Approaching rational epitope vaccine design for hepatitis C virus with meta-server and multivalent scaffolding.

TitleApproaching rational epitope vaccine design for hepatitis C virus with meta-server and multivalent scaffolding.
Publication TypeJournal Article
Year of Publication2015
AuthorsHe L, Cheng Y, Kong L, Azadnia P, Giang E, Kim J, Wood MR, Wilson IA, Law M, Zhu J
JournalSci Rep
Volume5
Pagination12501
Date Published08/04/2015
ISSN2045-2322
Abstract

Development of a prophylactic vaccine against hepatitis C virus (HCV) has been hampered by the extraordinary viral diversity and the poor host immune response. Scaffolding, by grafting an epitope onto a heterologous protein scaffold, offers a possible solution to epitope vaccine design. In this study, we designed and characterized epitope vaccine antigens for the antigenic sites of HCV envelope glycoproteins E1 (residues 314-324) and E2 (residues 412-423), for which neutralizing antibody-bound structures are available. We first combined six structural alignment algorithms in a "scaffolding meta-server" to search for diverse scaffolds that can structurally accommodate the HCV epitopes. For each antigenic site, ten scaffolds were selected for computational design, and the resulting epitope scaffolds were analyzed using structure-scoring functions and molecular dynamics simulation. We experimentally confirmed that three E1 and five E2 epitope scaffolds bound to their respective neutralizing antibodies, but with different kinetics. We then investigated a "multivalent scaffolding" approach by displaying 24 copies of an epitope scaffold on a self-assembling nanoparticle, which markedly increased the avidity of antibody binding. Our study thus demonstrates the utility of a multi-scale scaffolding strategy in epitope vaccine design and provides promising HCV immunogens for further assessment in vivo.

DOI10.1038/srep12501
Alternate JournalSci Rep
PubMed ID26238798
Grant ListUM1 AI100663 / AI / NIAID NIH HHS / United States
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