Summary Lassa fever is an acute hemorrhagic fever caused by the zoonotic Lassa virus (LASV). The LASV glycoprotein complex (GPC) mediates viral entry and is the sole target for neutralizing antibodies. Immunogen design is complicated by the metastable nature of recombinant GPCs and the antigenic differences among phylogenetically distinct LASV lineages. Despite the sequence diversity of the GPC, structures of most lineages are lacking. We present the development and characterization of prefusion-stabilized, trimeric GPCs of LASV lineages II, V, and VII, revealing structural conservation despite sequence diversity. High-resolution structures and biophysical characterization of the GPC in complex with GP1-A-specific antibodies suggest their neutralization mechanisms. Finally, we present the isolation and characterization of a trimer-preferring neutralizing antibody belonging to the GPC-B competition group with an epitope that spans adjacent protomers and includes the fusion peptide. Our work provides molecular detail information on LASV antigenic diversity and will guide efforts to design pan-LASV vaccines. Graphical abstract Highlights • Stabilization of diverse Lassa virus glycoproteins enables their structural characterization • mAb 12.1F, belonging to the GP1-A cluster, inhibits matriglycan and LAMP-1 binding • GP1-A mAbs show glycan dependence with 19.7E demonstrating lineage-dependent binding • A trimer-preferring Ab S370.7 targets the GPC-B epitope Perrett et al. structurally characterize Lassa glycoproteins from four lineages (II, IV, V, and VII) and determine the molecular interactions critical for GP1-A NAb engagement. They then use these stable glycoproteins to isolate an antibody from convalescent patient serum.
【저자키워드】 neutralizing antibody, cryo-EM, arenavirus, Lassa fever, structure-based vaccine design, Lassa mammarenavirus, prefusion glycoprotein,