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Title: Vaccination against Hepatitis C - Characterising the host immune response and its implications for a successful therapeutic vaccine
Author: Halliday, John
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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This thesis explores the firs t-ever administration of a prime/ boost combination of aden ovirus and MVA vector based vaccin es that target hepatitis C virus (HeV) infection to humans. Therapeutic application of these vaccines in patients with chronic HeV infection is first detailed. together with an interrogation of the immune responses genera ted. Vaccination safely ind uces novel T cells that target HeV immunogen in 5/11 vacci nated patients. However, assessment of circulating virus reveals significant sequence differences between autologous virus and the corresponding peptide in the vaccine immunogen. Further analysis shows that T cells induced by vaccination are poorly cross-reactive aga inst autologous virus epitopes. Compared with vaccination in healthy individuals, T cell responses are red uced in their frequency, magnitude and breadth in Hev infected patients who receive combination with standard HCV treatment IF N) / ribaviri n). vaccination, (pegylated either alone or in interferon-a (PEGTo help explain the reason for attenuated vaccin e responses in Hev infected patients, I next explored baseline and PEG-IFN/ribavirin induced differences in circulating lymphocyte subpopulations. At baseline, high proportions of regulato ry T cells and NK~ rl&ht cells suggest both adaptive and innate immunity is altered by chronic HCV infection. During the first 28 days of therapy, complex changes in the activation, differentiation status and cytokine profiles of circulating lymphocytes are observed over tim e. Intriguingly, PEG-IFN causes a transient but significant decrease in circulating lymphocytes that express CXCR3, a liver homing ch emokine receptor. Finally, the hypothesis that HCV th erapy ind uces CXCR3 mediated hepatic sequestration of lymphocytes was explored. In-vivo, PEG-IFN caused a transient but profound elevation of plasma IP-10 (a CXCR3-b inding chemokin e) and this co rrelated with declines in circulating CXCR3· CDS· T cells in HCV infected patients. Although in-vitro experiments show IFN-a drives hepatocytes to produce IP-10, it also causes lymphocytes to down-regulate CXCR3. Unfortunately, exogenous IFN-a does not objectively demonstrate hepatic enrichment of CXCR3·lymphocytes in a murine model.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available