title: Hepatitis C virus hypervariable region 1 variants presented on hepatitis B virus capsid-like particles induce cross-neutralizing antibodies.
abstract: Hepatitis C virus (HCV) infection is still a serious global health burden. Despite improved therapeutic options, a preventative vaccine would be desirable especially in undeveloped countries. Traditionally, highly conserved epitopes are targets for antibody-based prophylactic vaccines. In HCV-infected patients, however, neutralizing antibodies are primarily directed against hypervariable region I (HVRI) in the envelope protein E2. HVRI is the most variable region of HCV, and this heterogeneity contributes to viral persistence and has thus far prevented the development of an effective HVRI-based vaccine. The primary goal of an antibody-based HCV vaccine should therefore be the induction of cross-reactive HVRI antibodies. In this study we approached this problem by presenting selected cross-reactive HVRI variants in a highly symmetric repeated array on capsid-like particles (CLPs). SplitCore CLPs, a novel particulate antigen presentation system derived from the HBV core protein, were used to deliberately manipulate the orientation of HVRI and therefore enable the presentation of conserved parts of HVRI. These HVRI-CLPs induced high titers of cross-reactive antibodies, including neutralizing antibodies. The combination of only four HVRI CLPs was sufficient to induce antibodies cross-reactive with 81 of 326 (24.8%) naturally occurring HVRI peptides. Most importantly, HVRI CLPs with AS03 as an adjuvant induced antibodies with a 10-fold increase in neutralizing capability. These antibodies were able to neutralize infectious HCVcc isolates and 4 of 19 (21%) patient-derived HCVpp isolates. Taken together, these results demonstrate that the induction of at least partially cross-neutralizing antibodies is possible. This approach might be useful for the development of a prophylactic HCV vaccine and should also be adaptable to other highly variable viruses.
authors.affiliation: Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Milena
authors.initials: M
authors.lastname: Lange
authors.affiliation: Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Fiedler
authors.affiliation: Division of Experimental Virology, TWINCORE, Hannover, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Bankwitz
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Osburn
authors.affiliation: Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Sergei
authors.initials: S
authors.lastname: Viazov
authors.affiliation: Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Olena
authors.initials: O
authors.lastname: Brovko
authors.affiliation: Virology and Immunology Unit, National Cancer Institute, Cairo, Egypt.
authors.forename: Abdel-Rahman
authors.initials: AR
authors.lastname: Zekri
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Yury
authors.initials: Y
authors.lastname: Khudyakov
authors.affiliation: Department of Internal Medicine II, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Nassal
authors.affiliation: Department of Recombinant biotechnology, Latvian Biomedical Research and Study Centre, Riga, Latvia.
authors.forename: Paul
authors.initials: P
authors.lastname: Pumpens
authors.affiliation: Division of Experimental Virology, TWINCORE, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
authors.affiliation: Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Timm
authors.affiliation: Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.affiliation: Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Walker
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis*; D000914:Antibodies, Viral / Q000096:biosynthesis*; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D056738:Cross Protection; D004338:Drug Combinations; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D016174:Hepacivirus / Q000276:immunology*; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D056724:Immunity, Humoral; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D011136:Polysorbates / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013185:Squalene / Q000008:administration & dosage; D014761:Viral Hepatitis Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D024502:alpha-Tocopherol / Q000008:administration & dosage
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D036022:Capsid Proteins; D004338:Drug Combinations; C400562:HVR1 protein, Hepatitis C virus; D011136:Polysorbates; D011994:Recombinant Proteins; D014761:Viral Hepatitis Vaccines; D014764:Viral Proteins; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol