The COVID-19 pandemic that started in China has spread within 3 months to the entire globe. We tested the hypothesis that the vaccination against tuberculosis by Bacille Calmette–Guérin vaccine (BCG) correlates with a better outcome for COVID-19 patients. Our analysis covers 55 countries complying with predetermined thresholds on the population size and number of deaths per million (DPM). We found a strong negative correlation between the years of BCG administration and the DPM along with the progress of the pandemic, corroborated by permutation tests. The results from multivariable regression tests with 23 economic, demographic, health-related, and pandemic restriction-related quantitative properties, substantiate the dominant contribution of BCG years to the COVID-19 outcomes. The analysis of countries according to an age-group partition reveals that the strongest correlation is attributed to the coverage in BCG vaccination of the young population (0–24 years). Furthermore, a strong correlation and statistical significance are associated with the degree of BCG coverage for the most recent 15 years, but no association was observed in these years for other broadly used vaccination protocols for measles and rubella. We propose that BCG immunization coverage, especially among the most recently vaccinated population, contribute to attenuation of the spread and severity of the COVID-19 pandemic.

Bacillus Calmette–Guerin (BCG) is a live attenuated form of Mycobacterium bovis that was developed 100 years ago as a vaccine against tuberculosis (TB) and has been used ever since to vaccinate children globally. It has also been used as the first-line treatment in patients with nonmuscle invasive bladder cancer (NMIBC), through repeated intravesical applications. Numerous studies have shown that BCG induces off-target immune effects in various pathologies. Accumulating data argue for the critical role of the immune system in the course of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we tested whether repeated exposure to BCG during the treatment of NMIBC is associated with the risk of developing AD and PD. We presented a multi-center retrospective cohort study with patient data collected between 2000 and 2019 that included 12,185 bladder cancer (BC) patients, of which 2301 BCG-treated patients met all inclusion criteria, with a follow-up of 3.5 to 7 years. We considered the diagnosis date of AD and nonvascular dementia cases for BC patients. The BC patients were partitioned into those who underwent a transurethral resection of the bladder tumor followed by BCG therapy, and a disjoint group that had not received such treatment. By applying Cox proportional hazards (PH) regression and competing for risk analyses, we found that BCG treatment was associated with a significantly reduced risk of developing AD, especially in the population aged 75 years or older. The older population (≥75 years, 1578 BCG treated, and 5147 controls) showed a hazard ratio (HR) of 0.726 (95% CI: 0.529–0.996; p-value = 0.0473). While in a hospital-based cohort, BCG treatment resulted in an HR of 0.416 (95% CI: 0.203–0.853; p-value = 0.017), indicating a 58% lower risk of developing AD. The risk of developing PD showed the same trend with a 28% reduction in BCG-treated patients, while no BCG beneficial effect was observed for other age-related events such as Type 2 diabetes (T2D) and stroke. We attributed BCG’s beneficial effect on neurodegenerative diseases to a possible activation of long-term nonspecific immune effects. We proposed a prospective study in elderly people for testing intradermic BCG inoculation as a potential protective agent against AD and PD.

COVID-19 has spread to 210 countries within 3 months. We tested the hypothesis that the vaccination with BCG correlates with a better outcome for COVID-19 patients. Our analysis covers 55 countries, complying with predetermined thresholds on population size and deaths per million (DPM). We found a strong negative correlation between the years of BCG administration and a lower DPM along with the pandemic progression in time. The results from multivariable regression tests with 22 economical, demographic, and health-related quantitative properties for each country substantiate the dominant contribution of BCG administration years to the COVID-19 outcomes. Analyzing countries according to an age-group partition reveals that the strongest correlation is attributed to the coverage in BCG vaccination of the young population and mostly to recent years immunization. We propose that BCG immunization coverage, especially among the most recently vaccinated contributes to attenuation of the spread and severity of the COVID-19 pandemic.

IMPORTANCE Despite years of investigation and billions of dollars, there is no cure or even a disease-slowing remedy for Alzheimer disease (AD). Most studies thus far have focused on amyloid beta plaques and neurofibrillary tangles as therapeutic targets, and only a few on modulating the associated inflammatory process. OBJECTIVE To determine if exposure to Bacillus Calmette Guerin (BCG) during treatment of non-muscle-invasive bladder cancer (NMIBC) is associated with a lower risk of developing AD. DESIGN, SETTING AND PARTICIPANTS Multicenter retrospective study of 12,185 bladder cancer patients including 2301 BCG treated patients between 2000 and 2019 meeting all inclusion criteria. Data was retrieved from two tertiary hospital systems in Israel and the United States, and the largest Israeli health provider database, with a median follow up of 3.5 to 7 years. MAIN OUTCOMES AND MEASURES The primary outcome was time to the first occurrence of AD/Dementia events following a diagnosis of bladder cancer by trans-urethral resection (TURBT) in BCG treated patients, and in bladder cancer patients not receiving BCG (control group). RESULTS BCG treatment was associated with a significantly reduced risk of developing AD in bladder cancer patients older than 75 years following BCG treatment. A competing risk model using Cox Proportional-Hazard (PH) analysis applied to the largest medical records data showed a Hazard Ratio (HR) of 0.726 (95% CI: 0.529 to 0.996, P = 0.0473). The results were duplicated in analyzing NMIBC patients from a tertiary hospital with a HR of 0.416 (95% CI: 0.203 to 0.853, P = 0.017). A reduction in the risk (by 28%) for developing Parkinson disease (PD) was also shown in bladder cancer patients subjected to BCG immunotherapy. CONCLUSIONS AND RELEVANCE BCG treatment for bladder cancer patients was associated with a significantly reduced risk for developing AD and PD in the elderly population (>75 years), and in NMIBC patients from a tertiary hospital. Prospective studies in elderly inoculated with intradermic BCG should be initiated to evaluate the potential protective effect of BCG against AD and PD.