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

AbstractDengue 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 we show for the first time that mD2VLP particles 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 through cryo-electron microscopy reconstruction. Mice vaccinated with highly matured virus-like particles derived from DENV serotype 2 (mD2VLP) can generate higher cross reactive (CR) neutralization antibodies (NtAbs) and were protected against all 4 serotypes of DENV through clonal expansion supported by hybridoma and B-cell repertoire analysis. Our results revealed that a “epitope-resurfaced” mature-form dengue VLP has the potential to induce quaternary structure-recognizing broad CR NtAbs.

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

eLife ◽

10.7554/elife.38970 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 9

Author(s):

Wen-Fan Shen ◽

Jedhan Ucat Galula ◽

Jyung-Hurng Liu ◽

Mei-Ying Liao ◽

Cheng-Hao Huang ◽

...

Keyword(s):

Dengue Virus ◽

Quaternary Structure ◽

Neutralizing Antibody ◽

Icosahedral Symmetry ◽

E Proteins ◽

Protein Dimers ◽

Virus Like Particle ◽

Arboviral Diseases ◽

Potential Vaccine ◽

Microscopy Examination

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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Structural and Functional Characterization of a CrosssReactive Dengue Virus Neutralizing Antibody That Recognizes a Cryptic Epitope

SSRN Electronic Journal ◽

10.2139/ssrn.3155754 ◽

2018 ◽

Author(s):

Jie Li ◽

Daniel Watterson ◽

Chiung-Wen Chang ◽

Xiao-Yan Che ◽

Xiao-Quan Li ◽

...

Keyword(s):

Dengue Virus ◽

Functional Characterization ◽

Neutralizing Antibody ◽

Cryptic Epitope

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Immune Cell Phenotypes that Determine Disease Severity and Long-Term Neutralizing Antibody Titers after Natural Dengue Virus Infection

SSRN Electronic Journal ◽

10.2139/ssrn.3565008 ◽

2020 ◽

Author(s):

Angeline Rouers ◽

Melissa Chng ◽

Bernett Lee ◽

Menaka P. Rajapakse ◽

Kaval Kaur ◽

...

Keyword(s):

Virus Infection ◽

Dengue Virus ◽

Disease Severity ◽

Immune Cell ◽

Neutralizing Antibody ◽

Dengue Virus Infection ◽

Antibody Titers ◽

Cell Phenotypes

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Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys

Molecular Therapy ◽

10.1016/j.ymthe.2017.06.020 ◽

2017 ◽

Vol 25 (10) ◽

pp. 2323-2331 ◽

Cited By ~ 1

Author(s):

Diogo M. Magnani ◽

Michael J. Ricciardi ◽

Varian K. Bailey ◽

Martin J. Gutman ◽

Núria Pedreño-Lopez ◽

...

Keyword(s):

Dengue Virus ◽

Rhesus Monkeys ◽

Neutralizing Antibody

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Development of Bacteriophage Virus-Like Particle Vaccines Displaying Conserved Epitopes of Dengue Virus Non-Structural Protein 1

Vaccines ◽

10.3390/vaccines9070726 ◽

2021 ◽

Vol 9 (7) ◽

pp. 726

Author(s):

Nikole L. Warner ◽

Kathryn M. Frietze

Keyword(s):

Dengue Virus ◽

Population Based ◽

Ns1 Protein ◽

Structural Protein ◽

Denv Serotypes ◽

Conserved Regions ◽

Virus Like Particle ◽

Dependent Cell ◽

Infected Cells ◽

Plasma Leakage

Dengue virus (DENV) is a major global health problem, with over half of the world’s population at risk of infection. Despite over 60 years of efforts, no licensed vaccine suitable for population-based immunization against DENV is available. Here, we describe efforts to engineer epitope-based vaccines against DENV non-structural protein 1 (NS1). NS1 is present in DENV-infected cells as well as secreted into the blood of infected individuals. NS1 causes disruption of endothelial cell barriers, resulting in plasma leakage and hemorrhage. Immunizing against NS1 could elicit antibodies that block NS1 function and also target NS1-infected cells for antibody-dependent cell cytotoxicity. We identified highly conserved regions of NS1 from all four DENV serotypes. We generated synthetic peptides to these regions and chemically conjugated them to bacteriophage Qβ virus-like particles (VLPs). Mice were immunized two times with the candidate vaccines and sera were tested for the presence of antibodies that bound to the cognate peptide, recombinant NS1 from all four DENV serotypes, and DENV-2-infected cells. We found that two of the candidate vaccines elicited antibodies that bound to recombinant NS1, and one candidate vaccine elicited antibodies that bound to DENV-infected cells. These results show that an epitope-specific vaccine against conserved regions of NS1 could be a promising approach for DENV vaccines or therapeutics to bind circulating NS1 protein.

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