Immunogenetics of BCG Vaccination and Pediatric Tuberculosis

We examined genetic variation associated with BCG-induced innate immune responses and susceptibility to pediatric tuberculosis (TB) disease. South African study participants were enrolled at the South African Tuberculosis Vaccine Initiative (SATVI) as part of a larger BCG vaccination study. This area has one of the highest rates of TB incidence in the world. Infants were vaccinated with BCG at birth, and a nested case-control study was performed over a 2-year prospective observation period, which resulted in 135 infant TB cases and 521 controls. Whole blood was collected from BCG vaccinated infants at 10 weeks of age. Genotyping was performed with the llumina MegaEx Beadchip, and GWAS was performed against TB disease to assess for associations between genetic variants and susceptibility to TB. In addition, a subset of infants were assessed for BCG-induced innate immune responses (N=198). For these, whole blood was stimulated with BCG or media and flow cytometry was used to measure BCG-induced PDL1, CD40, and cytokine expression in myeloid (mDC) and plasmacytoid (pDC) dendritic cells, monocytes, and neutrophils. Cellular GWAS was then performed to associate genetic variants with BCG-induced immune responses.]]>
Participants were defined as having “definite TB” if they had a positive MTb culture or, a positive smear, or a positive MTb PCR from one of their samples. Participants with a chest radiograph compatible with or suggestive of TB combined with one or more additional laboratory or clinical features consistent with TB (smear negative, cough > 2 weeks, PPD skin test ≥ 15mm, failure to thrive, and recent weight loss) were defined as having “probable TB.” Individuals without radiography consistent with TB who were diagnosed with TB by the treating physician and had 2 or more clinical features suggestive of TB were defined as “possible TB.” All others were described as “not TB.” All infants were also tested for HIV infection and positive tests resulted in exclusion from the study. The following were additional exclusion criteria at 10 weeks of age: Mother known to be infected with HIV BCG not received by infant within 24 hours of birth Significant perinatal complications in the infant Any acute or chronic disease in the infant at the time of enrollment Clinically apparent anemia in the infant Household contact with any person with TB disease or any person who was coughing ]]>