{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T07:39:16Z","timestamp":1792741156782,"version":"4.5.0"},"reference-count":125,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T00:00:00Z","timestamp":1731888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003653","name":"Korea National Institute of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003653","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>As Bacille Calmette-Gu\u00e9rin (BCG) vaccine\u2019s effectiveness is limited to only children, the development of new tuberculosis (TB) vaccines is being studied using several platforms, and a novel TB vaccine that overcomes this limitation is required. In this study, we designed an effective multi-epitope vaccine against <jats:italic>Mycobacterium tuberculosis<\/jats:italic> using immunoinformatic analysis. First, we selected 11 highly antigenic proteins based on previous research: Ag85A, Ag85B, Ag85C, ESAT-6, MPT64, Rv2660c, TB10.4, HspX, GlfT2, Fas, and IniB. Among these antigens, 10 linear B-cell epitopes, 9 helper T-cell epitopes, and 16 cytotoxic T-cell epitopes were predicted to design the multi-epitope vaccine. To improve the immunogenicity of the candidate vaccine, three different adjuvants, griselimycin, human beta-defensin 3 (HBD3), and 50s ribosomal protein (50sRP), were attached with linker sequences to the vaccine model. The immunogenic, antigenic, allergenic, and physicochemical properties of the resulting designed multi-epitope vaccines were predicted <jats:italic>in silico<\/jats:italic>. Moreover, 3D structural modeling, refinement, and validation were used to select a model for further evaluation. Molecular docking analysis revealed a consistent and significant binding affinity of the candidate vaccine for toll-like receptors (TLRs), TLR-2, -3, and -4. Immune simulation performed using C-ImmSim demonstrated that three rounds of immunization with multi-epitope vaccines induced a high production of cytokines and immunoglobulins related with both cellular and humoral immune response. Moreover, we constructed vaccine candidate composed of 50sRP and evaluated its immunogenicity in a mouse model. Consequently, this <jats:italic>in silico<\/jats:italic>-engineered multi-epitope structure can elicit adaptive immune responses and represents a promising novel candidate for TB vaccine development.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1474346","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T06:12:05Z","timestamp":1731910325000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["In silico analysis for the development of multi-epitope vaccines against Mycobacterium tuberculosis"],"prefix":"10.3389","volume":"15","author":[{"given":"Jin-Seung","family":"Yun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A Reum","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Min","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunkyung","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Jun","family":"Ha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dokeun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Sook","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,18]]},"reference":[{"key":"B1","volume-title":"Global Tuberculosis Report 2021","year":"2021"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/srep23089","article-title":"Mycobacterial escape from macrophage phagosomes to the cytoplasm represents an alternate adaptation mechanism","volume":"6","author":"Jamwal","year":"2016","journal-title":"Sci Rep"},{"key":"B3","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1111\/j.1600-065X.2008.00589.x","article-title":"T-cell activation through immunological synapses and kinapses","volume":"221","author":"Dustin","year":"2008","journal-title":"Immunol Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0174-z","article-title":"Moving tuberculosis vaccines from theory to practice","volume":"19","author":"Andersen","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2005.01.059","article-title":"Developing an epitope-driven tuberculosis (Tb) vaccine","volume":"23","author":"De Groot","year":"2005","journal-title":"Vaccine"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1419","article-title":"Advances in tuberculosis vaccine strategies","volume":"4","author":"Skeiky","year":"2006","journal-title":"Nat Rev Microbiol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"4409","DOI":"10.1038\/s41598-019-40833-x","article-title":"In-silico design of a multi-epitope vaccine candidate against onchocerciasis and related filarial diseases","volume":"9","author":"Shey","year":"2019","journal-title":"Sci Rep"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3310\/hta17370","article-title":"Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus calmette-gu\u00e9rin vaccination against tuberculosis","volume":"17","author":"Abubakar","year":"2013","journal-title":"Health Technol Assess"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/s2214-109x(22)00325-4","article-title":"Infant bcg vaccination is beneficial, but not sufficient","volume":"10","author":"Hatherill","year":"2022","journal-title":"Lancet