Table 1.
Recombinant bacille Calmette-Guérin (rBCG) vaccine candidates and their protective efficacy against Mycobacterium tuberculosis (Mtb) challenge.
| Name | Description | Results of testing | Reference |
|---|---|---|---|
| BCG:RD1-2F9/BCG:RD1/BCG:ESX-1 | Bacille Calmette-Guérin (BCG) with the RD1 gene cluster inserted (Rv3861–Rv3885). Expresses early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP10) | Mice: comparable efficacy in the lungs, moderate decrease in spleen bacterial burdens. Increased virulence Guinea pigs: strong decrease in spleen bacterial loads, reduced pathology |
(73, 74) |
| rBCG E6 | rBCG over-expressing antigen ESAT-6 | Guinea pigs: comparable protection to BCG | (75) |
| rBCG30 | rBCG over-expressing antigen 85B (Ag85B) | Guinea pigs: increased survival Safe and immunogenic in Phase I clinical trials |
(76, 77) |
| rBCG(mbtB30) | rBCG over-expressing Ag85B, with disrupted synthesis of the siderophore mycobactin, preventing normal iron acquisition | Guinea pigs: slight decrease in bacterial burdens Mice: safer in severe combined immunodeficiency (SCID) mice |
(78) |
| rBCG-1173:A | rBCG expressing Ag85A | Mice: slight decrease in bacterial burdens | (79) |
| rBCG:XB | rBCG expressing Ag85B and latency antigen HspX | Mice: strong decrease in bacterial burdens | (80) |
| (H)PE-ΔMPT64-BCG | rBCG expressing MPT64 fused to the PE domain of the PE_PGRS33 protein of Mtb that localizes to the cell wall | Mice: slight decrease in bacterial burdens | (81) |
| BCG:ESAT-L28A/L29S | rBCG:ESX-1 variant with mutations in the ESAT-6 gene | Mice: moderate decrease in spleen bacterial burdens, no difference in lung bacterial burdens. Attenuated Guinea pigs: strong decrease in spleen bacterial burdens |
(82) |
| BCG:ESX-1Mmar | rBCG with the insertion of the esx1 locus of Mycobacterium marinum | Mice: moderate reduction in bacterial loads in lungs and spleens after virulent Mtb challenge. As safe as BCG | (83) |
| BCG-IL-4, BCG-IL-6, BCG-GM-CSF, BCG-IFN-γ, BCG-IL-2 | rBCG expressing murine interleukin (IL)-4, IL-6, GM-CSF, IFN-γ, and IL-2 | No efficacy data | (84) |
| BCG secreting IL-2 | BCG secreting IL-2 | No efficacy data | (85) |
| rBCG-mIL-18 | BCG secreting mouse IL-18 | Mice: attenuated. Efficacy against Mtb not tested | (86) |
| BCG-IL-18 | BCG secreting mouse IL-18 | Mice: no difference in virulence compared to BCG. Efficacy against Mtb not tested | (87) |
| rBCG/IL-18 | rBCG expressing IL-18 | Mice: decreased protective efficacy against virulent Mycobacterium bovis challenge compared to BCG | (88) |
| rBCG/IL-2 | rBCG expressing IL-2 | Mice: did not increase protective efficacy against the virulent M. bovis challenge compared to BCG | (88) |
| BCG-IFN-gamma | rBCG secreting murine IFN-γ | Mice: did not increase protective efficacy against Mtb compared to BCG | (89) |
| rBCG-Ag85B-IL-15 | rBCG expressing a fusion protein of Ag85B and IL-15 | Mice: decreased bacterial burdens after intratracheal Mtb challenge, compared to BCG-Ag85B. No comparison performed with BCG | (90) |
| rBCG-Ag85B-ESAT-6-TNF-α | rBCG expressing the fusion protein Ag85B-ESAT-6-TNF-α | Efficacy against Mtb not tested | (91) |
| rBCG Ag85B-ESAT-6-IFN-γ | rBCG strain expressing the fusion protein Ag85B-ESAT-6-IFN-γ | Mice: slightly reduced bacterial burdens compared to BCG | (92) |
| BCGi | The Ipr1 (intracellular pathogen resistance 1) gene was inserted into BCG | Mice: decreased bacterial loads in the lungs and spleens after Mtb challenge | (93) |
| rBCG(MCP-3) | Insertion of the gene for the chemokine monocyte chemotactic protein 3 (MCP-3) into BCG | Mice: increased safety in immunodeficient mice. Efficacy comparable to BCG | (94) |
| VPM1002 (BCG ΔureC:hly) | BCG expressing the Listeria monocytogenes protein listeriolysin O (LLO) instead of urease C | Mice: increased safety in both immunocompetent and immunodeficient mice. Moderate to strongly decreased bacterial loads and pathology compared to BCG Safe in guinea pigs, rabbits, and non-human primates Successfully passed Phase II clinical trials |
(42, 95–97) |
| BCG ΔureC:hly ΔnuoG/VPM1002 ΔnuoG | BCG ΔureC:hly with deletion of nuoG, an anti-apoptotic gene | Mice: strong decrease in bacterial burdens compared to BCG, slight decrease in bacterial burdens compared to VPM1002 Safety equivalent to VPM1002 |
(96) |
| rBCGΔureC::hly (pMPIIB01) | BCG ΔureC:hly expressing the latency antigens Rv2659c, Rv3407, and Rv1733c | Mice: moderately reduced bacterial burdens compared to the parental strain in both lung and spleen; decreased lung pathology. Comparison to BCG not performed | (98) |
| BCG ΔureC:hly Δpdx1/VPM1002 Δpdx1 | BCG ΔureC:hly deficient in pyridoxine synthase, an enzyme required for synthesis of the essential vitamin B6 | Mice: safer in immunocompromised and wild-type mice compared to the parental strain. Homologous prime–boost regimen afforded similar protection to BCG | (99) |
| BCG ΔureC:hly_hIL7 and BCG ΔureC:hly_hIL18 | BCG ΔureC:hly expressing human IL-7 or human IL-18 | Mice: no increase in efficacy compared to the parental strain | (100) |
| AERAS-401 (BCG1331 ΔureC:ΩpfoAG137Q) | BCG with the ureC gene replaced with the PfoAG137Q gene for perfringolysin O | Mice: safe in immunocompromised SCID mice. No increase in efficacy compared to BCG | (101) |
| AERAS-422 (AFRO-1) | AERAS-401 incorporating genes coding for Ag85A, Ag85B, and TB10.4 | Mice: challenge with a virulent Mtb strain demonstrated increased survival after immunization with AERAS-442 compared to BCG Clinical trials discontinued [associated with the development of shingles (varicella-zoster virus reactivation)] |
(101) |
| rBCG-LTAK63lo | rBCG expressing LTAK63, a detoxified form of Escherichia coli heat labile toxin | Mice: greatly reduced bacterial burdens compared to BCG. At a high challenge dose, mice immunized with rBCG-LTAK63lo had reduced bacterial loads and increased survival. rBCG-LTAK63lo also increased protection against challenge with a virulent Mtb Beijing isolate | (102) |
| BCG Δzmp1 | BCG deficient in gene zmp1, a putative Zn(2+) metalloprotease | Guinea pigs: slight reduction in lung bacterial loads compared to BCG | (103) |
The table summarizes results from the testing of rBCG against TB in animal models. Unless otherwise specified, Mtb challenge was performed. Decreases in bacterial burdens were estimated from graphs if not specified and listed as follows for comparative purposes: up to 0.5 log decrease: slight; 0.5 to 1.0 log decrease: moderate; over 1.0 log decrease: strong.