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Building on prior research defining E1\/E2 antibody epitope clustering, we screened a phage display library derived from a chronic HCV patient against detergent-extracted full-length E1\/E2 from both the patient\u2019s acute-phase isolate (H77, genotype 1a) and a heterologous isolate (S52, genotype 3a). This approach yielded a panel of V<jats:sub>H<\/jats:sub>1-69 derived antibody fragments (Fabs) with similar characteristics. Interestingly, all members of the panel exhibited blocking activity against both antigenic region 2 and 3 (AR2 and AR3) in competition ELISAs, which contrasts with the behavior of most previously identified AR3-targeting antibodies. The V<jats:sub>H<\/jats:sub>1-69 derived binders had a high affinity for soluble E2 in both Fab and IgG formats, with dissociation constants in the low picomolar range. These Fab binders were broadly neutralizing against a panel of HCV cell culture viruses of genotype 1-6 with higher potency than the well-characterized reference Fab, AR3A. However, in the IgG format the antibodies had similar potency. These findings expand our understanding of potential targets for vaccine development by characterizing a panel of antibodies targeting an AR3 epitope also involving or occluding the back layer of E2. The broad neutralization and high affinity of these antibodies suggest a benefit to targeting both the back layer and the front layer of E2 in HCV vaccine designs to expand the repertoire of broadly neutralizing antibodies, thereby offering promise for the development of more effective preventive measures against this pervasive human pathogen.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012428","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T20:04:22Z","timestamp":1743192262000},"page":"e1012428","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Selection and characterization of a broadly neutralizing class of HCV anti-E2 VH1-69 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