1. Microbiology and Infectious Disease
  2. Structural Biology and Molecular Biophysics
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Epitope resurfacing on dengue virus-like particle vaccine preparation to induce broad neutralizing antibody

  1. Wen-Fan Shen
  2. Jedhan Ucat Galula
  3. Jyung-Hurng Liu
  4. Mei-Ying Liao
  5. Chang-Hao Huang
  6. Yu-Chun Wang
  7. Han-Chung Wu
  8. Jian-Jong Liang
  9. Yi-Ling Lin
  10. Matthew T Whitney
  11. Gwong-Jen J Chang
  12. Sheng-Ren Chen
  13. Shang-Rung Wu  Is a corresponding author
  14. Day-Yu Chao  Is a corresponding author
  1. National Chung-Hsing University, Taiwan, Republic of China
  2. Academia Sinica, Taiwan, Republic of China
  3. Centers for Disease Control and Prevention, United States
  4. National Cheng Kung University, Taiwan, Republic of China
Research Article
  • Cited 12
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Cite this article as: eLife 2018;7:e38970 doi: 10.7554/eLife.38970

Abstract

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.

Data availability

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.

The following data sets were generated

Article and author information

Author details

  1. Wen-Fan Shen

    PhD Program in Microbial Genomics, National Chung-Hsing University, Taichung, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.

  2. Jedhan Ucat Galula

    Graduate Institute of Microbiology and Public Health, National Chung-Hsing University, Taichung, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.

  3. Jyung-Hurng Liu

    Institute of Genomics and Bioinformatics, National Chung-Hsing University, Taichung, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7173-0372

  4. Mei-Ying Liao

    Graduate Institute of Microbiology and Public Health, National Chung-Hsing University, Taichung, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.

  5. Chang-Hao Huang

    Graduate Institute of Microbiology and Public Health, National Chung-Hsing University, Taichung, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.

  6. Yu-Chun Wang

    Graduate Institute of Microbiology and Public Health, National Chung-Hsing University, Taichung, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.

  7. Han-Chung Wu

    Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5185-1169

  8. Jian-Jong Liang

    Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.

  9. Yi-Ling Lin

    Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.

  10. Matthew T Whitney

    Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Gwong-Jen J Chang

    Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9959-6585

  12. Sheng-Ren Chen

    Institute of Oral Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.

  13. Shang-Rung Wu

    Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, Republic of China
    For correspondence
    shangrungwu@gmail.com
    Competing interests
    The authors declare that no competing interests exist.

  14. Day-Yu Chao

    Graduate Institute of Microbiology and Public Health, National Chung-Hsing University, Taichung, Taiwan, Republic of China
    For correspondence
    dychao@nchu.edu.tw
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7139-026X

Funding

Ministry of Science and Technology, Taiwan (104-2320-B-006-027)

  • Shang-Rung Wu

Ministry of Science and Technology, Taiwan (105-2320-B-006-017-MY3)

  • Shang-Rung Wu

Ministry of Science and Technology, Taiwan (104-2633-B-005-001)

  • Day-Yu Chao

Ministry of Science and Technology, Taiwan (MOST 106-2313-B-005-029)

  • Jyung-Hurng Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

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.

Reviewing Editor

  1. Arup K Chakraborty, Massachusetts Institute of Technology, United States

Publication history

  1. Received: June 6, 2018
  2. Accepted: October 18, 2018
  3. Accepted Manuscript published: October 18, 2018 (version 1)
  4. Version of Record published: November 13, 2018 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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