A dengue monovalent vaccine with novel structure provides cross-protection against four serotypes of dengue virus

AbstractDengue fever is caused by four different serotypes of dengue virus (DENV) which is the leading cause of worldwide arboviral diseases in humans. The vaccine candidates under development require a tetravalent immunogen to induce a balanced immunity against all four serotypes of dengue virus. Herein we show that mice vaccinated with highly matured virus-like particles derived from DENV serotype 2 (mD2VLP) can generate higher and broader neutralization antibodies (NtAbs) against all 4 serotypes of DENV through clonal expansion supported by hybridoma and B-cell repertoire analysis. The cryo-electron microscopy reconstruction showed 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. Most importantly, maternally transferred antibodies derived from mD2VLP-vaccinated female mice protected suckling mice from lethal challenge by all four serotypes of DENV. Our results support the fact that a universal dengue vaccine that protects against all four serotypes of dengue viruses can be achieved by using an immunogen such as mD2VLP.

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An epitope-resurfaced virus-like particle can induce broad neutralizing antibody against four serotypes of dengue virus

10.1101/351700 ◽

2018 ◽

Author(s):

Wen-Fan Shen ◽

Jedhan Ucat Galula ◽

Jyung-Hurng Liu ◽

Mei-Ying Liao ◽

Chang-Hao Huang ◽

...

Keyword(s):

Dengue Virus ◽

Quaternary Structure ◽

Neutralizing Antibody ◽

Icosahedral Symmetry ◽

E Proteins ◽

Cell Repertoire ◽

Virus Like Particles ◽

B Cell Repertoire ◽

Protein Dimers ◽

Virus Like Particle

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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Functional characterization and lineage analysis of broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

10.1101/790642 ◽

2019 ◽

Author(s):

Natasha D. Durham ◽

Aditi Agrawal ◽

Eric Waltari ◽

Derek Croote ◽

Fabio Zanini ◽

...

Keyword(s):

Dengue Virus ◽

B Cell ◽

Neutralizing Antibodies ◽

Somatic Hypermutation ◽

Functional Characterization ◽

Vaccine Design ◽

Protein Domain ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Domain I

AbstractEliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To delineate bNAb targets, we characterized 28 monoclonal antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies revealed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against flaviviruses with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested a memory origin and divergent somatic hypermutation pathways for these bNAbs, and a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a novel epitope that can be exploited for vaccine design.

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Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

eLife ◽

10.7554/elife.52384 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 5

Author(s):

Natasha D Durham ◽

Aditi Agrawal ◽

Eric Waltari ◽

Derek Croote ◽

Fabio Zanini ◽

...

Keyword(s):

Dengue Virus ◽

B Cell ◽

Neutralizing Antibodies ◽

Somatic Hypermutation ◽

Vaccine Design ◽

Protein Domain ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Dengue Virus Serotypes ◽

Domain I

Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To define bNAb targets, we characterized 28 antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified J9 and J8, two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies showed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against DENV with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested that J9 and J8 followed divergent somatic hypermutation pathways, and that a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a new epitope that can be exploited for vaccine design.

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Review for "Templated Insertions at VD and DJ junctions Create Unique B‐Cell Receptors in the Healthy B‐Cell Repertoire"

10.1002/eji.202048828/v1/review2 ◽

2018 ◽

Keyword(s):

B Cell ◽

B Cell Receptors ◽

Cell Repertoire ◽

Cell Receptors ◽

B Cell Repertoire

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Selection of the expressed B cell repertoire by infusion of normal immunoglobulin G in a patient with autoimmune thyroiditis

European Journal of Immunology ◽

10.1002/eji.1830231133 ◽

1993 ◽

Vol 23 (11) ◽

pp. 2945-2950 ◽

Cited By ~ 40

Author(s):

Gilles Dietrich ◽

Francisco J. Varela ◽

Vincent Hurez ◽

Majida Bouanani ◽

Michel D. Kazatchkine

Keyword(s):

B Cell ◽

Immunoglobulin G ◽

Autoimmune Thyroiditis ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Selection Of

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Monoclonal CD5+ and CD5- B-lymphocyte expansions are frequent in the peripheral blood of the elderly

Blood ◽

10.1182/blood-2003-09-3277 ◽

2004 ◽

Vol 103 (6) ◽

pp. 2337-2342 ◽

Cited By ~ 164

Author(s):

Paolo Ghia ◽

Giuseppina Prato ◽

Cristina Scielzo ◽

Stefania Stella ◽

Massimo Geuna ◽

...

