BCG-specific T cell proliferation and cytotoxic capacity in infants as risk of tuberculosis disease, following newborn BCG vaccination

Abstract

Includes bibliographical references.BCG is the only vaccine against tuberculosis and has been used for over 90 years. BCG efficacy is variable, especially in countries with high TB prevalence, where over a million deaths due to tuberculosis, are still reported annually. New TB vaccines are under development to either replace or boost the BCG vaccine. However, our understanding of the immune response required for protection against TB disease, remains inadequate. Identification of a protective immune response is only possible in a clinical trial of an efficacious vaccine, allowing comparison of vaccine-induced immune responses in protected and unprotected individuals. In the absence of such a vaccine, as is the case with TB, we can only explore biomarkers of risk of disease. The most commonly measured outcomes of anti-mycobacterial immunity in clinical trials, specific Th1 cells, are typically thought to be protective in TB. However, to date, human mycobacteria-specific Th1 responses have not correlated with risk of TB disease. New approaches are urgently required to identify other factors at play in conferring protection against TB. In this thesis, we explored BCG-specific cytotoxic T cells as candidate correlates of risk of TB disease in BCG-vaccinated infants. We hypothesized that reduced production of cytotoxic molecules by T cells in response to BCG are associated with risk of developing TB disease. We designed a case/control study nested within a large trial of newborn BCG-vaccination.Blood was collected at 10 weeks and infants, were followed up for two years.We compared outcomes in infants ultimately diagnosed with TB (at risk of TB disease) and two groups of healthy infants (not at risk of TB disease), the first group had household contact with TB cases, the second group were randomly selected from the community, which is endemic for TB. Amongst these groups, we designated a training and a test cohort to allow validation of candidate correlates of risk of TB