CoChat
Sign Up
Cited by 9Viral Infections and Outbreaks ResearchViral Infections and VectorsVirology and Viral Diseases

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane

Open access
Hastie, Kathryn M., Salie, Zhe Li, Ke, Zunlong, Halfmann, Peter J., DeWald, Lisa Evans, McArdle, Sara, Grinyó, Ariadna, Davidson, Edgar, Schendel, Sharon L., Hariharan, Chitra, Norris, Michael J., Yu, Xiaoying, Chennareddy, Chakravarthy, Xiong, Xiaoli, Heinrich, Megan, Holbrook, Michael R., Doranz, Benjamin, Crozier, Ian, Kawaoka, Yoshihiro, Branco, Luis M., Kuhn, Jens H., Briggs, John A. G., Worwa, Gabriella, Davis, Carl W., Ahmed, Rafi, Saphire, Erica Ollmann·2025·Nature Communications
DOI 10.1038/s41467-025-56452-2PMC PMC11791206

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP 1,2 ) are the standard of care for Ebola virus disease (EVD). Anti-GP 1,2 mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD. However, their neutralization mechanism is poorly understood because they target a GP 1,2 epitope that has evaded structural characterization. Using X-ray crystallography and cryo-electron tomography of mAb 3A6 complexed with its stalk–MPER epitope, we reveal a previously undescribed mechanism in which 3A6 binds to a conformation of GP 1,2 that is lifted from the virion membrane. We further show that in both domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high-viremia advanced disease stages and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. The findings reported here can guide design of next-generation highly potent anti-EBOV therapeutics and vaccines.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-025-56452-2

