Department of Bioengineering, Stanford University, Stanford, United States
Mallorie Fouch
Integral Molecular, Inc, Philadelphia, United States
Edgar Davidson
Integral Molecular, Inc, Philadelphia, United States
Olivia Smith
Chan Zuckerberg Biohub, San Francisco, United States
Esteban Carabajal
Chan Zuckerberg Biohub, San Francisco, United States
John E Pak
Chan Zuckerberg Biohub, San Francisco, United States
Benjamin J Doranz
Integral Molecular, Inc, Philadelphia, United States
Makeda Robinson
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, United States; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States
Ana M Sanz
Clinical Research Center, Fundación Valle del Lili, Cali, Colombia
Ludwig L Albornoz
Pathology and Laboratory Department, Fundación Valle del Lili, Cali, Colombia
Fernando Rosso
Clinical Research Center, Fundación Valle del Lili, Cali, Colombia; Department of Internal Medicine, Division of Infectious Diseases, Fundación Valle del Lili, Cali, Colombia
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, United States; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States
Chan Zuckerberg Biohub, San Francisco, United States; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
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 define bNAb targets, we characterized 28 antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified J9 and J8, two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies showed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against DENV with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested that J9 and J8 followed divergent somatic hypermutation pathways, and that a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a new epitope that can be exploited for vaccine design.