{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:37:04Z","timestamp":1791265024861,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T00:00:00Z","timestamp":1709942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shanghai Science and Technology Support Program, China","award":["21S11903200"],"award-info":[{"award-number":["21S11903200"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Compared with the traditional vaccine produced in embryonated chicken eggs, cell-based manufacturing represented by the Madin\u2013Darby canine kidney (MDCK) cell line has a larger production scale and reduces the risk of egg shortage in a pandemic. Establishing a culture system that enables high production of the influenza virus is a key issue in influenza vaccine production. Here, a serum-free suspension culture of MDCK (sMDCK) cells was obtained from adherent MDCK (aMDCK) cells by direct adaptation. Viral infection experiments showed that viral yields of influenza A\/B virus in sMDCK cells were higher than in aMDCK cells. Transcriptome analysis revealed that numerous interferon-stimulated genes (ISGs) exhibited reduced expression in sMDCK cells. To further clarify the mechanism of high viral production in sMDCK cells, we demonstrated the antiviral role of RIG-I and IFIT3 in MDCK cells by knockdown and overexpression experiments. Furthermore, suppression of the JAK\/STAT pathway enhances the viral accumulation in aMDCK cells instead of sMDCK cells, suggesting the reduction in the JAK\/STAT pathway and ISGs promotes viral replication in sMDCK cells. Taken together, we elucidate the relationship between the host innate immune response and the high viral productive property of sMDCK cells, which helps optimize cell production processes and supports the production of cell-based influenza vaccines.<\/jats:p>","DOI":"10.3390\/vaccines12030287","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T06:05:30Z","timestamp":1710137130000},"page":"287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Reduction in Interferon-Stimulated Genes Contributes to High-Yield Production of Influenza Virus in Suspension MDCK Cells"],"prefix":"10.3390","volume":"12","author":[{"given":"Qi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Virus and Vaccine, Shanghai Institute of Biological Products, Shanghai 200052, China"},{"name":"State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Virus and Vaccine, Shanghai Institute of Biological Products, Shanghai 200052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beibei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Virus and Vaccine, Shanghai Institute of Biological Products, Shanghai 200052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9310-1553","authenticated-orcid":false,"given":"Qian","family":"Ye","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Virus and Vaccine, Shanghai Institute of Biological Products, Shanghai 200052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feixia","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Virus and Vaccine, Shanghai Institute of Biological Products, Shanghai 200052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linting","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Virus and Vaccine, Shanghai Institute of Biological Products, Shanghai 200052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyue","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Virus and Vaccine, Shanghai Institute of Biological Products, Shanghai 200052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9857-4798","authenticated-orcid":false,"given":"Wen-Song","family":"Tan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuling","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Virus and Vaccine, Shanghai Institute of Biological Products, Shanghai 200052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1128\/CMR.00097-12","article-title":"Traditional and New Influenza Vaccines","volume":"26","author":"Wong","year":"2013","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1099\/jgv.0.000457","article-title":"Effects of egg-adaptation on receptor-binding and antigenic properties of recent influenza A (H3N2) vaccine viruses","volume":"97","author":"Parker","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.chom.2019.04.013","article-title":"Preventing an Antigenically Disruptive Mutation in Egg-Based H3N2 Seasonal Influenza Vaccines by Mutational Incompatibility","volume":"25","author":"Wu","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mili\u00e1n, E., and Kamen, A.A. (2015). Current and Emerging Cell Culture Manufacturing Technologies for Influenza Vaccines. BioMed Res. Int., 2015.","DOI":"10.1155\/2015\/504831"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"220","DOI":"10.4049\/jimmunol.1201060","article-title":"Toward Animal Cell Culture\u2013Based Influenza Vaccine Design: Viral Hemagglutinin N-Glycosylation Markedly Impacts Immunogenicity","volume":"190","author":"Seeberger","year":"2013","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S20","DOI":"10.1086\/514169","article-title":"Immunogenicity and Reactogenicity of Influenza Subunit Vaccines Produced in MDCK Cells or Fertilized Chicken Eggs","volume":"176","author":"Palache","year":"1997","journal-title":"J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2716","DOI":"10.1016\/S0264-410X(00)00508-9","article-title":"The human cell line PER.C6 provides a new manufacturing system for the production of influenza vaccines","volume":"19","author":"Pau","year":"2001","journal-title":"Vaccine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/S0264-410X(97)00301-0","article-title":"Development of a mammalian cell (Vero) derived candidate influenza virus vaccine","volume":"16","author":"Kistner","year":"1998","journal-title":"Vaccine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1083\/jcb.81.3.635","article-title":"Retention of differentiated properties in an established dog kidney epithelial cell line (MDCK)","volume":"81","author":"Rindler","year":"1979","journal-title":"J. