Development of novel vaccination strategies against murine pulmonary tuberculosis: The impact of vaccine formulation, route of immunization and host immune conditions

Tuberculosis (TB) has been a major worldwide threat to human health for several thousands of years. The failure of current BCG vaccine in controlling the global TB epidemic highlights an urgent need for improved TB vaccination regimens. The study presented in this thesis utilized a murine pulmonary TB model to (1) examine the efficacy of a number of vaccine formulations and vaccination regimens and (2) to understand the impact of vaccine formulation, the route of immunization and the host immune conditions on developing protective immunity against pulmonary TB.; We showed that co-immunization BCG with a viral-based GM-CSF transgene adjuvant formulation induced a marked enhancement on type 1 T cell immunity and subsequent immune protection against airway M. tuberculosis challenge as compared to BCG vaccination alone. Considering the lack of safe and effective mucosal vaccines capable of potent protection against pulmonary TB, we developed a brand new platform of TB vaccine, replication-deficient adenoviral TB vaccine expressing immunogenic mycobacterial antigen Ag85A (AdAg85A). We demonstrated that a single intranasal, but not intramuscular, immunization with AdAg85A provided potent protection against airway M. tuberculosis challenge at an improved level over that by cutaneous BCG vaccination. Systemic priming with an Ag85A DNA vaccine and mucosal boosting with AdAg85A conferred a further enhanced immune protection which was remarkably better than BCG vaccination. Finally, in order to understand the potential feasibility and requirements for the development of an effective TB vaccine used for CD4-deficient hosts such as HIV-infected patients, we examined the nature of CD8+ T cell responses to the subcutaneous immunization with BCG and the protective potential of CD8+ T cells in CD4 gene-deficient mice and wild type control C57BL/6 mice.; Findings described in this thesis significantly advance our understanding in terms of the nature of protective immunity and the rational design of a TB vaccination program for human clinic trials.