{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T02:00:04Z","timestamp":1784426404008,"version":"3.55.0"},"reference-count":41,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,13]],"date-time":"2025-04-13T00:00:00Z","timestamp":1744502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH-NHLBI","award":["2R15HL143545-02"],"award-info":[{"award-number":["2R15HL143545-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Mycobacterium tuberculosis (Mtb) vaccines are designed to prevent infection, prevent reactivation of latent infection, and\/or provide adjuvant therapy to standard TB treatment for active Mtb. Emerging vaccine technologies include reverse vaccinology, DNA and RNA vaccines, subunit vaccines, and multi-epitope vaccines. Currently, many different types of vaccine candidates are in clinical trials, though, to date, BCG remains the only approved Mtb vaccine. Mtb has a complex genome with numerous antigens, but not all are equally effective in eliciting immunity, so a critical challenge is the selection of antigens and epitopes that are most likely to induce a long-term, broad-spectrum protective immune response. Multi-epitope vaccines (MEVs) represent a new event horizon in vaccine development. Bioinformatic computer modeling is being used to maximize efficacy and minimalize adverse effects. Although no multi-epitope vaccines have proceeded to in vivo clinical trials, three candidate MEVs have made it through in silico tests. Multi-epitope vaccine candidate PP13138R, containing 13 HTL epitopes, 13 CTL epitopes, and 8 B cell epitopes in addition to both TLR2 and TLR4 agonists, aims to elicit a broad immune response that could address both active and latent Mtb infection. Similarly, immunoinformatic data were used to design and validate another MEV candidate based on the biomarker PE_PGRS17 with four B cell, nine HTL, and six CTL linked epitopes, with a griselimycin sequence as the adjuvant. A third novel prophylactic and therapeutic MEV was developed that targets Ag85A, AG85B, ESAT-6, and CFP-10 proteins with 12 CTL, 25 HTL, and 21 LBL epitopes with a CpG adjuvant.<\/jats:p>","DOI":"10.3390\/biology14040417","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T06:18:36Z","timestamp":1744611516000},"page":"417","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["New Advances in the Development and Design of Mycobacterium tuberculosis Vaccines: Construction and Validation of Multi-Epitope Vaccines for Tuberculosis Prevention"],"prefix":"10.3390","volume":"14","author":[{"given":"Osnat","family":"Barazani","sequence":"first","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9943-3626","authenticated-orcid":false,"given":"Thomas","family":"Erdos","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raafi","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Department of Biology, University of California, Riverside, CA 9252, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gursimratpreet","family":"Kaur","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-1160","authenticated-orcid":false,"given":"Vishwanath","family":"Venketaraman","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,13]]},"reference":[{"key":"ref_1","unstructured":"(2025, January 07). Global Tuberculosis Report 2024. Available online: https:\/\/www.who.int\/teams\/global-tuberculosis-programme\/tb-reports\/global-tuberculosis-report-2024."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1007\/s10096-020-03843-6","article-title":"Tuberculosis Vaccine Development: From Classic to Clinical Candidates","volume":"39","author":"Li","year":"2020","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1016\/S2666-5247(22)00359-7","article-title":"WHO\u2019s Global Tuberculosis Report 2022","volume":"4","author":"Bagcchi","year":"2023","journal-title":"Lancet Microbe"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Kazakova, A., Zhelnov, P., Sidorov, R., Rogova, A., Vasileva, O., Ivanov, R., Reshetnikov, V., and Muslimov, A. (2024). DNA and RNA Vaccines against Tuberculosis: A Scoping Review of Human and Animal Studies. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1457327"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1062963","DOI":"10.3389\/fcimb.2023.1062963","article-title":"Mycobacterium tuberculosis-Macrophage Interaction: Molecular Updates","volume":"13","author":"Bo","year":"2023","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hirano, S., and Kanno, S. (2015). Macrophage Receptor with Collagenous Structure (MARCO) Is Processed by Either Macropinocytosis or Endocytosis-Autophagy Pathway. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142062"},{"key":"ref_7","first-page":"51","article-title":"Differential Biological Activities of Human Interleukin-1 Alpha and Interleukin-1 Beta","volume":"2","author":"Radeke","year":"1991","journal-title":"Eur. Cytokine Netw."