Characterising the relationship between fowlpox virus and the mammalian immune system.

Abstract

Fowlpox viruses (FPV) are attractive platform vaccine vector candidates because their capacity for insertion of multiple heterologous genes makes them favourable for genetic modification. They also have strong adjuvant activity in their own right. As FPV does not replicate in mammalian cells, there is significantly less opposition associated with their clinical application, with a number already in use. However, a thorough understanding of the immunological relationship between FPV and the mammalian immune system is still lacking. The aim of this thesis was to construct a series of recombinant FPV vectors that co-expressed the nominal antigen chicken ovalbumin (OVA), (FPV[subscript]OVA), and/or murine interleukin-4 (mIL-4). These constructs were used for the characterisation of the relationship between FPV and the mammalian immune system and how this is altered by the co-expression of mIL-4. Immunisation with FPV[subscript]OVA resulted in rapid and highly localized OVA expression which induced strong CD8⁺ cytotoxic T cell (CTL) activity but only weak CD4⁺ T helper and antibody responses. In addition, presentation of FPV-derived antigen and the priming of antigen-specific CTL responses required a permissive bone marrow (BM)-derived cell as the antigen presenting cell (APC). Co-administration with FPV[subscript]mIL-4 resulted in a dramatic reduction in CTL activity that remained largely non-functional throughout the infection and a skewing of the T helper (Th) response towards Th2 with a reduction in interferon (IFN)-γ production by OVA-specific Th cells. These findings provide a sound basis for further characterization of how FPV interacts with the innate and adaptive arms of the immune system, how these can be manipulated via the co-administration of cytokines, and discovering if future rationally designed modifications result in FPV vectored vaccines that induce durable cellular and humoral immunity.