Bacillus Calmette–Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer’s biomarkers: results from two open-label clinical trials

作者：Marc S. Weinberg, Mahesh Chandra Kodali, Z Li, Jake A Galler, Arianna R. Tidball, William Reynolds, Cathrine Young, Kelli Devitte-McKee, Hadia Fatima, Pia Kivisäkk, Mandovi Chatterjee, Arpita Kulkarni, James M. Billingsly, Alexandra L. Bartlett, Shannan J. Ho Sui, Willem M. Kühtreiber, Jessica Gerber, Alison J. McManus, Rudolph E. Tanzi, Sudeshna Das, Denise L. Faustman, Steven E. Arnold · 发表于：Communications Medicine · 年份：2026 · DOI：10.1038/s43856-026-01691-7 · 被引用次数：1 · 研究领域：Immune responses and vaccinations、Tryptophan and brain disorders、Neuroinflammation and Neurodegeneration Mechanisms

BACKGROUND: Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We assessed whether BCG induces trained immunity-like responses in adults with and without Alzheimer's-related changes. METHODS: We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer's-related pathology; n = 11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart. Protocol-defined objectives included safety, neurocognitive outcomes, and longitudinal immune and Alzheimer's biomarker changes in blood and cerebrospinal fluid. Immune responses were assessed using cytokine assays and single-cell profiling. All enrolled participants were included where data were available; longitudinal changes were analyzed using mixed-effects models. RESULTS: Here we show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-β levels...