The Impact of Maternal Infection with Mycobacterium tuberculosis on the Infant Response to BCG Immunisation.

Abstract

Bacille Calmette Guerin (BCG) immunisation induces variable protection against tuberculosis (TB) in adolescents and adults. More information on how it protects, and when, is needed. The infant response to BCG immunisation in Uganda and the influence of maternal latent Mycobacterium tuberculosis (M.tuberculosis) infection (LTBI) and maternal BCG scar on these responses were examined. Innate responses from 29 mother-infant pairs was measured using a Luminex® assay. Gene expression profiles in unstimulated infant samples collected at 1 (n=42) and 6 (n=51) weeks after birth were also analysed. Frequencies of PPD-specific IFN-γ+CD4+ T cells after 24-hour stimulation of infant samples were assessed by flow cytometry, and the time course of BCG-induced responses measured using Luminex® assay. Immunoglobulin G to PPD and tetanus toxoid was measured in plasma samples. The impact of maternal LTBI and maternal BCG scar on infant responses was investigated. Maternal BCG scar was associated with an increased infant pro-inflammatory response. Interferon and inflammation pathways were down-regulated at 1 week, but up-regulated at 6 weeks in infants of mothers with LTBI. In contrast, these pathways were both up-regulated in infants of mothers with a BCG scar at 1 and 6 weeks. PPD-specific IFN-γ+CD4+ T cells increased at 1 week and decreased at 6 weeks after birth (p=0.031). Maternal LTBI was associated with lower frequencies of IFN-γ+CD4+ T cells (p=0.015) and IFN-γ+, TNF-α+ and IL-2+ CD4+ T cells, combined (p=0.002), at 1 week after BCG. BCG-induced responses peaked around 24 weeks of age, but were not associated with maternal LTBI. Antibody responses dropped rapidly at 1 week and were not associated with maternal LTBI. In conclusion, infant responses peaked around 24 weeks of age, and maternal BCG scar was associated with increased infant proinflammatory responses. There was evidence of a shorter-term influence of maternal LTBI on infant responses.