Optimising T cell vaccination strategies for the prevention of HCV infection

Thesis

There remains an unmet global need to develop a vaccine for the prevention of HCV infection. Adenoviral and MVA vectors have been established as promising tools in the development of a prophylactic HCV vaccine strategy. A Phase I trial in humans has demonstrated the induction of broad, robust and polyfunctional HCV specific T cells following prime-boost vaccination with heterologous AdCh3/MVA-NS encoding the HCV non-structural (NS) region. An important next step therefore is to optimise strategies in which viral vectored HCV vaccines are administered. Furthermore, with the emergence of highly efficacious yet prohibitively costly directly acting antiviral therapy to treat HCV infection, an imperative question is whether individuals cured of chronic HCV infection may be amenable to vaccination to prevent re-infection.

The first section of this thesis assesses re-boosting strategies of AdCh3/MVA-NS following initial prime-boost in healthy adult volunteers. The primary aim was to establish whether either the peak magnitude and/or the memory ‘set-point’ of the HCV specific T cell response could be improved. Re-vaccination with AdCh3/MVA-NS could be demonstrated to re-boost the antigen specific T cell response, however this was more effective following a longer interval between primary and secondary vaccination rounds.

Next, in a separate phase I study, I sought to establish whether the co-administration of distinct adenoviral vectors encoding both HIV-1 and HCV immunogens could be safely administered without compromising immunogenicity of either vector. Co-administration was shown to be safe and did not compromise the immunogenicity of either immunogen.

Thirdly, I addressed whether the reversal of T cell exhaustion is possible following DAA mediated HCV cure. A functional analysis of HCV specific T cells prior to commencing and following treatment was performed. Little recovery of proliferation or cytokine production was observed, furthermore T cell responses were significantly attenuated in comparison to spontaneous viral resolution and vaccine induced T cell responses.

Finally, I performed a detailed ex vivo phenotypic analysis of HCV specific CD4+ T cells induced by vaccination and compared them with spontaneous viral resolution. Phenotypic markers suggestive of highly functional effector and memory CD4+ T cells were observed.

Authors: Hartnell, F

• DOI: 10.5287/ora-o8nbvg46x
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English