HCV entry is mediated by the interactions between viral envelope glycoproteins and cell surface receptors such as CD81, scavenger receptor class B type I (SR-BI) and other host entry factors 11, 12. However, due to the poor fidelity of the viral RNA polymerase 9 and the high replication rate (10 12 virions/day), HCV exhibits extraordinary genetic diversity with over 30% sequence difference between genotypes 10, posing a significant challenge to the development of a broadly effective vaccine. Although small-molecule drugs are available for treatment 5, a prophylactic vaccine will offer a cost-effective means to prevent HCV transmission and to eventually eradicate the virus 6, 7, 8. Hepatitis C is a global health burden with approximately 180 million chronic carriers of hepatitis C virus (HCV) worldwide 1, 2, 3, 4. 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. 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. We experimentally confirmed that three E1 and five E2 epitope scaffolds bound to their respective neutralizing antibodies, but with different kinetics. 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 first combined six structural alignment algorithms in a “scaffolding meta-server” to search for diverse scaffolds that can structurally accommodate the HCV epitopes. 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. Scaffolding, by grafting an epitope onto a heterologous protein scaffold, offers a possible solution to epitope vaccine design.
Development of a prophylactic vaccine against hepatitis C virus (HCV) has been hampered by the extraordinary viral diversity and the poor host immune response.
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