BCG vaccination attenuates Schistosoma mansoni-associated rural–urban immune variation

<title>Abstract</title> <p> Helminth-driven immunomodulation contributes to immune heterogeneity in tropical environments. Whether it can be reversed by BCG revaccination, an inducer of trained immunity, remains unknown. We applied high-dimensional mass cytometry to profile immune variation in Ugandan adolescents across contrasting rural–urban and <italic>Schistosoma mansoni</italic> ( <italic>Sm</italic> ) exposure settings, before and four weeks after BCG revaccination. We studied untreated rural <italic>Sm</italic> ^{<italic>+</italic>} individuals, rural individuals who became <italic>Sm</italic> ^{<italic>–</italic>} following praziquantel treatment, and urban <italic>Sm</italic> ^{<italic>–</italic>} individuals. At baseline, rural, particularly <italic>Sm</italic> ^{<italic>+</italic>} , participants exhibited immune signatures of chronic stimulation and exhaustion, including expanded CD11c ⁺ T-bet ⁺ B, CRTH2 ^hi CD4 ⁺ T, and HLA-DR ⁺ CD38 ⁺ CD8 ⁺ T cells, alongside reduced NK cells with cytotoxic potential (CD16 ⁺ , NKp46 ⁺ , KLRG1 ^hi ) and non-classical/intermediate monocytes, contrasting with urban participants. Consistent with these phenotypic differences, polyclonal stimulation elicited broadly attenuated cytokine responses in rural, versus urban, individuals. Four weeks post-BCG, rural–urban immune divergence narrowed. Cytotoxic and inflammatory innate compartments, including CD16 ⁺ /NKp46 ⁺ /KLRG1 ^hi NK cells and non-classical/intermediate monocytes, expanded, predominantly in rural <italic>Sm</italic> ^{<italic>+</italic>} individuals. Adaptive phenotypes associated with chronic stimulation and immune exhaustion, such as CRTH2 ^hi CD4 ⁺ T and CD11c ⁺ T-bet ⁺ B-cell subsets, declined, indicating partial reversal of helminth-driven immunomodulation. These findings suggest that BCG can reprogram immune profiles shaped by chronic helminth exposure, highlighting substantial immune plasticity in schistosomiasis-endemic settings. </p>