Bacillus Calmette–Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer’s biomarkers: results from two open-label clinical trials
9 affiliations
- 1Harvard Medical School, Boston, MA, USA. [email protected]
- 2Massachusetts General Hospital, Boston, MA, USA. [email protected]
- 3Harvard Medical School, Boston, MA, USA
- 4Massachusetts General Hospital, Boston, MA, USA
- 5Department of Computational Biology, Cornell University, Ithaca, NY, USA
- 6Harvard T.H. Chan School of Public Health, Boston, MA, USA
- 7Department of Neurology, Genetics and Aging Research Unit, McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA
- 8Harvard Medical School, Boston, MA, USA. [email protected]
- 9Massachusetts General Hospital, Boston, MA, USA. [email protected]
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).
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BibTeX
@article{weinberg2026bacillus,
title = {{Bacillus Calmette–Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer’s biomarkers: results from two open-label clinical trials}},
author = {Marc S. Weinberg and Mahesh Chandra Kodali and Zhaozhi Li and Jake A Galler and Arianna R. Tidball and William Cody Reynolds and Cathrine Young and Kelli Devitte-McKee and Hadia A. Fatima and Pia Kivisäkk and Mandovi Chatterjee and Arpita Kulkarni and James M. Billingsly and Alexandra L. Bartlett and Shannan J. Ho Sui and Willem M. Kühtreiber and Jessica A. Gerber and Alison J. McManus and Rudolph E. Tanzi and Sudeshna Das and Denise Louise Faustman and Steven Edward Arnold},
journal = {Communications Medicine},
year = {2026},
month = jul,
doi = {10.1038/s43856-026-01691-7},
url = {https://doi.org/10.1038/s43856-026-01691-7},
note = {CC BY},
}
RIS
TY - JOUR
TI - Bacillus Calmette–Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer’s biomarkers: results from two open-label clinical trials
AU - Marc S. Weinberg
AU - Mahesh Chandra Kodali
AU - Zhaozhi Li
AU - Jake A Galler
AU - Arianna R. Tidball
AU - William Cody Reynolds
AU - Cathrine Young
AU - Kelli Devitte-McKee
AU - Hadia A. Fatima
AU - Pia Kivisäkk
AU - Mandovi Chatterjee
AU - Arpita Kulkarni
AU - James M. Billingsly
AU - Alexandra L. Bartlett
AU - Shannan J. Ho Sui
AU - Willem M. Kühtreiber
AU - Jessica A. Gerber
AU - Alison J. McManus
AU - Rudolph E. Tanzi
AU - Sudeshna Das
AU - Denise Louise Faustman
AU - Steven Edward Arnold
PY - 2026
DA - 2026/07/02
JO - Communications Medicine
DO - 10.1038/s43856-026-01691-7
UR - https://doi.org/10.1038/s43856-026-01691-7
AB - 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).
SN - 2730-664X
ER -