{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T14:33:42Z","timestamp":1778510022325,"version":"3.51.4"},"posted":{"date-parts":[[2024,6,4]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":49,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Primary infection with one of four dengue virus serotypes (DENV1-4) may generate antibodies that protect or enhance subsequent secondary heterotypic infections. However, the characteristics of heterotypic cross-reactive antibodies associated with protection from symptomatic infection and severe disease are not well-defined. We selected plasma samples collected before a secondary DENV heterotypic infection that was classified either as dengue fever (DF, n = 31) or dengue hemorrhagic fever\/dengue shock syndrome (DHF\/DSS, n = 33) from our longstanding pediatric cohort in Nicaragua. We screened various antibody properties to determine the features correlated with protection from DHF\/DSS. Protection was associated with high levels of binding of various antibody isotypes, IgG subclasses and effector functions, including antibody-dependent complement deposition, ADCD. Although the samples were derived from DENV-exposed, Zika virus (ZIKV)-na\u00efve individuals, the protective ADCD association was stronger when assays were conducted with recombinant ZIKV antigens. Further, we showed that a complement-mediated virion lysis (virolysis) assay conducted with ZIKV virions was strongly associated with protection, a finding reproduced in an independent sample set collected prior to secondary heterotypic inapparent versus symptomatic DENV infection. Virolysis was the main antibody feature correlated with protection from DHF\/DSS and severe symptoms, such as thrombocytopenia, hemorrhagic manifestations, and plasma leakage. Hence, anti-DENV antibodies that cross-react with ZIKV, target virion-associated epitopes, and mediate complement-dependent virolysis are correlated with protection from secondary symptomatic DENV infection and DHF\/DSS. These findings may support the rational design and evaluation of dengue vaccines and development of therapeutics.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>Complement-dependent virolysis mediated by a subset of ZIKV-cross-reactive antibodies protects from symptomatic DENV infection and severe disease.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.06.03.24308395","type":"posted-content","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T16:26:02Z","timestamp":1717518362000},"source":"Crossref","is-referenced-by-count":3,"title":["Complement-dependent virion lysis mediated by dengue-Zika virus cross-reactive antibodies correlates with protection from severe dengue disease"],"prefix":"10.64898","author":[{"suffix":"Jr.","given":"Antonio G.","family":"Dias","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elias","family":"Duarte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose Victor","family":"Zambrana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaime A.","family":"Cardona-Ospina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5036-0336","authenticated-orcid":false,"given":"Sandra","family":"Bos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vicky","family":"Roy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillermina","family":"Kuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angel","family":"Balmaseda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Galit","family":"Alter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7238-4037","authenticated-orcid":false,"given":"Eva","family":"Harris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024060704100620000_2024.06.03.24308395v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-023-05835-1"},{"key":"2024060704100620000_2024.06.03.24308395v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/S41564-020-0714-0"},{"key":"2024060704100620000_2024.06.03.24308395v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax4144"},{"key":"2024060704100620000_2024.06.03.24308395v1.4","unstructured":"World Health Organization, Ed., Dengue haemorrhagic fever: diagnosis, treatment, prevention and control (Geneva, 2. ed., 1997)."},{"key":"2024060704100620000_2024.06.03.24308395v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan6836"},{"key":"2024060704100620000_2024.06.03.24308395v1.6","doi-asserted-by":"crossref","first-page":"2.6.30","DOI":"10.1128\/microbiolspec.AID-0022-2014","article-title":"Dengue Antibody-Dependent Enhancement: Knowns and Unknowns","volume":"2","year":"2014","journal-title":"Microbiol. Spectr"},{"key":"2024060704100620000_2024.06.03.24308395v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a113932"},{"key":"2024060704100620000_2024.06.03.24308395v1.8","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/11.Supplement_4.S830"},{"key":"2024060704100620000_2024.06.03.24308395v1.9","doi-asserted-by":"publisher","DOI":"10.1084\/jem.146.1.201"},{"key":"2024060704100620000_2024.06.03.24308395v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc7303"},{"key":"2024060704100620000_2024.06.03.24308395v1.11","doi-asserted-by":"publisher","DOI":"10.1126\/science.aai8128"},{"key":"2024060704100620000_2024.06.03.24308395v1.12","doi-asserted-by":"crossref","first-page":"e1002726","DOI":"10.1371\/journal.pmed.1002726","article-title":"Prior dengue virus infection and risk of Zika: A pediatric cohort in Nicaragua","volume":"16","year":"2019","journal-title":"PLOS Med"},{"key":"2024060704100620000_2024.06.03.24308395v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav6618"},{"key":"2024060704100620000_2024.06.03.24308395v1.14","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb6143"},{"key":"2024060704100620000_2024.06.03.24308395v1.15","doi-asserted-by":"crossref","first-page":"eadn2199","DOI":"10.1126\/scitranslmed.adn2199","article-title":"Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1","volume":"16","year":"2024","journal-title":"Sci Transl Med"},{"key":"2024060704100620000_2024.06.03.24308395v1.16","doi-asserted-by":"crossref","first-page":"1081107","DOI":"10.3389\/fimmu.2022.1081107","article-title":"Recent updates on correlates of vaccine-induced