Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis

Mycobacterium bovis bacille Calmette-Guérin (BCG) is the most widely used live bacterial vaccine. However, limited information is available correlating route and dose of vaccination and induction of specific T cell responses with protection against tuberculosis. We compared efficacy of oral and systemic vaccination and correlated vaccine-induced T cell responses with protection in experimental tuberculosis of mice. After oral and systemic vaccination, we observed profound differences in persistence and dissemination of BCG and frequencies and location of specific IFN-gamma-secreting CD4(+) and CD8(+) T cells. Yet, both vaccination routes caused comparable levels of protection against aerosol challenge with Mycobacterium tuberculosis. Protection correlated best with rapid accumulation of specific CD8(+) T cells in infected tissues of challenged mice. In contrast, specific IFN-gamma production by CD4(+) T cells reflected the load of M. tuberculosis rather than the strength of protection. Our data question the measurement of IFN-gamma secretion by CD4(+) T cells and emphasize the need for new biomarkers for evaluation of tuberculosis vaccine efficacies.