Dengue fever is caused by four different serotypes of dengue virus (DENV) which is the leading cause of worldwide arboviral diseases in humans. Virus-like particles (VLPs) containing flavivirus prM/E proteins have been demonstrated to be a potential vaccine candidate; however, the structure of dengue VLP is poorly understood. Herein VLP derived from DENV serotype-2 were engineered becoming highly matured (mD2VLP) and showed variable size distribution with diameter of ~31nm forming the major population under cryo-electron microscopy examination. Furthermore, mD2VLP particles of 31nm diameter possess a T=1 icosahedral symmetry with a groove located within the E-protein dimers near the 2-fold vertices that exposed highly overlapping, cryptic neutralizing epitopes. Mice vaccinated with mD2VLP generated higher cross-reactive (CR) neutralization antibodies (NtAbs) and were fully protected against all 4 serotypes of DENV. Our results highlight the potential of 'epitope-resurfaced' mature-form D2VLPs in inducing quaternary structure-recognizing broad CR NtAbs to guide future dengue vaccine design.
The cryo-EM density map of mD2VLP has been deposited to Electron Microscopy Data Bank under accession number EMDB6926. All data generated or analyzed during this study are included in the manuscript and supporting files.
Electron Microscopy Data BankEMDB6926.
- Shang-Rung Wu
- Shang-Rung Wu
- Day-Yu Chao
- Jyung-Hurng Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was carried out in compliance with the guidelines for the care and use of laboratory animals of the National Laboratory Animal Center, Taiwan. The animal use protocol has been reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of National Chung Hsing University (Approval Number: 101-58). All efforts were made to minimize suffering of mice.
- Arup K Chakraborty, Massachusetts Institute of Technology, United States
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