Structure and antigenicity of the 2026 Bundibugyo virus glycoprotein
- 1University of Washington
Abstract
An outbreak of ebolavirus disease caused by a new zoonotic spillover of Bundibugyo virus (BDBV) is currently spreading at an unprecedented pace in the Democratic Republic of the Congo and Uganda. The outbreak has resulted in 7,733 cases with a case-fatality ratio of 48%, yet no BDBV-specific vaccines or therapeutics are available. The ebolavirus glycoprotein (GP) promotes viral entry and is the target of neutralizing antibodies and vaccine development. Here, we engineered a soluble, prefusion-stabilized GP trimer from a contemporary BDBV isolate and determined its cryo-electron microscopy structure bound to the broadly neutralizing antibody EBOV-515. It reveals the molecular basis for EBOV-515 cross-reactivity and suggests that the antibody inhibits viral entry by interfering with NPC1 engagement in addition to trapping GP in the prefusion conformation and hindering glycan cap cleavage. Mapping lineage-defining substitutions identified changes in GP1 and GP2, including R506S within an antigenic site targeted by multiple broadly neutralizing antibodies recognizing the fusion loop. Nevertheless, we found that several glycan cap-, GP base-, and HR2-directed antibodies cross-reacted and neutralized BDBV DRC/2026 GP pseudovirus with potency comparable or greater to that observed against earlier BDBV isolates and the Zaire ebolavirus Makona/2024 isolate. These findings define the antigenic properties of contemporary BDBV GP and delineate conserved epitopes as ideal targets for antibody therapeutics and for the development of pan-ebolavirus vaccines.
Related
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- Clinical Characteristics of Patients Infected with Bundibugyo Virus, DRC 2026
BibTeX
@misc{addetia2026structure,
title = {{Structure and antigenicity of the 2026 Bundibugyo virus glycoprotein}},
author = {A. Addetia and K. Uriu and C. Stewart and K. R. Sprouse and Y. Kaku and M. G. Kibria and O. Putri and S. T. Shah and Y. Fukushima and S. Kawakubo and Y.-J. Park and A. Saito and K. Sato and D. Veesler},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.761020},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.761020v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Structure and antigenicity of the 2026 Bundibugyo virus glycoprotein
AU - A. Addetia
AU - K. Uriu
AU - C. Stewart
AU - K. R. Sprouse
AU - Y. Kaku
AU - M. G. Kibria
AU - O. Putri
AU - S. T. Shah
AU - Y. Fukushima
AU - S. Kawakubo
AU - Y.-J. Park
AU - A. Saito
AU - K. Sato
AU - D. Veesler
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.761020
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.761020v1
AB - An outbreak of ebolavirus disease caused by a new zoonotic spillover of Bundibugyo virus (BDBV) is currently spreading at an unprecedented pace in the Democratic Republic of the Congo and Uganda. The outbreak has resulted in 7,733 cases with a case-fatality ratio of 48%, yet no BDBV-specific vaccines or therapeutics are available. The ebolavirus glycoprotein (GP) promotes viral entry and is the target of neutralizing antibodies and vaccine development. Here, we engineered a soluble, prefusion-stabilized GP trimer from a contemporary BDBV isolate and determined its cryo-electron microscopy structure bound to the broadly neutralizing antibody EBOV-515. It reveals the molecular basis for EBOV-515 cross-reactivity and suggests that the antibody inhibits viral entry by interfering with NPC1 engagement in addition to trapping GP in the prefusion conformation and hindering glycan cap cleavage. Mapping lineage-defining substitutions identified changes in GP1 and GP2, including R506S within an antigenic site targeted by multiple broadly neutralizing antibodies recognizing the fusion loop. Nevertheless, we found that several glycan cap-, GP base-, and HR2-directed antibodies cross-reacted and neutralized BDBV DRC/2026 GP pseudovirus with potency comparable or greater to that observed against earlier BDBV isolates and the Zaire ebolavirus Makona/2024 isolate. These findings define the antigenic properties of contemporary BDBV GP and delineate conserved epitopes as ideal targets for antibody therapeutics and for the development of pan-ebolavirus vaccines.
ER -