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ZIKV is becoming increasingly prevalent in DENV-endemic regions, raising the possibility that pre-existing immunity to one virus could modulate the response to a heterologous virus, although whether this would be beneficial or detrimental is unclear. Here, we analyzed sera from residents of a DENV-endemic region of Thailand to determine the prevalence of DENV-elicited antibodies capable of cross-neutralizing ZIKV. Sixty-one participants who were asymptomatic and unselected for viral serostatus were enrolled. Among them, 52 and 51 were seropositive for IgG antibody against DENV or ZIKV E proteins (ELISA assay), respectively. Notably, 44.23% (23\/52) of DENV seropositive participants had serological evidence of multiple exposures to DENV, and these subjects had strikingly higher titers and broader reactivities of neutralizing antibodies (NAbs) against ZIKV and DENV heterotypes compared with participants with serological evidence of a single DENV infection (25\/52, 48.1%). In total, 17 of the 61 participants (27.9%) had NAbs against ZIKV and all four DENV serotypes, and an additional 9 (14.8%) had NAbs against ZIKV and DENV1, 2, and 3. NAbs against DENV2 were the most prevalent (44\/61, 72.1%) followed by DENV3 (38\/61, 62.3%) and DENV1 (36\/61, 59.0%). Of note, anti-ZIKV NAbs were more prevalent than anti-DENV4 NAbs (27\/61, 44.3% and 21\/61, 34.4%, respectively). Primary ZIKV infection was detected in two participants, confirming that ZIKV co-circulates in this region. Thus, residents of DENV-endemic regions with repeated exposure to DENV have higher titers of NAbs against ZIKV than individuals with only a single DENV exposure. <\/jats:p>","DOI":"10.1038\/s41598-021-88933-x","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T10:07:04Z","timestamp":1620209224000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Repeated exposure to dengue virus elicits robust cross neutralizing antibodies against Zika virus in residents of Northeastern Thailand"],"prefix":"10.1038","volume":"11","author":[{"given":"Sararat","family":"Hattakam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Elong Ngono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"McCauley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujan","family":"Shresta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montarop","family":"Yamabhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,5]]},"reference":[{"key":"88933_CR1","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/nature12060","volume":"496","author":"S Bhatt","year":"2013","unstructured":"Bhatt, S. et al. The global distribution and burden of dengue. Nature 496, 504\u2013507. https:\/\/doi.org\/10.1038\/nature12060 (2013).","journal-title":"Nature"},{"key":"88933_CR2","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/S1473-3099(18)30718-7","volume":"19","author":"K Ruchusatsawat","year":"2019","unstructured":"Ruchusatsawat, K. et al. Long-term circulation of Zika virus in Thailand: An observational study. Lancet Infect. Dis. 19, 439\u2013446. https:\/\/doi.org\/10.1016\/S1473-3099(18)30718-7 (2019).","journal-title":"Lancet Infect. Dis."},{"key":"88933_CR3","doi-asserted-by":"publisher","unstructured":"Angelo, K. M. et al. Zika among international travellers presenting to GeoSentinel sites, 2012\u20132019: Implications for clinical practice. J. Travel Med. 27, https:\/\/doi.org\/10.1093\/jtm\/taaa061 (2020).","DOI":"10.1093\/jtm\/taaa061"},{"key":"88933_CR4","doi-asserted-by":"publisher","unstructured":"Hamer, D. H. & Chen, L. H. Zika in Angola and India. J. Travel Med. 26, https:\/\/doi.org\/10.1093\/jtm\/taz012 (2019).","DOI":"10.1093\/jtm\/taz012"},{"key":"88933_CR5","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1038\/s41467-019-08845-3","volume":"10","author":"P Andrade","year":"2019","unstructured":"Andrade, P. et al. Impact of pre-existing dengue immunity on human antibody and memory B cell responses to Zika. Nat. Commun. 10, 938. https:\/\/doi.org\/10.1038\/s41467-019-08845-3 (2019).","journal-title":"Nat. Commun."},{"key":"88933_CR6","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.3201\/eid2006.140138","volume":"20","author":"V-M Cao-Lormeau","year":"2014","unstructured":"Cao-Lormeau, V.-M. et al. Zika virus, French polynesia, South pacific, 2013. Emerg. Infect. Dis. 20, 1085\u20131086. https:\/\/doi.org\/10.3201\/eid2006.140138 (2014).","journal-title":"Emerg. Infect. 