Protection against Tuberculosis with Homologous or Heterologous Protein/Vector Vaccine Approaches Is Not Dependent on CD8+ T Cells

Abstract

Considerable effort has been directed to develop Mycobacterium tuberculosis (Mtb) vaccines to boost BCG or for those who cannot be immunized with BCG. We hypothesized that CD4+ and CD8+ T cell responses with a heterologous prime/boost vaccine approach could induce long-lived vaccine efficacy against Mtb 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 (TB) vaccine, ID93/GLA-SE, which induces potent Th1 CD4 T cells. Ad5-ID93 generates ID93-specific CD8+ T-cell responses and induces protection against Mtb. 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 Mtb. In a MHC class I deficient mouse model, all groups including the Ad5-ID93 group elicited an antigen-specific CD4+ T-cell response and significantly fewer antigen-specific CD8+ T cells, but were still protected against Mtb, suggesting that CD4+ Th1 T cells could compensate for the loss of CD8+ T cells. Lastly, the order of the heterologous immunizations was critical. Long-lived 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-γ-producing CD4+ T cells six months following the last immunization. Our findings provide insight into the development of vaccines not only for tuberculosis but other diseases requiring T cell immunity.

High‐frequency vaccine‐induced CD8+ T cells specific for an epitope naturally processed during infection with Mycobacterium tuberculosis do not confer protection

“…This is in contrast to adoptive transfer models, where CD8 + T cells have been shown to protect against M. tb . infection , but in agreement with other studies showing no or limited protective effect of vaccine‐promoted CD8 + T cells and with data showing that CD8 + T cells do not add significantly to the protection afforded by CD4 + T cells . In a recent study, Woodworth et al used a rVV (Vaccinia Virus) approach to prime CD8 + T‐cell responses to the H2‐K d ‐restricted TB10.4 20–28 epitope , which were greatly expanded by the infection but in agreement with our data, this response had no impact on bacterial loads.…”

Epitope‐specific CD4+, but not CD8+, T‐cell responses induced by recombinant influenza A viruses protect against Mycobacterium tuberculosis infection

“…Reduced direct contact of the TB10.4‐specific CD8 + T cells with M. tuberculosis ‐infected macrophages within the granuloma or relative differences in cytokine production compared to CD4 + T cells, may contribute to the lack of protection in PR8.TB10.4‐immunized mice. A similar lack of correlation between the induction of strong M. tuberculosis ‐specific CD8 + T‐cell responses and protective immunity has been reported for other experimental TB vaccines in mice . For example, stimulation of high levels of TB10.4 ‐ specific CD8 + T cells with peptide in a cationic adjuvant formulation also failed to protect against pulmonary TB .…”

Vaccination Produces CD4 T Cells with a Novel CD154–CD40-Dependent Cytolytic Mechanism

“…However cytokine-producing CD8 T cells are not evident (29). To determine whether immunization produced cytolytic CD8 T cells that were not detectable by cytokine secretion we employed an in vivo killing assay.…”