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1084\/jem.20051782","article-title":"TLR9 Regulates Th1 Responses and Cooperates with TLR2 in Mediating Optimal Resistance to Mycobacterium tuberculosis","volume":"202","author":"Bafica","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Prezzemolo, T., Guggino, G., La Manna, M.P., Di Liberto, D., Dieli, F., and Caccamo, N. (2014). Functional Signatures of Human CD4 and CD8 T Cell Responses to Mycobacterium tuberculosis. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00180"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"372","DOI":"10.4049\/jimmunol.162.1.372","article-title":"Activation of Human CD8+ Alpha Beta TCR+ Cells by Mycobacterium tuberculosis via an Alternate Class I MHC Antigen-Processing Pathway","volume":"162","author":"Canaday","year":"1999","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Guirado, E., and Schlesinger, L. (2013). Modeling the Mycobacterium tuberculosis Granuloma\u2014the Critical Battlefield in Host Immunity and Disease. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00098"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ehlers, S., and Schaible, U.E. (2013). The Granuloma in Tuberculosis: Dynamics of a Host\u2013Pathogen Collusion. Front. Immunol., 3.","DOI":"10.3389\/fimmu.2012.00411"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1128\/IAI.00135-15","article-title":"Toll-Like Receptor 2-Dependent Extracellular Signal-Regulated Kinase Signaling in Mycobacterium tuberculosis-Infected Macrophages Drives Anti-Inflammatory Responses and Inhibits Th1 Polarization of Responding T Cells","volume":"83","author":"Richardson","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sharma, B., Upadhyay, R., Dua, B., Khan, N.A., Katoch, V.M., Bajaj, B., and Joshi, B. (2015). Mycobacterium tuberculosis Secretory Proteins Downregulate T Cell Activation by Interfering with Proximal and Downstream T Cell Signalling Events. BMC Immunol., 16.","DOI":"10.1186\/s12865-015-0128-6"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Brace, P.T., Tezera, L.B., Bielecka, M.K., Mellows, T., Garay, D., Tian, S., Rand, L., Green, J., Jogai, S., and Steele, A.J. (2017). Mycobacterium tuberculosis Subverts Negative Regulatory Pathways in Human Macrophages to Drive Immunopathology. PLOS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006367"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/s41586-019-1915-7","article-title":"Host-Mediated Ubiquitination of a Mycobacterial Protein Suppresses Immunity","volume":"577","author":"Wang","year":"2020","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Saini, N.K., Baena, A., Ng, T.W., Venkataswamy, M.M., Kennedy, S.C., Kunnath-Velayudhan, S., Carre\u00f1o, L.J., Xu, J., Chan, J., and Larsen, M.H. (2016). Suppression of Autophagy and Antigen Presentation by Mycobacterium tuberculosis PE_PGRS47. Nat. Microbiol., 1.","DOI":"10.1038\/nmicrobiol.2016.133"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/eji.201848071","article-title":"Mycobacterium tuberculosis PPE18 Protein Inhibits MHC Class II Antigen Presentation and B Cell Response in Mice","volume":"51","author":"Dolasia","year":"2021","journal-title":"Eur. J. Immunol."},{"key":"ref_19","unstructured":"(2025, January 05). TB-Trials. Available online: https:\/\/tbtrialtrack.who.int\/#\/."},{"key":"ref_20","unstructured":"(2025, January 05). Clinical Pipeline\u2014Sortable. Available online: https:\/\/newtbvaccines.org\/tb-vaccine-pipeline\/clinical-sortable\/."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/S1473-3099(18)30421-3","article-title":"WHO Preferred Product Characteristics for New Vaccines against Tuberculosis","volume":"18","author":"Schrager","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_22","first-page":"226","article-title":"Non-Tuberculous Mycobacteria Have Diverse Effects on BCG Efficacy against Mycobacterium tuberculosis","volume":"94","author":"Poyntz","year":"2014","journal-title":"Tuberc. Edinb. Scotl."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e167762","DOI":"10.1172\/JCI167762","article-title":"Host Genetic Background Is a Barrier to Broadly Effective Vaccine\u2013Mediated Protection against Tuberculosis","volume":"133","author":"Lai","year":"2024","journal-title":"J. Clin. Invest."