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NPJ Vaccines 4, 38. https:\/\/doi.org\/10.1038\/s41541-019-0133-5 (2019).","journal-title":"NPJ Vaccines"},{"key":"88933_CR10","doi-asserted-by":"publisher","first-page":"e1002726","DOI":"10.1371\/journal.pmed.1002726","volume":"16","author":"A Gordon","year":"2019","unstructured":"Gordon, A. et al. Prior dengue virus infection and risk of Zika: A pediatric cohort in Nicaragua. PLoS Med. 16, e1002726. https:\/\/doi.org\/10.1371\/journal.pmed.1002726 (2019).","journal-title":"PLoS Med."},{"key":"88933_CR11","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1126\/science.aav6618","volume":"363","author":"I Rodriguez-Barraquer","year":"2019","unstructured":"Rodriguez-Barraquer, I. et al. Impact of preexisting dengue immunity on Zika virus emergence in a dengue endemic region. Science 363, 607. https:\/\/doi.org\/10.1126\/science.aav6618 (2019).","journal-title":"Science"},{"key":"88933_CR12","doi-asserted-by":"publisher","unstructured":"Pedroso, C.F.C., Feldmann, M., Sarno, M., Luz, E., Moreira-Soto, A., Cabral, R., & Netto, E.M.B.C., K\u00fcmmerer, B.M., Drexler, J.F. Cross-protection of dengue virus infection against congenital Zika syndrome, Northeastern Brazil. Emerg. Infect. Dis., 1485\u20131493, https:\/\/doi.org\/10.3201\/eid2508.190113 (2019).","DOI":"10.3201\/eid2508.190113"},{"key":"88933_CR13","doi-asserted-by":"publisher","first-page":"3042","DOI":"10.1038\/s41467-018-05458-0","volume":"9","author":"JA Regla-Nava","year":"2018","unstructured":"Regla-Nava, J. A. et al. Cross-reactive dengue virus-specific CD8+ T cells protect against Zika virus during pregnancy. Nat. Commun. 9, 3042. https:\/\/doi.org\/10.1038\/s41467-018-05458-0 (2018).","journal-title":"Nat. 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Dengue virus immunity increases Zika virus-induced damage during pregnancy. Immunity 50, 751-762.e755. https:\/\/doi.org\/10.1016\/j.immuni.2019.01.005 (2019).","journal-title":"Immunity"},{"key":"88933_CR19","doi-asserted-by":"publisher","unstructured":"Rathore, A.P.S., Saron, W.A.A., Lim, T., Jahan, N. & St. John, A.L. Maternal immunity and antibodies to dengue virus promote infection and Zika virus\u2013induced microcephaly in fetuses. Sci. Adv. 5, eaav3208, https:\/\/doi.org\/10.1126\/sciadv.aav3208 (2019).","DOI":"10.1126\/sciadv.aav3208"},{"key":"88933_CR20","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.chom.2018.10.008","volume":"24","author":"MG Zimmerman","year":"2018","unstructured":"Zimmerman, M. G. et al. Cross-reactive dengue virus antibodies augment Zika virus infection of human placental macrophages. Cell Host Microbe 24, 731-742.e736. https:\/\/doi.org\/10.1016\/j.chom.2018.10.008 (2018).","journal-title":"Cell Host Microbe"},{"key":"88933_CR21","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/s41426-018-0199-6","volume":"7","author":"K Hermanns","year":"2018","unstructured":"Hermanns, K. et al. Zika virus infection in human placental tissue explants is enhanced in the presence of dengue virus antibodies in-vitro. Emerg. Microbes Infect 7, 198\u2013198. https:\/\/doi.org\/10.1038\/s41426-018-0199-6 (2018).","journal-title":"Emerg. Microbes Infect"},{"key":"88933_CR22","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1126\/science.aaf8505","volume":"353","author":"K Stettler","year":"2016","unstructured":"Stettler, K. et al. Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection. Science 353, 823. https:\/\/doi.org\/10.1126\/science.aaf8505 (2016).","journal-title":"Science"},{"key":"88933_CR23","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1093\/infdis\/jiy482","volume":"219","author":"S Watanabe","year":"2019","unstructured":"Watanabe, S., Tan, N. W. W., Chan, K. W. K. & Vasudevan, S. G. Dengue virus and Zika virus serological cross-reactivity and their impact on pathogenesis in mice. J. Infect. Dis. 219, 223\u2013233. https:\/\/doi.org\/10.1093\/infdis\/jiy482 (2019).","journal-title":"J. Infect. Dis."