Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M.tb), remains a global health problem and although BCG offers some protection against childhood disseminated disease and other mycobacterial infections, its efficacy against pulmonary TB varies between 0 and 80%. Modified Vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel TB vaccine designed to boost mycobacterium-specific CD4+ T cell response primed by BCG. MVA85A induces strong interferon (IFN)-γ responses, a cytokine known to be essential for protection following M.tb infection. A strong IFN-γ response is not a correlate of protection and in terms of the adaptive response, interleukin (IL)-17 is emerging as an important cytokine following vaccination as it is thought to help boost IFN-γ production by CD4+ T cells. This thesis shows that MVA85A induces IL-17 in PBMC and whole blood of human BCG – MVA85A vaccinees. This is replicated in mice receiving BCG – MVA85A intranasally. The administration of cholera toxin (CT) with BCG enhances IL-17 and confers improved protection following M.tb challenge, which is partially dependent on IL-17 and on the mucosal route of administration. Since CT is not a suitable adjuvant in humans, an alternative IL-17-inducing pathway was investigated. In human BCG – MVA85A-vaccinated volunteers, blocking the hydrolysing ability of the CD39, an apyrase responsible for hydrolysing pro-inflammatory ATP, enhances IL-17 production. Challenge of BCG – MVA85A-vaccinated CD39-/- mice with M.tb slightly improved the protective capacity of the vaccine, suggesting that a pathway dependent on ATP-driven inflammation may be a target for improving the immunogenicity of a vaccine against M.tb disease. Overall, this thesis has confirmed the important role of IL-17 in vaccine-induced protection against TB disease and identifies a possible target pathway for improvement of a novel vaccine.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:639943 |
| Date | January 2012 |
| Creators | Griffiths, Kristin Lisa |
| Contributors | McShane, Helen; Fletcher, Helen |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:3d7f5e42-59b8-4fda-a1a8-6a764ea219df |
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