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Although infection by a given flavivirus is thought to confer lifelong protection, some of the patient's antibodies cross\u2010react with other flaviviruses without cross\u2010neutralizing. The original antigenic sin phenomenon may amplify such antibodies upon subsequent heterologous flavivirus infection, potentially aggravating disease by antibody\u2010dependent enhancement (ADE). The most striking example is provided by the four different dengue viruses, where infection by one serotype appears to predispose to more severe disease upon infection by a second one. A similar effect was postulated for sequential infections with Zika and dengue viruses. In this review, we analyze the molecular determinants of the dual antibody response to flavivirus infection or vaccination in humans. We highlight the role of conserved partially cryptic epitopes giving rise to cross\u2010reacting and poorly neutralizing, ADE\u2010prone antibodies. We end by proposing a strategy for developing an epitope\u2010focused vaccine approach to avoid eliciting undesirable antibodies while focusing the immune system on producing protective antibodies only.<\/jats:p>","DOI":"10.15252\/embr.201745302","type":"journal-article","created":{"date-parts":[[2017,12,27]],"date-time":"2017-12-27T20:10:34Z","timestamp":1514405434000},"page":"206-224","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":254,"title":["The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design"],"prefix":"10.1038","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9953-7988","authenticated-orcid":false,"given":"F\u00e9lix A","family":"Rey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Stiasny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Christine","family":"Vaney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariano","family":"Dellarole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7191-4331","authenticated-orcid":false,"given":"Franz X","family":"Heinz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,27]]},"reference":[{"key":"BFEMBR201745302_CR1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","volume":"496","author":"S Bhatt","year":"2013","unstructured":"Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O et al (2013) The global distribution and burden of dengue. 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