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Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design.

ABSTRACT: HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions-such as the epitopes of broadly neutralizing antibodies (bNAbs)-and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1?A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1?A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1?A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.

SUBMITTER: Cowton VM

PROVIDER: S-EPMC7794244 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design.

Cowton Vanessa M VM Owsianka Ania M AM Fadda Valeria V Ortega-Prieto Ana Maria AM Cole Sarah J SJ Potter Jane A JA Skelton Jessica K JK Jeffrey Nathan N Di Lorenzo Caterina C Dorner Marcus M Taylor Garry L GL Patel Arvind H AH

NPJ vaccines 20210108 1

HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions-such as the epitopes of broadly neutralizing antibodies (bNAbs)-and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesi ...[more]

PMID: 33420102

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Project description:BackgroundMiddle East respiratory syndrome (MERS) is caused by MERS coronavirus (MERS-CoV). Thus far, MERS outbreaks have been reported from Saudi Arabia (2013 and 2014) and South Korea (2015). No specific vaccine has yet been reported against MERS.PurposeTo address the urgent need for an MERS vaccine, in the present study, we have designed two multi-epitope vaccines (MEVs) against MERS utilizing several in silico methods and tools.MethodsThe design of both the multi-epitope vaccines (MEVs) are composed of cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) epitopes, screened form thirteen different proteins of MERS-CoV. Both the MEVs also carry potential B-cell linear epitope regions, B-cell discontinuous epitopes as well as interferon-γ-inducing epitopes. Human β-defensin-2 and β-defensin-3 were used as adjuvants to enhance the immune response of MEVs. To design the MEVs, short peptide molecular linkers were utilized to link screened most potential CTL epitopes, HTL epitopes and the adjuvants. Tertiary models for both the MEVs were generated, refined, and further studied for their molecular interaction with toll-like receptor 3. The cDNAs of both MEVs were generated and analyzed in silico for their expression in a mammalian host cell line (human).ResultsScreened CTL and HTL epitopes were found to have high propensity for stable molecular interaction with HLA alleles molecules. CTL epitopes were also found to have favorable molecular interaction within the cavity of transporter associated with antigen processing. The selected CTL and HTL epitopes jointly cover upto 94.0% of worldwide human population. Both the CTL and HTL MEVs molecular models have shown to have stable binding and complex formation propensity with toll-like receptor 3. The cDNA analysis of both the MEVs have shown high expression tendency in mammalian host cell line (human).ConclusionAfter multistage in silico analysis, both the MEVs are predicted to elicit humoral as well as cell mediated immune response. Epitopes of the designed MEVs are predicted to cover large human population worldwide. Hence both the designed MEVs could be tried in vivo as potential vaccine candidates against MERS.

Project description:Zika virus is an infectious virus, that belongs to Flaviviridae family, which is transferred to humans through mosquito vectors and severely threatens human health; but, apart from available resources, no effective and secure vaccine is present against Zika virus, to prevent such infections. In current study, we employed structural vaccinology approach to design an epitope-based vaccine against Zika virus, which is biocompatible, and secure and might trigger an adaptive and innate immune response by using computational approaches. We first retrieved the protein sequence from National Center for Biotechnology Information (NCBI) database and carried out for BLAST P. After BLAST P, predicted protein sequences were shortlisted and checked for allergic features and antigenic properties. Final sequence of Zika virus, with accession number (APO40588.1) was selected based on high antigenic score and non-allergenicity. Final protein sequence used various computational approaches including antigenicity testing, toxicity evaluation, allergenicity, and conservancy assessment to identify superior B-cell and T-cell epitopes. Two B-cell epitopes, five MHC-six MHC-II epitopes and I were used to construct an immunogenic multi-epitope-based vaccine by using suitable linkers. A 50S ribosomal protein was added at N terminal to improve the immunogenicity of vaccine. In molecular docking, strong interactions were presented between constructed vaccine and Toll-like receptor 9 (- 1100.6 kcal/mol), suggesting their possible relevance in the immunological response to vaccine. The molecular dynamics simulations ensure the dynamic and structural stability of constructed vaccine. The results of C-immune simulation revealed that constructed vaccine activate B and T lymphocytes which induce high level of antibodies and cytokines to combat Zika infection. The constructed vaccine is an effective biomarker with non-sensitization, nontoxicity; nonallergic, good immunogenicity, and antigenicity, however, experimental assays are required to verify the results of present study.

Project description:BackgroundYellow fever is a mosquito-borne viral hemorrhagic disease transmitted by several species of virus-infected mosquitoes endemic to tropical regions of Central and South America and Africa. Earlier in the twentieth century, mass vaccination integrated with mosquito control was implemented to eradicate the yellow fever virus. However, regular outbreaks occur in these regions which pose a threat to travelers and residents of Africa and South America. There is no specific antiviral therapy, but there can be an effective peptide-based vaccine candidate to combat infection caused by the virus. Therefore, the study aims to design a multi-epitope-based subunit vaccine (MESV) construct against the yellow fever virus to reduce the time and cost using reverse vaccinology (RV) approach.MethodsYellow fever virus contains 10,233 nucleotides that encode for 10 proteins (C, prM, E, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) including 3 structural and 7 non-structural proteins. Structural proteins-precursor membrane protein (prM) and envelope protein (E)-were taken as a target for B cell and T cell epitope screening. Further, various immunoinformatics approaches were employed to FASTA sequences of structural proteins to retrieve B cell and T cell epitopes. MESV was constructed from these epitopes based on allergenicity, antigenicity and immunogenicity, toxicity, conservancy, and population coverage followed by structure prediction. The efficacy of the MESV construct to bind with human TLR-3, TLR-4, and TLR-8 were evaluated using molecular docking and simulation studies. Finally, in-silico cloning of vaccine construct was performed withpBR322 Escherichia coli expression system using codon optimization.ResultsPredicted epitopes evaluated and selected for MESV construction were found stable, non-allergenic, highly antigenic, and global population coverage of 68.03% according to in-silico analysis. However, this can be further tested in in-vitro and in-vivo investigations. Epitopes were sequentially merged to construct a MESV consisting of 393 amino acids using adjuvant and linkers. Molecular docking and simulation studies revealed stable and high-affinity interactions. Furthermore, in-silico immune response graphs showed effective immune response generation. Finally, higher CAI value ensured high gene expression of vaccine in the host cell.ConclusionThe designed MESV construct in the present in-silico study can be effective in generating an immune response against the yellow fever virus. Therefore, to prevent yellow fever, it can be an effective vaccine candidate. However, further downstream, in-vitro study is required.

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Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design.

Publications

Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design.

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