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s10517-021-05246-9","article-title":"Efficacy of BCG Vaccination Depends on Host Genetics","volume":"171","author":"Nikonenko","year":"2021","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41541-023-00750-7","article-title":"Key Advances in Vaccine Development for Tuberculosis\u2014Success and Challenges","volume":"8","author":"Lai","year":"2023","journal-title":"npj Vaccines"},{"key":"ref_26","unstructured":"(2025, January 07). Home|ClinicalTrials.Gov, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7239","DOI":"10.1016\/j.vaccine.2020.09.055","article-title":"DAR-901 Vaccine for the Prevention of Infection with Mycobacterium tuberculosis among BCG-Immunized Adolescents in Tanzania: A Randomized Controlled, Double-Blind Phase 2b Trial","volume":"38","author":"Munseri","year":"2020","journal-title":"Vaccine"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sharma, S.K., Katoch, K., Sarin, R., Balambal, R., Kumar Jain, N., Patel, N., Murthy, K.J.R., Singla, N., Saha, P.K., and Khanna, A. (2017). Efficacy and Safety of Mycobacterium Indicus Pranii as an Adjunct Therapy in Category II Pulmonary Tuberculosis in a Randomized Trial. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-03514-1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s12026-022-09284-x","article-title":"Reverse Vaccinology Approach to Design a Multi-Epitope Vaccine Construct Based on the Mycobacterium tuberculosis Biomarker PE_PGRS17","volume":"70","author":"Moodley","year":"2022","journal-title":"Immunol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Goodswen, S.J., Kennedy, P.J., and Ellis, J.T. (2023). A Guide to Current Methodology and Usage of Reverse Vaccinology towards in Silico Vaccine Discovery. FEMS Microbiol. Rev., 47.","DOI":"10.1093\/femsre\/fuad004"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Jiang, F., Peng, C., Cheng, P., Wang, J., Lian, J., and Gong, W. (2023). PP19128R, a Multiepitope Vaccine Designed to Prevent Latent Tuberculosis Infection, Induced Immune Responses In Silico and In Vitro Assays. Vaccines, 11.","DOI":"10.3390\/vaccines11040856"},{"key":"ref_32","unstructured":"Hyypia, E. (2025, January 05). Bill & Melinda Gates Medical Research Institute Initiates Phase 3 Clinical Trial of Tuberculosis Vaccine Candidate. Available online: https:\/\/www.gatesmri.org\/mri-initiates-phase-3-clinical-trial-tuberculosis-vaccine-candidate\/."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1007\/s40121-023-00806-0","article-title":"Safety and Immunogenicity of the ID93\u2009+ GLA-SE Tuberculosis Vaccine in BCG-Vaccinated Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial","volume":"12","author":"Choi","year":"2023","journal-title":"Infect. Dis. Ther."},{"key":"ref_34","unstructured":"(2025, January 07). GamTBvac. Available online: https:\/\/newtbvaccines.org\/vaccine\/gamtbvac\/."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1093\/infdis\/jiae170","article-title":"Safety and Immunogenicity of the H56:IC31 Tuberculosis Vaccine Candidate in Adults Successfully Treated for Drug-Susceptible Pulmonary Tuberculosis: A Phase 1 Randomized Trial","volume":"230","author":"Tait","year":"2024","journal-title":"J. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1016\/j.vaccine.2024.02.087","article-title":"Reverse Engineering Protection: A Comprehensive Survey of Reverse Vaccinology-Based Vaccines Targeting Viral Pathogens","volume":"42","author":"Ponne","year":"2024","journal-title":"Vaccine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/978-94-017-7444-4_11","article-title":"Antigenicity, Immunogenicity, Allergenicity","volume":"8","author":"Zhang","year":"2015","journal-title":"Allergy Bioinforma."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/cmi.2017.92","article-title":"Multi-Epitope Vaccines: A Promising Strategy against Tumors and Viral Infections","volume":"15","author":"Zhang","year":"2018","journal-title":"Cell. Mol. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Xu, J., Hu, Z., and Fan, X. (2023). Advances in Protein Subunit Vaccines against Tuberculosis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1238586"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bibi, S., Ullah, I., Zhu, B., Adnan, M., Liaqat, R., Kong, W.-B., and Niu, S. (2021). In Silico Analysis of Epitope-Based Vaccine Candidate against Tuberculosis Using Reverse Vaccinology. Sci. Rep., 11.","DOI":"10.1038\/s41598-020-80899-6"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"286","DOI":"10.24171\/j.phrp.2024.0026","article-title":"Novel Prophylactic and Therapeutic Multi-Epitope Vaccine Based on Ag85A, Ag85B, ESAT-6, and CFP-10 of Mycobacterium tuberculosis Using an Immunoinformatics Approach","volume":"15","author":"Nugraha","year":"2024","journal-title":"Osong Public Health Res. Perspect."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/4\/417\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:13:43Z","timestamp":1760030023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/4\/417"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,13]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["biology14040417"],"URL":"https:\/\/doi.org\/10.3390\/biology14040417","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,13]]}}}