BACILLUS CALMETTE-GUERIN (BCG) VACCINE IMPACT ON DEMENTIA RISK IN BLADDER CANCER PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

 

M. Ibrahim¹, P. Kim¹, R. Marawar¹, K.I. Avgerinos¹

 

1. Department of Neurology, Wayne State University, Michigan, United States

Corresponding Author: Konstantinos I. Avgerinos, Department of Neurology, Wayne State University School of Medicine, 4201 St. Antoine, Detroit Michigan, United States. Email:konstantinos.avgerinos@wayne.edu

J Prev Alz Dis 2024;
Published online May 22, 2024, http://dx.doi.org/10.14283/jpad.2024.94

 

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Abstract

BACKGROUND: The BCG vaccine has been traditionally administered to prevent TB. It has been additionally used in bladder cancer patients as a therapy with success. Some observational studies found that bladder cancer patients receiving BCG may have reduced dementia risk, however, the evidence is not conclusive.
OBJECTIVE: To investigate the impact of BCG vaccine on dementia risk in bladder cancer patients.
METHODS: Six databases were searched from inception to January 13, 2024, for published and unpublished studies that examine the association between BCG and dementia risk in bladder cancer patients. We conducted meta-analyses using a random-effects model.
RESULTS: Eight retrospective cohort studies were included in the systematic review and seven in the meta-analyses. Because there were studies with overlapping populations, two separate main analyses were performed reassuring the avoidance of overlap. The first analysis showed that compared to controls, BCG did not reduce dementia risk [5 studies pooled, n=88,852, HR = 0.65, 95% CI (0.40, 1.06), I2 = 85%] whereas there was a marginally significant risk reduction in the second analysis [6 studies pooled, n=70,025, HR = 0.63, 95% CI (0.40, 0.97), I2 = 83%]. Sensitivity analysis excluding the unpublished studies did not affect the outcome importantly. Additional meta-analysis showed that BCG did not reduce the risk of Alzheimer’s disease.
CONCLUSION: This meta-analysis of observational studies found that BCG administration in bladder cancer patients has likely a minimally positive impact on dementia risk if any. To better understand the effect of BCG on dementia, randomized controlled trials are needed.

Key words: Alzheimer’s, dementia, BCG, vaccines, immune system.

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Introduction

Dementia currently affects more than 57.4 million individuals worldwide and is projected to affect more than 152.8 million people by 2050 (1). Alzheimer’s disease (AD) and AD-related dementias (ADRDs) namely frontotemporal degeneration dementia (FTD), Lewy body dementia (LBD), vascular contributions to cognitive decline/dementia (VCID), and mixed-etiology dementias (MEDs) are the most common forms of dementia. The most frequently prescribed medications for AD include acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and an NMDA receptor antagonist (memantine), but these medications temporarily improve symptoms of dementia without altering the disease course itself (2). Occasionally, these medications may be used for LBD, VCID and MED, but for FTD, there is not enough supportive evidence (3, 4, 5).
Neuropathology studies have shown that dementias are characterized by brain deposition of proteinaceous aggregates such as amyloid-beta (Aβ) and tau deposits in AD, TDP43 and tau in FTD, and α-synuclein and Aβ in LBD (6). A common approach in dementia therapeutics research is the development of drugs that aim to clear these aggregates from the brain (6). For AD, the first fully FDA-approved disease-modifying drug against Aβ aggregates (Lecanemab) is promising but there is some controversy over the clinical significance of its effects (7). For other dementia types, there are no promising therapeutics underway. Thus, alternative approaches should be considered to tackle the dementia epidemic.
Recently, more light has been shed on the role of the immune system in the context of dementia. For example, in AD, microglia, the primary (innate) immune system cells of the central nervous system (CNS) may be initially associated with beneficial inflammatory responses that can become destructive later in the course of the disease (8, 9). Additionally, peripheral immune cells, including monocytes, T cells, and B cells, have been shown to interact with CNS immune cells (8, 10). Peripheral immune dysregulation, such as increased levels of peripheral inflammatory mediators, has been linked to increased dementia risk (8, 10).
The Bacillus Calmette–Guérin (BCG) vaccine has been used for more than 100 years in tuberculosis (TB) prevention (11). Interestingly, by modulating the immune system, BCG has been shown to exert a plethora of additional non-specific effects including protection against other infections, anti-cancer activity, benefits in type 1 diabetes, and possibly benefits in neuroimmune and neurodegenerative disorders (12, 13, 14). The most successful use of BCG vaccine outside TB has been its intravesicular administration for treatment of non–muscle-invasive bladder cancer (NMIBC) (12). Intriguingly, some epidemiologic evidence shows that individuals who have been administered BCG for NMIBC, may have decreased dementia risk but the finding is not conclusive (14, 15, 16, 17). Results from a previous meta-analysis showed a reduced risk for dementia in those with bladder cancer who received BCG, however the result may have been inflated due to possible inclusion of overlapping populations while important unpublished data were not considered in the analysis (17, 18). Moreover, a new well-designed observational study was recently published and the addition of its data into a new pooled analysis would be very helpful in reaching a more conclusive result (15). Unfortunately, there are no epidemiologic studies to investigate the association of BCG vaccine with dementia outside bladder cancer, most likely because the routine BCG administration for TB prevention has been stopped in many countries. Therefore, we performed a comprehensive systematic review and meta-analysis including all published and unpublished data of observational studies examining the association of BCG vaccine administration with dementia risk in bladder cancer patients. Our aim was to shed more light on the potential of BCG vaccine as dementia risk reduction strategy.

