Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 45, Issue 1, Pages 309-316Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.201444686
Keywords
Adenovirus; Epitopes; Hepatitis C virus; T cells; Vaccination; Variability
Categories
Funding
- Wellcome Trust (UK)
- Medical Research Council (UK)
- James Martin School for 21st Century, Oxford (UK)
- Cancer Research UK [C399/A2291]
- MRC [MR/K010239/1, G0701694, G0901723] Funding Source: UKRI
- Medical Research Council [G0701694, MR/K010239/1, G0901723, 1890672] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10204] Funding Source: researchfish
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI082630] Funding Source: NIH RePORTER
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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- 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.
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