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 57

  1. Kuhn, J. H., Amarasinghe, G. K. & Perry, D. L. Filoviridae. In Fields virology, Vol. 1 (eds. Howley, P. M., Knipe, D. M. & Whelan, S. P. J.) 449-503 (Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, Pennsylvania, USA, 2020).
  2. Yu, X. & Saphire, E. O. Development and structural analysis of antibody therapeutics for filoviruses. Pathogens 11, 374 (2022). · DOI
  3. Sanchez, A. et al. Biochemical analysis of the secreted and virion glycoproteins of Ebola virus. J. Virol. 72, 6442–6447 (1998). · DOI
  4. Volchkov, V. E., Feldmann, H., Volchkova, V. A. & Klenk, H.-D. Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Proc. Natl Acad. Sci. USA 95, 5762–5767 (1998). · DOI
  5. Wang, H. et al. Ebola viral glycoprotein bound to its endosomal receptor Niemann-Pick C1. Cell 164, 258–268 (2016). · DOI
  6. Chandran, K., Sullivan, N. J., Felbor, U., Whelan, S. P. & Cunningham, J. M. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308, 1643–1645 (2005). · DOI
  7. Lee, J. E. et al. Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor. Nature 454, 177–182 (2008). · DOI
  8. Lee, J. et al. Structure of the Ebola virus envelope protein MPER/TM domain and its interaction with the fusion loop explains their fusion activity. Proc. Natl Acad. Sci. USA 114, E7987–E7996 (2017). · DOI
  9. Bornholdt, Z. A. et al. Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak. Science 351, 1078–1083 (2016). · DOI
  10. Corti, D. et al. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science 351, 1339–1342 (2016). · DOI
  11. Davis, C. W. et al. Longitudinal analysis of the human B cell response to Ebola virus infection. Cell 177, 1566–1582.e1517 (2019). · DOI
  12. Ehrhardt, S. A. et al. Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV. Nat. Med. 25, 1589–1600 (2019). · DOI
  13. Flyak, A. I. et al. Cross-reactive and potent neutralizing antibody responses in human survivors of natural ebolavirus infection. Cell 164, 392–405 (2016). · DOI
  14. Saphire, E. O. et al. Systematic analysis of monoclonal antibodies against Ebola virus GP defines features that contribute to protection. Cell 174, 938–952.e913 (2018). · DOI · Paper page
  15. Milligan, J. C. et al. Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses. Cell 185, 995–1007.e1018 (2022). · DOI
  16. Schoeder, C. T. et al. Epitope-focused immunogen design based on the ebolavirus glycoprotein HR2-MPER region. PLoS Pathog. 18, e1010518 (2022). · DOI
  17. Rayaprolu, V. et al. Structure of the Inmazeb cocktail and resistance to Ebola virus escape. Cell Host Microbe 31, 260–272.e267 (2023). · DOI
  18. King, L. B. et al. Cross-reactive neutralizing human survivor monoclonal antibody BDBV223 targets the ebolavirus stalk. Nat. Commun. 10, 1788 (2019). · DOI
  19. Murin, C. D. et al. Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proc. Natl Acad. Sci. USA 111, 17182–17187 (2014). · DOI
  20. Davidson, E. et al. Mechanism of binding to Ebola virus glycoprotein by the ZMapp, ZMAb, and MB-003 cocktail antibodies. J. Virol. 89, 10982–10992 (2015). · DOI
  21. Halfmann, P. et al. Generation of biologically contained Ebola viruses. Proc. Natl Acad. Sci. USA 105, 1129–1133 (2008). · DOI
  22. He, L. et al. Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines. Nat. Commun. 12, 2633 (2021). · DOI
  23. Zhao, Y. et al. Toremifene interacts with and destabilizes the Ebola virus glycoprotein. Nature 535, 169–172 (2016). · DOI
  24. Mirdita, M. et al. ColabFold: making protein folding accessible to all. Nat. Methods 19, 679–682 (2022). · DOI · Paper page
  25. Tomori, O. & Kolawole, M. O. Ebola virus disease: current vaccine solutions. Curr. Opin. Immunol. 71, 27–33 (2021). · DOI
  26. Flyak, A. I. et al. Broadly neutralizing antibodies from human survivors target a conserved site in the Ebola virus glycoprotein HR2-MPER region. Nat. Microbiol 3, 670–677 (2018). · DOI
  27. Pascal, K. E. et al. Development of clinical-stage human monoclonal antibodies that treat advanced Ebola virus disease in nonhuman primates. J. Infect. Dis. 218, S612–S626 (2018). · DOI
  28. Benton, D. J. et al. Influenza hemagglutinin membrane anchor. Proc. Natl Acad. Sci. USA 115, 10112–10117 (2018). · DOI
  29. Rantalainen, K. et al. HIV-1 envelope and MPER antibody structures in lipid assemblies. Cell Rep. 31, 107583 (2020). · DOI
