{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T14:31:21Z","timestamp":1772634681528,"version":"3.50.1"},"reference-count":63,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,4,12]],"date-time":"2018-04-12T00:00:00Z","timestamp":1523491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Vaccination against the seasonal influenza virus is the best way to prevent infection. Nevertheless, vaccine efficacy remains far from optimal especially in high-risk populations such as the elderly. Recent technological advancements have facilitated rapid and precise identification of the B and T cell epitopes that are targets for protective responses. While these discoveries have undoubtedly brought the field closer to \u201cuniversal\u201d influenza virus vaccines, choosing the correct antigen is only one piece of the equation. Achieving efficacy and durability requires a detailed understanding of the diverse host factors and pathways that are required for attaining optimal responses. Sequencing technologies, systems biology, and immunological studies have recently advanced our understanding of the diverse aspects of the host response required for vaccine efficacy. In this paper, we review the critical role of the host response in determining efficacious responses and discuss the gaps in knowledge that will need to be addressed if the field is to be successful in developing new and more effective influenza virus vaccines.<\/jats:p>","DOI":"10.3390\/vaccines6020023","type":"journal-article","created":{"date-parts":[[2018,4,12]],"date-time":"2018-04-12T12:19:27Z","timestamp":1523535567000},"page":"23","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["\u201cGnothi Seauton\u201d: Leveraging the Host Response to Improve Influenza Virus Vaccine Efficacy"],"prefix":"10.3390","volume":"6","author":[{"given":"Hannah","family":"Stacey","sequence":"first","affiliation":[{"name":"Michael G. DeGroote Institute for Infectious Diseases Research, McMaster Immunology Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neda","family":"Barjesteh","sequence":"additional","affiliation":[{"name":"Michael G. DeGroote Institute for Infectious Diseases Research, McMaster Immunology Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Mapletoft","sequence":"additional","affiliation":[{"name":"Michael G. DeGroote Institute for Infectious Diseases Research, McMaster Immunology Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3426-5069","authenticated-orcid":false,"given":"Matthew","family":"Miller","sequence":"additional","affiliation":[{"name":"Michael G. DeGroote Institute for Infectious Diseases Research, McMaster Immunology Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12283","DOI":"10.1073\/pnas.1400472111","article-title":"History of vaccination","volume":"111","author":"Plotkin","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Miller, M.S., and Palese, P. (2014). Peering into the crystal ball: Influenza pandemics and vaccine efficacy. Cell, 157.","DOI":"10.1016\/j.cell.2014.03.023"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.vaccine.2005.08.105","article-title":"Antibody response to influenza vaccination in the elderly: A quantitative review","volume":"24","author":"Goodwin","year":"2006","journal-title":"Vaccine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ijo.2011.208","article-title":"Obesity is associated with impaired immune response to influenza vaccination in humans","volume":"36","author":"Sheridan","year":"2012","journal-title":"Int. J. Obes."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.coviro.2016.02.002","article-title":"Novel universal influenza virus vaccine approaches","volume":"17","author":"Krammer","year":"2016","journal-title":"Curr. Opin. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"405","DOI":"10.4161\/hv.22908","article-title":"Correlates of protection to influenza virus, where do we go from here?","volume":"9","author":"Cox","year":"2013","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1096\/fj.11-190017","article-title":"Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice","volume":"26","author":"Cummins","year":"2012","journal-title":"FASEB J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1080\/21645515.2015.1119345","article-title":"Impact of host genetic polymorphisms on vaccine induced antibody response","volume":"12","author":"Linnik","year":"2016","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"D35","DOI":"10.1016\/j.vaccine.2008.07.065","article-title":"NIH Public Access","volume":"26","author":"Poland","year":"2008","journal-title":"Vaccine"},{"key":"ref_11","unstructured":"Talaat, K.R., Halsey, N.A., Cox, A.B., Coles, C.L., Durbin, A.P., Ramakrishnan, A., and Bream, J.H. (2017). Rapid changes in serum cytokines and chemokines in response to inactivated influenza vaccination. Influenza Other Respir. Viruses, 1\u20139."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Egli, A., Santer, D.M., O\u2019Shea, D., Barakat, K., Syedbasha, M., Vollmer, M., Baluch, A., Bhat, R., Groenendyk, J., and Joyce, M.A. (2014). IL-28B is a Key Regulator of B- and T-Cell Vaccine Responses against Influenza. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004556"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1093\/infdis\/jiw126","article-title":"Autoimmune Variant PTPN22 C1858T Is Associated with Impaired Responses to Influenza Vaccination","volume":"214","author":"Crabtree","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_14","first-page":"1","article-title":"Integrative genomic analysis of the human immune response to influenza vaccination","volume":"2013","author":"Franco","year":"2013","journal-title":"eLife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2165\/00129785-200404050-00002","article-title":"Human genetics and responses to influenza vaccination: Clinical implications","volume":"4","author":"Lambkin","year":"2004","journal-title":"Am. J. Pharmacogenom."