To analyze the effect of vaccine delivery systems on antigen recognition and vaccine efficacy, we compared immune responses in mice immunized either with an adenovirus vector expressing a fusion of Ag85B and ESAT-6 or with the recombinant fusion protein in a liposomal adjuvant. Both vaccines induced high levels of antigen-specific IFN-c production. The adjuvanted protein vaccine induced primarily a CD4 T cell response directed to the epitope Ag85B 241-255 and gave efficient protection against subsequent Mycobacterium tuberculosis infection. In contrast, the adenoviral construct induced a strong CD8 response predominantly targeted to the epitope ESAT-6 15-29 and no significant protection against infection. Vaccination with the protein vaccine resulted in highly accelerated recall of Ag85B 241-255 -specific T cells immediately post M. tuberculosis challenge whereas the ESAT-6 15-29 epitope was barely recognized during infection. Delivery of the viral construct in cationic liposomes switched the immune response to a protective one dominated by CD4 T cells targeted to the Ag85B [241][242][243][244][245][246][247][248][249][250][251][252][253][254][255] epitope. These data demonstrate that the nature of the T cell response to a vaccine antigen is more important than its magnitude with respect to protective efficacy and that vaccine-mediated changes in immunodominance can result in T cell responses of limited relevance during the natural infection.

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