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No specific prophylaxis or treatment exists for WNV or related orthoflavivirus infections, and the determinants of human disease severity remain poorly understood. Here, we report that neutralizing autoantibodies against type I interferons do not impair antiviral antibody development. Among the fully human monoclonal antibodies with potent neutralizing activity against WNV that were discovered, W010 targets a unique epitope within the envelope protein domain III (EDIII) and confers both pre- and post-exposure protection in a murine WNV model, even when interferon signaling is impaired. A second protective antibody, W014, exhibits broad cross-neutralization of other pathogenic orthoflavivirus members, including Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus. These findings identify key neutralizing epitopes on WNV EDIII and provide candidates for the development of antibody-based interventions against encephalitic orthoflavivirus infections.<\/jats:p>","DOI":"10.64898\/2026.04.02.715800","type":"posted-content","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T08:35:14Z","timestamp":1775464514000},"source":"Crossref","is-referenced-by-count":0,"title":["Human antibodies against West Nile and related orthoflaviviruses"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6355-6781","authenticated-orcid":false,"given":"Tom\u00e1s","family":"Cervantes Rinc\u00f3n","sequence":"first","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera italiana, 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2975-2182","authenticated-orcid":false,"given":"Tereza","family":"Frckova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic"},{"name":"Veterinary Research Institute, Brno, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaria I.","family":"Contejean","sequence":"additional","affiliation":[{"name":"Stanford Biosciences, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7826-6924","authenticated-orcid":false,"given":"Jasmine","family":"Cantergiani","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera italiana, 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6352-1346","authenticated-orcid":false,"given":"Kevin","family":"Groen","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5048-8633","authenticated-orcid":false,"given":"Benedetta","family":"Cena","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera italiana, 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5199-8390","authenticated-orcid":false,"given":"Simone G.","family":"Moro","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera italiana, 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0746-7629","authenticated-orcid":false,"given":"Filippo","family":"Bianchini","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera italiana, 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6331-7716","authenticated-orcid":false,"given":"Luca","family":"Simonelli","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera italiana, 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0924-6395","authenticated-orcid":false,"given":"David","family":"Jarrossay","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera italiana, 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6525-401X","authenticated-orcid":false,"given":"Silvia","family":"Tosolini","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera italiana, 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2917-575X","authenticated-orcid":false,"given":"Roger","family":"Kuratli","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna R. 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