 

Methods

We reported our methods and results in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement (19).

Eligibility criteria

Our intention was to study the association between BCG with dementia in any context. However, the identified studies were only on the use of BCG as a therapy in bladder cancer, therefore our investigation was restricted in this population. We included observational human studies of any design that investigated the effect of BCG vaccine administration on dementia risk compared to control (i.e., no BCG vaccine administration) in patients with bladder cancer. No restrictions were posed in terms of demographic characteristic of patients, cancer stage, or treatment scheme.

Information sources

PubMed, Ovid MEDLINE, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched for literature from inception to January 13, 2024. Details of the search strategy are shown in supplemental material.

Selection process

Results from the literature search were imported in a reference manager software. Following deduplication, records were first screened at title and abstract level. Potentially eligible records were assessed at the full-text level. Reasons for exclusion of studies were recorded. The selection process was performed by two authors separately (MI, PK) and any disagreements were resolved by a third reviewer (KA).

Data collection process

For each included study, we extracted data related to the study (year of publication, study design, databases/registries data of the original studies were acquired from) and participant characteristics (number of patients who received treatment and those who were controls, age, sex, bladder cancer stage at baseline, number of BCG doses received in the intervention group, dementia ICD-9/10 codes used). We additionally extracted data for the outcomes of interest (hazard ratio (HR) with 95% CI for ADRD and AD risk, and variables which the statistical models were adjusted for). Data extraction was performed by two reviewers independently (MI, PK) and arbitrated by a third reviewer (KA).

Risk of bias assessment

Risk of bias was assessed with the “Risk Of Bias In Non-randomized Studies – of Exposure” (ROBINS-E) tool (20). We assessed for bias arising from confounding, measurement of the exposure and outcomes, selection of study participants, post-exposure interventions, missing data, and selection of reported results. Individual domains of risk of bias and studies could be characterized as “low risk”, “some concerns,” or “high risk”. Risk of bias was assessed by two reviewers independently (MI, PK) and disagreements were resolved by a third reviewer (KA). Publication bias was assessed with inspection of generated funnel plots and the Egger’s statistic.

