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There are no approved vaccines or therapeutics, and the incidence of POWV infection in humans is rising. Here, we isolated and characterized a panel of human monoclonal antibodies (mAbs) from a convalescent donor using single B-cell sorting with POWV EDIII and full-length E ectodomain as antigen bait. Binding and neutralization assays with both POWV reporter virus particles and an authentic strain identified multiple neutralizing mAbs that target distinct epitopes across the E glycoprotein, including EDIII lateral ridge\/C-C' loop and non-EDIII regions. Four neutralizing mAbs were evaluated in a lethal mouse challenge, two of which conferred substantial protection. These findings define key targets of the human antibody response to POWV and highlight candidates for the development of human monoclonal antibody therapy for this emerging virus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Powassan virus is an emerging tick-borne orthoflavivirus with steadily increasing case numbers. With an approximately 10% case-fatality rate and no approved therapeutics or vaccines available, POWV represents a potential public health threat. Our results showing that human monoclonal antibodies can protect mice against POWV in a lethal challenge model provide a foundation for developing future effective immunotherapies against this virus.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.02105-25","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T13:08:01Z","timestamp":1777554481000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Protective human antibodies against Powassan virus"],"prefix":"10.1128","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9355-5501","authenticated-orcid":true,"given":"Georgia","family":"Fallon","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05cf8a891","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, Albert Einstein College of Medicine","place":["Bronx, 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