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1086\/338014","article-title":"Associations between Human Leukocyte Antigens and Nonresponsiveness to Influenza Vaccine","volume":"185","author":"Gelder","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Moss, A.J., Gaughran, F.P., Karasu, A., Gilbert, A.S., Mann, A.J., Gelder, C.M., Oxford, J.S., Stephens, H.A., and Lambkin-Williams, R. (2013). Correlation between Human Leukocyte Antigen Class II Alleles and HAI Titers Detected Post-Influenza Vaccination. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071376"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1038\/ng1104-1133","article-title":"The Collaborative Cross, a community resource for the genetic analysis of complex traits","volume":"36","author":"Churchill","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e00171-11","DOI":"10.1128\/mBio.00171-11","article-title":"H5N1 influenza virus pathogenesis in genetically diverse mice is mediated at the level of viral load","volume":"2","author":"Boon","year":"2011","journal-title":"mBio"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1534\/g3.111.001800","article-title":"Expression Quantitative Trait Loci for Extreme Host Response to Influenza A in Pre-Collaborative Cross Mice","volume":"2","author":"Bottomly","year":"2012","journal-title":"G3: Genes|Genomes|Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ferris, M.T., Aylor, D.L., Bottomly, D., Whitmore, A.C., Aicher, L.D., Bell, T.A., Bradel-Tretheway, B., Bryan, J.T., Buus, R.J., and Gralinski, L.E. (2013). Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003196"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12864-016-2483-y","article-title":"Influenza H3N2 infection of the collaborative cross founder strains reveals highly divergent host responses and identifies a unique phenotype in CAST\/EiJ mice","volume":"17","author":"Leist","year":"2016","journal-title":"BMC Genom."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"26437","DOI":"10.1038\/srep26437","article-title":"Genetically diverse CC-founder mouse strains replicate the human influenza gene expression signature","volume":"6","author":"Elbahesh","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1016\/j.celrep.2017.10.093","article-title":"Extensive Homeostatic T Cell Phenotypic Variation within the Collaborative Cross","volume":"21","author":"Graham","year":"2017","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.immuni.2010.10.006","article-title":"Systems vaccinology","volume":"33","author":"Pulendran","year":"2010","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrd4529","article-title":"Advances in the development of influenza virus vaccines","volume":"14","author":"Krammer","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1750-2659.2008.00053.x","article-title":"FluBlok, a recombinant hemagglutinin influenza vaccine","volume":"2","author":"Cox","year":"2008","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S1473-3099(01)00016-0","article-title":"Yellow fever: An update","volume":"1","author":"Monath","year":"2001","journal-title":"Lancet Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/ni.1688","article-title":"Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans","volume":"10","author":"Querec","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/ni.2067","article-title":"Systems biology of vaccination for seasonal influenza in humans","volume":"12","author":"Nakaya","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1586\/erv.13.35","article-title":"Immunological assessment of influenza vaccines and immune correlates of protection","volume":"12","author":"Reber","year":"2013","journal-title":"Expert Rev. Vaccines"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.immuni.2014.08.009","article-title":"TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination","volume":"41","author":"Oh","year":"2014","journal-title":"Immunity"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hoek, K.L., Samir, P., Howard, L.M., Niu, X., Prasad, N., Galassie, A., Liu, Q., Allos, T.M., Floyd, K.A., and Guo, Y. (2015). A cell-based systems biology assessment of human blood to monitor immune responses after influenza vaccination. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0118528"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/ni.2789","article-title":"Molecular signatures of antibody responses derived from a systems biology study of five human vaccines","volume":"15","author":"Li","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.immuni.2012.12.008","article-title":"Systems scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines","volume":"38","author":"Obermoser","year":"2013","journal-title":"Immunity"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1073\/pnas.1321060111","article-title":"Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination","volume":"111","author":"Furman","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1146\/annurev-cellbio-100616-060718","article-title":"Sex and Gender Differences in the Outcomes of Vaccination over the Life Course","volume":"33","author":"Flanagan","year":"2017","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/ni.3328","article-title":"Adjuvanted influenza-H1N1 vaccination reveals lymphoid signatures of age-dependent early responses and of clinical adverse events","volume":"17","author":"Sobolev","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1073\/pnas.1519690113","article-title":"Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood","volume":"113","author":"Nakaya","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Howard, L.M., Hoek, K.L., Goll, J.B., Samir, P., Galassie, A., Allos, T.M., Niu, X., Gordy, L.E., Creech, C.B., and Prasad, N. (2017). Cell-based systems biology analysis of human AS03-adjuvanted H5N1 avian influenza vaccine responses: A phase i randomized controlled trial. