Specific T Cell Frequency and Cytokine Expression Profile Do Not Correlate with Protection against Tuberculosis after Bacillus Calmette-Guérin Vaccination of Newborns

Abstract

Rationale: Immunogenicity of new tuberculosis (TB) vaccines is commonly assessed by measuring the frequency and cytokine expression profile of T cells. Objectives: We tested whether this outcome correlates with protection against childhood TB disease after newborn vaccination with bacillus Calmette-Guérin (BCG). Methods: Whole blood from 10-week-old infants, routinely vaccinated with BCG at birth, was incubated with BCG for 12 hours, followed by cryopreservation for intracellular cytokine analysis. Infants were followed for 2 years to identify those who developed culture-positive TB-these infants were regarded as not protected against TB. Infants who did not develop TB disease despite exposure to TB in the household, and another group of randomly selected infants who were never evaluated for TB, were also identified-these groups were regarded as protected against TB. Cells from these groups were thawed, and CD4, CD8, and gd T cell-specific expression of IFN-g, TNF-a, IL-2, and IL-17 measured by flow cytometry. Measurements and Main Results: A total of 5,662 infants were enrolled; 29 unprotected and two groups of 55 protected infants were identified. There was no difference in frequencies of BCGspecific CD4, CD8, and gd T cells between the three groups of infants. Although BCG induced complex patterns of intracellular cytokine expression, there were no differences between protected and unprotected infants. Conclusions: The frequency and cytokine profile of mycobacteriaspecific T cells did not correlate with protection against TB. Critical components of immunity against Mycobacterium tuberculosis, such as CD4 T cell IFN-g production, may not necessarily translate into immune correlates of protection against TB disease.

Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

“…Concerning the qualitative differences in immune responses observed between TB disease and LTBI, conflicting findings were previously reported, particularly on the role of IFN-γ + TNF-α + IL-2 + triple positive T cells, which has been proposed as a hallmark of TB disease [30][31][32], as well as of LTBI [33][34][35]. In addition, recent vaccine trials have revealed that these multifunctional triple positive cells not necessarily offer protection in humans [36,37]. Although a number of differences in the experimental setup can be identified between these studies, none of them can directly explain these conflicting results.…”

Novel Vaccination Strategies against Tuberculosis

“…Studies in both animal models and human clinical trials have shown that the IFN-g response to BCG vaccination is not predictive of subsequent protection from TB (Elias et al 2005;Mittrucker et al 2007;Kagina et al 2010), and recent data suggest that instead of boosting "more of the same" Th1 response it may be better to promote responses that are insufficiently promoted by BCG and mediated by T cells devoid of or low in IFN-g expression (Goldsack and Kirman 2007;Lindenstrom et al 2013). …”

Advances in tuberculosis

“…Although vaccine immunogenicity is currently measured based on the prototypic TH1 cell cytokine (IFN ) responses from cells in peripheral blood, recent data raise concern that these parameters may not correlate with risk of disease (Kagina et al, 2010). Th1 specific cytokine responses, including of polyfunctional T cells, measured at 10 weeks post-immunization did not correlate with risk of disease in BCG vaccinated newborns followed for two years.…”