Correlates of Immune Protection from Tuberculosis

Abstract

Due to the failure of chemotherapy and the only available vaccine, BCG, to control tuberculosis (TB) disease, there is an urgent need to develop new vaccines and therapeutics. The identification of correlates of immune protection or "biomarkers" will facilitate the rational design of vaccines and drugs for the prevention and clearance of TB infection. Although it is known that IFN-gamma is essential for protective immunity, animal and human studies have found that IFN-gamma alone is not sufficient for the prevention of TB disease. There is evidence that IL-23, a recently described member of the IL-12 family of cytokines, is important in the immuno-pathogenesis of TB. There is also evidence that regulatory T cells (Treg) are present in TB disease and that Treg may suppress effector T cell responses. In the last five years, clinical studies have been able to use Mycobacterium tuberculosis specific antigens, such as ESAT-6, to focus on recently infected, healthy contacts of TB patients in endemic countries. Advances in techniques such as multi-parameter flow cytometry and DNA microarray analysis will enable us to study these cohorts in great detail and facilitate the identification of immune correlates for the rational design of drugs and vaccines for the treatment and prevention of TB.

Correlates of Protection Induced by Vaccination

“…Immunity correlates best with CD4 ϩ cells that produce cytokines, particularly interleukin 23 (IL-23), which stimulates IL-17-producing CD4 ϩ cells, which in turn stimulate gamma interferon at the time of challenge, and it is the presence of the last in the lungs that is protective (46,75,106). However, CD8…”

The immune responses of central and effector memory BCG-specific CD4+ T cells in BCG-vaccinated PPD+ donors were modulated by Treg cells

“…Several studies have demonstrated that Treg are increased both at disease sites and in peripheral blood in patients with TB (Hougardy et al 2007;Li et al 2007;Guyot-Revol et al 2006). Naturally occurring CD4 + CD25 + T cells (nTreg), which constitutively express Foxp3, have been suggested to inhibit the effector functions of CD4 + and CD8 + T cells (Fletcher 2007;Belkaid and Rouse 2005;Hilchey and Bernstein 2007).…”

Challenges of Immunogenicity Assays For Vaccines

“…In some cases, the immune parameter found to be a valid correlate of protection in one population may not prove to be as strongly correlating in another. CD4 T cells producing IFN-g have been indicated to correlate with protection against tuberculosis disease in adults [8], while the cytokine profile of T cells of newborns after vaccination did not show correlation with protection against disease [9]. While antibody levels against Varicella-Zoster can serve as a measure of vaccine efficacy in adults, in a recent study in older subjects higher cell-mediated immunity levels were associated with reduced herpes zoster disease severity, while antibody levels were associated with more severe disease [10].…”