Investigation of pre-existing mycobacterial immunity on the immunogenicity and efficacy of new TB vaccines

Individuals are exposed by different routes to many species of mycobacteria. In this thesis a number of murine models of mycobacterial exposure were developed, including BCG and recombinant BCG (rBCGΔUreC:Hly) primed models, environmental mycobacterial exposure models and a latent M. tuberculosis model. These models were used to assess the immunogenicity and efficacy of recombinant viral vectors expressing the M. tuberculosis antigen 85A, including modified vaccinia Ankara virus (MV A85A) and adenovirus (adeno 85A). A phase I clinical trial of MV A85A in human latent infection was also conducted. In the BCG primed model, MV A85A and aden085A boosted Ag 85A specific IFNy producing CD4 T cells similarly. However aden085A induced significantly more Ag 85A specific IFNy producing CD8+ T cells, which were of a different phenotype to those boosted by MVA85A. Following M tuberculosis challenge, MVA85A boosting conferred some protective advantage but aden085A diminished BCG induced protection at 4 weeks. However at 12 weeks MVA85A also diminished BCG induced protection. The recombinant BCG vaccine was poorly immunogenic and conferred no protection against M tuberculosis challenge, even when boosted with MVA85A. Several intranasal models of M avium exposure were developed to simulate natural environmental mycobacterial exposure. M avium was found to be highly virulent in both BALB/c and C57BlI6 mice and no effective antibiotic regimens were found to eradicate the infection. However, live intranasal M. avium primed an M. tuberculosis Ag 85A specific response, which could be boosted by MV A85A. Intranasal heat killed mycobacteria had no effect or suppressed the Ag 85A specific response following MV A85A. In a murine latency model, MVA85A administered once or twice was highly immunogenic. However, vaccination had no effect on either the bacterial load or pathology following reactivation. In the phase I clinical trial of MVA85A in latent tuberculosis, MVA85A boosted an Ag 85A specific response as effectively as in individuals who had been BCG primed. Vaccination did not affect the T cellular response to any other mycobacterial antigens assessed. These data demonstrate that MVA85A and Aden085A are highly immunogenic, but can both increase or reduce the protection afforded by BCG. Vaccine induced IFNy production does not correlate with protection in any of the models tested. Further investigation is required to understand the interaction of M tuberculosis with its host following vaccination