},{"key":"88933_CR24","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/j.chom.2018.09.015","volume":"24","author":"AM Fowler","year":"2018","unstructured":"Fowler, A. M. et al. Maternally acquired Zika antibodies enhance dengue disease severity in mice. Cell Host Microbe 24, 743-750.e745. https:\/\/doi.org\/10.1016\/j.chom.2018.09.015 (2018).","journal-title":"Cell Host Microbe"},{"key":"88933_CR25","doi-asserted-by":"publisher","first-page":"10498","DOI":"10.1038\/s41598-017-10901-1","volume":"7","author":"J George","year":"2017","unstructured":"George, J. et al. Prior exposure to Zika virus significantly enhances peak dengue-2 viremia in Rhesus Macaques. Sci. Rep. 7, 10498. https:\/\/doi.org\/10.1038\/s41598-017-10901-1 (2017).","journal-title":"Sci. Rep."},{"key":"88933_CR26","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1126\/science.abb6143","volume":"369","author":"LC Katzelnick","year":"2020","unstructured":"Katzelnick, L. C. et al. Zika virus infection enhances future risk of severe dengue disease. Science 369, 1123. https:\/\/doi.org\/10.1126\/science.abb6143 (2020).","journal-title":"Science"},{"key":"88933_CR27","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1016\/j.cell.2019.07.018","volume":"178","author":"ND Grubaugh","year":"2019","unstructured":"Grubaugh, N. D. et al. Travel surveillance and genomics uncover a hidden Zika outbreak during the waning epidemic. Cell 178, 1057-1071.e1011. https:\/\/doi.org\/10.1016\/j.cell.2019.07.018 (2019).","journal-title":"Cell"},{"key":"88933_CR28","doi-asserted-by":"publisher","unstructured":"Halstead, S. B. & Yamarat, C. Recent epidemics of hemorrhagic fever in Thailand. Observations related to pathogenesis of a \u201cnew\u201d dengue disease. Am. J. Public Health Nations Health 55, 1386\u20131395, https:\/\/doi.org\/10.2105\/ajph.55.9.1386 (1965).","DOI":"10.2105\/ajph.55.9.1386"},{"key":"88933_CR29","doi-asserted-by":"publisher","first-page":"17193","DOI":"10.1038\/s41598-018-35643-6","volume":"8","author":"W Sornjai","year":"2018","unstructured":"Sornjai, W., Jaratsittisin, J., Auewarakul, P., Wikan, N. & Smith, D. R. Analysis of Zika virus neutralizing antibodies in normal healthy Thais. Sci. Rep. 8, 17193. https:\/\/doi.org\/10.1038\/s41598-018-35643-6 (2018).","journal-title":"Sci. Rep."},{"key":"88933_CR30","doi-asserted-by":"publisher","first-page":"13498","DOI":"10.1038\/s41598-019-49569-0","volume":"9","author":"W Sornjai","year":"2019","unstructured":"Sornjai, W., Ramphan, S., Wikan, N., Auewarakul, P. & Smith, D. R. High correlation between Zika virus NS1 antibodies and neutralizing antibodies in selected serum samples from normal healthy Thais. Sci. Rep. 9, 13498. https:\/\/doi.org\/10.1038\/s41598-019-49569-0 (2019).","journal-title":"Sci. Rep."},{"key":"88933_CR31","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3390\/pathogens8010030","volume":"8","author":"A Phumee","year":"2019","unstructured":"Phumee, A. et al. Molecular epidemiology and genetic diversity of Zika virus from field-caught mosquitoes in various regions of Thailand. Pathogens 8, 30 (2019).","journal-title":"Pathogens"},{"key":"88933_CR32","doi-asserted-by":"publisher","first-page":"773","DOI":"10.3201\/eid2305.161630","volume":"23","author":"HC Matthew","year":"2017","unstructured":"Matthew, H. C. et al. Lack of durable cross-neutralizing antibodies against zika virus from dengue virus infection. Emerg. Infect. Dis. 23, 773. https:\/\/doi.org\/10.3201\/eid2305.161630 (2017).","journal-title":"Emerg. Infect. 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PLoS Pathog. 15, e1007474. https:\/\/doi.org\/10.1371\/journal.ppat.1007474 (2019).","journal-title":"PLoS Pathog."},{"key":"88933_CR41","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1089\/vim.2008.0007","volume":"21","author":"JT Roehrig","year":"2008","unstructured":"Roehrig, J. T., Hombach, J. & Barrett, A. D. T. Guidelines for plaque-reduction neutralization testing of human antibodies to dengue viruses. Viral Immunol. 21, 123\u2013132. https:\/\/doi.org\/10.1089\/vim.2008.0007 (2008).","journal-title":"Viral Immunol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-88933-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-88933-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-88933-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T07:43:50Z","timestamp":1670053430000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-88933-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,5]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["88933"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-88933-x","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,5]]},"assertion":[{"value":"6 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9634"}}