MTBVAC is a candidate vaccine against tuberculosis in humans currently in research trials. It is based on a genetically modified form of the Mycobacterium tuberculosis pathogen isolated from humans.[1]
Development and manufacturing
editThe vaccine was constructed at the University of Zaragoza in the laboratory of the Mycobacterial Genetics group, in collaboration with Dr. Brigitte Gicquel of the Pasteur Institute in Paris.[2] Currently, the University of Zaragoza has an industrial partner: the Spanish biotechnology company BIOFABRI, belonging to ZENDAL group, responsible for the industrial and clinical development of MTBVAC, studying its immunity and safety in two Phase IIa trials in newborn babies and adults in South Africa.[3] For the Clinical Development of MTBVAC, the tuberculosis vaccine project enjoys the advice and support of the European TBVI (since 2008) and since 2016, of IAVI for the clinical development in adults and adolescents.
Construction and molecular characterization
editMTBVAC discovery follows the principles of vaccination as per Luis Pasteur: isolation of the human pathogen, attenuation by rational inactivation of selected genes, protection assays in animal models, and evaluation in humans.[2]
The main advantage of using live vaccines based on rational attenuation of M. tuberculosis is their ability to keep the genetic repertoire encoding immunodominant antigens that are absent in BCG,[4] whereas chromosomal deletions in virulence genes provide assurance for safety and genetic stability. Such vaccines are expected to safely induce more specific and longer lasting immune responses in humans that can provide protection against all forms of the disease.[2] This is the rationale that has been followed in the development of the live-attenuated MTBVAC.
The rational attenuation of MTBVAC was achieved by inactivation of the phoP and fadD26 genes,[2] following the international guidelines to progress live vaccines into clinical development.[5] Similar to BCG, which was conceived in the early 1900s as an attenuated strain of Mycobacterium bovis causing TB in cows and transmitted to humans mainly through ingestion of unpasteurized milk, the discovery of MTBVAC starts with an unusual outbreak of a multidrug-resistant M. bovis killing more than 100 HIV- positive individuals in Spain in the early 1990s.[6] From that outbreak, Prof Carlos Martin and his group identified the phoP gene as a key player in M. tuberculosis virulence.[7] The gene phoP encodes the transcription factor PhoP of the two-component system PhoP/PhoR essential for M. tuberculosis virulence.[8][9] PhoP was shown to regulate between 2 and 4% of M. tuberculosis genes, most of which participate in well-known virulence pathways of the tubercle bacillus.[10] As a consequence of the phoP inactivation, MTBVAC can produce but is unable to export ESAT-6, which results in virulence attenuation, but yet maintains the epitopes present in this immunogenic protein. Other relevant virulence genes regulated by PhoP are involved in biosynthesis of the polyketide-derived acyltrehaloses (DAT, PAT) and sulfolipids (SL), which are front-line lipid constituents of the cell wall interfering with the recognition of M. tuberculosis by the immune system.[10] Finally, PhoP is able to modulate protein secretion, and inactivation of phoP in MTBVAC results in higher secretion of immunogenic proteins such as the Ag85 complex 6.[8] The fadD26 gene is the first gene in an operon required for the biosynthesis and export of phthiocerol dimycocerosates (PDIM), the main virulence-associated cell-wall lipids of M. tuberculosis[2]
Preclinical research
editRigorous preclinical studies in different TB-relevant animal models - mice, guinea pigs and non-human primates - conducted between 2001 and 2011 have shown adequate attenuation, safety and improved immunogenicity and protective efficacy against M. tuberculosis challenge as compared to BCG, thus fulfilling regulatory WHO guidelines and the Geneva consensus requirements for progressing live mycobacterial vaccines to first-in-human Phase 1 clinical evaluation.[3] A successful trial in rhesus macaques was reported in 2021.[11]
Clinical trials
editThe safety and immunogenicity of new vaccines need to be determined in a reduced number of healthy volunteers. Phase 1 studies (can be first-in-human) to define the safety of different ascending doses are usually conducted in small groups of no more than 100 volunteers per trial. These are followed by medium-sized Phase 2 trials (can be > 100) to corroborate safety and determine the optimal therapeutic dose (detailed immunogenicity profile in the case of new vaccines) that helps select the final dose for Phase 3 efficacy evaluation.[3]
The MTBVAC clinical development started with a first-in-human study in healthy adult volunteers in Lausanne, Switzerland (NCT02013245);[12] followed by one additional Phase 1 study in healthy newborns in South Africa in collaboration with South African TuBerculosis Vaccine Initiative (SATVI) (NCT02729571)[13] to corroborate the safety and greater immunogenic potential of MTBVAC in this age-group relative to BCG. Two dose-defining Phase 2 studies were conducted at SATVI covering adults with and without previous exposure to M. tuberculosis (NCT02933281) (ended in Sep 2021) and healthy newborns (NCT03536117) that will be finalized in March 2022.[3]
Data from the Phase II clinical trials will help define the final (safest and most immunogenic) dose of MTBVAC, triggering the initiation of a multi-center Phase 3 efficacy trial in newborn babies by the second quarter of 2022. Supported by the European & Developing Countries Clinical Trials Partnership (EDCTP funding), this Phase 3 trial will encompass TB-endemic regions of Sub-Saharan Africa, including South Africa, Madagascar and Senegal (registered on ClinicalTrials.gov, NCT04975178).[3][14]
References
edit- ^ Martin C (2020). "Update on TB Vaccine Pipeline". Applied Sciences. 10 (7): 2632. doi:10.3390/app10072632.
