title: Cross-reactivity of hepatitis C virus specific vaccine-induced T cells at immunodominant epitopes.
abstract: Viral diversity is a challenge to the development of a hepatitis C virus (HCV) vaccine. Following vaccination of humans with adenoviral vectors, we determined the capacity of T cells to target common viral variants at immundominant epitopes ex vivo. We identified two major variants for epitopes NS3(1073) and NS3(1446), and multiple variants for epitope NS3(1406) that occurred in >5% of genotype 1 and 3 sequences at a population level. Cross-reactivity of vaccine-induced T cells was determined using variant peptides in IFN-γ ELISPOT assays. Vaccine-induced T cells targeted approximately 90% of NS3(1073) genotype 1 sequences and 50% of NS3(1446) genotype 1 and 3 sequences. For NS3(1406), 62% of subtype-1b sequences were targeted. Next, we assessed whether an in vitro priming system, using dendritic cells and T cells from healthy donors, could identify a variant of NS3(1406) that was maximally cross-reactive. In vitro priming assays showed that of those tested the NS3(1406) vaccine variant was the most immunogenic. T cells primed with genotype 1 variants from subtype 1a or 1b were broadly cross-reactive with other variants from the same subtype. We conclude that immunization with candidate HCV adenoviral vaccines generates cross-reactive T cells at immunodominant epitopes. The degree of cross-reactivity varies between epitopes and may be HCV-subtype specific.
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Christabel
authors.initials: C
authors.lastname: Kelly
authors.forename: Leo
authors.initials: L
authors.lastname: Swadling
authors.forename: Anthony
authors.initials: A
authors.lastname: Brown
authors.forename: Stefania
authors.initials: S
authors.lastname: Capone
authors.forename: Antonella
authors.initials: A
authors.lastname: Folgori
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Eleanor
authors.initials: E
authors.lastname: Barnes
mesh_terms: D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003429:Cross Reactions; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D061251:Primary Cell Culture; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014611:Vaccination; D014761:Viral Hepatitis Vaccines / Q000008:administration & dosage; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: Adenovirus; Epitopes; Hepatitis C virus; T cells; Vaccination; Variability