Abstract
BACKGROUND: Tuberculosis disease (TB) caused 214,000 pediatric deaths in 2022. A growing body of evidence suggests that HIV exposed uninfected infants (iHEU) are at increased risk for Mycobacterium tuberculosis (Mtb) infection. Harnessing the power of the maternal immune system to protect infants has shown promise in other infections. Yet no well powered study has evaluated the association between maternal mycobacterial-specific T cell memory and infant protection from Mtb infection. To address this knowledge gap, we examined the hypothesis that previously undescribed maternal factors modulate infant immunity to bacillus Calmette-Guèrin (BCG) and Mtb. [Figure: see text] METHODS: This study was nested within a randomized controlled trial of isoniazid to prevent Mtb infection in 300 iHEU (iTIPS) who were vaccinated with BCG at birth, randomized to isoniazid or placebo at 6-10 weeks, and had Quantiferon-Plus (with IFNγ, IL2, IP10, TNF measured in supernatant) (QFT-4) at 14 months, and/or tuberculin skin testing (TST) at 14 and 24 months. Paired maternal peripheral blood mononuclear cells were collected at the 6-10 week visit. The majority (73%) of mothers started antiretroviral therapy before pregnancy, 26.3% during pregnancy, and 0.7% after pregnancy. Frequency of self-reported history of TB disease was 10.7%. We assessed the response of maternal T cells to Mtb whole cell lysate (TBWCL), a proxy for BCG, and ESAT-6/CFP-10 (E6C10), an Mtb specific peptide pool, by flow cytometry with a T cell panel including surface, memory, and activation markers and IL2, IL17A, IFNγ, and TNF. RESULTS: Our preliminary analysis of 166 of 235 maternal samples with flow cytometry revealed that mothers of infants with positive TST or QFT-4 had significantly fewer CD8(+)IL2(+) cells in response to TBWCL (median 0.0037% vs 0.0117%, p=0.032) (Fig 1). Conversely mothers of these infants had significantly higher CD4(+)TNFa(+) responses to E6C10 (median 0.0458% vs 0%, p=0.0014) and CD4(+)IFNγ(+) responses to TBWCL (median 0.0533% vs 0.0302%, p=0.0395). CONCLUSION: These results establish that maternal mycobacterial-specific immune signatures are associated with infant outcomes, which we plan to further investigate by comparing these maternal signatures with infant T cell response to TBWCL and determining the role of maternal microchimeric cells. DISCLOSURES: Sylvia M. LaCourse, MD, MPH, Merck: Grant/Research Support|UpToDate: Royalties