Keyword(s):

B Cell ◽

Peripheral Blood ◽

B Lymphocyte ◽

The Elderly ◽

Lymphocytic Leukemia ◽

Pcr Analysis ◽

Cell Repertoire ◽

Healthy Elderly ◽

B Cell Repertoire ◽

Igh Genes

Abstract The responsiveness and diversity of peripheral B-cell repertoire decreases with age, possibly because of B-cell clonal expansions, as suggested by the incidence of serum monoclonal immunoglobulins and of monoclonal chronic lymphocytic leukemia (CLL)–like B lymphocytes in clinically silent adults. We phenotyped peripheral blood cells from 500 healthy subjects older than 65 years with no history or suspicion of malignancies and no evidence of lymphocytosis. In 19 cases (3.8%) a κ/λ ratio of more than 3:1 or less than 1:3 was found: 9 were CD5+, CD19+, CD23+, CD20low, CD79blow, sIglow (classic CLL-like phenotype); 3 were CD5+, CD19+, CD23+, CD20high, CD79blow, sIglow (atypical CLL-like), and 7 were CD5-, CD19+, CD20high, CD23-, CD79bbright, FMC7+, sIgbright (non–CLL-like). In 2 subjects, 2 phenotypically distinct unrelated clones were concomitantly evident. No cases were CD10+. Polymerase chain reaction (PCR) analysis demonstrated a monoclonal rearrangement of IgH genes in 15 of 19 cases. No bcl-1 or bcl-2 rearrangements were detected. Using a gating strategy based on CD20/CD5/CD79 expression, 13 additional CLL-like B-cell clones were identified (cumulative frequency of classic CLL-like: 5.5%). Thus, phenotypically heterogeneous monoclonal B-lymphocyte expansions are common among healthy elderly individuals and are not limited to classic CLL-like clones but may have the phenotypic features of different chronic lymphoproliferative disorders, involving also CD5- B cells.

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Analysis of Monoclonal Rheumatoid Factors obtained from the B-Cell Repertoire in Rheumatoid Arthritis

Scandinavian Journal of Immunology ◽

10.1111/j.1365-3083.1992.tb02845.x ◽

1992 ◽

Vol 35 (2) ◽

pp. 149-157 ◽

Cited By ~ 5

Author(s):

M. ABDERRAZIK ◽

M. MOYNIER ◽

R JEFFFRIS ◽

R. A. K. MAGEED ◽

B. COMBE ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

B Cell ◽

Rheumatoid Factors ◽

Cell Repertoire ◽

B Cell Repertoire

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Persistence of Viremia and Production of Neutralizing Antibodies Differentially Regulated by Polymorphic APOBEC3 and BAFF-R Loci in Friend Virus-Infected Mice

Journal of Virology ◽

10.1128/jvi.02516-09 ◽

2010 ◽

Vol 84 (12) ◽

pp. 6082-6095 ◽

Cited By ~ 27

Author(s):

Sachiyo Tsuji-Kawahara ◽

Tomomi Chikaishi ◽

Eri Takeda ◽

Maiko Kato ◽

Saori Kinoshita ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Early Stage ◽

Chromosome 15 ◽

Cell Repertoire ◽

Viral Loads ◽

Functional Polymorphisms ◽

B Cell Repertoire ◽

Retroviral Replication ◽

Different Strains ◽

Host Genes

ABSTRACT Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The Rfv3 gene influences the persistence of viremia and production of virus-neutralizing antibodies in mice infected with Friend mouse retrovirus complex (FV). This locus has been mapped within a narrow segment of mouse chromosome 15 harboring the APOBEC3 and BAFF-R loci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of the APOBEC3 allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derived APOBEC3 exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at the APOBEC3 locus affect the production of neutralizing antibodies remain unclear. Here we show that the APOBEC3 genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derived APOBEC3 still produce FV-neutralizing antibodies in the presence of primed T helper cells. Instead, higher viral loads at a very early stage of FV infection caused by either a lack of the B6-derived APOBEC3 or a lack of the wild-type BAFF-R resulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in the APOBEC3- or BAFF-R-deficient mice. In contrast to mice deficient in the B6-derived APOBEC3, which cleared viremia by 4 weeks after FV infection, mice lacking the functional BAFF-R allele exhibited sustained viremia, indicating that the polymorphisms at the BAFF-R locus may better explain the Rfv3-defining phenotype of persistent viremia.

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