biostudies-literatureLubow JFred Hutchinson Cancer Center Translational Data Science Integrated Research CenterCongressionally Directed Medical Research ProgramsHoward Hughes Medical InstituteNIAID NIH HHSChan Zuckerberg Biohub - San FranciscoDr. Ralph and Marian Falk Medical Research TrustFred Hutchinson Cancer Center Diverse Trainee FundFred Hutch/University of Washington/Seattle Children’s Cancer ConsortiumNIHScientific Computing Infrastructure at Fred HutchDr. Ralph & Marian Falk Medical Research TrustNCI NIH HHSNIGMS NIH HHSNIH HHSe1011722https://www.ebi.ac.uk/biostudies/studies/S-EPMC10586629biostudies-literatureUnknown19(10)Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasures that avoid enhancement of infection associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following repeated DENV infections. We identified several new bnAbs with comparable or superior breadth and potency to known bnAbs, and with distinct recognition determinants. Unlike all known flavivirus bnAbs, which are IgG1, one newly identified cross-flavivirus bnAb (F25.S02) was derived from IgA1. Both IgG1 and IgA1 versions of F25.S02 and known bnAbs displayed neutralizing activity, but only IgGPLoS pathogensSingle B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses.PMC10586629R01 GM129325Viral Pathogenesis and Evolution Training Grant T32 AI083203T32 AI007509P30 CA015704Catalyst and Transformational AwardsW81XWH1910235ORIP grant S10OD028685New Collaborations AwardR01 AI146028T32 AI083203U19 AI057229S10 OD028685Flow Cytometry (RRID:SCR_022613), and the Genomics & Bioinformatics (RRID:SCR_022606), (P30 CA015704)Doranz BJSanz AMEinav SDuran VRebellon-Sanchez DELevoir LMKikawa CRosso FGoo LRalph DKBelmont LCartwright-Acar CHLubow JKannan SDavidson EContreras MMatsen Iv FAfalseSingle B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses.Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasures that avoid enhancement of infection associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following repeated DENV infections. We identified several new bnAbs with comparable or superior breadth and potency to known bnAbs, and with distinct recognition determinants. Unlike all known flavivirus bnAbs, which are IgG1, one newly identified cross-flavivirus bnAb (F25.S02) was derived from IgA1. Both IgG1 and IgA1 versions of F25.S02 and known bnAbs displayed neutralizing activity, but only IgG2023-01-01T00:00:00Z2023 Oct2026-05-29T04:24:01.969Z2025-02-19T01:53:03.893ZS-EPMC105866293781264010.1371/journal.ppat.1011722