- ^ a b c d e Arbues A, Aguilo JI, Gonzalo-Asensio J, Marinova D, Uranga S, Puentes E, et al. (October 2013). "Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials". Vaccine. 31 (42): 4867–4873. doi:10.1016/j.vaccine.2013.07.051. PMID 23965219. S2CID 6225547.
- ^ a b c d e Martín C, Marinova D, Aguiló N, Gonzalo-Asensio J (December 2021). "MTBVAC, a live TB vaccine poised to initiate efficacy trials 100 years after BCG". Vaccine. 39 (50): 7277–7285. doi:10.1016/j.vaccine.2021.06.049. PMID 34238608. S2CID 235777018.
- ^ Brosch R, Gordon SV, Marmiesse M, Brodin P, Buchrieser C, Eiglmeier K, et al. (March 2002). "A new evolutionary scenario for the Mycobacterium tuberculosis complex". Proceedings of the National Academy of Sciences of the United States of America. 99 (6): 3684–3689. Bibcode:2002PNAS...99.3684B. doi:10.1073/pnas.052548299. PMC 122584. PMID 11891304.
- ^ Kamath AT, Fruth U, Brennan MJ, Dobbelaer R, Hubrechts P, Ho MM, et al. (May 2005). "New live mycobacterial vaccines: the Geneva consensus on essential steps towards clinical development". Vaccine. 23 (29): 3753–3761. doi:10.1016/j.vaccine.2005.03.001. PMID 15893612.
- ^ Rivero A, Márquez M, Santos J, Pinedo A, Sánchez MA, Esteve A, et al. (January 2001). "High rate of tuberculosis reinfection during a nosocomial outbreak of multidrug-resistant tuberculosis caused by Mycobacterium bovis strain B". Clinical Infectious Diseases. 32 (1): 159–161. doi:10.1086/317547. PMID 11112675.
- ^ Pérez E, Samper S, Bordas Y, Guilhot C, Gicquel B, Martín C (July 2001). "An essential role for phoP in Mycobacterium tuberculosis virulence". Molecular Microbiology. 41 (1): 179–187. doi:10.1046/j.1365-2958.2001.02500.x. PMID 11454210. S2CID 22014385.
- ^ a b Solans L, Gonzalo-Asensio J, Sala C, Benjak A, Uplekar S, Rougemont J, et al. (May 2014). "The PhoP-dependent ncRNA Mcr7 modulates the TAT secretion system in Mycobacterium tuberculosis". PLOS Pathogens. 10 (5): e1004183. doi:10.1371/journal.ppat.1004183. PMC 4038636. PMID 24874799.
- ^ Gonzalo-Asensio J, Malaga W, Pawlik A, Astarie-Dequeker C, Passemar C, Moreau F, et al. (August 2014). "Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator". Proceedings of the National Academy of Sciences of the United States of America. 111 (31): 11491–11496. Bibcode:2014PNAS..11111491G. doi:10.1073/pnas.1406693111. PMC 4128152. PMID 25049399.
- ^ a b Gonzalo Asensio J, Maia C, Ferrer NL, Barilone N, Laval F, Soto CY, et al. (January 2006). "The virulence-associated two-component PhoP-PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis". The Journal of Biological Chemistry. 281 (3): 1313–1316. doi:10.1074/jbc.C500388200. PMID 16326699.
- ^ "Researchers demonstrate protection offered by novel TB vaccine candidate in animal model". IAVI. 2021-01-13. Retrieved 2023-10-27.
- ^ Spertini F, Audran R, Chakour R, Karoui O, Steiner-Monard V, Thierry AC, et al. (December 2015). "Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial". The Lancet. Respiratory Medicine. 3 (12): 953–962. doi:10.1016/S2213-2600(15)00435-X. PMID 26598141.
- ^ Tameris M, Mearns H, Penn-Nicholson A, Gregg Y, Bilek N, Mabwe S, et al. (September 2019). "Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial". The Lancet. Respiratory Medicine. 7 (9): 757–770. doi:10.1016/S2213-2600(19)30251-6. PMID 31416768. S2CID 201018182.
- ^ "NCT04975178". www.clinicaltrials.gov. Retrieved 2023-10-27.