Glob Health"},{"key":"B10","doi-asserted-by":"publisher","first-page":"15309","DOI":"10.1038\/s41598-018-33499-4","article-title":"Age-related waning of immune responses to bcg in healthy children supports the need for a booster dose of bcg in tb endemic countries","volume":"8","author":"Whittaker","year":"2018","journal-title":"Sci Rep"},{"key":"B11","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1164\/rccm.201208-1385OC","article-title":"Induction and regulation of T-cell immunity by the novel tuberculosis vaccine M72\/as01 in South African adults","volume":"188","author":"Day","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-013-9949-3","article-title":"A randomized, controlled dose-finding phase ii study of the M72\/as01 candidate tuberculosis vaccine in healthy ppd-positive adults","volume":"33","author":"Montoya","year":"2013","journal-title":"J Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/qad.0000000000000343","article-title":"Safety and immunogenicity of the M72\/as01 candidate tuberculosis vaccine in hiv-infected adults on combination antiretroviral therapy: A phase I\/ii, randomized trial","volume":"28","author":"Thacher","year":"2014","journal-title":"Aids"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1803484","article-title":"Phase 2b controlled trial of M72\/as01e vaccine to prevent tuberculosis","volume":"379","author":"Van Der Meeren","year":"2018","journal-title":"New Engl J Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1909953","article-title":"Final analysis of a trial of M72\/as01e vaccine to prevent tuberculosis","volume":"381","author":"Tait","year":"2019","journal-title":"New Engl J Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph191811579","article-title":"Pan-genome-assisted computational design of a multi-epitopes-based vaccine candidate against helicobacter cinaedi","volume":"19","author":"Ismail","year":"2022","journal-title":"Int J Environ Res Public Health"},{"key":"B17","doi-asserted-by":"publisher","first-page":"21929","DOI":"10.1038\/s41598-021-01283-6","article-title":"An integrated computational framework to design a multi-epitopes vaccine against mycobacterium tuberculosis","volume":"11","author":"Albutti","year":"2021","journal-title":"Sci Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02280","article-title":"A web resource for designing subunit vaccine against major pathogenic species of bacteria","volume":"9","author":"Nagpal","year":"2018","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11071647","article-title":"Design of a multi-epitope vaccine against tuberculosis from mycobacterium tuberculosis pe_Pgrs49 and pe_Pgrs56 proteins by reverse vaccinology","volume":"11","author":"Ruaro-Moreno","year":"2023","journal-title":"Microorganisms"},{"key":"B20","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1159\/000354206","article-title":"In silico analysis and experimental validation of mycobacterium tuberculosis -specific proteins and peptides of mycobacterium tuberculosis for immunological diagnosis and vaccine development","author":"Mustafa","year":"2013","journal-title":"Med Princ Pract"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0284264","article-title":"In silico esxg esxh rational epitope selection: candidate epitopes for vaccine design against pulmonary tuberculosis","volume":"18","author":"Martinez-Olivares","year":"2023","journal-title":"PLoS One"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.830497","article-title":"Peptide-based vaccines for tuberculosis","volume":"13","author":"Gong","year":"2022","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.tube.2004.09.005","article-title":"Analyzing mycobacterium tuberculosis proteomes for candidate vaccine epitopes","volume":"85","author":"McMurry","year":"2005","journal-title":"Tuberculosis (Edinb)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"6774","DOI":"10.1038\/s41467-021-27029-6","article-title":"A phase I\/ii randomized trial of H56:Ic31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients","volume":"12","author":"Jenum","year":"2021","journal-title":"Nat Commun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/aac.05742-11","article-title":"Antigen 85c inhibition restricts mycobacterium tuberculosis growth through disruption of cord factor biosynthesis","volume":"56","author":"Warrier","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.581579","article-title":"The three mycobacterium tuberculosis antigen 85 isoforms have unique substrates and activities determined by non-active site regions","volume":"289","author":"Backus","year":"2014","journal-title":"J Biol Chem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2019.10.102","article-title":"A phase I trial evaluating the safety and immunogenicity of a candidate tuberculosis vaccination regimen, Chadox1 85a prime - mva85a boost in healthy uk adults","volume":"38","author":"Wilkie","year":"2020","journal-title":"Vaccine"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.155655","article-title":"Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans","volume":"7","author":"Jeyanathan","year":"2022","journal-title":"JCI