title: The core domain of hepatitis C virus glycoprotein E2 generates potent cross-neutralizing antibodies in guinea pigs.
abstract: A vaccine that prevents hepatitis C virus (HCV) infection is urgently needed to support an emerging global elimination program. However, vaccine development has been confounded because of HCV's high degree of antigenic variability and the preferential induction of type-specific immune responses with limited potency against heterologous viral strains and genotypes. We showed previously that deletion of the three variable regions from the E2 receptor-binding domain (Δ123) increases the ability of human broadly neutralizing antibodies (bNAbs) to inhibit E2-CD81 receptor interactions, suggesting improved bNAb epitope exposure. In this study, the immunogenicity of Δ123 was examined. We show that high-molecular-weight forms of Δ123 elicit distinct antibody specificities with potent and broad neutralizing activity against all seven HCV genotypes. Antibody competition studies revealed that immune sera raised to high-molecular-weight Δ123 was poly specific, given that it inhibited the binding of human bNAbs directed to three major neutralization epitopes on E2. By contrast, the immune sera raised to monomeric Δ123 predominantly blocked the binding of a non-neutralizing antibody to Δ123, while having reduced ability to block bNAb binding to E2, and neutralization was largely toward the homologous genotype. This increased ability of oligomeric Δ123 to generate bNAbs correlates with occlusion of the non-neutralizing face of E2 in this glycoprotein form.
  
  
  
  The results from this study reveal new information on the antigenic and immunogenic potential of E2-based immunogens and provide a pathway for the development of a simple, recombinant protein-based prophylactic vaccine for HCV with potential for universal protection. (Hepatology 2017;65:1117-1131).
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.|Department of Microbiology, Monash University, Clayton, Australia.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Vietheer
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Boo
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.|Department of Microbiology, Monash University, Clayton, Australia.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.|Department of Microbiology and Immunology at The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: Kathleen
authors.initials: K
authors.lastname: McCaffrey
authors.affiliation: CSL Limited, Parkville, Australia.
authors.forename: Stirling
authors.initials: S
authors.lastname: Edwards
authors.affiliation: CSL Limited, Parkville, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Owczarek
authors.affiliation: CSL Limited, Parkville, Australia.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Hardy
authors.affiliation: CSL Limited, Parkville, Australia.
authors.forename: Louis
authors.initials: L
authors.lastname: Fabri
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.|Department of Microbiology and Immunology at The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Center
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.|Department of Microbiology, Monash University, Clayton, Australia.
authors.forename: Pantelis
authors.initials: P
authors.lastname: Poumbourios
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.|Department of Microbiology and Immunology at The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.|Department of Microbiology, Monash University, Clayton, Australia.
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Drummer
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000918:Antibody Specificity / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000235:genetics; D005838:Genotype; D006168:Guinea Pigs; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology; D018937:Hepatitis C Antibodies / Q000276:immunology; D011897:Random Allocation; D018709:Statistics, Nonparametric; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000276:immunology; D014761:Viral Hepatitis Vaccines / Q000494:pharmacology*
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D018937:Hepatitis C Antibodies; D014759:Viral Envelope Proteins; D014761:Viral Hepatitis Vaccines; C091015:glycoprotein E2, Hepatitis C virus