Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Lassa virus (LASV) causes hemorrhagic fever and is prevalent in West Africa.
• Antibodies targeting the LASV surface glycoprotein (GPC) are crucial for protection.
• The specific features enabling potent and broad neutralization by GPC-B antibodies remain unclear.

Purpose of the Study:

• To elucidate the structural basis of potent and broadly neutralizing antibody responses against LASV GPC.
• To identify specific antibody-glycoprotein interactions that enhance neutralization.
• To guide the development of improved LASV therapeutics and vaccines.

Main Methods:

• Comparative analysis of three crystal structures of LASV GPC complexed with GPC-B antibodies.
• Characterization of antibody epitope binding and preservation of GPC conformation.
• Structure-guided amino acid substitutions in antibodies to enhance neutralization.

Main Results:

• All GPC-B antibodies recognized an overlapping epitope on adjacent GPC monomers, maintaining the prefusion trimeric conformation.
• Specific GPC-antibody interactions were identified that correlate with enhanced neutralization potency.
• Structure-guided modifications significantly increased antibody neutralization potency and breadth across all major LASV lineages.

Conclusions:

• Defining critical antibody residues for potent and broad neutralization is essential for LASV control.
• Understanding germline antibody precursors provides further insights for therapeutic and vaccine design.
• This work provides a foundation for developing effective countermeasures against Lassa virus.