Data synthesis

To calculate pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) for the outcome of interest, random-effects meta-analyses were performed using the inverse variance method. Out of several tau2 estimators of the between-study heterogeneity, we implemented the Restricted Maximum Likelihood (REML) which is arguably the most unbiased approach and preferrable over the classically used Der-Simonian Laird estimator (21). To quantify between-study heterogeneity, we calculated the I2 statistic considering the following interpretation: I2 < 25% indicated low heterogeneity, 25%-50% indicated moderate heterogeneity, and > 75% suggested high heterogeneity.
The present systematic review and meta-analysis included US-based and non-US-based studies. Regarding the US-based included studies, one study (Makrakis et al.) (22) analyzed data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, a national cancer registry that receives data from multiple registries/states. The other US-based included studies (Weinberg et al., Kim et al.) (14, 23) of our meta-analysis used data that were sent to the SEER database via the Massachusetts and New York registries, respectively (https://seer.cancer.gov/registries/list.html), which was confirmed after contacting the PIs of these registries. Therefore, to avoid overlapping populations when pooling data, we performed two separate main analyses as follows: one meta-analysis that included all non-US-based studies (16, 17, 24) and of all the US-based studies, the study performed based on national registry data (Makrakis et al.) (22); an alternative meta-analysis which included all non-US-based studies (16, 17, 24) and all US-based studies (14, 23) except the one that reported results from the national registry (Makrakis et al.) (22). Moreover, we performed a separate analysis including studies that reported outcome specifically on AD, excluding other dementia types.
We performed a sensitivity analysis after excluding studies that were unpublished (i.e., their results were only reported in conference proceedings and did not undergo peer-review (17)). Subgroup analyses by age and sex were conducted. Analyses were performed in R with the use of “meta” and “dmetar” statistical packages.

 

Results

Search results

Literature search initially identified 748 records. Following deduplication, screening at the title and the full-text level, seven records corresponding to eight studies met the eligibility criteria for inclusion in the systematic review. Of the eight included studies in the systematic review, seven reported HRs (95 CI%) for the outcomes of interest and were included in the meta-analysis. The flow diagram of study selection is depicted in figure 1.

 

Study and participant characteristics

Study and participant characteristics are presented in table 1. All included studies were designed as retrospective cohorts. Of the eight included studies in the systematic review, seven were peer-reviewed manuscripts (14-16, 22-24) and one was an abstract presented at a conference (17). Included studies were published from 2019 to 2023. Four studies were conducted in the USA (14, 22-24), two in Israel (16, 24), one in Denmark (17), and one in Sweden (15). Four studies included patients with NMIBC only (14, 17, 22, 23), two included NMIBC and muscle-invasive bladder cancer (MIBC) (16, 24), and one did not specifically report the stage of bladder cancer (24). In all studies, most patients were males (>70%) and mean age ranged from 69 to 83. In terms of BCG vaccine scheme, two studies did not report the dosages, two studies generally described whether they involved induction with or without maintenance, others determined the minimum doses for inclusion, whereas few studies reported the doses in greater detail. In terms of follow-up for dementia diagnosis, one did not report average follow-up, four studies expressed follow-up period as a mean which ranged from ~3.5 to 7.2 years, and three studies expressed follow-up period as a median which ranged from 3 to 8 years. Figure S1 in supplementary material shows results of assessment for risk of bias. For all studies there was only some concern for bias.

NMIBC: non-muscle invasive bladder cancer; MIBC: muscle-invasive bladder cancer; AD: Alzheimer’s disease; ADRD: Alzheimer’s disease related dementias

 

BCG vaccine effect on dementia risk

Our two main meta-analyses showed numerically similar effects of BCG on dementia risk compared to control, however, the first did not reach statistical significance whereas the second did. More specifically, the first meta-analysis which included all non-US-based studies and out of all US-based studies included the one that reported results based on a national registry database, showed that compared to control group, BCG group did not decrease the risk of ADRD [5 studies pooled, n=88,852, HR = 0.65, 95% CI (0.40, 1.06), I2 = 85%] (figure 2a). Although there was some asymmetry concerning for publication bias based on inspection of the funnel plot, the Egger’s statistic (p=0.63) showed there was no publication bias (figure 2b).

 

In the alternative meta-analysis which included all non-US-based studies and all US-based studies except the one reporting findings from the national registry, there was a marginally significant reduction for dementia risk in the BCG group compared to control [6 studies pooled, n=70,025, HR = 0.63, 95% CI (0.40, 0.97), I2 = 83%] (figure 3a). Despite some asymmetry of the funnel plot, the Egger’s statistic (p=0.17) revealed that there was no publication bias (figure 3b). Taken together, these findings indicate that if there is any true benefit of BCG on dementia risk in bladder cancer patients, this is minimal.