Insight"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00327","article-title":"Mycobacterium tuberculosis virulent factor esat-6 drives macrophage differentiation toward the pro-inflammatory M1 phenotype and subsequently switches it to the anti-inflammatory M2 phenotype","volume":"8","author":"Refai","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2007.03476.x","article-title":"Reduced apoptosis and increased inflammatory cytokines in granulomas caused by tuberculous compared to non-tuberculous mycobacteria: role of mpt64 antigen in apoptosis and immune response","volume":"150","author":"Mustafa","year":"2007","journal-title":"Clin Exp Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00354-19","article-title":"Screening mycobacterium tuberculosis secreted proteins identifies mpt64 as a eukaryotic membrane-binding bacterial effector","volume":"4","author":"Stamm","year":"2019","journal-title":"mSphere"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3109\/00365548.2014.982167","article-title":"Latency-associated protein rv2660c of mycobacterium tuberculosis augments expression of proinflammatory cytokines in human macrophages by interacting with tlr2","volume":"47","author":"Yihao","year":"2015","journal-title":"Infect Dis (Lond)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1128\/iai.02086-05","article-title":"High frequency of cd4+ T cells specific for the tb10.4 protein correlates with protection against mycobacterium tuberculosis infection","volume":"74","author":"Hervas-Stubbs","year":"2006","journal-title":"Infect Immun"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/iai.74.2.861-868.2006","article-title":"Deletion of the mycobacterium tuberculosis alpha-crystallin-like hspx gene causes increased bacterial growth in vivo","volume":"74","author":"Hu","year":"2006","journal-title":"Infect Immun"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/s41541-019-0148-y","article-title":"Identification of antigens presented by mhc for vaccines against tuberculosis","volume":"5","author":"Bettencourt","year":"2020","journal-title":"NPJ Vaccines"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2016.70","article-title":"Subunit vaccine H56\/caf01 induces a population of circulating cd4 T cells that traffic into the mycobacterium tuberculosis-infected lung","volume":"10","author":"Woodworth","year":"2017","journal-title":"Mucosal Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2285","article-title":"A Multistage Tuberculosis Vaccine That Confers Efficient Protection before and after Exposure","volume":"17","author":"Aagaard","year":"2011","journal-title":"Nat Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines9111273","article-title":"Enhancement of the local cd8(+) T-cellular immune response to mycobacterium tuberculosis in bcg-primed mice after intranasal administration of influenza vector vaccine carrying tb10.4 and hspx antigens","volume":"9","author":"Vasilyev","year":"2021","journal-title":"Vaccines (Basel)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3390\/vaccines9040394","article-title":"Mucosal influenza vector vaccine carrying tb10.4 and hspx antigens provides protection against mycobacterium tuberculosis in mice and Guinea pigs","volume":"9","author":"Sergeeva","year":"2021","journal-title":"Vaccines"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00267-10","article-title":"Surface expression of mpt64 as a fusion with the pe domain of pe_Pgrs33 enhances mycobacterium bovis bcg protective activity against mycobacterium tuberculosis in mice","volume":"78","author":"Sali","year":"2010","journal-title":"Infect Immun"},{"key":"B41","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/978-3-540-30220-9_16","article-title":"Bcepred: prediction of continuous B-cell epitopes in antigenic sequences using physico-chemical properties","author":"Saha","year":"2004","journal-title":"Artif Immune Syst"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx346","article-title":"Bepipred-2.0: improving sequence-based B-cell epitope prediction using conformational epitopes","volume":"45","author":"Jespersen","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21078","article-title":"Prediction of continuous B-cell epitopes in an antigen using recurrent neural network","volume":"65","author":"Saha","year":"2006","journal-title":"Proteins"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2010.03268.x","article-title":"Mhc class ii epitope predictive algorithms","volume":"130","author":"Nielsen","year":"2010","journal-title":"Immunology"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn254","article-title":"Immune epitope database analysis resource (Iedb-ar)","volume":"36","author":"Zhang","year":"2008","journal-title":"Nucleic Acids Res"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1186\/1745-6150-8-30","article-title":"Designing of interferon-gamma inducing mhc class-ii binders","volume":"8","author":"Dhanda","year":"2013","journal-title":"Biol Direct"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60327-118-9_14","article-title":"Application of machine learning techniques in predicting mhc