Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

Area of Science:

• Immunology
• Virology
• Vaccine Development

Background:

• Dengue virus (DENV) serotypes 1-4 pose a significant global health threat.
• Developing vaccines that elicit broadly neutralizing antibodies (bNAbs) against all DENV serotypes is a critical challenge.
• Understanding bNAb targets is essential for rational vaccine design.

Purpose of the Study:

• To identify and characterize novel broadly neutralizing antibodies (bNAbs) against all four dengue virus serotypes (DENV1-4).
• To define the epitope targeted by these bNAbs and understand their B cell evolutionary pathways.
• To explore the potential of these findings for future DENV vaccine design.

Main Methods:

• Transcriptomic analysis of single plasmablasts from DENV-infected individuals.
• Characterization of 28 antibodies from expanded and hypermutated clonal families.
• Mutagenesis studies to identify antibody recognition determinants.
• B cell repertoire analysis from acute-phase peripheral blood.

Main Results:

• Identified two somatically related bNAbs, J9 and J8, that potently neutralize DENV1-4.
• Determined that the major recognition targets for J9 and J8 are in E protein domain I, representing a novel epitope.
• Showed that J9 and J8 followed divergent somatic hypermutation pathways with limited mutations sufficient for neutralization.

Conclusions:

• Multiple B cell evolutionary pathways can lead to the generation of DENV bNAbs.
• A new epitope in E protein domain I can be targeted by DENV bNAbs.
• These findings provide a promising new target for the development of effective DENV vaccines.