{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T23:12:50Z","timestamp":1776294770167,"version":"3.50.1"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,15]],"date-time":"2022-05-15T00:00:00Z","timestamp":1652572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shenzhen Science and Technology Program","award":["KQTD20200909113758004"],"award-info":[{"award-number":["KQTD20200909113758004"]}]},{"name":"Shenzhen Science and Technology Program","award":["2020KZDZX1181"],"award-info":[{"award-number":["2020KZDZX1181"]}]},{"name":"COVID-19 Prevention and Control Special Project of Guangdong Education Department","award":["KQTD20200909113758004"],"award-info":[{"award-number":["KQTD20200909113758004"]}]},{"name":"COVID-19 Prevention and Control Special Project of Guangdong Education Department","award":["2020KZDZX1181"],"award-info":[{"award-number":["2020KZDZX1181"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Despite the existence of various types of vaccines and the involvement of the world\u2019s leading pharmaceutical companies, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains the most challenging health threat in this century. Along with the increased transmissibility, new strains continue to emerge leading to the need for more vaccines that would elicit protectiveness and safety against the new strains of the virus. Nucleic acid vaccines seem to be the most effective approach in case of a sudden outbreak of infection or the emergence of a new strain as it requires less time than any conventional vaccine development. Hence, in the current study, a DNA vaccine encoding the trimeric prefusion-stabilized ectodomain (S1+S2) of SARS-CoV-2 S-protein was designed by introducing six additional prolines mutation, termed HexaPro. The three-dose regimen of designed DNA vaccine immunization in mice demonstrated the generation of protective antibodies.<\/jats:p>","DOI":"10.3390\/v14051049","type":"journal-article","created":{"date-parts":[[2022,5,15]],"date-time":"2022-05-15T09:48:22Z","timestamp":1652608102000},"page":"1049","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Development of DNA Vaccine Candidate against SARS-CoV-2"],"prefix":"10.3390","volume":"14","author":[{"given":"Xingyun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5982-8230","authenticated-orcid":false,"given":"Nino","family":"Rcheulishvili","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengfei","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nuo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengqi","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4793-2636","authenticated-orcid":false,"given":"Dimitri","family":"Papukashvili","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunjiao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3335-6794","authenticated-orcid":false,"given":"Peng George","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41591-020-0820-9","article-title":"The proximal origin of SARS-CoV-2","volume":"26","author":"Andersen","year":"2020","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105951","DOI":"10.1016\/j.ijantimicag.2020.105951","article-title":"Coronavirus disease 2019 (COVID-19): Current status and future perspectives","volume":"55","author":"Li","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/s41467-021-27668-9","article-title":"National identity predicts public health support during a global pandemic","volume":"13","author":"Cichocka","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathological findings of COVID-19 associated with acute respiratory distress syndrome","volume":"8","author":"Xu","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e039426","DOI":"10.1136\/bmjopen-2020-039426","article-title":"Impact of COVID-19 pandemic on mental health of young people and adults: A systematic review protocol of observational studies","volume":"10","author":"Sales","year":"2020","journal-title":"BMJ Open"},{"key":"ref_6","unstructured":"World Health Organization (WHO) (2022, April 09). COVID-19 Explorer. Available online: https:\/\/covid19.who.int\/."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.csbj.2020.12.033","article-title":"Novel coronavirus disease (COVID-19) pandemic: A recent mini review","volume":"19","author":"Rehman","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/S0140-6736(21)00947-8","article-title":"Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: An observational study using national surveillance data","volume":"397","author":"Haas","year":"2021","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3459","DOI":"10.2147\/IDR.S315727","article-title":"Overview of the main anti-Sars-CoV-2 vaccines: Mechanism of action, efficacy and safety","volume":"14","author":"Mascellino","year":"2021","journal-title":"Infect. Drug Resist."