binders","volume":"409","author":"Lata","year":"2007","journal-title":"Methods Mol Biol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-015-0490-8","article-title":"Cd8 T cells and mycobacterium tuberculosis infection","volume":"37","author":"Lin","year":"2015","journal-title":"Semin Immunopathol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00350","article-title":"Immune response to mycobacterium tuberculosis: A narrative review","volume":"7","author":"de Martino","year":"2019","journal-title":"Front Pediatr"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-8-424","article-title":"Large-scale validation of methods for cytotoxic T-lymphocyte epitope prediction","volume":"8","author":"Larsen","year":"2007","journal-title":"BMC Bioinf"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200425811","article-title":"An integrative approach to ctl epitope prediction: A combined algorithm integrating mhc class I binding, tap transport efficiency, and proteasomal cleavage predictions","volume":"35","author":"Larsen","year":"2005","journal-title":"Eur J Immunol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1038\/s41598-020-80899-6","article-title":"In silico analysis of epitope-based vaccine candidate against tuberculosis using reverse vaccinology","volume":"11","author":"Bibi","year":"2021","journal-title":"Sci Rep"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4690","article-title":"Targeting dnan for tuberculosis therapy using novel griselimycins","volume":"348","author":"Kling","year":"2015","journal-title":"Science"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702130104","article-title":"Human -defensin-3 activates professional antigen-presenting cells via toll-like receptors 1 and 2","volume":"104","author":"Funderburg","year":"2007","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B55","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1093\/intimm\/12.5.691","article-title":"Defensins act as potent adjuvants that promote cellular and humoral immune responses in mice to a lymphoma idiotype and carrier antigens","volume":"12","author":"Tani","year":"2000","journal-title":"Int Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0104351","article-title":"A potential protein adjuvant derived from mycobacterium tuberculosis rv0652 enhances dendritic cells-based tumor immunotherapy","volume":"9","author":"Lee","year":"2014","journal-title":"PLoS One"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/263952","article-title":"Prediction of il4 inducing peptides","volume":"2013","author":"Dhanda","year":"2013","journal-title":"Clin Dev Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-3239-0_22","article-title":"A web-based method for the identification of il6-based immunotoxicity in vaccine candidates","volume":"2673","author":"Dhall","year":"2023","journal-title":"Methods Mol Biol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaa259","article-title":"Computer-aided prediction and design of il-6 inducing peptides: il-6 plays a crucial role in Covid-19","volume":"22","author":"Dhall","year":"2020","journal-title":"Briefings Bioinf"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/srep42851","article-title":"Computer-aided designing of immunosuppressive peptides based on il-10 inducing potential","volume":"7","author":"Nagpal","year":"2017","journal-title":"Sci Rep"},{"key":"B61","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/s43141-022-00411-7","article-title":"In silico designing of a recombinant multi-epitope antigen for leprosy diagnosis","volume":"20","author":"Lemes","year":"2022","journal-title":"J Genet Eng Biotechnol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1007\/s40203-021-00098-7","article-title":"Prediction and identification of T cell epitopes of covid-19 with balanced cytokine response for the development of peptide based vaccines","volume":"9","author":"Medha","year":"2021","journal-title":"In Silico Pharmacol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-8-4","article-title":"Vaxijen: A server for prediction of protective antigens, tumour antigens and subunit vaccines","volume":"8","author":"Doytchinova","year":"2007","journal-title":"BMC Bioinf"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq551","article-title":"High-throughput prediction of protein antigenicity using protein microarray data","volume":"26","author":"Magnan","year":"2010","journal-title":"Bioinformatics"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0073957","article-title":"In silico approach for predicting toxicity of peptides and proteins","volume":"8","author":"Gupta","year":"2013","journal-title":"PLoS One"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt619","article-title":"Allergenfp: allergenicity prediction by descriptor fingerprints","volume":"30","author":"Dimitrov","year":"2014","journal-title":"Bioinformatics"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx345","article-title":"Protein-sol: A web tool for predicting protein solubility from sequence","volume":"33","author":"Hebditch","year":"2017","journal-title":"Bioinf (Oxford England)"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/16.4.404","article-title":"The