More than a century ago, two scientists spent years trying to tame the deadly bacterium that causes tuberculosis. They administered the first dose of the vaccine, now called Bacillus Calmette–Guérin (BCG), to an infant whose mother had died of the disease.1
Since then, with billions of doses given, the shot has surprised scientists with its capabilities beyond preventing tuberculosis. Researchers have found that BCG also helps prevent type 1 diabetes, reduce multiple sclerosis relapse, and treat bladder cancer. Scientists have uncovered how BCG programs the peripheral immune system to induce these effects.2-4
However, the vaccine’s impact on the central nervous system (CNS) and immune cells within it remains poorly understood, despite retrospective studies revealing a link between the vaccine and the brain: People who received BCG for bladder cancer also showed reduced incidence of Alzheimer’s disease (AD).5
Now, in a small clinical trial, researchers found that BCG triggered immune remodeling in the cerebrospinal fluid (CSF) of older adults and reduced AD-related biomarkers.6 The findings, published in Communications Medicine, suggest that vaccine-induced immune reprogramming could be used as a strategy to target early neurodegeneration.
“This is…an initial milestone that shows formally that BCG has a biological effect on the brain,” said study coauthor Mahesh Chandra Kodali, a neuroimmunologist at Harvard Medical School.
Kodali and his colleagues conducted a small clinical trial to investigate the effect of BCG-induced trained immunity in the central nervous system.
Mahesh Chandra Kodali
This study is “very interesting,” said Mihai Netea, who studies BCG-induced immunity at Radboud University and was not involved in the study. “[It] provides an explanation for the epidemiological observation regarding the effects of BCG…and also supports the findings in experimental models in mice.”
BCG Induces Trained Immunity in the CNS
In vitro and in vivo studies have indicated that BCG induces a type of long-term immune state called trained immunity. This involves epigenetic and metabolic reprogramming of innate immune cells to mount a response against unrelated pathogens. This differs from adaptive immunity wherein T and B cells build long-lasting memory against specific pathogens.
To investigate whether BCG-induced trained immunity also governs its effects against AD in humans, Kodali and his team recruited 23 people aged 55 years and older. Of these, 11 showed AD pathology, and 12 did not.
The participants donated their peripheral blood and CSF samples before and after receiving BCG vaccinations. In addition to examining the biofluids, the researchers also isolated immune cells from them. “We also wanted to study the effects on the cells itself,” explained Kodali.
To study BCG-induced immune responses, the researchers exposed blood- and CSF-derived immune cells to bacterial cell wall components. This triggered the expression of trained immunity-associated transcriptional profiles in cells from the BCG-vaccinated samples, indicating that the vaccination influenced trained immunity in both peripheral blood and CNS compartments. However, heat-killed BCG induced responses only in cells derived from the blood and not in those from the CSF.
Kodali and his colleagues isolated cells from the cerebrospinal fluid of older patients who received the BCG vaccination to study the vaccination’s effects on immune cells in the central nervous system.
Mahesh Chandra Kodali
“This suggested some compartment-specificity, and it also suggested how peripheral BCG vaccine exerts its effects in terms of changing the function of the CSF cells over time,” explained Kodali.
Next, the researchers compared the transcriptional landscape in immune cells derived from individuals’ CSF before and after they received the BCG vaccination. They observed transcriptional changes in genes involved in both metabolic and immunoregulatory pathways, consistent with trained immunity-like changes.
BCG Altered AD-Related Biomarkers in the CSF of Older Adults
Finally, Kodali and his colleagues sought to understand how BCG-induced trained immunity in the CNS influences AD. They assessed levels of amyloid beta—a protein whose buildup drives AD pathology—in the CSF of the trial participants before and after they received BCG vaccinations.
Amyloid beta levels declined in the CSF of healthy participants without AD and increased in the bloodstream. However, this change did not occur in people with AD, suggesting that BCG may influence early disease stage by clearing the protein’s buildup from the CNS.
“This is the first biological evidence that shows that a peripheral intervention can lead to a functional change in the CNS,” said Kodali.
Observing BCG-induced alterations in the CNS was not entirely surprising, “but it's still very novel and very important,” said Netea. “[This] is indeed a crucial discovery that demonstrates…that this is happening not only in experimental models in mice and so on, but it’s also happening in humans. This describes what is probably one of the most important mechanisms through which BCG induces these effects.”
However, he added that more work must be done to study whether BCG could serve as an intervention for AD. Large, randomized controlled clinical trials can help scientists better assess the potential of BCG to influence neurodegenerative diseases, he said.
Kodali agreed that further studies would help determine whether BCG helps prevent AD. More work is also needed to investigate whether BCG could be used as a therapeutic for AD and neurodegenerative diseases, and if so, until what stage of the disease it would be effective. Overall, the current study results indicate the need for larger multi-center clinical trials, for which preparations are underway, he said.
Such studies could help determine if a century-old vaccination will continue rewriting its own history, becoming one of medicine’s biggest overachievers.
- Luca S, Mihaescu T. History of BCG vaccine. Maedica (Bucur). 2013;8(1):53-58.
- Kühtreiber WM, et al. Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations. NPJ Vaccines. 2018;3:23.
- Ristori G, et al. Use of Bacille Calmette-Guèrin (BCG) in multiple sclerosis. Neurology. 1999;53(7):1588-1589.
- Herr HW, Morales A. History of bacillus Calmette-Guerin and bladder cancer: An immunotherapy success story. J Urol. 2008;179(1):53-56.
- Gofrit ON, et al. Bacillus Calmette-Guérin (BCG) therapy lowers the incidence of Alzheimer's disease in bladder cancer patients. PLoS One. 2019;14(11):e0224433.
- Weinberg MS, et al. Bacillus Calmette-Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer's biomarkers: Results from two open-label clinical trials. Commun Med (Lond). 2026;6(1):358.