  30. Smith, K. et al. Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen. Nat. Protoc. 4, 372–384 (2009). · DOI
  31. Avsic-Zupanc, T. et al. Isolation of a strain of a Hantaan virus from a fatal case of hemorrhagic fever with renal syndrome in Slovenia. Am. J. Trop. Med Hyg. 51, 393–400 (1994). · DOI
  32. Trombley, A. R. et al. Comprehensive panel of real-time TaqMan polymerase chain reaction assays for detection and absolute quantification of filoviruses, arenaviruses, and New World hantaviruses. Am. J. Trop. Med Hyg. 82, 954–960 (2010). · DOI
  33. Kabsch, W. XDS. Acta Crystallogr D. Biol. Crystallogr 66, 125–132 (2010). · DOI · Paper page
  34. Vonrhein, C. et al. Data processing and analysis with the autoPROC toolbox. Acta Crystallogr D. Biol. Crystallogr 67, 293–302 (2011). · DOI
  35. Evans, P. R. An introduction to data reduction: space-group determination, scaling and intensity statistics. Acta Crystallogr D. Biol. Crystallogr 67, 282–292 (2011). · DOI
  36. Evans, P. R. & Murshudov, G. N. How good are my data and what is the resolution? Acta Crystallogr D. Biol. Crystallogr 69, 1204–1214 (2013). · DOI
  37. McCoy, A. J. et al. Phaser crystallographic software. J. Appl Crystallogr 40, 658–674 (2007). · DOI · Paper page
  38. Winn, M. D. et al. Overview of the CCP4 suite and current developments. Acta Crystallogr D. Biol. Crystallogr 67, 235–242 (2011). · DOI · Paper page
  39. Waterhouse, A. et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 46, W296–w303 (2018). · DOI
  40. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr D. Biol. Crystallogr 60, 2126–2132 (2004). · DOI · Paper page
  41. Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr D. Struct. Biol. 75, 861–877 (2019). · DOI · Paper page
  42. Folta-Stogniew, E. Oligomeric states of proteins determined by size-exclusion chromatography coupled with light scattering, absorbance, and refractive index detectors. in Methods in Molecular Biology, Vol. 328: New and Emerging Proteomic Techniques, Vol. 328 (eds. Nedelkov, D. & Nelson, R. W.) 97-112 (Humana Press, Totowa, NJ, USA, 2006). · DOI
  43. Wen, J., Arakawa, T. & Philo, J. S. Size-exclusion chromatography with on-line light-scattering, absorbance, and refractive index detectors for studying proteins and their interactions. Anal. Biochem 240, 155–166 (1996). · DOI
  44. Murin, C. D. et al. Structural basis of pan-ebolavirus neutralization by an antibody targeting the glycoprotein fusion loop. Cell Rep. 24, 2723–2732.e2724 (2018). · DOI
  45. West, B. R. et al. Structural basis of pan-ebolavirus neutralization by a human antibody against a conserved, yet cryptic epitope. mBio 9, e01674–01618 (2018). · DOI
  46. Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017). · DOI · Paper page
  47. Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017). · DOI · Paper page
  48. Wan, W. et al. Ebola and Marburg virus matrix layers are locally ordered assemblies of VP40 dimers. Elife 9, e59225 (2020). · DOI
  49. Ke, Z. et al. Structures and distributions of SARS-CoV-2 spike proteins on intact virions. Nature 588, 498–502 (2020). · DOI
  50. Kremer, J. R., Mastronarde, D. N. & McIntosh, J. R. Computer visualization of three-dimensional image data using IMOD. J. Struct. Biol. 116, 71–76 (1996). · DOI
  51. Nickell, S. et al. TOM software toolbox: acquisition and analysis for electron tomography. J. Struct. Biol. 149, 227–234 (2005). · DOI
  52. Förster, F., Medalia, O., Zauberman, N., Baumeister, W. & Fass, D. Retrovirus envelope protein complex structure in situ studied by cryo-electron tomography. Proc. Natl Acad. Sci. USA 102, 4729–4734 (2005). · DOI
  53. Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput Chem. 25, 1605–1612 (2004). · DOI
  54. Qu, K. et al. Structure and architecture of immature and mature murine leukemia virus capsids. Proc. Natl Acad. Sci. USA 115, E11751–E11760 (2018). · DOI
  55. Bharat, T. A. M., Russo, C. J., Löwe, J., Passmore, L. A. & Scheres, S. H. W. Advances in single-particle electron cryomicroscopy structure determination applied to sub-tomogram averaging. Structure 23, 1743–1753 (2015). · DOI
  56. Bennett, R. S. et al. Kikwit Ebola virus disease progression in the rhesus monkey animal model. Viruses 12, 753 (2020). · DOI
  57. Shurtleff, A. C. et al. Standardization of the filovirus plaque assay for use in preclinical studies. Viruses 4, 3511–3530 (2012). · DOI

