Brief Title: A Pilot Study of the Effects of Bacillus Calmette-Guérin (BCG) Immunization on Cerebrospinal Fluid and Blood-based Biomarkers in Older Adults.

PRIMARY OUTCOMES

Primary Outcome 1 - Measure:

Primary Outcome 1 - Timeframe: N/A

CONDITION

• Healthy

ELIGIBILITY

Inclusion Criteria:
Study subjects meeting all the following criteria will be allowed to enroll in the study:
1. Age 55-80 inclusive;

- 2. Montreal Cognitive Assessment (MoCA ) ≥18;

- 3. Normal cognition as defined by Montreal Cognitive Assessment (MoCA) ