Epitope resurfacing on dengue virus-like particle vaccine preparation to induce broad neutralizing antibody

Wen Fan Shen, Jedhan Ucat Galula, Jyung Hurng Liu, Mei Ying Liao, Cheng Hao Huang, Yu Chun Wang, Han Chung Wu, Jian Jong Liang, Yi Ling Lin, Matthew T. Whitney, Gwong Jen J. Chang, Sheng Ren Chen, Shang-Rung Wu, Day Yu Chao

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 ~31 nm forming the major population under cryo-electron microscopy examination. Furthermore, mD2VLP particles of 31 nm 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.

Original languageEnglish
Article numbere38970
JournaleLife
Volume7
DOIs
Publication statusPublished - 2018 Oct 1

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Virus-Like Particle Vaccines
Dengue Vaccines
Dengue Virus
Neutralizing Antibodies
Viruses
Epitopes
Virion
Cryoelectron Microscopy
Dengue
Antibodies
Vaccines
Dimers
Electron microscopy
Proteins
Population
Serogroup

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Shen, W. F., Galula, J. U., Liu, J. H., Liao, M. Y., Huang, C. H., Wang, Y. C., ... Chao, D. Y. (2018). Epitope resurfacing on dengue virus-like particle vaccine preparation to induce broad neutralizing antibody. eLife, 7, [e38970]. https://doi.org/10.7554/eLife.38970
Shen, Wen Fan ; Galula, Jedhan Ucat ; Liu, Jyung Hurng ; Liao, Mei Ying ; Huang, Cheng Hao ; Wang, Yu Chun ; Wu, Han Chung ; Liang, Jian Jong ; Lin, Yi Ling ; Whitney, Matthew T. ; Chang, Gwong Jen J. ; Chen, Sheng Ren ; Wu, Shang-Rung ; Chao, Day Yu. / Epitope resurfacing on dengue virus-like particle vaccine preparation to induce broad neutralizing antibody. In: eLife. 2018 ; Vol. 7.
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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 ~31 nm forming the major population under cryo-electron microscopy examination. Furthermore, mD2VLP particles of 31 nm 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.",
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Shen, WF, Galula, JU, Liu, JH, Liao, MY, Huang, CH, Wang, YC, Wu, HC, Liang, JJ, Lin, YL, Whitney, MT, Chang, GJJ, Chen, SR, Wu, S-R & Chao, DY 2018, 'Epitope resurfacing on dengue virus-like particle vaccine preparation to induce broad neutralizing antibody', eLife, vol. 7, e38970. https://doi.org/10.7554/eLife.38970

Epitope resurfacing on dengue virus-like particle vaccine preparation to induce broad neutralizing antibody. / Shen, Wen Fan; Galula, Jedhan Ucat; Liu, Jyung Hurng; Liao, Mei Ying; Huang, Cheng Hao; Wang, Yu Chun; Wu, Han Chung; Liang, Jian Jong; Lin, Yi Ling; Whitney, Matthew T.; Chang, Gwong Jen J.; Chen, Sheng Ren; Wu, Shang-Rung; Chao, Day Yu.

In: eLife, Vol. 7, e38970, 01.10.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epitope resurfacing on dengue virus-like particle vaccine preparation to induce broad neutralizing antibody

AU - Shen, Wen Fan

AU - Galula, Jedhan Ucat

AU - Liu, Jyung Hurng

AU - Liao, Mei Ying

AU - Huang, Cheng Hao

AU - Wang, Yu Chun

AU - Wu, Han Chung

AU - Liang, Jian Jong

AU - Lin, Yi Ling

AU - Whitney, Matthew T.

AU - Chang, Gwong Jen J.

AU - Chen, Sheng Ren

AU - Wu, Shang-Rung

AU - Chao, Day Yu

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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 ~31 nm forming the major population under cryo-electron microscopy examination. Furthermore, mD2VLP particles of 31 nm 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.

AB - 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 ~31 nm forming the major population under cryo-electron microscopy examination. Furthermore, mD2VLP particles of 31 nm 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.

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