Metadata

Authors
Hastie, K. M., Salie, Z. L., Ke, Z., Halfmann, P. J., DeWald, L. E., McArdle, S., Grinyó, A., Davidson, E., Schendel, S. L., Hariharan, C., Norris, M. J., Yu, X., Chennareddy, C., Xiong, X., Heinrich, M., Holbrook, M. R., Doranz, B., Crozier, I., Kawaoka, Y., Branco, L. M., Kuhn, J. H., Briggs, J. A. G., Worwa, G., Davis, C. W., Ahmed, R., & Saphire, E. O.
Affiliations
  • La Jolla Institute for Immunology (US)
  • MRC Laboratory of Molecular Biology (GB)
  • University of Wisconsin–Madison (US)
  • National Institutes of Health (US)
  • Integral Molecular (United States) (US)
  • Emory University (US)
  • Zalgen (United States) (US)
  • Frederick National Laboratory for Cancer Research (US)
Corresponding author
  • Kuhn, Jens H.
  • Briggs, John A. G.
  • Worwa, Gabriella
  • Davis, Carl W.
  • Ahmed, Rafi
  • Saphire, Erica Ollmann
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-02-03
Volume
16
Issue
1
Pages
1293-1293
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-56452-2
PMC
PMC11791206
OpenAlex
W4407101507
Cited by
9
References
1
Citations by year
2026: 4 · 2025: 3
FWCI
5.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
Funders
  • U.S. Department of Defense (W31P4Q1410010)
  • U.S. Department of Energy (DE‐ AC02‐06CH11357, 76SF00515, AC02‐06CH11357, DE–AC02–76SF00515, P41GM103393, AC02‐76SF00515, 06CH11357, DE-AC02-)
  • U.S. Department of Health and Human Services (HHSN272201800013C, 75N91019D00024, HHSN261201500003I, HHSN272201400058C)
  • Battelle (DE-AC02-06CH11357, HHSN272200700016I)
  • Eli Lilly and Company
  • Emory University
  • National Center for Global Health and Medicine
  • Frederick National Laboratory for Cancer Research (75N91019D00024, HHSN261201500003I)
  • European Commission (HORIZON2020, DE-AC02-06CH11357, DE-AC02-76SF00515)
  • Chinese Academy of Sciences
  • University of Toronto
  • Max-Planck-Gesellschaft
  • National Institutes of Health (75N91019D00024, 75N91019F00130, HHSN272201800013C, ACB-12002, 1s10od012289-01a1, HHSN26100043, DE-AC02–06CH11357, HHSN272201400058C, HHSN261201500003I, DE-AC02-76SF00515, AGM-12006)
  • Defense Advanced Research Projects Agency (W31P4Q-14-1-0010, W31P4Q)
  • Office of Science (AC02-76SF00515, P41GM103393, AC02‐06CH11357, DE-AC02-76SF0051 5, DE-AC02, 06CH11357, 76SF00515, DE-AC02-06CH11357)
  • University of California, San Diego
  • Medical Research Council (MC_UP_1201/16)
  • Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
  • Institute of Medical Science, University of Tokyo
  • National Cancer Institute (DE-AC02-06CH11357, ACB12002, 75N91019F00130, 75N91019D00024, HHSN261201500003I, HHSN261201500003C, AGM-12006)
  • National Institute of General Medical Sciences (S10 OD012289, DE-AC02-06CH11357, AGM-12006, DE-AC02-76SF00515, ACB-12002, P41GM103393)
  • National Institute of Allergy and Infectious Diseases (75N91019D00024, HHSN261201500003I, HHS N272200700016I, HHSN272201400058C, 75N91019F00130, HHSN272201800013C, U19AI142790)
  • Basic Energy Sciences (DE-AC02, P41GM103393, DE-AC- 02-06CH11357, AC02‐06CH11357, 76SF00515, AC02-76SF00515, 06CH11357, DE-AC-02-76SF00515)
  • Biological and Environmental Research (P41 GM103393, DEAC0206CH11357, DE- AC0276SF00515)
  • Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357, S10 OD012289, DE-AC02-76SF00515)
  • H2020 European Research Council (648432)
  • SLAC National Accelerator Laboratory (DEAC02−76SF00515, AC02‐76SF00515, DE-AC02-06CH11357, P41GM103393)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Viral Infections and Outbreaks Research
  • Health Sciences › Medicine › Infectious Diseases › Viral Infections and Vectors
  • Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
Keywords
Ebola virus, membrane-proximal external region, therapeutic antibodies, guinea pig model, rhesus monkey model, neutralization, cryo-electron tomography, X-ray crystallography

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review