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TitleDefining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses.
Journal, issue, pagesCell Rep, Vol. 43, Issue 9, Page 114708, Year 2024
Publish dateSep 24, 2024
AuthorsPhilip J M Brouwer / Hailee R Perrett / Tim Beaumont / Haye Nijhuis / Sabine Kruijer / Judith A Burger / Ilja Bontjer / Wen-Hsin Lee / James A Ferguson / Martin Schauflinger / Helena Müller-Kräuter / Rogier W Sanders / Thomas Strecker / Marit J van Gils / Andrew B Ward /
PubMed AbstractLassa fever continues to be a major public health burden in West Africa, yet effective therapies or vaccines are lacking. The isolation of protective neutralizing antibodies against the Lassa virus ...Lassa fever continues to be a major public health burden in West Africa, yet effective therapies or vaccines are lacking. The isolation of protective neutralizing antibodies against the Lassa virus glycoprotein complex (GPC) justifies the development of vaccines that can elicit strong neutralizing antibody responses. However, Lassa vaccine candidates have generally been unsuccessful at doing so, and the associated antibody responses to these vaccines remain poorly characterized. Here, we establish an electron microscopy-based epitope mapping workflow that enables high-resolution structural characterization of polyclonal antibodies to the GPC. By applying this method to rabbits vaccinated with a recombinant GPC vaccine and a GPC-derived virus-like particle, we reveal determinants of neutralization that involve epitopes of the GPC-A competition cluster. Furthermore, by identifying undescribed immunogenic off-target epitopes, we expose the challenges that recombinant GPC vaccines face. By enabling detailed polyclonal antibody characterization, our work ushers in a next generation of more rational Lassa vaccine design.
External linksCell Rep / PubMed:39243373 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 25.0 Å
Structure data

EMDB-41715, PDB-8tye:
Lassa GPC (strain Josiah) bound to rabbit polyclonal fusion-peptide-targeting antibody FP-1
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-43141, PDB-8vcv:
Lineage IV Lassa virus glycoprotein (Josiah) in complex with rabbit polyclonal antibody (GPC-C epitope)
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-43168, PDB-8ve8:
Lineage IV Lassa virus glycoprotein (Josiah) in complex with rabbit polyclonal antibody (GP1-A epitope)
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-43174: GPCysRRLL-I53-50A in complex with rabbit 187 wk 30 GPC-A, base, and fusion peptide epitope pAbs
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-43175: GPCysRRLL-I53-50A in complex with rabbit 187 wk 18 GPC-A, base, and fusion peptide epitope pAbs
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-43176: GPCysRRLL-I53-50A in complex with rabbit 188 wk 30 base epitope pAbs
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-43177: GPCysRRLL-I53-50A in complex with rabbit 189 wk 30 GPC-A and base epitope pAbs
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-43178: GPCysRRLL-I53-50A in complex with rabbit 189 wk 18 GPC-A and base epitope pAbs
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-43179: GPCysRRLL-I53-50A in complex with rabbit 190 wk 30 fusion peptide and base epitope pAbs
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-43180: GPCysRRLL-I53-50A in complex with rabbit 191 wk 30 base epitope pAbs
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-43181: GPCysRRLL-I53-50A in complex with rabbit 192 wk 30 base and fusion peptide epitope pAbs
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-43182: GPCysRRLL-I53-50A in complex with base-targeting mAb LAVA05
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-43183: GPCysRRLL-I53-50A in complex with base-targeting mAb LAVA06
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-45624, PDB-9cj7:
Lineage IV Lassa virus glycoprotein (Josiah) in complex with monoclonal antibody 8.9F
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-45625, PDB-9cj8:
Lineage IV Lassa virus glycoprotein (Josiah) in complex with rabbit polyclonal antibody (LAVA01-like epitope)
Method: EM (single particle) / Resolution: 3.74 Å

EMDB-45643, PDB-9ck7:
Lineage IV Lassa virus glycoprotein (Josiah) in complex with polyclonal antibody (GPC-A epitope) from rabbit 187
Method: EM (single particle) / Resolution: 3.45 Å

EMDB-45644, PDB-9ck8:
Lineage IV Lassa virus glycoprotein (Josiah) in complex with polyclonal antibody (GPC-A epitope) from rabbit 189
Method: EM (single particle) / Resolution: 3.04 Å

EMDB-45905: Lineage IV Lassa virus glycoprotein (Josiah) in complex with polyclonal antibody (Base-2 epitope) from rabbit 190
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • lassa virus josiah
  • oryctolagus cuniculus (rabbit)
  • lassa virus (strain mouse/sierra leone/josiah/1976)
  • thermotoga maritima (strain atcc 43589 / dsm 3109 / jcm 10099 / nbrc 100826 / msb8) (bacteria)
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Lassa virus glycoprotein complex / GPC / immune complex / antibody / polyclonal antibody / base antibody / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / Lassa / GPC-C / glycoprotein / GP1-A / monoclonal antibody / 8.9F / LL-1 / GPC-A

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