{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T22:29:31Z","timestamp":1787783371892,"version":"build-2784847793"},"reference-count":54,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["792494"],"award-info":[{"award-number":["792494"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003086","name":"Eusko Jaurlaritza","doi-asserted-by":"publisher","award":["Mathematical Modeling Applied to Health Project"],"award-info":[{"award-number":["Mathematical Modeling Applied to Health Project"]}],"id":[{"id":"10.13039\/501100003086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003086","name":"Eusko Jaurlaritza","doi-asserted-by":"publisher","award":["BERC  2018-2021"],"award-info":[{"award-number":["BERC  2018-2021"]}],"id":[{"id":"10.13039\/501100003086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["BCAM Severo Ochoa accreditation SEV-2017-0718"],"award-info":[{"award-number":["BCAM Severo Ochoa accreditation SEV-2017-0718"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Indonesian RistekDikti","award":["2018-2021"],"award-info":[{"award-number":["2018-2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Dengue fever is a viral mosquito-borne infection and a major international public health concern. With 2.5 billion people at risk of acquiring the infection around the world, disease severity is influenced by the immunological status of the individual, seronegative or seropositive, prior to natural infection. Caused by four antigenically related but distinct serotypes, DENV-1 to DENV-4, infection by one serotype confers life-long immunity to that serotype and a period of temporary cross-immunity (TCI) to other serotypes. The clinical response on exposure to a second serotype is complex with the so-called antibody-dependent enhancement (ADE) process, a disease augmentation phenomenon when pre-existing antibodies to previous dengue infection do not neutralize but rather enhance the new infection, used to explain the etiology of severe disease. In this paper, we present a minimalistic mathematical model framework developed to describe qualitatively the dengue immunological response mediated by antibodies. Three models are analyzed and compared: (i) primary dengue infection, (ii) secondary dengue infection with the same (homologous) dengue virus and (iii) secondary dengue infection with a different (heterologous) dengue virus. We explore the features of viral replication, antibody production and infection clearance over time. The model is developed based on body cells and free virus interactions resulting in infected cells activating antibody production. Our mathematical results are qualitatively similar to the ones described in the empiric immunology literature, providing insights into the immunopathogenesis of severe disease. Results presented here are of use for future research directions to evaluate the impact of dengue vaccines.<\/jats:p>","DOI":"10.3390\/biology10090941","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:04:23Z","timestamp":1632211463000},"page":"941","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Modeling Dengue Immune Responses Mediated by Antibodies: A Qualitative Study"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8764-0240","authenticated-orcid":false,"given":"Afrina Andriani","family":"Sebayang","sequence":"first","affiliation":[{"name":"Department of Mathematics, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7209-4670","authenticated-orcid":false,"given":"Hilda","family":"Fahlena","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0854-2050","authenticated-orcid":false,"given":"Vizda","family":"Anam","sequence":"additional","affiliation":[{"name":"Basque Centre for Applied Mathematics (BCAM), Alameda Mazarredo, 14, 48009 Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4477-5639","authenticated-orcid":false,"given":"Dami\u00e1n","family":"Knopoff","sequence":"additional","affiliation":[{"name":"Basque Centre for Applied Mathematics (BCAM), Alameda Mazarredo, 14, 48009 Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9315-5586","authenticated-orcid":false,"given":"Nico","family":"Stollenwerk","sequence":"additional","affiliation":[{"name":"Basque Centre for Applied Mathematics (BCAM), Alameda Mazarredo, 14, 48009 Bilbao, Spain"},{"name":"Dipartimento di Matematica, Universita degli Studi di Trento, Via Sommarive 14, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8354-9944","authenticated-orcid":false,"given":"Ma\u00edra","family":"Aguiar","sequence":"additional","affiliation":[{"name":"Basque Centre for Applied Mathematics (BCAM), Alameda Mazarredo, 14, 48009 Bilbao, Spain"},{"name":"Dipartimento di Matematica, Universita degli Studi di Trento, Via Sommarive 14, 38123 Trento, Italy"},{"name":"Ikerbasque, Basque Foundation for Science, Euskadi Plaza, 5, 48009 Bilbo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4972-3256","authenticated-orcid":false,"given":"Edy","family":"Soewono","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Institut Teknologi Bandung, Bandung 40132, Indonesia"},{"name":"Center for Mathematical Modeling and Simulation, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_2","first-page":"3","article-title":"Dengue hemorrhagic fever: Two infections and antibody-dependent enhancement, a brief history and personal memoir","volume":"54","author":"Halstead","year":"2002","journal-title":"Rev. Cuba. Med. Trop."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0065-3527(03)60011-4","article-title":"Neutralization and antibody-dependent enhancement of dengue viruses. Advances in Virus Research","volume":"60","author":"Halstead","year":"2003","journal-title":"Adv. Virus Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1172\/JCI21512","article-title":"Dengue: Defining protective versus pathologic immunity","volume":"113","author":"Rothman","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Clapham, H.E., Cummings, D.A.T., and Johansson, M.A. (2017). Immune status alters the probability of apparent illness due to dengue virus infection: Evidence from a pooled analysis across multiple cohort and cluster studies. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005926"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rothman, A. (2010). Cellular Immunology of Sequential Dengue Virus Infection and Its Role in Disease Pathogenesis, Springer. Dengue Virus. Current Topics in Microbiology and Immunology.","DOI":"10.1007\/978-3-642-02215-9"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/s41577-019-0123-x","article-title":"Adaptive immune responses to primary and secondary dengue virus infections","volume":"19","author":"Rathore","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1136\/pgmj.2004.019638","article-title":"Dengue Viral Infections","volume":"80","author":"Malavige","year":"2004","journal-title":"Postgrad Med. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"617","DOI":"10.15446\/revfacmed.v62n4.45593","article-title":"Dengue Disease diagnosis: A puzzle to be solved","volume":"62","author":"Castellanos","year":"2014","journal-title":"Rev. Fac. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"418","DOI":"10.4269\/ajtmh.1989.40.418","article-title":"An enzyme-linked immunosorbent assay to characterize dengue infections where dengue and Japanese encephalitis co-circulate","volume":"40","author":"Innis","year":"1989","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Pal, S., Dauner, A.L., Mitra, I., Forshey, B.M., Garcia, P., Morrison, A.C., and Wu, S.J.L. (2014). Evaluation of dengue NS1 antigen rapid tests and ELISA kits using clinical samples. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0113411"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Changal, K.H., Raina, A.H., Raina, A., Raina, M., Bashir, R., Latief, M., Mir, T., and Changal, Q.H. (2016). Differentiating secondary from primary dengue using IgG to IgM ratio in early dengue: An observation hospital bases clinico-serogical study from North India. BMC Infect. Dis., 16.","DOI":"10.1186\/s12879-016-2053-6"},{"key":"ref_13","unstructured":"Betts, J.G., Young, K.A., Wise, J.A., Johnson, E., Poe, B., Kruse, D.H., Korol, O., Johnson, J.E., Womble, M., and DeSaix, P. (2019). Anatomy and Physiology, OpenStax. Available online: https:\/\/opentextbc.ca\/anatomyandphysiologyopenstax\/chapter\/the-adaptive-immune-response-b-lymphocytes-and-antibodies\/."},{"key":"ref_14","unstructured":"Sathe, A., and Cusick, J.K. (2021). Biochemistry, Immunoglobulin M, StatPearls Publishing."