{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:07:20Z","timestamp":1790690840959,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["115760"],"award-info":[{"award-number":["115760"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Compared to free antigens, antigens immobilized on scaffolds, such as nanoparticles, generally show improved immunogenicity. Conventionally, antigens are conjugated to scaffolds through genetic fusion or chemical conjugation, which may result in impaired assembly or heterogeneous binding and orientation of the antigens. By combining two emerging technologies\u2014i.e., self-assembling multimeric protein scaffold particles (MPSPs) and bacterial superglue\u2014these shortcomings can be overcome and antigens can be bound on particles in their native conformation. In the present work, we assessed whether this technology could improve the immunogenicity of a candidate subunit vaccine against the zoonotic Rift Valley fever virus (RVFV). For this, the head domain of glycoprotein Gn, a known target of neutralizing antibodies, was coupled on various MPSPs to further assess immunogenicity and efficacy in vivo. The results showed that the Gn head domain, when bound to the lumazine synthase-based MPSP, reduced mortality in a lethal mouse model and protected lambs, the most susceptible RVFV target animals, from viremia and clinical signs after immunization. Furthermore, the same subunit coupled to two other MPSPs (Geobacillus stearothermophilus E2 or a modified KDPG Aldolase) provided full protection in lambs as well.<\/jats:p>","DOI":"10.3390\/vaccines9030301","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T23:59:41Z","timestamp":1616543981000},"page":"301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Vaccine Efficacy of Self-Assembled Multimeric Protein Scaffold Particles Displaying the Glycoprotein Gn Head Domain of Rift Valley Fever Virus"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9790-2438","authenticated-orcid":false,"given":"Paul J.","family":"Wichgers Schreur","sequence":"first","affiliation":[{"name":"Department of Virology, Wageningen Bioveterinary Research, 8221 RA Lelystad, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirriam","family":"Tacken","sequence":"additional","affiliation":[{"name":"Department of Virology, Wageningen Bioveterinary Research, 8221 RA Lelystad, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Gutjahr","sequence":"additional","affiliation":[{"name":"Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3229-8377","authenticated-orcid":false,"given":"Markus","family":"Keller","sequence":"additional","affiliation":[{"name":"Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucien","family":"van Keulen","sequence":"additional","affiliation":[{"name":"Department of Virology, Wageningen Bioveterinary Research, 8221 RA Lelystad, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jet","family":"Kant","sequence":"additional","affiliation":[{"name":"Department of Virology, Wageningen Bioveterinary Research, 8221 RA Lelystad, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"van de Water","sequence":"additional","affiliation":[{"name":"Department of Virology, Wageningen Bioveterinary Research, 8221 RA Lelystad, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Virology, Wageningen Bioveterinary Research, 8221 RA Lelystad, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1197-8288","authenticated-orcid":false,"given":"Martin","family":"Eiden","sequence":"additional","affiliation":[{"name":"Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Rissmann","sequence":"additional","affiliation":[{"name":"Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicitas","family":"von Arnim","sequence":"additional","affiliation":[{"name":"Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Brix","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Veterinary Research Center GmbH &amp; Co. KG, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Charreyre","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim, 69007 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Christophe","family":"Audonnet","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim, 69007 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0215-185X","authenticated-orcid":false,"given":"Martin H.","family":"Groschup","sequence":"additional","affiliation":[{"name":"Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0329-0176","authenticated-orcid":false,"given":"Jeroen","family":"Kortekaas","sequence":"additional","affiliation":[{"name":"Department of Virology, Wageningen Bioveterinary Research, 8221 RA Lelystad, The Netherlands"},{"name":"Laboratory of Virology, Wageningen University and Research, 6708 PB Wageningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.3389\/fimmu.2018.02224","article-title":"Nanoparticle Vaccines Against Infectious Diseases","volume":"9","author":"Pati","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Butkovich, N., Li, E., Ramirez, A., Burkhardt, A.M., and Wang, S.W. (2020). Advancements in protein nanoparticle vaccine platforms to combat infectious disease. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., e1681.","DOI":"10.1002\/wnan.1681"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kelly, H.G., Tan, H.X., Juno, J.A., Esterbauer, R., Ju, Y., Jiang, W., Wimmer, V.C., Duckworth, B.C., Groom, J.R., and Caruso, F. (2020). Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation. JCI Insight, 5.","DOI":"10.1172\/jci.insight.136653"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nature12202","article-title":"Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies","volume":"499","author":"Kanekiyo","year":"2013","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.cell.2019.01.046","article-title":"Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus","volume":"176","author":"Marcandalli","year":"2019","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0140-6736(15)60721-8","article-title":"Efficacy and safety of RTS,S\/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: Final results of a phase 3, individually randomised, controlled trial","volume":"386","author":"Rts","year":"2015","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e00494","DOI":"10.1016\/j.btre.2020.e00494","article-title":"Second career of a biosynthetic enzyme: Lumazine synthase as a virus-like nanoparticle in vaccine development","volume":"27","author":"Ladenstein","year":"2020","journal-title":"Biotechnol. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.virol.2010.08.026","article-title":"HIV-1 Gag p17 presented as virus-like particles on the E2 scaffold from Geobacillus stearothermophilus induces sustained humoral and cellular immune responses in the absence of IFNgamma production by CD4+ T cells","volume":"407","author":"Caivano","year":"2010","journal-title":"Virology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/nature18010","article-title":"Design of a hyperstable 60-subunit protein dodecahedron","volume":"535","author":"Hsia","year":"2016","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.tibtech.2014.08.001","article-title":"Superglue from bacteria: Unbreakable bridges for protein nanotechnology","volume":"32","author":"Veggiani","year":"2014","journal-title":"Trends Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E690","DOI":"10.1073\/pnas.1115485109","article-title":"Peptide tag forming a rapid covalent bond to a protein, through engineering a bacterial adhesin","volume":"109","author":"Zakeri","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.3389\/fimmu.2018.01432","article-title":"New Routes and Opportunities for Modular Construction of Particulate Vaccines: Stick, Click, and Glue","volume":"9","author":"Brune","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wuerth, J.D., and Weber, F. (2016). Phleboviruses and the Type I Interferon Response. Viruses, 8.","DOI":"10.3390\/v8060174"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1038\/emi.2014.71","article-title":"The Rift Valley fever accessory proteins NSm and P78\/NSm-GN are distinct determinants of virus propagation in vertebrate and invertebrate hosts","volume":"3","author":"Kreher","year":"2014","journal-title":"Emerg. Microbes Infect."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kading, R.C., Crabtree, M.B., Bird, B.H., Nichol, S.T., Erickson, B.R., Horiuchi, K., Biggerstaff, B.J., and Miller, B.R. (2014). Deletion of the NSm virulence gene of Rift Valley fever virus inhibits virus replication in and dissemination from the midgut of Aedes aegypti mosquitoes. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0002670"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13335","DOI":"10.1128\/JVI.01238-07","article-title":"NSm protein of Rift Valley fever virus suppresses virus-induced apoptosis","volume":"81","author":"Won","year":"2007","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1128\/JVI.02192-12","article-title":"The C-terminal region of Rift Valley fever virus NSm protein targets the protein to the mitochondrial outer membrane and exerts antiapoptotic function","volume":"87","author":"Terasaki","year":"2013","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20617","DOI":"10.1038\/srep20617","article-title":"Chimpanzee Adenovirus Vaccine Provides Multispecies Protection against Rift Valley Fever","volume":"6","author":"Warimwe","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4394","DOI":"10.1016\/j.vaccine.2010.04.048","article-title":"Rift Valley fever virus immunity provided by a paramyxovirus vaccine vector","volume":"28","author":"Kortekaas","year":"2010","journal-title":"Vaccine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41467-017-02789-2","article-title":"Shielding and activation of a viral membrane fusion protein","volume":"9","author":"Halldorsson","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.1016\/j.vaccine.2012.03.027","article-title":"Efficacy of three candidate Rift Valley fever vaccines in sheep","volume":"30","author":"Kortekaas","year":"2012","journal-title":"Vaccine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2330","DOI":"10.1016\/j.vaccine.2009.12.062","article-title":"Rift Valley fever virus subunit vaccines confer complete protection against a lethal virus challenge","volume":"28","author":"Kortekaas","year":"2010","journal-title":"Vaccine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1089\/vbz.2012.1160","article-title":"Vertical transmission of Rift Valley fever virus without detectable maternal viremia","volume":"13","author":"Antonis","year":"2013","journal-title":"Vector Borne Zoonotic Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12622","DOI":"10.1128\/JVI.00841-11","article-title":"Creation of a nonspreading Rift Valley fever virus","volume":"85","author":"Kortekaas","year":"2011","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41541-020-00212-4","article-title":"Safety and efficacy of four-segmented Rift Valley fever virus in young sheep, goats and cattle","volume":"5","author":"Oreshkova","year":"2020","journal-title":"NPJ Vaccines"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/j.vaccine.2015.01.077","article-title":"Four-segmented Rift Valley fever virus induces sterile immunity in sheep after a single vaccination","volume":"33","author":"Kant","year":"2015","journal-title":"Vaccine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10883","DOI":"10.1128\/JVI.00961-14","article-title":"Creation of Rift Valley fever viruses with four-segmented genomes reveals flexibility in bunyavirus genome packaging","volume":"88","author":"Oreshkova","year":"2014","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1016\/j.vaccine.2010.01.001","article-title":"Intramuscular