Immunization of Zika virus envelope protein domain III induces specific and neutralizing immune responses against Zika virus

Yang, Ming; Dent, Matthew; Lai, Huafang; Sun, Haiyan; Chen, Qiang

doi:10.1016/j.vaccine.2017.04.052

Cited by 91 publications

(75 citation statements)

References 37 publications

(56 reference statements)

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“…We used a previously published mechanical dissociation method to prepare single-cell suspension of the spleens from immunized mice (Jungblut et al, 2008;Yang et al, 2017). Cultures of splenocytes at 5 9 10 6 cells/mL were stimulated with 10 lg/mL of PzE.…”

Section: Spleen Cell Culture and Cytokine Productionmentioning

confidence: 99%

Plant‐produced Zika virus envelope protein elicits neutralizing immune responses that correlate with protective immunity against Zika virus in mice

Yang

Sun

Lai

et al. 2017

Plant Biotechnology Journal

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Summary The global Zika virus (ZIKV) outbreak and its link to fetal and newborn microcephaly and severe neurological complications in adults call for the urgent development of ZIKV vaccines. In response, we developed a subunit vaccine based on the ZIKV envelope (E) protein and investigated its immunogenicity in mice. Transient expression of ZIKV E (zE) resulted in its rapid accumulation in leaves of Nicotiana benthamiana plants. Biochemical analysis revealed that plant-produced ZIKV E (PzE) exhibited specific binding to a panel of monoclonal antibodies that recognize various zE conformational epitopes. Furthermore, PzE can be purified to >90% homogeneity with a one-step Ni2+ affinity chromatography process. PzE are found to be highly immunogenic, as two doses of PzE elicited both potent zE-specific antibody and cellular immune responses in mice. The delivery of PzE with alum induced a mixed Th1/Th2 immune response, as the antigen-specific IgG isotypes were a mixture of high levels of IgG1/IgG2c and splenocyte cultures from immunized mice secreted significant levels of IFN-gamma, IL-4 and IL-6. Most importantly, the titers of zE-specific and neutralizing antibodies exceeded the threshold that correlates with protective immunity against multiple strains of ZIKV. Thus, our results demonstrated the feasibility of plant-produced ZIKV protein antigen as effective, safe and affordable vaccines against ZIKV.

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Section: Spleen Cell Culture and Cytokine Productionmentioning

confidence: 99%

Plant‐produced Zika virus envelope protein elicits neutralizing immune responses that correlate with protective immunity against Zika virus in mice

Yang

Sun

Lai

et al. 2017

Plant Biotechnology Journal

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“…It is very likely that antibodies against ZV E3 can neutralize ZV infection. Recently, ZVderived E3 [24,25], ZV-derived E3 displayed on immunogenic virus-like particles [26,27], or ZV-derived E3 fused with the Fc region of human IgG [28] was found to induce neutralizing immune responses against ZV when formulated with adjuvants. The neutralizing immunogenicity on neutralizing epitopes was further enhanced by masking of a non-neutralizing epitope surrounding residue 375 of ZV E3 [29].…”

Section: Introductionmentioning

confidence: 99%

Recombinant lipidated Zika virus envelope protein domain III elicits durable neutralizing antibody responses against Zika virus in mice

et al. 2020

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Background: The emergence of Zika virus (ZV) in tropical and subtropical areas of the world has created an urgent need for vaccines against ZV. However, approved vaccines that prevent ZV infection are not available. To develop an effective vaccine against ZV infection, a lipidated form of ZV envelope protein domain III that possesses an intrinsic adjuvant property was rationally designed. Our goal was to examine the immunogenicity of recombinant lipidated ZV envelope protein domain III (rLZE3) and evaluate its potential as a vaccine candidate against ZV.Methods: Recombinant ZV envelope protein domain III (rZE3) and rLZE3 were prepared with an Escherichia colibased system. Dendritic cell surface marker expression and cytokine production upon stimulation were analyzed to evaluate the function of rLZE3. Neutralizing antibody capacities were evaluated using focus reduction neutralization tests after immunization. To investigate the protective immunity in immunized mice, serum samples collected from immunized mice were adoptively transferred into AG129 mice, and then viremia levels and survival times were examined after ZV challenge.Results: rLZE3 alone but not rZE3 alone efficiently activated dendritic cells in vitro and was taken up by dendritic cells in vivo. Immunization of C57BL/6 mice with rLZE3 alone (without exogenous adjuvant) could induce ZVspecific neutralizing antibody responses. Furthermore, serum samples obtained from rLZE3-immunized mice provided protection as indicated by a reduction in viremia levels and prolongation of survival times after ZV challenge. Conclusion: These results indicate that rLZE3 is an excellent vaccine candidate and has great potential that should be evaluated in further preclinical studies.

