Neutralizing Antibodies against Lassa Virus Lineage I

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Lassa virus (LASV) causes Lassa fever (LF), with seven lineages circulating in West Africa.
• Lineage I (LI) LASV is notably resistant to antibody neutralization, impacting vaccine development.
• Current LASV vaccine candidates primarily use the Lineage I (LIV) GP sequence.

Purpose of the Study:

• To elucidate the structural basis of Lineage I LASV's antibody evasion.
• To identify specific mutations in LI responsible for reduced antibody efficacy.
• To understand LI's viral entry mechanisms and dependence on host factors.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine structures of LI GP with antibodies.
• Complementary structural and biochemical analyses.
• Assessment of viral entry dependence on LAMP1 and fusion pH.

Main Results:

• Two cryo-EM structures revealed LI GP complexed with GPC-A and GPC-B antibodies.
• Single-amino-acid substitutions in LI were identified as key to immune evasion.
• LI shows increased dependence on LAMP1 for entry and requires a more acidic pH for fusion compared to LIV.

Conclusions:

• Genetic diversity in LASV, particularly LI, poses challenges for broad vaccine and therapeutic design.
• Specific LI mutations confer resistance to potent LIV-targeting antibodies.
• Future LASV vaccine platforms should consider incorporating LI-like mutations for a broadly neutralizing response.