Strategies to improve BCG-mediated protection from Mycobacterium tuberculosis

Goonetilleke, Nilu (2004). Strategies to improve BCG-mediated protection from Mycobacterium tuberculosis. PhD thesis The Open University.



Background: Host resistance to pulmonary tuberculosis is associated with the induction of IFN-y secreting T cells in the lung. Recombinant viruses used in heterologous prime-boost immunisation regimens can evoke powerful T cell immune responses and are promising candidates for novel tuberculosis vaccines. In this thesis, the immunogenicity and protection protective efficacy of viral vectors expressing the immunodominant antigen, 85A were investigated in murine and macaque models of tuberculosis disease.
Results: Recombinant modified vaccinia virus Ankara, expressing the Mycobacterium tuberculosis antigen 85A (MVA85A), strongly boosted BCG-induced antigen 85A specific- CD4+ and CD8+ T cell responses in BALB/c and C57BL/6 mice. A comparison of intranasal and parenteral immunisation of BCG showed that whilst both routes elicited comparable T cell responses in the spleen, only intranasal delivery elicited specific T cell responses in the lung lymph nodes and these responses were further boosted by intranasal delivery of MVA85A. Following aerosol challenge of BALB/c with Mycobacterium tuberculosis, intranasal boosting of BCG with either BCG or MVA85A afforded unprecedented levels of protection in both the lungs (2.5 log) and spleens (1.5 log) compared to naive controls. Protection in the lung correlated with the induction of antigen 85A specific IFN-y secreting T cells in the lung lymph nodes.
In rhesus macaques, aerosol delivery of BCG induced comparable kinetics and frequencies of T cells in the peripheral blood compared to intradermal BCG without producing abnormal pathology. MVA85A vaccination induced low level Ag85A-specific CD4+ and CD8+ T cell responses in the blood. Further vaccination with another attenuated poxvirus, Fowlpox expressing antigen 85A significantly increased 85A-specific T cell response in 5 of 6 outbred macaques. Analysis of lymphocytes in broncheo-alveolar lavage showed that vaccination with either BCG or M.85A/F.85A induced high frequencies of 85A-specific T cells in the respiratory compartment.
Conclusions: These findings support further evaluation of mucosally targeted prime-boost vaccination approaches for tuberculosis.

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