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Immune Cells in Cancer · Journal article
The Journal of Immunology · July 28, 2026
Encouraging direction, but not yet definitive.
BCG vaccination induces age-specific, reproducible shifts in extracellular monocyte metabolism in both controlled in vitro training and prospective in vivo newborn cohorts, with overlapping signatures implicating amino acid, lipid, and ketone pathways. The study identifies candidate metabolic mechanisms underlying BCG-induced trained immunity but does not quantify effect sizes, statistical significance, or correlation with clinical protection.
Mechanistic integration study: controlled in vitro monocyte training platform plus prospective open-label randomized cohort. In vitro: newborn (N=10) and adult (N=12) CD33+ monocytes from US-based BCG-naive participants. In vivo: Gambian newborn cohort (NCT03246230), 44–50 per arm, prospectively randomized to early vs delayed BCG, with collection before and at days 1 and 7 post-vaccination. Intervention: BCG vaccine given at birth (early) or day 7 (delayed); in vitro BCG stimulation of monocytes. Compared with: In vitro: RPMI control and untrained monocytes. In vivo: early BCG (birth) vs delayed BCG (day 7). n = 10. In vitro: US-based participant recruitment; in vivo: The Gambia.
Arginine biosynthesis pathway was highly and significantly enriched in vitro after primary BCG stimulation and training in both newborn and adult monocytes Newborn BCG-trained immunity showed significant upregulation of female sex steroids and downregulation of most other lipid pathways compared to adults Early vs delayed BCG in vivo resulted in significant downregulation of amino acid and upregulation of acylcholine pathways on day 1, followed by increases in lysophospholipids and acylcholines and decreases in pyruvate, lactate and α-ketoglutarate on day 7
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These findings suggest metabolic reprogramming as a mechanistic basis for BCG-mediated trained immunity in newborns, informing vaccine immunogenicity and off-target protection. However, the lack of clinical outcome correlation or quantified effect sizes means results remain exploratory and hypothesis-generating for future targeted mechanistic studies.
Mechanistic integration of in vitro and in vivo metabolomics in newborns reveals distinct BCG-induced metabolic signatures that may explain trained immunity, but lacks quantified effect sizes, clinical endpoints, or comparative statistical contrasts.
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Quoted from the source exactly as published.
These findings suggest metabolic reprogramming as a mechanistic basis for BCG-mediated trained immunity in newborns, informing vaccine immunogenicity and off-target protection. However, the lack of clinical outcome correlation or quantified effect sizes means results remain exploratory and hypothesis-generating for future targeted mechanistic studies.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Abstract Introduction BCG protects infants against tuberculosis as well as unrelated infections via incompletely understood mechanisms, including metabolic reprogramming of innate immune cells. We sought to characterize age-specific shifts in extracellular metabolism of human monocytes (Mo) induced by BCG stimulation in vitro, determine how they contribute to metabolic reprogramming, and integrate observations in vitro with results from human newborns in vivo. Methods In a human in vitro Mo training platform, newborn (NB = 10) and adult (AD = 12) CD33+ Mo from US-based BCG-naive participants were stimulated with RPMI (control) or BCG for 24h, washed, cultured for 6 days and stimulated with LPS for 24h to assess trained immunity. Day 1 (D1) and D7 supernatants were subjected to mass-spectrometry-based global metabolomics and data integrated with those from an in vivo prospectively randomized newborn cohort from The Gambia (NCT03246230), where BCG was given early (birth) vs delayed (D7) and peripheral blood collected before and 1 or 7 days post-BCG (N = 44-50/group). Results Arginine biosynthesis was highly and significantly enriched in vitro after both primary BCG stimulation and training in both NB and AD. NB BCG trained immunity was characterized by significant upregulation of female sex steroids and downregulation of most other lipid pathways compared to AD. In vivo, early vs delayed BCG resulted in significant downregulation of amino acid (AA) and upregulation of acylcholine pathways on D1, followed by increases in lysophospholipids and acylcholines and decreases in pyruvate, lactate and α-ketoglutarate on D7. In vivo-in vitro integration revealed overlapping signatures featuring decreases in key AA, phospholipids and acylglycines on D1, and sphingolipids, N-acetylglutamate, α-ketoglutarate and leucine/valine metabolites on D7. Conclusion Human in vitro modeling recapitulates distinct signatures of BCG primary and trained immunity in newborns that may contribute to BCG immunogenicity and off-target effects in vivo. Funding Source NIH/NIAID K08AI168487, U19AI118608, U19Al168643 Topic Categories Translational and Interventional Immunology (TI)
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