), also used in the formulation of the malaria vaccine (RTS, S/AS01, GlaxoSmithKline) and the recombinant zoster vaccine Shigrix, GlaxoSmithKline [69]. It was evaluated in a IIb efficacy trial in in Kenya, South Africa and Zambia among _Mtb_-infected HIV-negative adults whose data showed 54.0% protective efficacy in _Mtb_-infected young adult women [69] (Figure 2). The immunogenicity analysis after end of the three-year follow-up showed that M72/AS01 elicited an immune response and provided protection against progression to pulmonary TB disease for at least three years [70]. This is the first time a proof-of-principle trial demonstrates vaccine-induced protection against clinical TB disease. However, whether M72/AS01 could provide protection against TB among _Mtb_-uninfected and HIV-negative individuals and in people from other geographical areas remain key questions to be answered. M72/AS01E has been exclusively licensed to the Medical Research Institute of Bill and Melinda Gates Foundation for further development.  
GamTbvac is a fusion protein comprising _Mtb_ antigens Ag85A and ESAT6-CFP-10 with the dextran-binding domain immobilized on dextran. It is formulated with an adjuvant consisting of a DEAE-dextran core and CpG oligodeoxynucleotides (TLR9 agonist) (Figure 3). GamTbvac is undergoing a Phase IIa safety and immunogenicity evaluation in healthy BCG-vaccinated adults, following a successful Phase 1 safety and immunogenicity trial in Russia [47] (Figure 2).  
Figure 3: The diversity of TB vaccine candidates in clinical trials. Schematic table showing the main characteristics of the vaccine candidates. The table is coloured according to vaccine strategies indicated in Figure 2 and contains representative information for each candidate, including the mycobacterial origin from each vaccine and their antigenic content.