psipred protein structure prediction server","volume":"16","author":"McGuffin","year":"2000","journal-title":"Bioinformatics"},{"key":"B69","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nmeth.3213","article-title":"The I-tasser suite: protein structure and function prediction","volume":"12","author":"Yang","year":"2015","journal-title":"Nat Methods"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt458","article-title":"Galaxyrefine: protein structure refinement driven by side-chain repacking","volume":"41","author":"Heo","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B71","article-title":"Rampage","year":""},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10286","article-title":"Structure validation by C\u03b1 Geometry: \u03d5,\u03a8 and C\u03b2 Deviation","volume":"50","author":"Lovell","year":"2003","journal-title":"Proteins: Structure Function Bioinf"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-514","article-title":"Ellipro: A new structure-based tool for the prediction of antibody epitopes","volume":"9","author":"Ponomarenko","year":"2008","journal-title":"BMC Bioinf"},{"key":"B74","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s10989-021-10348-z","article-title":"In silico design and characterization of multi-epitopes vaccine for sars-cov2 from its spike protein","volume":"28","author":"Kathwate","year":"2022","journal-title":"Int J Pept Res Ther"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2015.09.014","article-title":"The haddock2.2 web server: user-friendly integrative modeling of biomolecular complexes","volume":"428","author":"van Zundert","year":"2016","journal-title":"J Mol Biol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku339","article-title":"Imods: internal coordinates normal mode analysis server","volume":"42","author":"L\u00f3pez-Blanco","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki376","article-title":"Jcat: A novel tool to adapt codon usage of a target gene to its potential expression host","volume":"33","author":"Grote","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2020.1770127","article-title":"Design of Multi-Epitope Vaccine Candidate against Sars-Cov-2: A in-Silico Study","volume":"39","author":"Abraham Peele","year":"2021","journal-title":"J Biomol Struct Dyn"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009862","article-title":"Computational immunology meets bioinformatics: the use of prediction tools for molecular binding in the simulation of the immune system","volume":"5","author":"Rapin","year":"2010","journal-title":"PLoS One"},{"key":"B80","doi-asserted-by":"publisher","first-page":"3504","DOI":"10.1038\/s41598-023-30445-x","article-title":"In silico design of a polypeptide as a vaccine candidate against ascariasis","volume":"13","author":"Evangelista","year":"2023","journal-title":"Sci Rep"},{"key":"B81","doi-asserted-by":"publisher","first-page":"75","DOI":"10.7774\/cevr.2016.5.1.75","article-title":"In silico analysis of brucella abortus omp2b and in vitro expression of somp2b","volume":"5","author":"Golshani","year":"2016","journal-title":"Clin Exp Vaccine Res"},{"key":"B82","doi-asserted-by":"publisher","first-page":"3155","DOI":"10.1038\/s41467-022-30914-3","article-title":"Viral coinfection promotes tuberculosis immunopathogenesis by type I ifn signaling-dependent impediment of th1 cell pulmonary influx","volume":"13","author":"Kang","year":"2022","journal-title":"Nat Commun"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.866873","article-title":"Insight into novel anti-tuberculosis vaccines by using immunoinformatics approaches","volume":"13","author":"Khan","year":"2022","journal-title":"Front Microbiol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.947852","article-title":"In silico analysis of peptide-based biomarkers for the diagnosis and prevention of latent tuberculosis infection","volume":"13","author":"Cheng","year":"2022","journal-title":"Front Microbiol"},{"key":"B85","doi-asserted-by":"publisher","first-page":"1802242","DOI":"10.1183\/13993003.02242-2018","article-title":"Il-4 subverts mycobacterial containment in mycobacterium tuberculosis-infected human macrophages","volume":"54","author":"Pooran","year":"2019","journal-title":"Eur Respir J"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2004.06.005","article-title":"Il-4 in tuberculosis: implications for vaccine design","volume":"25","author":"Rook","year":"2004","journal-title":"Trends Immunol"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2021.105166","article-title":"Cytokine storm in tuberculosis and il-6 involvement","volume":"97","author":"Boni","year":"2022","journal-title":"Infection Genet Evol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit037","article-title":"Role of interleukin 6 in innate immunity to mycobacterium tuberculosis infection","volume":"207","author":"Martinez","year":"2013","journal-title":"J Infect Dis"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181748","article-title":"Thpdb: database of fda-approved peptide and protein therapeutics","volume":"12","author":"Usmani","year":"2017","journal-title":"PLoS