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100124","DOI":"10.1016\/j.metop.2021.100124","article-title":"COVID-19 vaccines: Current evidence and considerations","volume":"12","author":"Tavilani","year":"2021","journal-title":"Metab. Open"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41392-022-00950-y","article-title":"Advances in COVID-19 mRNA vaccine development","volume":"23","author":"Fang","year":"2022","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrd.2017.243","article-title":"mRNA vaccines-a new era in vaccinology","volume":"17","author":"Pardi","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"354","DOI":"10.3389\/fimmu.2013.00354","article-title":"Synthetic DNA vaccines: Improved vaccine potency by electroporation and co-delivered genetic adjuvants","volume":"4","author":"Flingai","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3390\/vaccines1030225","article-title":"Vector Design for Improved DNA Vaccine Efficacy, Safety and Production","volume":"1","author":"Williams","year":"2013","journal-title":"Vaccines"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2110817118","DOI":"10.1073\/pnas.2110817118","article-title":"An ultra-low-cost electroporator with microneedle electrodes (ePatch) for SARS-CoV-2 vaccination","volume":"118","author":"Xia","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1080\/14760584.2021.1987223","article-title":"DNA vaccines for SARS-CoV-2: Toward third-generation vaccination era","volume":"20","author":"Chavda","year":"2021","journal-title":"Expert Rev. Vaccines"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1038\/s41467-022-28882-9","article-title":"Cryo-EM structure of a SARS-CoV-2 omicron spike protein ectodomain","volume":"13","author":"Ye","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1126\/science.abd0826","article-title":"Structure-based design of prefusion-stabilized SARS-CoV-2 spikes","volume":"369","author":"Hsieh","year":"2020","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/all.15091","article-title":"Development and preclinical evaluation of virus-like particle vaccine against COVID-19 infection","volume":"77","author":"Yilmaz","year":"2022","journal-title":"Allergy Eur. J. Allergy Clin. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.chom.2020.11.012","article-title":"D614G Spike Mutation Increases SARS-CoV-2 Susceptibility to Neutralization","volume":"29","author":"Weissman","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"579250","DOI":"10.3389\/fimmu.2020.579250","article-title":"Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines","volume":"11","author":"Flanagan","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41577-020-00480-0","article-title":"Viral targets for vaccines against COVID-19","volume":"21","author":"Dai","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1080\/21645515.2015.1074363","article-title":"Intranasal vaccination of recombinant H5N1 HA1 proteins fused with foldon and Fc induces strong mucosal immune responses with neutralizing activity: Implication for developing novel mucosal influenza vaccines","volume":"11","author":"Yu","year":"2015","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1126\/science.abf2303","article-title":"Structural impact on SARS-CoV-2 spike protein by D614G substitution","volume":"372","author":"Zhang","year":"2021","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1126\/science.abc6284","article-title":"DNA vaccine protection against SARS-CoV-2 in rhesus macaques","volume":"369","author":"Yu","year":"2020","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3699","DOI":"10.1038\/s41596-020-0394-5","article-title":"Quantification of SARS-CoV-2 neutralizing antibody by a pseudotyped virus-based assay","volume":"15","author":"Nie","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1038\/s41467-020-16505-0","article-title":"Immunogenicity of a DNA vaccine candidate","volume":"11","author":"Smith","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.cmi.2021.10.005","article-title":"Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: A narrative review","volume":"28","author":"Fiolet","year":"2022","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ijid.2021.11.009","article-title":"Real-world effectiveness of COVID-19 vaccines: A literature review and meta-analysis","volume":"114","author":"Zheng","year":"2022","journal-title":"Int. J. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41591-021-01230-y","article-title":"Looking beyond COVID-19 vaccine phase 3 trials","volume":"27","author":"Kim","year":"2021","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10760296211056648","DOI":"10.1177\/10760296211056648","article-title":"An Update on the Status of Vaccine Development for SARS-CoV-2 Including Variants. Practical Considerations for COVID-19 Special Populations","volume":"28","author":"Kantarcioglu","year":"2022","journal-title":"Clin. Appl. Thromb Hemost."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s40249-021-00915-3","article-title":"Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: A systematic review and meta-analysis","volume":"10","author":"Liu","year":"2021","journal-title":"Infect. Dis. Poverty"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/s41573-021-00283-5","article-title":"mRNA vaccines for infectious diseases: Principles, delivery and clinical translation","volume":"20","author":"Chaudhary","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/d41586-021-02483-w","article-title":"The tangled history of mRNA vaccines","volume":"597","author":"Dolgin","year":"2021","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"633776","DOI":"10.3389\/fcell.2021.633776","article-title":"A Guide to Nucleic Acid Vaccines in the Prevention and Treatment of Infectious Diseases and Cancers: From Basic Principles to Current Applications","volume":"9","author":"Qin","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3390\/biologics1030020","article-title":"Nucleic Acid Vaccines for COVID-19: A Paradigm Shift in the Vaccine Development Arena","volume":"1","author":"Chavda","year":"2021","journal-title":"Biologics"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Liu, M.A. (2019). A