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Title: Understanding the link between interleukin 17 and vaccine-induced protection in tuberculosis
Author: Griffiths, Kristin Lisa
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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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.
Supervisor: McShane, Helen; Fletcher, Helen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biology ; Medical Sciences ; Infectious diseases ; Immunology ; Vaccinology ; tuberculosis ; T cells ; cytokines ; interleukin 17 ; cholera toxin