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“…(21) Recently, a set of monoclonal antibodies against various flaviviruses, including ZIKV has been tested. (22)(23)(24)(25) These virus-neutralizing antibodies were primarily found to target the DIII domain of viral E protein. Interestingly, six of the ten ZIKV residues that we found crucial for ZIKV stability (Lys340, Gln344, Thr353, Glu393, Lys394, Lys395) belong to DIII domain.…”

Section: Discussionmentioning

confidence: 99%

Breaking the “unbreakable” ZIKA virus envelope

Pindi

Chirasani

Homaidur

et al. 2018

Preprint

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The rapid spread of zika virus (ZIKV) and its association with microcephaly and Guillain-Barre syndrome have raised major concerns worldwide. Studies have shown that ZIKV can survive in harsh conditions, e.g. high fever; in sharp contrast to the dengue virus (DENV) of same Flaviviridae family. In spite of recent cryo-EM structures that showed similar architecture of the ZIKV and DENV envelopes, little is known of what makes ZIKV envelope so robust and unique. Here, we present a detailed analysis of the constituent raft-raft and protein-protein interactions on ZIKV and DENV envelopes to undermine their differential stability at near-atomic to atomic level using coarse-grained (CG) and all-atom (AA) molecular dynamics simulations.Our results from CG simulations show that, at high temperatures, ZIKV envelope retains its structural integrity, while DENV2 disintegrate through the formation of holes at 5-and 3-fold vertices. Protein structural network from AA simulations shows a stronger inter-raft communications in ZIKV through multiple electrostatic and Hbond interactions. Particularly, the intricate network of interlocking DE-loop and FGloop among five DIII domains in ZIKA vertices was exceedingly robust that makes this envelope stable, even at high temperatures. Our results are validated by alanine mutations to the CD-loop residues Gln350 and Thr351 that showed no effect on ZIKA stability, in close accordance with a recent mutagenesis study. These detailed information, which were difficult to extract experimentally, broadened our understanding of the flaviviruses and can accelerate the structure-based drug designing processes aiming ZIKA and DENV therapeutics. IMPORTANCEThe rapid spread of zika virus (ZIKV) and its association with severe birth defects have raised worldwide concern. Recent studies have shown that ZIKV can survive in harsh conditions, e.g. high fever, unlike dengue (DENV) and other flaviviruses. Here, we unravel the molecular basis of ZIKV unprecedented stability over DENV at high temperatures, mimicking fever. Our study, based on coarse-grained and all-atom molecular dynamics simulations, could not only explore the mechanism of DENV envelope breaking at high temperatures, but also captured atomic-level contacts and interactions at raft-raft and protein-protein interfaces that keep ZIKV envelope intact All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/345884 doi: bioRxiv preprint first posted online Jun. 13, 2018; 3 in similar conditions. The obtained results are validated by in-silico and reported invitro mutagenesis studies by showing the presence of specific H-bonding and electrostatic interactions among ZIKV E protein residues. At the end, our study was successful to define potential ZIKV epitopes and provide residue-level insights for designing specific ZIKV antibodies and small molecule ...

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Immunization of Zika virus envelope protein domain III induces specific and neutralizing immune responses against Zika virus

Cited by 91 publications

References 37 publications

Plant‐produced Zika virus envelope protein elicits neutralizing immune responses that correlate with protective immunity against Zika virus in mice

Plant‐produced Zika virus envelope protein elicits neutralizing immune responses that correlate with protective immunity against Zika virus in mice

Recombinant lipidated Zika virus envelope protein domain III elicits durable neutralizing antibody responses against Zika virus in mice

Breaking the “unbreakable” ZIKA virus envelope

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