protection","volume":"13","year":"2023","journal-title":"Front. Immunol"},{"key":"2024060704100620000_2024.06.03.24308395v1.17","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/s41467-023-44330-8","article-title":"Protection against symptomatic dengue infection by neutralizing antibodies varies by infection history and infecting serotype","volume":"15","year":"2024","journal-title":"Nat. Commun"},{"key":"2024060704100620000_2024.06.03.24308395v1.18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1522136113"},{"key":"2024060704100620000_2024.06.03.24308395v1.19","doi-asserted-by":"crossref","first-page":"e147066","DOI":"10.1172\/JCI147066","article-title":"Dengue vaccine breakthrough infections reveal properties of neutralizing antibodies linked to protection","volume":"131","year":"2021","journal-title":"J. Clin. Invest"},{"key":"2024060704100620000_2024.06.03.24308395v1.20","doi-asserted-by":"crossref","first-page":"366","DOI":"10.7883\/yoken.66.366","article-title":"Correlation between complement component levels and disease severity in dengue patients in Indonesia","volume":"66","year":"2013","journal-title":"Jpn. J. Infect. Dis"},{"key":"2024060704100620000_2024.06.03.24308395v1.21","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/s41467-021-21384-0","article-title":"A tetravalent live attenuated dengue virus vaccine stimulates balanced immunity to multiple serotypes in humans","volume":"12","year":"2021","journal-title":"Nat. Commun"},{"key":"2024060704100620000_2024.06.03.24308395v1.22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005554"},{"key":"2024060704100620000_2024.06.03.24308395v1.23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0009258"},{"key":"2024060704100620000_2024.06.03.24308395v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abm3151"},{"key":"2024060704100620000_2024.06.03.24308395v1.25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002462"},{"key":"2024060704100620000_2024.06.03.24308395v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwp092"},{"key":"2024060704100620000_2024.06.03.24308395v1.27","doi-asserted-by":"crossref","first-page":"9294","DOI":"10.1073\/pnas.1804672115","article-title":"Seroprevalence, risk factor, and spatial analyses of Zika virus infection after the 2016 epidemic in Managua","volume":"115","year":"2018","journal-title":"Nicaragua. Proc. Natl. Acad. Sci"},{"key":"2024060704100620000_2024.06.03.24308395v1.28","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01123-16"},{"key":"2024060704100620000_2024.06.03.24308395v1.29","doi-asserted-by":"publisher","DOI":"10.3201\/eid2305.161630"},{"key":"2024060704100620000_2024.06.03.24308395v1.30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030441"},{"key":"2024060704100620000_2024.06.03.24308395v1.31","doi-asserted-by":"crossref","first-page":"107642","DOI":"10.1016\/j.celrep.2020.107642","article-title":"Maternal Anti-Dengue IgG Fucosylation Predicts Susceptibility to Dengue Disease in Infants","volume":"31","year":"2020","journal-title":"Cell Rep"},{"key":"2024060704100620000_2024.06.03.24308395v1.32","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aal5088"},{"key":"2024060704100620000_2024.06.03.24308395v1.33","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ade2798"},{"key":"2024060704100620000_2024.06.03.24308395v1.34","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007736"},{"key":"2024060704100620000_2024.06.03.24308395v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00871-z"},{"key":"2024060704100620000_2024.06.03.24308395v1.36","doi-asserted-by":"publisher","DOI":"10.1101\/2024.04.05.24305281"},{"key":"2024060704100620000_2024.06.03.24308395v1.37","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1021\/acs.jproteome.6b00608","article-title":"De Novo MS\/MS Sequencing of Native Human Antibodies","volume":"16","year":"2017","journal-title":"J. Proteome Res"},{"key":"2024060704100620000_2024.06.03.24308395v1.38","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.cels.2021.08.008","article-title":"Human plasma IgG1 repertoires are simple, unique, and dynamic","volume":"12","year":"2021","journal-title":"Cell Syst"},{"key":"2024060704100620000_2024.06.03.24308395v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3849"},{"key":"2024060704100620000_2024.06.03.24308395v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/nature18938"},{"key":"2024060704100620000_2024.06.03.24308395v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.11.010"},{"key":"2024060704100620000_2024.06.03.24308395v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/nature14130"},{"key":"2024060704100620000_2024.06.03.24308395v1.43","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3390\/antib12020036","article-title":"Complement Activation by an Anti-Dengue\/Zika Antibody with Impaired Fc\u03b3 Receptor Binding Provides Strong Efficacy and Abrogates Risk of Antibody-Dependent Enhancement","volume":"12","year":"2023","journal-title":"Antibodies"},{"key":"2024060704100620000_2024.06.03.24308395v1.44","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41541-016-0003-3","article-title":"A potent neutralizing antibody with therapeutic potential against all four serotypes of dengue virus","volume":"2","year":"2017","journal-title":"Npj Vaccines"},{"key":"2024060704100620000_2024.06.03.24308395v1.45","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1999.61.893"},{"key":"2024060704100620000_2024.06.03.24308395v1.46","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.30.3.545-551.1992"},{"key":"2024060704100620000_2024.06.03.24308395v1.47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002116"},{"key":"2024060704100620000_2024.06.03.24308395v1.48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3156.2006.01641.x"},{"key":"2024060704100620000_2024.06.03.24308395v1.49","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v033.i01"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.06.03.24308395","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:02:28Z","timestamp":1768507348000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.06.03.24308395"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,4]]},"references-count":49,"URL":"https:\/\/doi.org\/10.1101\/2024.06.03.24308395","relation":{},"subject":[],"published":{"date-parts":[[2024,6,4]]},"subtype":"preprint"}}