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Cryo-EM structure of African horse sickness virus VP2 receptor-binding protein enables nanoparticle vaccine design.
Abstract: African horse sickness virus (AHSV) is a lethal equine pathogen with no licensed vaccine other than vaccines containing attenuated virus, which pose safety risks. Endemic to sub-Saharan Africa, AHSV has caused epizootics in Spain and Portugal, Cyprus, Morocco, the Middle East, India and Pakistan and, most recently, Thailand. Here, we resolve the 3.11 Å cryo-EM structure of full-length VP2 from AHSV serotype 4, adopting its native triskelion architecture and shedding light on an α-helical domain anchoring the triskelion core, which is absent in other structurally characterized orbiviruses. Structure-guided mapping identified a subdomain of VP2 as a key target of neutralizing antibodies. Displayed on nanoparticles using the SpyCatcher/SpyTag technology, the domain conferred complete protection from clinical disease after viral challenge infection in mice and elicited robust and long-lasting immune responses in horses, the target species of AHSV. These findings provide a structural blueprint for the next generation of recombinant vaccines against AHSV and related orbiviruses.
© 2026. The Author(s).
Publication Date: 2026-07-04 PubMed ID: 42401561PubMed Central: PMC13478182DOI: 10.1038/s41467-026-75067-9Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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Overview
- This research elucidates the detailed structure of the African horse sickness virus (AHSV) VP2 protein using cryo-electron microscopy (cryo-EM).
- It uses this structural insight to guide the design of a new nanoparticle-based vaccine that offers protection against AHSV infection in mice and induces strong immune responses in horses.
Introduction to African Horse Sickness Virus (AHSV)
- AHSV is a deadly virus affecting horses, with high mortality and no widely licensed safe vaccines except for some that use attenuated (weakened) virus strains, which carry safety concerns.
- The virus is endemic to sub-Saharan Africa but has also caused outbreaks in other regions including parts of Europe, the Middle East, Asia, and most recently Thailand.
- Controlling the spread of AHSV is critical for equine health and the equine industry globally.
Structural Determination of VP2 Protein
- The researchers used cryo-electron microscopy (cryo-EM) to resolve the three-dimensional structure of the full-length VP2 protein from AHSV serotype 4 at a high resolution of 3.11 angstroms.
- VP2 is a receptor-binding protein that forms a triskelion, a 3-part structure unique in shape and critical for the virus’s ability to infect host cells.
- The structure revealed an alpha-helical domain that anchors the triskelion core, a feature not seen in previously studied orbivirus VP2 proteins, indicating unique aspects of AHSV.
- This structural insight illuminates how VP2 functions in viral attachment and entry, and provides a target for vaccine development.
Identification of Neutralizing Antibody Targets
- Using structure-guided mapping (applying the detailed structure to identify important regions), the team pinpointed a specific subdomain within VP2 that is targeted by neutralizing antibodies.
- Neutralizing antibodies are immune proteins that can block virus infection effectively, making this subdomain an ideal vaccine target.
Nanoparticle Vaccine Design and Testing
- The identified VP2 subdomain was displayed on nanoparticles by using SpyCatcher/SpyTag technology, a method for modular and stable attachment of antigens on nanoparticles to enhance immune recognition.
- This nanoparticle-displayed VP2 subdomain vaccine provided complete protection from clinical disease in mice after they were challenged with live virus, demonstrating strong efficacy.
- In horses, which are the natural hosts and target species, immunization with the nanoparticle vaccine elicited robust and durable immune responses, indicating vaccine suitability and effectiveness.
Implications and Future Directions
- The study provides a structural blueprint for designing next-generation recombinant vaccines, which are safer as they do not use live virus.”),
- Such vaccines may also be applicable to related orbiviruses, potentially widening the impact of this research.
- Overall, this research advances both the fundamental understanding of AHSV biology and the applied science of vaccine design to combat a major equine pathogen.
Cite This Article
APA
Martínez-Castillo A, Aebischer A, Toneatti P, Fu L, Vitour D, Sailleau C, Hoffmann B, Franzke K, Eschbaumer M, Weber S, Calvo Pinilla E, Ortego J, Gil-Cartón D, Bréard E, Zientara S, Kortekaas J, Beer M, Abrescia NG.
(2026).
Cryo-EM structure of African horse sickness virus VP2 receptor-binding protein enables nanoparticle vaccine design.
Nat Commun, 17(1), 8475.
https://doi.org/10.1038/s41467-026-75067-9 Publication
Researcher Affiliations
- Structure and Cell Biology of Viruses Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald, Germany.
- UMR VIROLOGIE, INRAE, École Nationale Vétérinaire d'Alfort, ANSES Laboratoire de Santé Animale, Paris-Est University, Maisons-Alfort, France.
- Structure and Cell Biology of Viruses Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.
- UMR VIROLOGIE, INRAE, École Nationale Vétérinaire d'Alfort, ANSES Laboratoire de Santé Animale, Paris-Est University, Maisons-Alfort, France.
- UMR VIROLOGIE, INRAE, École Nationale Vétérinaire d'Alfort, ANSES Laboratoire de Santé Animale, Paris-Est University, Maisons-Alfort, France.
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald, Germany.
- Institute of Infectology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald, Germany.
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald, Germany.
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald, Germany.
- Centro de Investigación en Sanidad Animal, CISA-CSIC, Valdeolmos, Madrid, Spain.
- Centro de Investigación en Sanidad Animal, CISA-CSIC, Valdeolmos, Madrid, Spain.
- Biofisika Institute (CSIC-UPV/EHU), Science Park of the UPV/EHU, Leioa, Spain.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
- UMR VIROLOGIE, INRAE, École Nationale Vétérinaire d'Alfort, ANSES Laboratoire de Santé Animale, Paris-Est University, Maisons-Alfort, France.
- UMR VIROLOGIE, INRAE, École Nationale Vétérinaire d'Alfort, ANSES Laboratoire de Santé Animale, Paris-Est University, Maisons-Alfort, France.
- Boehringer Ingelheim Animal Health, Saint Priest, France.
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald, Germany.
- Structure and Cell Biology of Viruses Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain. nabrescia@cicbiogune.es.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain. nabrescia@cicbiogune.es.
MeSH Terms
- Animals
- African Horse Sickness Virus / immunology
- African Horse Sickness Virus / ultrastructure
- African Horse Sickness Virus / genetics
- Cryoelectron Microscopy
- Horses
- African Horse Sickness / prevention & control
- African Horse Sickness / immunology
- African Horse Sickness / virology
- Viral Vaccines / immunology
- Antibodies, Neutralizing / immunology
- Capsid Proteins / immunology
- Capsid Proteins / chemistry
- Capsid Proteins / ultrastructure
- Capsid Proteins / genetics
- Capsid Proteins / metabolism
- Nanovaccines
- Mice
- Antibodies, Viral / immunology
- Female
- Protein Subunit Vaccines
- Nanoparticles / chemistry
- Vaccines, Synthetic / immunology
Grant Funding
- Wellcome Trust
Conflict of Interest Statement
Competing interests: The authors declare no competing interests.
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