Recent advances in human flavivirus vaccines

Scherwitzl, Iris; Mongkolsapaja, Juthathip; Screaton, Gavin

doi:10.1016/j.coviro.2017.04.002

Cited by 40 publications

(31 citation statements)

References 76 publications

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“…The size of the minimal ensemble was varied from 1 to 20 (1,2,3,4,6,8,20) to test the effect of ensemble size on the quality of the fitting. Starting from the atomic models of the respective full-length sfRNAs, which were assembled with the available atomic models of individual subdomains as template in Rosetta, conformational pools were generated for the respective sfRNAs using the Xplor-NIH package, which follows a simulated annealing protocol driven by molecular dynamic simulation in torsion angle space that is subject to a target function comprising of bond length, bond angles, improper dihedral angles which specify chirality and planarity of functional groups, a quartic van der Waals repulsion, and R g terms to prevent atomic overlap, a multidimensional torsion angle database potential to improve backbone and sidechain conformation.…”

Section: Ensemble Optimization Methodsmentioning

confidence: 99%

“…The respective conformational pool was used to search a minimal sub-ensemble that collectively reproduces the SAXS profile using the genetic algorithm GAJOE. The size of the minimal ensemble was varied from 1 to 20 (1,2,3,4,6,8,20) to test the effect of ensemble size on the quality of the fitting. Similar procedures were carried out for EOM analysis of xrRNA12 of DENV2, ZIKV, and WNV, and xrRNA34 of DENV2.…”

Section: Ensemble Optimization Methodsmentioning

confidence: 99%

“…Mosquito-borne flaviviruses, such as Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV), are important human pathogens that cause several million deaths and hundreds of millions of cases each year [5][6][7]. Due to the lack of effective antiviral drugs and vaccines against these viruses, they pose a significant threat to human health and are serious concerns in many parts of the world [8]. Flaviviruses are enveloped RNA viruses with singlestranded, positive sense genomic RNA (gRNA) of approximately 10-11 kb in length which consists of a single open reading frame (ORF) flanked by highly structured 5 0 and 3 0 untranslated regions (UTR).…”

Section: Introductionmentioning

confidence: 99%

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Long non‐coding subgenomic flavivirus RNAs have extended 3D structures and are flexible in solution

Zhang

Liu

et al. 2019

EMBO Reports

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Most mosquito‐borne flaviviruses, including Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV), produce long non‐coding subgenomic RNAs (sfRNAs) in infected cells that link to pathogenicity and immune evasion. Until now, the structural characterization of these lncRNAs remains limited. Here, we studied the 3D structures of individual and combined subdomains of sfRNAs, and visualized the accessible 3D conformational spaces of complete sfRNAs from DENV2, ZIKV, and WNV by small angle X‐ray scattering (SAXS) and computational modeling. The individual xrRNA1s and xrRNA2s adopt similar structures in solution as the crystal structure of ZIKV xrRNA1, and all xrRNA1‐2s form compact structures with reduced flexibility. While the DB12 of DENV2 is extended, the DB12s of ZIKV and WNV are compact due to the formation of intertwined double pseudoknots. All 3′ stem‐loops (3′SLs) share similar rod‐like structures. Complete sfRNAs are extended and sample a large conformational space in solution. Our work not only provides structural insight into the function of flavivirus sfRNAs, but also highlights strategies of visualizing other lncRNAs in solution by SAXS and computational methods.

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Section: Ensemble Optimization Methodsmentioning

confidence: 99%

Section: Ensemble Optimization Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Long non‐coding subgenomic flavivirus RNAs have extended 3D structures and are flexible in solution

Zhang

Liu

et al. 2019

EMBO Reports

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“…All of the leading DENV vaccine candidates in clinical development are based on a tetravalent strategy (Scherwitzl, Mongkolsapaja, & Screaton, 2017), which assumes that the use of representative viral strains from each serotype will elicit a balanced and potent polyclonal antibody response to minimize the risk of ADE. However, the suboptimal efficacy and safety profile of a recently licensed DENV vaccine has been partly attributed to its inability to generate a balanced neutralizing antibody response to all four serotypes (Hadinegoro et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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

Durham

Agrawal

Waltari

et al. 2019

Preprint

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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 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. E monomeric subunits within the dimer. A subset of these E dimer epitope (EDE)-specific bNAbs potently neutralize not only DENV1-4, but also ZIKV, owing to the high conservation of the EDE, which overlaps the prM binding site on E ( Barba-Spaeth et al., 2016;Dejnirattisai et al., 2015;Rouvinski et al., 2015). The exciting discovery of the EDE class of bNAbs highlights the potential for an epitope-focused flavivirus vaccine strategy.As multiple specificities are likely required to provide maximum coverage of diverse circulating viral variants (Bell et al., 2019;Doria-Rose et al., 2012;Goo, Jalalian-Lechak, Richardson, & Overbaugh, 2012;Katzelnick et al., 2015; Keeffe et al., 2018; Kong et al., 2015), in this study, we aimed to define novel sites on the flavivirus E protein that can be targeted by bNAbs. By characterizing 28 monoclonal antibodies from the plasmablasts of two DENV-infected individuals, we identified J8 and J9, clonally related bNAbs that neutralized DENV1-4 in the low picomolar range. The major recognition determinants for J8 and J9 were in E protein DI, distinct from previously characterized bNAbs. Analysis of the corresponding B cell repertoire revealed divergent evolution of J8 and J9, suggesting multiple evolutionary pathways to generate bNAbs within this lineage. Our work identifies both viral and host determinants of the development of DENV bNAbs that can guide immunogen design and evaluation. Results Identification of cross-reactive neutralizing antibodies from clonally expanded plasmablasts of DENV-infected individualsWe previously profiled the single-cell transcriptomics of peripheral blood mononuclear cells (PBMCs) from six dengue patients and four healthy individuals (Zanini et al., 2018). In two DENV-infected patients (013 and 020), we identified 15 clonal families comprising a total of 38 unique paired heavy (VH) and light (VL) chain IgG1 plasmablast sequences, some of which were hypermutated (1.67% to 10.77% for VH, 0.67% to 7.22% for...

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“…During virus maturation, prM is cleaved by host furin to form pr and M, and the pr dissociates from the virions. E protein is the key component in vaccine formulation of flaviviruses (21). Progress in vaccine development against ZIKV has been made in multiple platforms, including DNA plasmid-based (22,23), mRNA-based (24)(25)(26), and rhesus adenovirus-vectored (RhAd52) (27) vaccines incorporating the ZIKV prM/E or M/E genes, as well as inactivated (23,27) and live attenuated vaccines (28).…”

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confidence: 99%

Recombinant Chimpanzee Adenovirus Vaccine AdC7-M/E Protects against Zika Virus Infection and Testis Damage

Song

Dai

et al. 2018

J Virol

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Recent advances in human flavivirus vaccines

Cited by 40 publications

References 76 publications

Long non‐coding subgenomic flavivirus RNAs have extended 3D structures and are flexible in solution

Long non‐coding subgenomic flavivirus RNAs have extended 3D structures and are flexible in solution

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

Recombinant Chimpanzee Adenovirus Vaccine AdC7-M/E Protects against Zika Virus Infection and Testis Damage

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