A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus

Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furt...

Full description

Saved in:
Bibliographic Details
Published in:Science translational medicine 2022-10, Vol.14 (668), p.eabq0991-eabq0991
Main Authors: Li, Haoyang, Buck, Tierra, Zandonatti, Michelle, Yin, Jieyun, Moon-Walker, Alex, Fang, Jingru, Koval, Anatoliy, Heinrich, Megan L, Rowland, Megan M, Diaz Avalos, Ruben, Schendel, Sharon L, Parekh, Diptiben, Zyla, Dawid, Enriquez, Adrian, Harkins, Stephanie, Sullivan, Brian, Smith, Victoria, Chukwudozie, Onyeka, Watanabe, Reika, Robinson, James E, Garry, Robert F, Branco, Luis M, Hastie, Kathryn M, Saphire, Erica Ollmann
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antibodies, Neutralizing
Antiviral Agents
Cryoelectron Microscopy
Electron microscopy
Epitopes
Glycoproteins
Glycosylation
Humans
Infectious diseases
Lassa Fever
Lassa virus
Mammals
Polysaccharides
Vaccines
Viral Vaccines
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furthermore, neutralizing antibodies against LASV are rare. Here, we describe biochemical analyses and high-resolution cryo-electron microscopy structures of a therapeutic cocktail of three broadly protective antibodies that target the LASV glycoprotein complex (GPC), previously identified from survivors of multiple LASV infections. Structural and mechanistic analyses reveal compatible neutralizing epitopes and complementary neutralization mechanisms that offer high potency, broad range, and resistance to escape. These antibodies either circumvent or exploit specific glycans comprising the extensive glycan shield of GPC. Further, they require mammalian glycosylation, native GPC cleavage, and proper GPC trimerization. These findings guided engineering of a next-generation GPC antigen suitable for future neutralizing antibody and vaccine discovery. Together, these results explain protective mechanisms of rare, broad, and potent antibodies and identify a strategy for the rational design of therapeutic modalities against LF and related infectious diseases.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.abq0991