title: Approaching rational epitope vaccine design for hepatitis C virus with meta-server and multivalent scaffolding.
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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Linling
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Yushao
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] International AIDS Vaccine Initiative, Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Leopold
authors.initials: L
authors.lastname: Kong
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Parisa
authors.initials: P
authors.lastname: Azadnia
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Erick
authors.initials: E
authors.lastname: Giang
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Core Microscopy Facility, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Wood
authors.affiliation: 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] International AIDS Vaccine Initiative, Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Mansun
authors.initials: M
authors.lastname: Law
authors.affiliation: 1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [2] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000378:metabolism; D000956:Antigens, Viral / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D015195:Drug Design; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D057809:HEK293 Cells; D016174:Hepacivirus / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D014761:Viral Hepatitis Vaccines / Q000235:genetics* / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; C087035:E1 protein, Hepatitis C virus; D000939:Epitopes; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; D014761:Viral Hepatitis Vaccines