A single residue in the yellow fever virus envelope protein modulates virion architecture and antigenicity
Yellow fever virus (YFV) is a re-emerging flavivirus that causes severe hepatic disease and mortality in humans. Despite being researched for over a century, the structure of YFV has remained elusive. Here we use a chimeric virus platform to resolve the first high resolution cryo-EM structures of YFV. Stark differences in particle morphology and homogeneity are observed between vaccine and virulent strains of YFV, and these are found to have significant implications on antibody recognition and neutralisation. We identify a single residue (R380) in the YFV<sub>17D</sub> envelope protein that stabilises the virion surface, and leads to reduced exposure of the cross-reactive fusion loop epitope. The differences in virion morphology between YFV strains also contribute to the reduced sensitivity of the virulent YFV virions to vaccine-induced antibodies. These findings have significant implications for YFV biology, vaccinology and structure-based flavivirus antigen design.
Authors
- Jody Hobson‐Peters (ORCID: https://orcid.org/0000-0003-0139-9829)
- James Jung (ORCID: https://orcid.org/0000-0001-6830-8165)
- Fasséli Coulibaly (ORCID: https://orcid.org/0000-0003-3380-2117)
- Timothy Grant (ORCID: https://orcid.org/0000-0002-4855-8703)
- Alberto A. Amarilla (ORCID: https://orcid.org/0000-0002-6640-3377)
- Daniel Watterson (ORCID: https://orcid.org/0000-0001-5957-2853)
- Natalee D. Newton (ORCID: https://orcid.org/0000-0002-5617-8639)
- Roy A. Hall (ORCID: https://orcid.org/0000-0001-5778-1387)
- Benjamin Liang (ORCID: https://orcid.org/0000-0003-3304-4715)
- Connor A. P. Scott (ORCID: https://orcid.org/0000-0001-9535-1863)
- Summa Bibby (ORCID: https://orcid.org/0000-0002-5747-7657)
- Yu Shang Low (ORCID: https://orcid.org/0000-0001-9583-0282)
- Paul R. Young (ORCID: https://orcid.org/0000-0002-2040-5190)
- Morgan E. Freney (ORCID: https://orcid.org/0000-0002-4764-3519)
- Naphak Modhiran (ORCID: https://orcid.org/0000-0003-3205-4970)
- J.M. Balk (ORCID: https://orcid.org/0009-0007-6985-9939)
- Yi Tian Ting (ORCID: https://orcid.org/0000-0001-7718-8396)
Institutions
- Howard Hughes Medical Institute (US)
- University of Wisconsin–Madison (US)
- The University of Queensland (AU)
- Janelia Research Campus (US)
- Australian Regenerative Medicine Institute (AU)
- Morgridge Institute for Research (US)
- Monash University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1038/s41467-025-63038-5
- Citations
- 4
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 7.51
Funders
- Australian Nuclear Science and Technology Organisation
- Australian Synchrotron
- National Health and Medical Research Council