One"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1093\/database\/bay025","article-title":"Antitbpdb: A knowledgebase of anti-tubercular peptides","volume":"2018","author":"Usmani","year":"2018","journal-title":"Database (Oxford)"},{"key":"B91","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s12860-022-00437-2","article-title":"In silico prediction, characterization, docking studies and molecular dynamics simulation of human P97 in complex with P37 cofactor","volume":"23","author":"Mirzadeh","year":"2022","journal-title":"BMC Mol Cell Biol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4682-10-22","article-title":"Homology modeling and virtual screening approaches to identify potent inhibitors of veb-1 \u0392-lactamase","volume":"10","author":"Messaoudi","year":"2013","journal-title":"Theor Biol Med Model"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00461","article-title":"Toll-like receptor signaling pathways","volume":"5","author":"Kawasaki","year":"2014","journal-title":"Front Immunol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.6.3155","article-title":"Toll-like receptor 4 expression is required to control chronic mycobacterium tuberculosis infection in mice","volume":"169","author":"Abel","year":"2002","journal-title":"J Immunol"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-2600(18)30077-8","article-title":"Safety and immunogenicity of the novel tuberculosis vaccine id93\u2008+\u2008Gla-se in bcg-vaccinated healthy adults in South Africa: A randomised, double-blind, placebo-controlled phase 1 trial","volume":"6","author":"Penn-Nicholson","year":"2018","journal-title":"Lancet Respir Med"},{"key":"B96","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1007\/s00894-023-05570-z","article-title":"In silico analysis and molecular docking studies of natural compounds of withania somnifera against bovine nlrp9","volume":"29","author":"Ali","year":"2023","journal-title":"J Mol Modeling"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1007\/s11030-022-10515-4","article-title":"Modeling of mt. P495, an mrna-based vaccine against the phosphate-binding protein psts1 of mycobacterium tuberculosis","volume":"27","author":"Shahrear","year":"2023","journal-title":"Mol Divers"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11030525","article-title":"Cell surface fibroblast activation protein-2 (Fap2) of fusobacterium nucleatum as a vaccine candidate for therapeutic intervention of human colorectal cancer: an immunoinformatics approach","volume":"11","author":"Padma","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.109639","article-title":"Reverse vaccinology assisted design of a novel multi-epitope vaccine to target wuchereria bancrofti cystatin: an immunoinformatics approach","volume":"115","author":"Das","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1007\/s13596-020-00523-w","article-title":"In silico molecular docking and molecular dynamic simulation of potential inhibitors of 3c-like main proteinase (3clpro) from severe acute respiratory syndrome coronavirus-2 (Sars-Cov-2) using selected African medicinal plants","volume":"22","author":"Isa","year":"2022","journal-title":"Adv Traditional Med"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2020.03.020","article-title":"Predicting protein functional motions: an old recipe with a new twist","volume":"118","author":"Grudinin","year":"2020","journal-title":"Biophys J"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.3390\/biology11020246","article-title":"The role of tlr2 in infectious diseases caused by mycobacteria: from cell biology to therapeutic target","volume":"11","author":"Hu","year":"2022","journal-title":"Biol (Basel)"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2014.01.015","article-title":"Tlr3 regulates mycobacterial rna-induced il-10 production through the pi3k\/akt signaling pathway","volume":"26","author":"Bai","year":"2014","journal-title":"Cell Signalling"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2017.02.021","article-title":"Tlr2 contributes to trigger immune response of pleural mesothelial cells against mycobacterium bovis bcg and M","volume":"95","author":"Hwanga","year":"2017","journal-title":"Tuberculosis Infection. Cytokine"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-023-01510-8","article-title":"Prediction of protein solubility based on sequence physicochemical patterns and distributed representation information with deepsolue","volume":"21","author":"Wang","year":"2023","journal-title":"BMC Biol"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.909011","article-title":"Pathogenesis of Sars-Cov-2 and mycobacterium tuberculosis coinfection","volume":"13","author":"Shah","year":"2022","journal-title":"Front Immunol"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2020.102452","article-title":"Can we use interleukin-6 (Il-6) blockade for coronavirus disease 2019 (Covid-19)-induced cytokine release syndrome (Crs)","volume":"111","author":"Liu","year":"2020","journal-title":"J Autoimmun"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2020.00189","article-title":"Severe Covid-19: