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This thesis explores the first-ever administration of a prime/boost combination of adenovirus and MVA vector based vaccines that target hepatitis C virus (HCV) infection to humans. Therapeutic application of these vaccines in patients with chronic HCV infection is first detailed, together with an interrogation of the immune responses generated. Vaccination safely induces novel T cells that target HCV immunogen in 5/11 vaccinated 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 against autologous virus epitopes. Compared with vaccination in healthy individuals, T cell responses are reduced in their frequency, magnitude and breadth in HCV infected patients who receive vaccination, either alone or in combination with standard HCV treatment (pegylated interferon-α (PEG-IFN)/ribavirin). To help explain the reason for attenuated vaccine responses in HCV infected patients, I next explored baseline and PEG-IFN/ribavirin induced differences in circulating lymphocyte subpopulations. At baseline, high proportions of regulatory T cells and NKbright 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 time. Intriguingly, PEG-IFN causes a transient but significant decrease in circulating lymphocytes that express CXCR3, a liver homing chemokine receptor. Finally, the hypothesis that HCV therapy induces CXCR3 mediated hepatic sequestration of lymphocytes was explored. In-vivo, PEG-IFN caused a transient but profound elevation of plasma IP-10 (a CXCR3-binding chemokine) and this correlated with declines in circulating CXCR3+ CD8+ T cells in HCV infected patients. Although in-vitro experiments show IFN-α drives hepatocytes to produce IP-10, it also causes lymphocytes to down-regulate CXCR3. Unfortunately, exogenous IFN-α does not objectively demonstrate hepatic enrichment of CXCR3+ lymphocytes in a murine model.

This thesis concerns the process of creativity. The role of the body is considered to be crucial and phenomenology is the adopted philosophical approach. The methodology is investigative and interrogative rather than didactic and emphasizes relationship. The aim is to tease out rather than to offer magisterial theory. The adopted voice varies being objective, personal and conversational. Dreams, unconscious errors and slips are featured. There is emphasis upon psyche throughout. There are two sections: critical analysis and creative work. The author's physical experience at a poetry reading is recounted. Bachelard's ideas about the poetic image are reviewed. Discovery and making are contrasted and some ideas of the psychological writers, Shorter and Coltart, are examined. Keats's notion of 'Negative Capability' appears alongside some recent medical research in the neurosciences. The implications of Jaynes's 'bicameral mind' are evaluated together with Plato's attack on poetry in Republic. The nature of the Iliadic mind is interrogated. Poetry's bodily impact and the notion of katokoche (bodily possession by the muses) are explored. Recent neuro-scientific research into memory is investigated. How the senses are implicated in the process of making is questioned using comment from writers themselves about the nature of poetry. Reverberation is acknowledged, in both theory and practice. The 'gut brain' and its relationship to the head brain and Merleau-Ponty's ideas about the body as subject are complemented. The Romantics and the emergence of the modem psyche are scrutinized. Keats's 'Ode to Psyche' is critiqued. The emergence of a new language and the centrality of sexuality are considered. Some modem psychological ideas on creativity follow. Robert Nash's notion of the scholarly personal narrative [SPN] aids exploration of the influences and development of the author as a writer. The notion of the hunter is central and the valencies, marriages and associations of words are explored. A coda concludes the critical work. The creative work under the title of 'Blood Stories' comprises three prose pieces and forty-six poems. The Bibliography is followed by the Appendix comprising a Synopsis of Process and the work concludes with the End Notes.