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0167488"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.cell.2014.03.031","article-title":"Global analyses of human immune variation reveal baseline predictors of postvaccination responses","volume":"157","author":"Tsang","year":"2014","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3308","DOI":"10.1128\/JVI.02871-14","article-title":"High Preexisting Serological Antibody Levels Correlate with Diversification of the Influenza Vaccine Response","volume":"89","author":"Andrews","year":"2015","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1093\/infdis\/jix074","article-title":"Serial vaccination and the antigenic distance hypothesis: Effects on influenza vaccine effectiveness during A(H3N2) epidemics in Canada, 2010-2011 to 2014-2015","volume":"215","author":"Skowronski","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Miller, M.S., Gardner, T.J., Krammer, F., Aguado, L.C., Tortorella, D., Basler, C.F., and Palese, P. (2013). Neutralizing antibodies against previously encountered influenza virus strains increase over time: A longitudinal analysis. Sci. Transl. Med., 5.","DOI":"10.1126\/scitranslmed.3006637"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/3-540-32636-7_2","article-title":"Dendritic Cells: Translating Innate to Adaptive Immunity","volume":"311","author":"Hemmi","year":"2006","journal-title":"Curr. Top. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"320","DOI":"10.3390\/vaccines3020320","article-title":"Vaccine Adjuvants: From 1920 to 2015 and Beyond","volume":"3","author":"Pasquale","year":"2015","journal-title":"Vaccines"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Moser, M., and Leo, O. (2010). Key concepts in immunology. Vaccine, C2\u2013C13.","DOI":"10.1016\/j.vaccine.2010.07.022"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.cell.2006.02.019","article-title":"Translating innate immunity into immunological memory: Implications for vaccine development","volume":"124","author":"Pulendran","year":"2006","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/ni.2514","article-title":"IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8+ T cell responses to influenza A virus","volume":"14","author":"Pang","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1146\/annurev.immunol.18.1.767","article-title":"Immunobiology of dendritic cells","volume":"18","author":"Banchereau","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1016\/j.celrep.2017.02.026","article-title":"Macrophage Death following Influenza Vaccination Initiates the Inflammatory Response that Promotes Dendritic Cell Function in the Draining Lymph Node","volume":"18","author":"Chatziandreou","year":"2017","journal-title":"Cell Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8946","DOI":"10.1128\/JVI.01110-14","article-title":"Nucleotide Oligomerization and Binding Domain 2-Dependent Dendritic Cell Activation Is Necessary for Innate Immunity and Optimal CD8+ T Cell Responses to Influenza A Virus Infection","volume":"88","author":"Lupfer","year":"2014","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2014.00331","article-title":"Mucosal resident memory CD4 T cells in protection and immunopathology","volume":"5","author":"Turner","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nri.2015.3","article-title":"Tissue-resident memory T cells: Local specialists in immune defence","volume":"16","author":"Mueller","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/mi.2014.133","article-title":"Antibody-targeted vaccination to lung dendritic cells generates tissue-resident memory CD8 T cells that are highly protective against influenza virus infection","volume":"8","author":"Wakim","year":"2015","journal-title":"Mucosal Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Stoel, M., Pool, J., De Vries-Idema, J., Zaaraoui-Boutahar, F., Bijl, M., Andeweg, A.C., Wilschut, J., and Huckriede, A. (2015). Innate responses induced by whole inactivated virus or subunit influenza vaccines in cultured dendritic cells correlate with immune responses in vivo. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125228"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.4049\/jimmunol.1400222","article-title":"Mucosal Polyinosinic-Polycytidylic Acid Improves Protection Elicited by Replicating Influenza Vaccines via Enhanced Dendritic Cell Function and T Cell Immunity","volume":"193","author":"Hassan","year":"2014","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/S1473-3099(11)70295-X","article-title":"Efficacy and effectiveness of influenza vaccines: A systematic review and meta-analysis","volume":"12","author":"Osterholm","year":"2012","journal-title":"Lancet Infect. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wu, N.C., Zost, S.J., Thompson, A.J., Oyen, D., Nycholat, C.M., McBride, R., Paulson, J.C., Hensley, S.E., and Wilson, I.A. (2017). A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine. PLOS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006682"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Black, S., and Rappuoli, R. (2010). A crisis of public confidence in vaccines. Sci. Transl. Med., 2.","DOI":"10.1126\/scitranslmed.3001738"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/ni.2039","article-title":"Immunological mechanisms of vaccination","volume":"12","author":"Pulendran","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1038\/nm.3409","article-title":"Key roles of adjuvants in modern vaccines","volume":"19","author":"Reed","year":"2013","journal-title":"Nat. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"51","DOI":"10.4110\/in.2015.15.2.51","article-title":"Recent advances of vaccine adjuvants for infectious diseases","volume":"15","author":"Lee","year":"2015","journal-title":"Immune Netw."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/6\/2\/23\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:00:27Z","timestamp":1760194827000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/6\/2\/23"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,12]]},"references-count":63,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["vaccines6020023"],"URL":"https:\/\/doi.org\/10.3390\/vaccines6020023","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,12]]}}}