Key Takeaways
- The Bacillus Calmette-Guérin (BCG) vaccine is known to induce "trained immunity," a form of long-lasting reprogramming of innate immune responses.
- In a pilot study, BCG changed how immune cells behaved and altered biomarkers in people without Alzheimer's pathology.
- The next step is a large randomized trial to determine whether BCG can reduce risks of cognitive decline or Alzheimer's disease.
The bacillus Calmette-Guérin (BCG) vaccine, commonly used against tuberculosis, changed how immune cells behaved and altered markers linked to Alzheimer's disease in a pilot study involving two open-label trials.
In a year-long study, BCG vaccination induced persistent, trained immunity-like changes in cerebrospinal fluid (CSF), including enhanced innate immune responsiveness, reported Steven Arnold, MD, of Massachusetts General Hospital in Boston, and co-authors in Communications Medicine.
In participants without Alzheimer's-related pathology at baseline, the immune changes were accompanied by decreased amyloid-beta levels in CSF and increased amyloid levels in blood. This shift was not seen in participants who had Alzheimer's pathology, suggesting that the timing of BCG administration might affect early Alzheimer's dynamics and protein clearance from the central nervous system, the researchers noted.
BCG is known to induce "trained immunity," a form of long-lasting reprogramming of innate immune responses. It was first used in the 1920s against tuberculosis and was approved by the FDA in 1990 to treat bladder cancer. Retrospective studies of people with non-muscle-invasive bladder cancer have linked BCG treatment with reduced risks of Alzheimer's and other dementias.
This pilot study provides "early human evidence that BCG vaccination can alter immune activity not only in the blood, but also in immune cells found in the cerebrospinal fluid, the fluid surrounding the brain and spinal cord," Arnold said. "That is a key step in moving from epidemiologic observations toward a plausible biological mechanism," he told MedPage Today.
"This study was not designed to show that BCG prevents or treats Alzheimer's disease," Arnold added. "It was small, open-label, and designed to look at safety and biological mechanisms. But it gives us a biologically grounded rationale for testing whether immune training with BCG could be useful as an early prevention strategy for Alzheimer's disease."
Alzheimer's research suggests that the disease may involve not only amyloid and tau, but immune aging, impaired clearance mechanisms, and chronic neuroinflammatory dysfunction. The role vaccines play in these processes is unclear, but a growing body of literature supports protective associations between vaccines targeting pathogens like influenza, pneumonia, or herpes zoster (shingles) and Alzheimer's risk.
Trained immunity may offer a strategy to boost immune resilience in aging and neurodegeneration. Pierre Tariot, MD, of the Banner Alzheimer's Institute in Phoenix, who wasn't involved with the trials, noted that mounting evidence supports BCG as a candidate Alzheimer's prevention therapy.
"Mechanistic studies such as this one reveal two sequential phases of immune reprogramming suggesting durable, disease-modifying modulation of the aging neuroimmune environment," he told MedPage Today.
Arnold and colleagues conducted two 1-year, open-label clinical trials of adults ages 55 and older at a single center. One trial involved 12 participants without Alzheimer's-related pathology; the other included 11 people with Alzheimer's pathology and mild cognitive impairment or mild-to-moderate Alzheimer's disease.
People with prior BCG vaccination or tuberculosis exposure, immunosuppression or immunomodulatory therapies, recent metformin use, active or chronic infectious disease, or significant neurologic or psychiatric comorbidity were excluded from the study.
Participants received two intradermal BCG vaccinations 1 month apart. One non-serious case of injection site dermatitis was reported; no other adverse events were attributed to BCG.
The study tested a specific vaccination strategy in older adults and did not examine the effect of BCG vaccination in childhood, which is common in sub-Saharan Africa, Southeast Asia, and parts of Eastern Europe due to tuberculosis prevalence in these regions, the researchers noted. The trials had small sample sizes and followed participants for only 1 year.
"The next step is a large, randomized, controlled prevention trial to determine whether BCG can actually reduce the risk of cognitive decline or Alzheimer's disease, and to define which older adults might benefit most," Arnold said.
A group of investigators across the U.S. has met for more than a year to map out a large pragmatic prevention trial of BCG in older adults and has submitted an application to the NIH, he noted.
"If funded, the goal would be to test BCG in a real-world prevention framework, with careful safety monitoring and clinically meaningful outcomes, including cognitive trajectories and Alzheimer's-related biomarkers," Arnold said.