 

In addition, meta-analysis of hazard ratios on AD risk revealed that BCG does not confer a benefit [3 studies pooled, HR = 0.86, 95% CI (0.69, 1.09), I2 = 73%] (figure 4a). No evidence of publication bias was noted after inspection of the funnel plot and based on the Egger’s test (p=0.14) (figure 4b). Interestingly, Klinger et al. reported favorable effects of BCG against AD from a UCLA Health System cohort but unfortunately, these results were not included in the statistical synthesis because HRs could not be calculated. Findings from this cohort would have likely contributed to a more favorable pooled effect size, although it’s unknown if the result would have reached significance. Nevertheless, these data showed that out of 132 individuals who received BCG, no one (0%) was diagnosed with AD whereas, out of 2130 individuals who did not receive BCG, 79 (3.7%) were diagnosed with AD.

 

Sensitivity analyses

Our sensitivity analyses included a repeat of our main meta-analyses after excluding Sorup et al. study, which was only published in the proceedings of a conference and did not undergo peer-review. The first main analysis on BCG and dementia showed that BCG did not reduce the risk of dementia [5 studies pooled, HR = 0.65, 95 CI % (0.40, 1.06), I2 = 85 %]. In the sensitivity analysis (i.e., after excluding Sorup et al.) it was also shown that BCG did not reduce the risk of dementia [4 studies pooled, HR = 0.58, 95% CI (0.33, 1.05), I2 = 87%].
The second main analysis on BCG and dementia showed a marginal benefit for BCG group [6 studies pooled, HR = 0.63, 95% CI (0.40, 0.97), I2 = 83%], which remained in the sensitivity analysis (following Sorup et al. exclusion) [5 studies pooled, HR = 0.56, 95% CI (0.34, 0.93), I2 = 85%].
Finally, the initial analysis on BCG and AD did not show a benefit for BCG [3 studies pooled, HR = 0.86, 95% CI (0.69, 1.09), I2 = 73%]. Exclusion of unpublished data Sorup et al. showed a very similar result [2 studies pooled, HR = 0.82, 95% CI (0.62, 1.09), I2 = 77%]. Overall, the sensitivity analyses did not alter the findings of our main meta-analyses.

Subgroup analyses

For females receiving BCG compared to control, there was a reduction in dementia risk [3 studies pooled, HR = 0.71, 95% CI (0.55, 0.91), I2 = 0%]. No significant effect was found for males [2 studies pooled, HR = 0.92, 95% CI (0.72, 1.17), I2 = 93%]. In the subgroup analysis by age with a cut-off of 75 years, it was found that BCG had no effect on dementia risk in those who were 75 years old or less [3 studies pooled, HR = 0.92, 95% CI (0.72, 1.17), I2 = 93%], whereas there was a significant risk reduction for those above 75 [3 studies pooled, HR = 0.69, 95% CI (0.64, 0.75), I2 = 0%]. These findings should be seen with caution because they were based on pooling of data from few studies only.

 