inoculation of calves with an experimental Newcastle disease virus-based vector vaccine elicits neutralizing antibodies against Rift Valley fever virus","volume":"28","author":"Kortekaas","year":"2010","journal-title":"Vaccine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e52716","DOI":"10.7554\/eLife.52716","article-title":"Multimeric single-domain antibody complexes protect against bunyavirus infections","volume":"9","author":"Harmsen","year":"2020","journal-title":"Elife"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E7564","DOI":"10.1073\/pnas.1705176114","article-title":"Structures of phlebovirus glycoprotein Gn and identification of a neutralizing antibody epitope","volume":"114","author":"Wu","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1016\/j.celrep.2018.12.001","article-title":"A Protective Monoclonal Antibody Targets a Site of Vulnerability on the Surface of Rift Valley Fever Virus","volume":"25","author":"Allen","year":"2018","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/s41564-019-0411-z","article-title":"Neutralization mechanism of human monoclonal antibodies against Rift Valley fever virus","volume":"4","author":"Wang","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"14663","DOI":"10.1038\/ncomms14663","article-title":"Structure and assembly of scalable porous protein cages","volume":"8","author":"Sasaki","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/nmeth.4461","article-title":"Achieving better-than-3-A resolution by single-particle cryo-EM at 200 keV","volume":"14","author":"Herzik","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1002\/bit.21988","article-title":"Thermostability and molecular encapsulation within an engineered caged protein scaffold","volume":"101","author":"Dalmau","year":"2008","journal-title":"Biotechnol. Bioeng."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jviromet.2017.06.001","article-title":"A novel highly sensitive, rapid and safe Rift Valley fever virus neutralization test","volume":"248","author":"Paweska","year":"2017","journal-title":"J. Virol. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1186\/s12936-016-1574-1","article-title":"Bacterial superglue generates a full-length circumsporozoite protein virus-like particle vaccine capable of inducing high and durable antibody responses","volume":"15","author":"Janitzek","year":"2016","journal-title":"Malar. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12951-016-0181-1","article-title":"Bacterial superglue enables easy development of efficient virus-like particle based vaccines","volume":"14","author":"Thrane","year":"2016","journal-title":"J. Nanobiotechnol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19234","DOI":"10.1038\/srep19234","article-title":"Plug-and-Display: Decoration of Virus-Like Particles via isopeptide bonds for modular immunization","volume":"6","author":"Brune","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/s41586-019-1250-z","article-title":"Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques","volume":"570","author":"Escolano","year":"2019","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.nano.2018.11.009","article-title":"Ferritin nanoparticle-based SpyTag\/SpyCatcher-enabled click vaccine for tumor immunotherapy","volume":"16","author":"Wang","year":"2019","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18149","DOI":"10.1038\/s41598-020-74949-2","article-title":"A platform incorporating trimeric antigens into self-assembling nanoparticles reveals SARS-CoV-2-spike nanoparticles to elicit substantially higher neutralizing responses than spike alone","volume":"10","author":"Zhang","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"860","DOI":"10.3389\/fimmu.2019.00860","article-title":"A DNA Vaccine Encoding the Gn Ectodomain of Rift Valley Fever Virus Protects Mice via a Humoral Response Decreased by DEC205 Targeting","volume":"10","author":"Chrun","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bhardwaj, N., Heise, M.T., and Ross, T.M. (2010). Vaccination with DNA plasmids expressing Gn coupled to C3d or alphavirus replicons expressing gn protects mice against Rift Valley fever virus. PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000725"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gomes, A.C., Mohsen, M., and Bachmann, M.F. (2017). Harnessing Nanoparticles for Immunomodulation and Vaccines. Vaccines, 5.","DOI":"10.3390\/vaccines5010006"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1146\/annurev-immunol-041015-055254","article-title":"The Biology and Underlying Mechanisms of Cross-Presentation of Exogenous Antigens on MHC-I Molecules","volume":"35","author":"Cruz","year":"2017","journal-title":"Annu. Rev. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Hao, M., Zhang, G., Zhang, S., Chen, Z., Chi, X., Dong, Y., Fan, P., Liu, Y., Chen, Y., and Song, X. (2020). Characterization of Two Neutralizing Antibodies against Rift Valley Fever Virus Gn Protein. Viruses, 12.","DOI":"10.3390\/v12030259"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3109\/07388551.2014.923985","article-title":"Myceliophthora thermophila syn. Sporotrichum thermophile: A thermophilic mould of biotechnological potential","volume":"36","author":"Singh","year":"2016","journal-title":"Crit. Rev. Biotechnol."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/3\/301\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:39:35Z","timestamp":1760161175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/3\/301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,23]]},"references-count":48,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["vaccines9030301"],"URL":"https:\/\/doi.org\/10.3390\/vaccines9030301","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,23]]}}}