Comparison of Plasmid DNA and mRNA as Vaccine Technologies. Vaccines, 7.","DOI":"10.3390\/vaccines7020037"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41541-021-00292-w","article-title":"SARS-CoV-2 vaccines strategies: A comprehensive review of phase 3 candidates","volume":"6","author":"Kyriakidis","year":"2021","journal-title":"NPJ Vaccines"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"718753","DOI":"10.3389\/fbioe.2021.718753","article-title":"Development and Delivery Systems of mRNA Vaccines","volume":"9","author":"Liang","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2217\/fvl-2021-0170","article-title":"A brief review on DNA vaccines in the era of","volume":"17","author":"Shafaati","year":"2022","journal-title":"Future Virol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hobernik, D., and Bros, M. (2018). DNA Vaccines\u2014How Far From Clinical Use?. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113605"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.actbio.2018.08.033","article-title":"Engineering DNA vaccines against infectious diseases","volume":"15","author":"Lee","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1089\/hum.2017.197","article-title":"Therapeutic DNA Vaccines for Human Papillomavirus and Associated Diseases","volume":"29","author":"Cheng","year":"2018","journal-title":"Hum. Gene Ther."},{"key":"ref_45","first-page":"776","article-title":"DNA vaccines: Ready for prime time? Nature Reviews","volume":"9","author":"Kutzler","year":"2008","journal-title":"Genetics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.3389\/fimmu.2018.01963","article-title":"New vaccine technologies to combat outbreak situations","volume":"9","author":"Rauch","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Sundaram, A.K., Ewing, D., Liang, Z., Jani, V., Cheng, Y., Sun, P., Raviprakash, K., Wu, S., Petrovsky, N., and Defang, G. (2021). Immunogenicity of Adjuvanted Psoralen-Inactivated SARS-CoV-2 Vaccines and SARS-CoV-2 Spike Protein DNA Vaccines in BALB\/c Mice. Pathogens, 10.","DOI":"10.3390\/pathogens10050626"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Alluhaybi, K.A., Alharbi, R.H., Alhabbab, R.Y., Aljehani, N.D., Alamri, S.S., Basabrain, M., Alharbi, R., Abdulaal, W.H., Alfaleh, M.A., and Tamming, L. (2021). Cellular and humoral immunogenicity of a candidate dna vaccine expressing SARS-CoV-2 spike subunit 1. Vaccines, 9.","DOI":"10.20944\/preprints202106.0650.v1"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s13567-019-0698-z","article-title":"Recent advances in delivery of veterinary DNA vaccines against avian pathogens","volume":"50","author":"Jazayeri","year":"2019","journal-title":"Vet. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/j.1600-065X.2010.00980.x","article-title":"DNA vaccines: An historical perspective and view to the future","volume":"239","author":"Liu","year":"2011","journal-title":"Immunol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1038\/d41587-021-00023-5","article-title":"First COVID-19 DNA vaccine approved, others in hot pursuit","volume":"39","author":"Sheridan","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"118919","DOI":"10.1016\/j.lfs.2020.118919","article-title":"DNA vaccines against COVID-19: Perspectives and challenges","volume":"267","author":"Silveira","year":"2021","journal-title":"Life Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ymthe.2021.09.011","article-title":"COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models","volume":"30","author":"Conforti","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Borgoyakova, M.B., Karpenko, L.I., Rudometov, A.P., Volosnikova, E.A., Merkuleva, I.A., Starostina, E.V., Zadorozhny, A.M., Isaeva, A.A., Nesmeyanova, V.S., and Shanshin, D.V. (2022). Self-Assembled Particles Combining SARS-CoV-2 RBD Protein and RBD DNA Vaccine Induce Synergistic Enhancement of the Humoral Response in Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042188"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"587269","DOI":"10.3389\/fcimb.2020.587269","article-title":"SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development","volume":"10","author":"Wang","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1126\/science.abc6952","article-title":"A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2","volume":"369","author":"Chi","year":"2020","journal-title":"Science"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/s41586-020-2180-5","article-title":"Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor","volume":"581","author":"Lan","year":"2020","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s41586-020-2380-z","article-title":"Human neutralizing antibodies elicited by SARS-CoV-2 infection","volume":"584","author":"Ju","year":"2020","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.cell.2020.09.032","article-title":"Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant","volume":"183","author":"Yurkovetskiy","year":"2020","journal-title":"Cell"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/5\/1049\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:10:58Z","timestamp":1760137858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/5\/1049"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,15]]},"references-count":59,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["v14051049"],"URL":"https:\/\/doi.org\/10.3390\/v14051049","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,15]]}}}