Discussion

This systematic review and meta-analysis of all published and unpublished retrospective cohort studies revealed that intravesicular BCG administration in patients with bladder cancer may have a minimal impact only on decreasing the risk of dementia. Several individual observational studies previously showed a clear benefit although few other studies were negative. A previous meta-analysis found a clearly positive effect (18). However, based on the most up-to-date data and after implementing strategies that reduce methodological and statistical biases, we concluded that as of today, BCG administration in bladder cancer patients has a minimally positive impact on dementia risk if any.
Although our findings do not show a clear benefit, we believe that these results may be promising if seen in the context of the most recent research advances in dementia. Recently, a study of CSF proteomics revealed that there are five different molecular AD subtypes, one involving the innate immune system (25). Perhaps what we see as an inconsistent benefit may arise from the fact that there are specific individuals who might benefit from BCG vaccination rather than everyone.
Currently it is unknown whether and by which mechanisms BCG vaccination may reduce the risk of AD and other dementias. It is possible that BCG modulates both the innate and adaptive immune system in the periphery which subsequently crosstalks with the CNS, indirectly exerting effects on the milleu of immune cells within the brain (26). Regarding the innate immune system, a clinical study revealed that intravesicular installation of BCG vaccine increased killer cell activity in peripheral blood mononuclear cells (27). In APP/PS1 mice, BCG administration resulted in the recruitment of IL-10-secreting monocytes to the brain through perivascular spaces and the choroid plexus, and improved cognition (28). Overall, it has been suggested that BCG can induce rapid and strong responses of the innate immune system (monocytes/macrophages and natural-killer cells) via epigenetic changes in a process called trained immunity, which could result in effective immune responses in the context of dementias (29).
The BCG vaccine may also exert beneficial effects via its effect on adaptive immunity. Intravesicular BCG in humans has been shown to increase serum IL-2 (27), a cytokine which expands CD4+CD25+FoxP3+ regulatory T cells (30), which has been shown to reduce amyloid deposition and improve cognition in 3xTg-AD mice (31). In individuals with type 1 diabetes, multiple doses of BCG epigenetically induced regulatory T cells which are known to suppress T-cell responses and restore immune balance (32). An additional indication that BCG might optimize T-cell responses in the brain comes from a multiple sclerosis (MS) study which showed that BCG was associated with decrease in number of MS-associated MRI lesions and that vaccinated individuals had decreased need for disease modifying therapies (13).
Additional supportive evidence links BCG vaccine with a beneficial effect on the hallmark pathology of AD, the Aβ. More specifically, a clinical study in cognitively intact participants showed that BCG vaccine resulted in a favorable plasma increase of Aβ42/40 in individuals 65 years or younger, and in those with a high probability score for a positive amyloid PET scan (33). Evidence from animal models of AD also shows that BCG may act against neurodegeneration by enhancing dendritic complexity, increasing primary neurites and dendritic length, and increasing synaptic proteins( 34, 35).
Our meta-analysis has several strengths. As of today, the present study is the meta-analysis with the largest sample size on the topic. Our pooled analysis included studies which were conducted in four different countries, providing confidence for generalizability of our findings. Our study’s greatest strength is that we implemented strategies to reach an unbiased estimation of the pooled effect. Unlike previous studies, our meta-analysis avoided inclusion of overlapping populations, thereby avoiding inappropriate inflation of results. In particular, because there was population overlap between Makrakis (22) et al. with Weinberg et al. and Kim et al. (14, 23), we performed one analysis with the Makrakis et al. and the rest of the included studies, and a separate analysis with Weinberg et al/Kim et al. and the rest of the included studies. From a statistical perspective, we chose to implement the REML estimator for between-study heterogeneity which has been shown to provide less biased results compared to the commonly used Der Simonian-Laird (DL) estimator especially in meta-analyses with small number of studies and high heterogeneity such as the present one (21, 36). For confirmation, we additionally performed all analyses using the DL estimator and found that all results showed a clear benefit; however, we chose to present results from the most robust and unbiased approach (REML) which is likely closer to the truth.
In addition to the strengths of our study, we acknowledge that there were several limitations. First, there were some concerns for risk of bias across all included studies (figure S1) which may add to some uncertainty about our findings. Another issue was that the included studies were heterogenous in several aspects. For many included studies, the number of BCG instillations was only roughly estimated and, in some cases, not clearly reported. Aside from potential differences in the BCG administration schemes, there were differences in data censoring and follow-up periods of included studies which may have affected the results in an unknown way. Finally, the statistical models for hazard ratios did not always adjust for the same covariates. For example, in several included studies, individuals who received BCG treatment had less comorbidities than controls, which could have been a protective factor against dementia compared to controls. Although in these studies the outcome was adjusted for comorbidities, for other studies, it was not clear if comorbidities were taken into consideration which may have led to biased results.
In conclusion, using all published and unpublished data, and after implementing strategies that reduce methodological and statistical biases, this systematic review and meta-analysis of observational studies showed that BCG administration in bladder cancer patients has likely a statistically marginal impact on dementia risk if any. As a result, these findings do not provide sufficient evidence for the use of BCG for dementia prevention in the general population. However, recent research showed that several individuals with AD may be molecularly characterized by innate immune activation, whereas others have different dysfunctions (25). This raises the possibility that BCG-induced immunomodulation for prevention of dementia may be a promising research idea to pursue in individuals with certain characteristics, especially those with immune system disturbances. To better understand the effect of BCG on dementia, randomized controlled trials are needed.

 

Conflict of Interest: On behalf of all authors, the corresponding author states that there is no conflict of interest.

 

SUPPLEMENTARY MATERIAL1

 

SUPPLEMENTARY MATERILA2

 

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