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"C106","DOI":"10.1152\/ajpcell.1981.240.3.C106","article-title":"Growth and differentiated properties of a kidney epithelial cell line (MDCK)","volume":"240","author":"Saier","year":"1981","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3338","DOI":"10.1073\/pnas.76.7.3338","article-title":"Growth of Madin-Darby canine kidney epithelial cell (MDCK) line in hormone-supplemented, serum-free medium","volume":"76","author":"Taub","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4269","DOI":"10.1016\/j.vaccine.2015.02.077","article-title":"Monitoring changes in proteome during stepwise adaptation of a MDCK cell line from adherence to growth in suspension","volume":"33","author":"Kluge","year":"2015","journal-title":"Vaccine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jviromet.2010.09.029","article-title":"Adaptation of a Madin\u2013Darby canine kidney cell line to suspension growth in serum-free media and comparison of its ability to produce avian influenza virus to Vero and BHK21 cell lines","volume":"171","author":"Harmsen","year":"2011","journal-title":"J. Virol. Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14802","DOI":"10.1073\/pnas.0905912106","article-title":"Conversion of MDCK cell line to suspension culture by transfecting with human siat7e gene and its application for influenza virus production","volume":"106","author":"Chu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/j.vaccine.2013.11.044","article-title":"Production of high-titer human influenza A virus with adherent and suspension MDCK cells cultured in a single-use hollow fiber bioreactor","volume":"32","author":"Tapia","year":"2014","journal-title":"Vaccine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5693","DOI":"10.1016\/j.vaccine.2013.09.051","article-title":"Comparison of influenza virus yields and apoptosis-induction in an adherent and a suspension MDCK cell line","volume":"31","author":"Peschel","year":"2013","journal-title":"Vaccine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2770","DOI":"10.1016\/j.vaccine.2014.02.016","article-title":"High cell density cultivations by alternating tangential flow (ATF) perfusion for influenza A virus production using suspension cells","volume":"32","author":"Genzel","year":"2014","journal-title":"Vaccine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1002\/biot.201600384","article-title":"Ezrin and HNRNP expression correlate with increased virus release rate and early onset of virus-induced apoptosis of MDCK suspension cells","volume":"11","author":"Kluge","year":"2016","journal-title":"Biotechnol. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.coi.2016.05.016","article-title":"Standing on three legs: Antiviral activities of RIG-I against influenza viruses","volume":"42","author":"Weber","year":"2016","journal-title":"Curr. Opin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wang, Z., Ye, S., Yao, C., Wang, J., Mao, J., Xu, L., Liu, Y., Fu, C., Lu, G., and Li, S. (2021). Antiviral Activity of Canine RIG-I against Canine Influenza Virus and Interactions between Canine RIG-I and CIV. Viruses, 13.","DOI":"10.3390\/v13102048"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.tim.2014.12.003","article-title":"Mx GTPases: Dynamin-like antiviral machines of innate immunity","volume":"23","author":"Haller","year":"2015","journal-title":"Trends Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Pekosz, A., Khaperskyy, D.A., Emara, M.M., Johnston, B.P., Anderson, P., Hatchette, T.F., and McCormick, C. (2014). Influenza A Virus Host Shutoff Disables Antiviral Stress-Induced Translation Arrest. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004217"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4502","DOI":"10.1128\/MCB.24.10.4502-4512.2004","article-title":"TRAF Family Proteins Link PKR with NF-\u03baB Activation","volume":"24","author":"Gil","year":"2023","journal-title":"Mol. Cell. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nature10921","article-title":"IFITM3 restricts the morbidity and mortality associated with influenza","volume":"484","author":"Everitt","year":"2012","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"632798","DOI":"10.3389\/fimmu.2021.632798","article-title":"Comprehensive Transcriptomic Analysis Identifies Novel Antiviral Factors Against Influenza A Virus Infection","volume":"12","author":"Zhou","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e13989","DOI":"10.7717\/peerj.13989","article-title":"IRF7-deficient MDCK cell based on CRISPR\/Cas9 technology for enhancing influenza virus replication and improving vaccine production","volume":"10","author":"Mayuramart","year":"2022","journal-title":"PeerJ"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Qiao, Z., Liao, Y., Pei, M., Qiu, Z., Liu, Z., Jin, D., Zhang, J., Ma, Z., and Yang, X. (2022). RSAD2 Is an Effective Target for High-Yield Vaccine Production in MDCK Cells. Viruses, 14.","DOI":"10.3390\/v14112587"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ye, Q., Phan, T., Hu, W.-S., Liu, X., Fan, L., Tan, W.-S., and Zhao, L. (2021). Transcriptomic Characterization Reveals Attributes of High Influenza Virus Productivity in MDCK Cells. Viruses, 13.","DOI":"10.3390\/v13112200"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.biologicals.2007.10.002","article-title":"Monitoring influenza virus content in vaccine production: Precise assays for the quantitation of hemagglutination and neuraminidase activity","volume":"36","author":"Kalbfuss","year":"2008","journal-title":"Biologicals"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/btpr.539","article-title":"High-density microcarrier cell cultures for influenza virus production","volume":"27","author":"Bock","year":"2011","journal-title":"Biotechnol. Prog."