},{"key":"ref_15","first-page":"1","article-title":"Dengue antibody-dependent enhancement: Knowns and unknown","volume":"6","author":"Halstead","year":"2014","journal-title":"Microbiol. Spectr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0065-3527(03)59005-4","article-title":"Antigenic structure of flavirus proteins","volume":"59","author":"Roehrig","year":"2003","journal-title":"Adv. Virus Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.mbs.2007.08.004","article-title":"Vaccination in disease models with antibody-dependent enhancement","volume":"211","author":"Billings","year":"2008","journal-title":"Math. Biosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1038\/nrmicro2460","article-title":"Dengue: A continuing global threat","volume":"8","author":"Guzman","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1126\/science.1185181","article-title":"Cross-Reacting Antibodies Enhance Dengue Virus Infection in Humans","volume":"328","author":"Dejnirattisai","year":"2010","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1128\/JVI.00220-10","article-title":"Cell Type and Host Genetic Polymorphisms Influence Antibody-Dependent Enhancement of Dengue Virus Infection","volume":"85","author":"Boonnak","year":"2011","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/s41577-020-00410-0","article-title":"The role of IgG Fc receptors in antibody-dependent enhancement","volume":"20","author":"Bournazos","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S0140-6736(14)60572-9","article-title":"Dengue","volume":"385","author":"Guzman","year":"2015","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1086\/315215","article-title":"Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity","volume":"181","author":"Vaughn","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"990","DOI":"10.4269\/ajtmh.2008.78.990","article-title":"Influence of the dengue serotype, previous dengue infection, and plasma viral load on clinical presentation and outcome during a dengue-2 and dengue-4 co-epidemic","volume":"78","author":"Thomas","year":"2008","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1006\/viro.2002.1704","article-title":"High levels of plasma dengue viral load during defervescence in patients with dengue hemorrhagic fever: Implications for pathogenesis","volume":"305","author":"Wang","year":"2003","journal-title":"Virology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1086\/528805","article-title":"Dengue and dengue hemorrhagic fever among adults: Clinical outcomes related to viremia, serotypes, and antibody response","volume":"197","author":"Guilarde","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1506223","article-title":"Efficacy and long term safety of a dengue vaccine in regions of endemic disease","volume":"373","author":"Hadinegoro","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1056\/NEJMoa1903869","article-title":"Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents","volume":"381","author":"Biswal","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/S0140-6736(20)30414-1","article-title":"Efficacy of a tetravalent dengue vaccine in healthy children aged 4\u201316 years: A randomised, placebo-controlled, phase 3 trial","volume":"395","author":"Biswal","year":"2020","journal-title":"Lancet"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/S1473-3099(16)30168-2","article-title":"The risks behind Dengvaxia recommendation","volume":"16","author":"Aguiar","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S1473-3099(17)30752-1","article-title":"Dengvaxia: Age as surrogate for serostatus","volume":"18","author":"Aguiar","year":"2018","journal-title":"Lancet Infect."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/cid\/cix882","article-title":"Dengvaxia efficacy dependency on serostatus: A closer look at more recent data","volume":"66","author":"Aguiar","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2374","DOI":"10.3390\/v3122374","article-title":"The human antibody response to dengue virus infection","volume":"3","author":"Wahala","year":"2011","journal-title":"Viruses"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Aguiar, M., and Stollenwerk, N. (2020). The impact of serotype cross-protection on vaccine trials: DENVax as a case study. Vaccines, 8.","DOI":"10.20944\/preprints202009.0671.v1"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"White, L.J., Young, E.F., Stoops, M.J., Henein, S.R., Adams, E.C., Baric, R.S., and de Silva, A.M. (2021). Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003). PLoS Negl. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0009258"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.jtbi.2011.08.043","article-title":"The role of seasonality and import in a minimalistic multi-strain dengue model capturing differences between primary and secondary infections: Complex dynamics and its implications for data analysis","volume":"289","author":"Aguiar","year":"2011","journal-title":"J. Theor. Biol."},{"key":"ref_37","first-page":"8462","article-title":"Carnival or football, is there a real risk for acquiring dengue fever in Brazil during holidays seasons","volume":"5","author":"Aguiar","year":"2015","journal-title":"Nat. Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5572","DOI":"10.1016\/j.vaccine.2020.06.079","article-title":"Ethics of a Partially Effective Dengue Vaccine: Lessons from the Philippines","volume":"38","author":"Halstead","year":"2020","journal-title":"Vaccine"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Aguiar, M., Stollenwerk, N., and Halstead, S.B. (2016). Modeling the impact of the newly licensed dengue vaccine in endemic countries. PLoS Negl. Trop. Dis., 10.","DOI":"10.1101\/074062"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5614\/cbms.2017.1.1.1","article-title":"Mathematical models of dengue fever epidemiology: Multi-strain dynamics, immunological aspects associated to disease severity and vaccines","volume":"1","author":"Aguiar","year":"2017","journal-title":"Commun. Biomath. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1016\/S0140-6736(18)30865-1","article-title":"Dengue vaccination: A more ethical approach is needed","volume":"391","author":"Aguiar","year":"2018","journal-title":"Lancet"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1080\/14760584.2017.1276831","article-title":"Consider stopping dengvaxia administration without immunological screening","volume":"16","author":"Aguiar","year":"2017","journal-title":"Expert Rev. Vaccines"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.mcm.2008.06.016","article-title":"A with-in host dengue infection model with immune response","volume":"41","author":"Nuraini","year":"2009","journal-title":"Math. Comp. Model."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"177","DOI":"10.4236\/am.2012.32028","article-title":"A within host dengue infection model with immune response and Beddington-DeAngelis incidence rate","volume":"3","author":"Ansari","year":"2012","journal-title":"Appl. Math."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"20140094","DOI":"10.1098\/rsif.2014.0094","article-title":"Within-Host viral dynamics of dengue serotype 1 infection","volume":"11","author":"Clapham","year":"2014","journal-title":"J. R. Soc. Interface"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1007\/s00285-013-0749-4","article-title":"Virus antibody dynamics in primary and secondary dengue infections","volume":"69","author":"Gujarati","year":"2014","journal-title":"J. Math. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Clapham, H.E., Quyen, T.H., Kien, D.T.H., Dorigatti, I., Simmons, C.P., and Ferguson, N.M. (2016). Modelling Virus and Antibody Dynamics during Dengue Virus Infection Suggests a Role for Antibody in Virus Clearance. PLoS Comput. Biol., 12.","DOI":"10.1371\/journal.pcbi.1004951"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ben-Shachar, R., and Koelle, K. (2014). Minimal within-host dengue models highlight the spesific roles of the immune response in primary and secondary infections. J. R. Soc. Interface, 12.","DOI":"10.1098\/rsif.2014.0886"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3390\/v3020160","article-title":"Flavirus cell entry and membrane fusion","volume":"3","author":"Smit","year":"2011","journal-title":"Viruses"},{"key":"ref_50","unstructured":"Janeway, C.A., Travers, P., and Walport, M. (2021, August 19). Immunobiology: The Immune System in Health and Disease, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK27162\/."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1046\/j.1440-1711.2003.01157.x","article-title":"Evasion of innate and adaptive immunity by flaviviruses","volume":"81","author":"Diamond","year":"2003","journal-title":"Immunol. Cell Biol."},{"key":"ref_52","unstructured":"(2021, August 23). White Cell Count. Available online: http:\/\/www.gpnotebook.com\/simplepagr.cfm?ID=1013645382."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3929","DOI":"10.1128\/JVI.77.7.3929-3938.2003","article-title":"American Genotype structures Decrease Dengue Virus Output from Human Monocytes and Dendric Cells","volume":"77","author":"Cologna","year":"2003","journal-title":"J. Virol."},{"key":"ref_54","first-page":"46","article-title":"Immune evasion strategies of flaviviruses","volume":"31","author":"Ye","year":"2013","journal-title":"Vacine"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/10\/9\/941\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:37Z","timestamp":1760166157000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/10\/9\/941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,20]]},"references-count":54,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["biology10090941"],"URL":"https:\/\/doi.org\/10.3390\/biology10090941","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,20]]}}}