Peripheral and Central Nervous System Immune Effects of Bacillus Calmette‐Guérin (BCG) Vaccination in older adults with and without cognitive impairment

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Abstract Background The live‐attenuated vaccine Bacillus Calmette‐Guérin (BCG), is widely used for the prevention of tuberculosis, and has myriad non‐specific beneficial effects in T1DM, multiple sclerosis, decreasing all‐cause childhood mortality, etc. Alzheimer’s Disease (AD) is a complex neurological disease. The innate immune system, intimately involved in the early and late phases of AD, may prove an ideal target for mono‐ or multi‐pronged therapy against AD. Data from multiple population health studies find that BCG treatment for bladder cancer is linked with decreased incidence of AD. Preclinical data also supports an AD‐beneficial effect of the vaccine. While mechanisms of some of these non‐specific vaccine effects have been elucidated, the mechanism behind BCG’s putative central nervous system (CNS) benefits is unclear. Here, we conducted a pilot open‐label study of the BCG (Tokyo strain) in the older adults to study CNS beneficial effects, particularly as they pertain to AD. Methods Baseline measures of participants (N = 16) with or without mild cognitive impairment (MCI) included cognitive and neuropsychological testing, phlebotomy, and lumbar puncture (LP), followed by an initial intradermal BCG, with a booster given 1mo later. Neuropsychological testing, phlebotomy and LP were repeated at 3mo, 6mo (no LP), and 12mo. The primary endpoints include 1) the safety of the vaccine in older adults and 2) target engagement. Secondary and exploratory endpoints include 1) functional, immunological, and AD‐related biomarker measures and 2) cognitive and neuropsychological effects. Results Our interim analysis demonstrated an overall improvement in repeatable battery for neuropsychological status (RBANS) total score index (TSI), notably in subsections of delayed recall, and visuospatial and constructional indices. Our results also show robust peripheral target engagement and the induction of trained immunity in the peripheral blood cells. We will further show the effects on various AD‐related biomarkers in plasma and cerebrospinal fluid. Conclusion These findings support that the BCG vaccine is safe in older adults and may improve cognition (enrollment of a placebo control group is underway). A further study including subjects with MCI and AD is ongoing. Our interventional studies with BCG begin to explore whether this strategy of retraining the neuroimmune axis can prevent and/or treat AD.

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