Functional characterization and lineage analysis of broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To delineate bNAb targets, we characterized 28 monoclonal antibodies belonging to expanded and hypermutated clonal famil...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Durham, Natasha D, Agrawal, Aditi, Waltari, Eric, Croote, Derek, Zanini, Fabio, Fouch, Mallorie, Davidson, Edgar, Smith, Olivia, Carabajal, Esteban, Pak, John E, Doranz, Benjamin J, Robinson, Makeda, Sanz, Ana Maria, Albornoz, Ludwig Luis, Rosso, Fernando, Einav, Shirit, Quake, Stephen R, Mccutcheon, Krista M, Goo, Leslie
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 02.10.2019
Subjects
Dengue fever
E protein
Epitopes
Immunoglobulins
Lymphocytes B
Monoclonal antibodies
Mutagenesis
Peripheral blood
Serotypes
Somatic hypermutation
Vaccines
Online AccessGet full text

Cover

More Information
Summary:Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To delineate bNAb targets, we characterized 28 monoclonal antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies revealed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against flaviviruses with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested a memory origin and divergent somatic hypermutation pathways for these bNAbs, and a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a novel epitope that can be exploited for vaccine design.
DOI:10.1101/790642