Bacillus Calmette–Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer’s biomarkers: results from two open-label clinical trials
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: 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 in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed. CONCLUSIONS: These findings suggest trained immunity-like responses in the central nervous system that may influence Alzheimer's-relevant pathways. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations. TRIAL REGISTRATION: ClinicalTrials.gov NCT04507126 (June 23, 2020) and NCT05004688 (August 6, 2021).
Source: Communications Medicine
Authors: Marc S. Weinberg, Mahesh Chandra Kodali, Zhaozhi Li, Jake A. Galler, Arianna R. Tidball, William Cody Reynolds, Cathrine Young, Kelli Devitte-McKee, Hadia A. Fatima, Pia Kivisäkk, Mandovi Chatterjee, Arpita Kulkarni, James M. Billingsly, Alexandra L. Bartlett, Shannan Ho Sui, Willem M. Kühtreiber, Jessica Gerber, Alison J. McManus, Rudolph E. Tanzi, Sudeshna Das, Denise L. Faustman, Steven E. Arnold
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,690
Funders: Alzheimer's Association, Harvard University, Cure Alzheimer's Fund, Harvard T.H. Chan School of Public Health, Massachusetts Life Sciences Center, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Center for Advancing Translational Sciences, Office of Extramural Research, National Institutes of Health
Awards: CNS immunomodulation from peripheral live vaccine challenge in AD, Fostering Research Mentorship and Training During Psychiatry Residency, G265784363, Translational Neuroscience Training for Clinicians, The Harvard Clinical and Translational Science Center, G4916683472, BCG Immunization effects on Biomarkers of Inflammation/Immune Response and Alzheimer’s Disease, G8913047308, Harvard Clinical and Translational Science Center, Massachusetts Alzheimer's Disease Research Center (MADRC)
OpenAlex ID: W7167127038