A review of recent progress with a look toward the future","volume":"8","author":"Xie","year":"2020","journal-title":"Front Public Health"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.3390\/jpm13010116","article-title":"Immunoinformatic-based multi-epitope vaccine design for co-infection of mycobacterium tuberculosis and Sars-Cov-2","volume":"13","author":"Peng","year":"2023","journal-title":"J Pers Med"},{"key":"B110","doi-asserted-by":"publisher","first-page":"2859","DOI":"10.1016\/j.immuni.2021.10.017","article-title":"Vaccination in a humanized mouse model elicits highly protective pfcsp-targeting anti-malarial antibodies","volume":"54","author":"Kratochvil","year":"2021","journal-title":"Immunity"},{"key":"B111","doi-asserted-by":"publisher","first-page":"8285","DOI":"10.1038\/s41598-017-08842-w","article-title":"Exploring leishmania secretory proteins to design B and T cell multi-epitope subunit vaccine using immunoinformatics approach","volume":"7","author":"Khatoon","year":"2017","journal-title":"Sci Rep"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2020.1850357","article-title":"Design of a multi-epitope-based vaccine targeting M-protein of Sars-Cov2: an immunoinformatics approach","volume":"40","author":"Ayyagari","year":"2022","journal-title":"J Biomol Struct Dyn"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1159\/000445059","article-title":"Design and evaluation of a multi-epitope peptide of human metapneumovirus","volume":"58","author":"Li","year":"2015","journal-title":"Intervirology"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/14.8.529","article-title":"Design of the linkers which effectively separate domains of a bifunctional fusion protein","volume":"14","author":"Arai","year":"2001","journal-title":"Protein Eng"},{"key":"B115","doi-asserted-by":"publisher","first-page":"15431","DOI":"10.1038\/s41598-021-92176-1","article-title":"Designing a multi-epitope vaccine candidate to combat mers-cov by employing an immunoinformatics approach","volume":"11","author":"Mahmud","year":"2021","journal-title":"Sci Rep"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1016\/j.mex.2023.102226","article-title":"Gud-ve visualization tool for physicochemical properties of proteins","volume":"10","author":"Chauhan","year":"2023","journal-title":"MethodsX"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2017.02.007","article-title":"A novel design of a multi-antigenic, multistage and multi-epitope vaccine against helicobacter pylori: an in silico approach","volume":"49","author":"Meza","year":"2017","journal-title":"Infect Genet Evol"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2022.105237","article-title":"Designing efficient multi-epitope peptide-based vaccine by targeting the antioxidant thioredoxin of bancroftian filarial parasite","volume":"98","author":"Gorai","year":"2022","journal-title":"Infect Genet Evol"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00316","article-title":"A comparative review of toll-like receptor 4 expression and functionality in different animal species","volume":"5","author":"Vaure","year":"2014","journal-title":"Front Immunol"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00163-y","article-title":"Emerging concepts in the science of vaccine adjuvants","volume":"20","author":"Pulendran B","year":"2021","journal-title":"Nat Rev Drug Discovery"},{"key":"B121","unstructured":"The Pipeline of Tuberculosis Vaccines\n          \n          \n            \n              Holleman\n              M\n            \n          \n          \n          2024"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.18609\/vac\/2022.027","article-title":"The quest for vaccine-induced immune correlates of protection against tuberculosis","volume":"1","author":"Nemes","year":"2022","journal-title":"Vaccine Insights"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.666290","article-title":"Peptides-based vaccine mp3rt induced protective immunity against mycobacterium tuberculosis infection in a humanized mouse model","volume":"12","author":"Gong","year":"2021","journal-title":"Front Immunol"},{"key":"B124","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1038\/s41598-017-01372-5","article-title":"A humanized mouse model identifies key amino acids for low immunogenicity of H7n9 vaccines","volume":"7","author":"Wada","year":"2017","journal-title":"Sci Rep"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.0c01434","article-title":"Catalytic mechanism of processive glft2: transition path sampling investigation of substrate translocation","volume":"5","author":"Jano\u0161","year":"2020","journal-title":"ACS Omega"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1474346\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T06:12:12Z","timestamp":1731910332000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1474346\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,18]]},"references-count":125,"alternative-id":["10.3389\/fimmu.2024.1474346"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1474346","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,18]]},"article-number":"1474346"}}