{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T15:07:49Z","timestamp":1780412869517,"version":"3.54.1"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2016,1,22]],"date-time":"2016-01-22T00:00:00Z","timestamp":1453420800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:p>Adenoviral vectors encoding hepatitis C virus (HCV) nonstructural (NS) proteins induce multispecific, high\u2010magnitude, durable CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T\u2010cell responses in healthy volunteers. We assessed the capacity of these vaccines to induce functional HCV\u2010specific immune responses and determine T\u2010cell cross\u2010reactivity to endogenous virus in patients with chronic HCV infection. HCV genotype 1\u2010infected patients were vaccinated using heterologous adenoviral vectors (ChAd3\u2010NSmut and Ad6\u2010NSmut) encoding HCV NS proteins in a dose escalation, prime\u2010boost regimen, with and without concomitant pegylated interferon\u2010\u03b1\/ribavirin therapy. Analysis of immune responses <jats:italic toggle=\"yes\">ex vivo<\/jats:italic> used human leukocyte antigen class I pentamers, intracellular cytokine staining, and fine mapping in interferon\u2010\u03b3 enzyme\u2010linked immunospot assays. Cross\u2010reactivity of T cells with population and endogenous viral variants was determined following viral sequence analysis. Compared to healthy volunteers, the magnitude of HCV\u2010specific T\u2010cell responses following vaccination was markedly reduced. CD8<jats:sup>+<\/jats:sup> HCV\u2010specific T\u2010cell responses were detected in 15\/24 patients at the highest dose, whereas CD4<jats:sup>+<\/jats:sup> T\u2010cell responses were rarely detectable. Analysis of the host circulating viral sequence showed that T\u2010cell responses were rarely elicited when there was sequence homology between vaccine immunogen and endogenous virus. In contrast, T cells were induced in the context of genetic mismatch between vaccine immunogen and endogenous virus; however, these commonly failed to recognize circulating epitope variants and had a distinct partially functional phenotype. Vaccination was well tolerated but had no significant effect on HCV viral load. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Vaccination with potent HCV adenoviral vectored vaccines fails to restore T\u2010cell immunity except where there is genetic mismatch between vaccine immunogen and endogenous virus; this highlights the major challenge of overcoming T\u2010cell exhaustion in the context of persistent antigen exposure with implications for cancer and other persistent infections. 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