Correlates of risk of TB disease in infants with differential response to BCG vaccination

Doctoral Thesis


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University of Cape Town

Studying prospective immune correlates of risk of TB disease following BCG vaccination is an important first step towards determining correlates of protection against TB, which can be identified only in a placebo-controlled randomized controlled trial (RCT) of an effective vaccine. To study correlates of risk of TB disease, we collected and stored blood from healthy 10-week old infants vaccinated with BCG at birth. During two years of follow up, infants who developed lung TB were defined as cases, while those who did not develop TB disease were defined as controls. We measured Th1/Th17 cytokine production by BCG-specific T cells, release of pro- and anti-inflammatory mediators, cytotoxic T cell potential and proliferation in response to BCG as potential correlates of risk of TB disease but none of these outcomes were different between cases and controls. However, transcriptional profiling of PBMC revealed two clusters of infants and interestingly, the gene expression profiles from cases and controls in the two clusters were in opposite directions. Based on this, we hypothesised that analysing the two clusters of infants separately will allow discovery of correlates of risk of TB, which were absent when clustering was not taken into account.

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