Research: Vaccination against Tuberculosis with whole cell Mycobacterial Vaccines
Associate Professor Tom Scriba has co-authored a article titled "Vaccination against Tuberculosis with whole cell Mycobacterial vaccines" appearing in the Journal of Infectious Diseases.
Background: Live attenuated and killed whole-cell vaccines (WCVs) offer promising vaccination strategies against tuberculosis. A number of WCV candidates, based on recombinant bacillus Calmette-Guerin (BCG), attenuated Mycobacterium tuberculosis, or related mycobacterial species are in various stages of preclinical or clinical development.
In this review, the authors (Scriba et al., 2016) discuss the vaccine candidates and key factors shaping the development pathway for live and killed WCVs and provide an update on progress.
Whole-Cell Vaccine Candidates for Tuberculosis in Clinical Development
| Vaccine Candidate | Backbone | Live/Dead | Modification(s) | Purpose | Safe in HIV-Positive Individuals | Clinical Trial Stage(s) | Reference(s) |
|---|---|---|---|---|---|---|---|
| VPM1002 | Recombinant BCG | Live | LLO inserted, ureC deletion | Prophylactic | Yes | Phase 2 | [6, 7] |
| MTBVAC | Attenuated M. tuberculosis | Live | phoP and fadD26 deletions | Prophylactic | Not tested in humans; safer than BCG in SCID mice | Phase 1 | [8, 9] |
| RUTI | Detoxified and fragmented M. tuberculosis cells | Dead | Polyantigenic liposomal preparation | Therapeutic | Yes | Phase 2 | [10] |
| M. indicus pranii | M. indicus pranii (formerly Mycobacterium w) | Dead | Heat killed | Therapeutic | Yes | Phase 2 | [11, 12] |
| M. vaccae or SRL172 or DAR-901 | M. vaccae or M. obuense (formerly thought to be M. vaccae) | Dead | Heat killed or irradiated | Therapeutic | Yes | Phase 3; phase 2b (sepsis) | [13–17] |
Abbreviations: BCG, bacillus Calmette-Guerin; HIV, human immunodeficiency virus; LLO, listeriolysin; M. indicus pranii, Mycobacterium indicus pranii; M. obuense, Mycobacterium obuense; M. tuberculosis, Mycobacterium tuberculosis; M. vaccae, Mycobacterium vaccae; SCID, severe combined immunodeficiency.
Table 2.
Whole-Cell Vaccine Candidates for Tuberculosis in Preclinical Development
| Candidate | Backbone | Live/Dead | Modification(s) | Purpose | Safe in HIV-Positive Individuals | Reference(s) |
|---|---|---|---|---|---|---|
| BCGΔzmp1 | Recombinant BCG | Live | zmp1 deletion | Prophylactic | Yes (safer than BCG in SCID mice) | [18] |
| MtbΔsigH | Recombinant M. tuberculosis | Live | sigH deletion | Prophylactic | Possibly, not stipulated | [19] |
| sigE mutant | Recombinant M. tuberculosis | Live | sigE deletion | Prophylactic | Yes (safer than BCG in nude mice) | [20] |
| ΔleuD ΔpanCD | Recombinant M. tuberculosis | Live | leuD and panCD deletions | Prophylactic | Yes (safer than BCG in SCID mice) | [21] |
| mc26020 | Recombinant M. tuberculosis | Live | lysA and panCD deletions | Prophylactic | Yes (safer than H37Rv in SCID and than BCG IFN-γ knockout mice) | [22, 23] |
| ΔsecA2 | Recombinant M. tuberculosis | Live | secA2 deletion | Prophylactic | Possibly, not stipulated | [24] |
| ΔlysA ΔsecA2 | Recombinant M. tuberculosis | Live | lysA and secA2 deletion | Prophylactic | Yes (safer than BCG in SCID mice) | [25] |
| mc26030 | Recombinant M. tuberculosis | Live | RD1 and panCD deletions | Prophylactic | Yes (safer than H37Rv in SCID and than BCG IFN-γ knockout mice) | [23, 26] |
| BCG::ESAT6-L28A/L29S | Recombinant BCG | Live | Reconstituted with ESX-1, ESAT-6 mutated L28A/L29S | Prophylactic | Yes (safer than BCG in SCID mice) | [27] |
| BCGΔsapM | Recombinant BCG | Live | sapM deletion | Prophylactic | Not definitive; persistence in immunocompetent mice equivalent to BCG | [28] |
Abbreviations: BCG, bacillus Calmette-Guerin; ESAT-6, early secretory antigenic target 6; HIV, human immunodeficiency virus; IFN-γ, interferon γ; M. tuberculosis, Mycobacterium tuberculosis; SCID, severe combined immunodeficiency.
Vaccines reviewed:
- VPM1002; at the most advanced stage of clinical development. VPM1002 successfully completed 2 phase 1 trials (National Clinical Trial [NCT] 00749034 [7, 31] and NCT 01113281) and 1 phase 2a trial in infants (NCT 01479972), which show that it is safe and immunogenic in adolescents/adults and infants. It is currently being assessed in large cohorts of newborns from human immunodeficiency virus (HIV)–positive and HIV-negative mothers (NCT 02391415).
- MTBVAC; is a live rationally attenuated derivative of the M. tuberculosis isolate MT103, which belongs to lineage 4 (Euro-American), one of the most widespread lineages of M. tuberculosis. MTBVAC contains all the genes present in M. tuberculosis strains commonly transmitted between humans by the aerosol route, including the genes that are deleted in Mycobacterium bovis and BCG.
Therapeutic vaccine
- Therapeutic, Ruti, a polyantigenic liposomal vaccine made of detoxified, fragmented M. tuberculosis cells targeting he prevention of active tuberculosis in subjects with LTBI.
- Mycobacterium indicus pranii which was found to have potential effects against tuberculosis when used as an aerosol-delivered adjunct to chemotherapy in animal models, including guinea pigs. However, in a recent phase 3 clinical trial in patients with tuberculous pericarditis, M. indicus pranii vaccination had no immunotherapeutic effect either alone or adjunctive to prednisolone.
- Vaccine preparations of the nontuberculous mycobacteria Mycobacterium vaccae and Mycobacterium obuense have also been extensively developed in preclinical studies and clinical trials. Killed M. vaccae was studied for use as an immunotherapeutic agent against leprosy and tuberculosis [37].
- Heat-killed preparations referred to as SRL172 and DAR-901, initially thought to be M. vaccae but recently identified as M. obuense, have also been tested in numerous trials [15, 38
These include a BCG mutant inactivated in zmp1, a gene involved in inflammasome inhibition, showed to be more better immunogenic and safetyt han BCG in mice and is more protective than BCG in mice and guinea pigs . Thought to be ready to enter phase 1 clinical trial.
M. tuberculosis strains, inactivated in the transcriptional regulator SigH [19] or in metabolic genes such as panCD or lysA, involved in pantothenate and lysine biosynthesis, respectively, among others [22, 39], are also in preclinical development and may enter phase 1 trials in the future.
Many questions in the development of tuberculosis WCVs remain. Much will be learned from the many preclinical studies and clinical studies currently underway. It is critical that rare and expensive efficacy trials in humans are appropriately leveraged to perform exploratory studies that maximize the knowledge gained.