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1093\/oxfordjournals.aje.a118408","article-title":"A Simple Method of Estimating Fifty PER Cent Endpoints12","volume":"27","author":"Reed","year":"1938","journal-title":"Am. J. Epidemiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9714","DOI":"10.1158\/0008-5472.CAN-05-4280","article-title":"Pyridone 6, A Pan-Janus\u2013Activated Kinase Inhibitor, Induces Growth Inhibition of Multiple Myeloma Cells","volume":"66","author":"Pedranzini","year":"2006","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: Tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkm882","article-title":"KEGG for linking genomes to life and the environment","volume":"36","author":"Kanehisa","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/nrmicro3346","article-title":"The sweet spot: Defining virus\u2013sialic acid interactions","volume":"12","author":"Reiss","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3109\/1040841X.2010.536523","article-title":"An overview of influenza A virus receptors","volume":"37","author":"Ge","year":"2011","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1073\/pnas.0607038104","article-title":"IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses","volume":"104","author":"Lenschow","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s00439-019-02092-8","article-title":"Mx genes: Host determinants controlling influenza virus infection and trans-species transmission","volume":"139","author":"Haller","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/35016611","article-title":"Gigantism in mice lacking suppressor of cytokine signalling-2","volume":"405","author":"Metcalf","year":"2000","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41419-019-1530-4","article-title":"MicroRNA-196a\/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK\/STAT pathway via targeting SOCS2","volume":"10","author":"Ren","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.bbrc.2010.11.104","article-title":"Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma","volume":"404","author":"Matsunaga","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hinay, A.A., Kakee, S., Kageyama, S., Tsuneki-Tokunaga, A., Perdana, W.Y., Akena, Y., Nishiyama, S., and Kanai, K. (2022). Pro-Inflammatory Cytokines and Interferon-Stimulated Gene Responses Induced by Seasonal Influenza A Virus with Varying Growth Capabilities in Human Lung Epithelial Cell Lines. Vaccines, 10.","DOI":"10.3390\/vaccines10091507"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/S0960-894X(02)00106-3","article-title":"Photochemical preparation of a pyridone containing tetracycle: A jak protein kinase inhibitor","volume":"12","author":"Thompson","year":"2002","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1146\/annurev.biochem.69.1.531","article-title":"Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin","volume":"69","author":"Skehel","year":"2000","journal-title":"Annu. Rev. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5311","DOI":"10.4049\/jimmunol.1103506","article-title":"Tripartite Motif-Containing Protein 38 Negatively Regulates TLR3\/4- and RIG-I\u2013Mediated IFN-\u03b2 Production and Antiviral Response by Targeting NAP1","volume":"188","author":"Zhao","year":"2012","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.bone.2018.05.009","article-title":"TRIM38 regulates NF-\u03baB activation through TAB2 degradation in osteoclast and osteoblast differentiation","volume":"113","author":"Kim","year":"2018","journal-title":"Bone"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1084\/jem.20161015","article-title":"Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5","volume":"214","author":"Hu","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chikhalya, A., Dittmann, M., Zheng, Y., Sohn, S.-Y., Rice, C.M., Hearing, P., and Shenk, T. (2021). Human IFIT3 Protein Induces Interferon Signaling and Inhibits Adenovirus Immediate Early Gene Expression. mBio, 12.","DOI":"10.1128\/mBio.02829-21"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Adamson, A.L., Hsu, Y.-L., Shi, S.-F., Wu, W.-L., Ho, L.-J., and Lai, J.-H. (2013). Protective Roles of Interferon-Induced Protein with Tetratricopeptide Repeats 3 (IFIT3) in Dengue Virus Infection of Human Lung Epithelial Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079518"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.4049\/jimmunol.1100963","article-title":"IFN-Induced TPR Protein IFIT3 Potentiates Antiviral Signaling by Bridging MAVS and TBK1","volume":"187","author":"Liu","year":"2011","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1099\/jgv.0.001149","article-title":"Better together: The role of IFIT protein\u2013protein interactions in the antiviral response","volume":"99","author":"Mears","year":"2018","journal-title":"J. Gen. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1038\/s41564-020-0778-x","article-title":"Influenza virus repurposes the antiviral protein IFIT2 to promote translation of viral mRNAs","volume":"5","author":"Tran","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.immuni.2012.03.013","article-title":"The JAK-STAT Pathway at Twenty","volume":"36","author":"Stark","year":"2012","journal-title":"Immunity"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type I interferon responses","volume":"14","author":"Ivashkiv","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"9880","DOI":"10.1128\/JVI.00909-08","article-title":"NF-\u03baB Signaling Differentially Regulates Influenza Virus RNA Synthesis","volume":"82","author":"Kumar","year":"2008","journal-title":"J. Virol."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/3\/287\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:11:23Z","timestamp":1760105483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/3\/287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,9]]},"references-count":56,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["vaccines12030287"],"URL":"https:\/\/doi.org\/10.3390\/vaccines12030287","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,9]]}}}