BCG Vaccine-Induced Trained Immunity May Help Protect Against Dementia

The results of a preclinical study headed by researchers at Johns Hopkins University School of Medicine suggest that the Bacillus Calmette-Guerin (BCG) vaccine, which is widely used to prevent tuberculosis and treat bladder cancer, may also have properties that reduce the risk for dementia. BCG is a live, weakened vaccine made from an altered strain of the bacterium Mycobacterium bovis.

The team found that in mice genetically engineered to develop biological symptoms of dementia (PS19 mice), those animals that received the BCG vaccine were less likely to show hallmark signs of the disease, such as neurofibrillary (tau) tangles (NFTs) in the brain, sustained immune cell activation, and memory loss compared to mice that received no vaccine. BCG-treated mice performed better in a novel object recognition test, and showed improved maintenance of body-weight and survival.

Research lead William Bishai, MD, PhD, co-director of the Johns Hopkins Center for Tuberculosis Research, believes that myeloid cells in the central nervous system and brain are using information from BCG to recognize and help the body respond to the formation of plaques and tangles characteristic of Alzheimer’s disease and related dementias. Bishai said, “We’re hard at work trying to understand the detailed mechanism for how it works, but this research points to early clues that aspects of trained immunity are likely driving this response.”

Trained immunity refers to the ability, in mammals, of innate immune system cells to take on an expanded role. Following an initial stimulus, innate immune cells, including monocytes and macrophages, may learn how to identify and respond to future threats that are different from the first. Typically, other immune system cells, such as T cells, take on this type of adaptive and learned response.

Bishai is senior and corresponding author of the team’s published paper in Science Advances, titled “BCG vaccination mitigates tau pathology and restores cognitive functions in PS19 mice,” in which the authors concluded “Our study strongly suggests that dementia protection by BCG is a credible observation that merits future basic research and large-scale prospective clinical trials to provide definitive answers.”

Observational studies in humans—those not designed to show cause and effect—have linked off-target effects of vaccines to a reduced incidence of dementia. “There is a growing appreciation that vaccines may have beneficial off-target effects such as reducing the risk of dementia,” the authors wrote. The shingles vaccine has been linked to a 20% reduced incidence of dementia, while several previous studies cited by the researchers found that BCG used as an immunotherapy for non-muscle invasive bladder cancer was linked to a 12% to 78% reduced risk of dementia throughout a three- to 15-year period.

“While less publicized, there is also considerable evidence that Bacille Calmette-Guérin or BCG, the live attenuated vaccine to prevent tuberculosis (TB) and treat bladder cancer, may also have dementia-preventive properties,” the team continued.

It’s been postulated that trained immunity is a mechanism by which BCG could protect against dementia, they noted. “Upon exposure to a first antigen such as BCG, innate immune cells, typically myeloid cells, have been shown to undergo epigenetic and metabolomic reprogramming such that upon exposure to a second, unrelated antigen, their immune response is greater than it was to the first,” they explained.

To test directly whether BCG could represent a preventive therapy for Alzheimer’s disease, the team turned to the PS19 (P301S) mouse model, which develops symptoms of dementia, specifically marked by tau pathology or a clumping of tau proteins in the brain representing late stages of the disease. ‘The overexpression of P301S tau is associated with AD-relevant pathological and functional features, including neuronal loss, microgliosis, neurofibrillary tangles (NFT) deposition, and cognitive impairment,” they wrote.

The team divided mice into cohorts that received the BCG vaccine and those that received a saline injection. An additional comparison group included age-matched mice that did not have dementia and that also received the saline injection. Mice in the BCG treatment group received the vaccine at three months of age. Multiple assessments, based on brain imaging, memory recall (through an object recognition test) and indicators of disease, including neuroinflammation and the expression of genes linked to Alzheimer’s disease, were conducted eight to nine months later.

The researchers found that those mice that received BCG were about five times more likely to have signs of reduced tau deposits in their brain. They were also four times less likely to have markers of sustained inflammation, signaling that their immune cells had already likely responded to tau by clearing out some of the tangles, and had created a stable or protective immune response.

The untreated mice showed activation of 716 genes connected to Alzheimer’s disease, cell death, and neuroinflammation. BCG administration normalized all but nine of these. Compared to untreated mice, the mice who received BCG were less likely to have signs of brain atrophy and also more likely to live longer and perform better on tasks related to remembering and identifying objects.

“BCG seems to be reducing the degree of hyperinflammation in the brain—which is a good thing—and it may be doing it through a trained immune cell mechanism,” said Bishai. “There are a number of other characteristics of trained immunity that we are studying in the lab now.”

In their paper the team wrote in summary, “We found that early BCG administration starting at three months of age reduced brain atrophy, p-tau levels, and neuronal loss measured at the later time point of eight to nine months. Simultaneously, BCG therapy restored glutamate levels in vivo and improved recognition-memory performance, body weight, and survival of PS19 mice, suggesting key disease modifying effects.”

This research, Bishai says, is believed to be the first to study BCG and dementia in mouse models with tau pathology (specifically showing how immune cells may play a role in clearing neurofibrillary tangles). “Mechanistically, our study identified BCG-induced trained immunity properties as playing key roles in the clearance of tau NFTs,” they stated. Others have found similar findings with BCG and improved cognition in amyloid mouse models—which represent earlier stages of the disease marked by plaque formation.

“This is a great example of translational science working in reverse—starting with an intriguing observation in people and then going back to the laboratory to understand why it might be happening,” commented co-author Barbara Slusher, PhD, professor of neurology at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Drug Discovery program.

Slusher cautions that researchers still need to understand more of the underlying biology before they can say who might benefit, when treatment would need to be given and whether the effect can be safely reproduced in people at risk for dementia. “If we can identify the specific immune changes that are protective, we may be able to develop even more targeted approaches for the prevention of Alzheimer’s disease.”

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