The Journal of Immunology Protection against Tuberculosis with Homologous or Heterologous Protein/Vector Vaccine Approaches Is Not Dependent on CD8 T Cells

Considerable effort has been directed to developMycobacterium tuberculosis vaccines to boost bacille Calmette-Guérin or for those who cannot be immunized with bacille Calmette-Guérin. We hypothesized that CD4 and CD8 T cell responses with a heterologous prime/boost vaccine approach could induce long-lived vaccine efficacy against M. tuberculosis in C57BL/6 mice. We produced an adenovirus vector expressing ID93 (Ad5-ID93) for induction of CD8 T cells to use with our candidate tuberculosis vaccine, ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE), which induces potent Th1 CD4 T cells. Ad5-ID93 generates ID93-specific CD8 T cell responses and induces protection against M. tuberculosis. When Ad5-ID93 is administered in a prime-boost strategy with ID93/GLA-SE, both CD4 and CD8 T cells are generated and provide protection against M. tuberculosis. In a MHC class I–deficient mouse model, all groups including the Ad5-ID93 group elicited an Ag-specific CD4 T cell response and significantly fewer Ag-specific CD8 T cells, but were still protected against M. tuberculosis, suggesting that CD4 Th1 T cells could compensate for the loss of CD8 T cells. Lastly, the order of the heterologous immunizations was critical. Longlived vaccine protection was observed only when Ad5-ID93 was given as the boost following an ID93/GLA-SE prime. The homologous ID93/GLA-SE prime/boost regimen also induced long-lived protection. One of the correlates of protection between these two approaches was an increase in the total number of ID93-specific IFN-g–producing CD4 T cells 6 mo following the last immunization. Our findings provide insight into the development of vaccines not only for tuberculosis, but other diseases requiring T cell immunity. The Journal of Immunology, 2013, 191: 2514–2525.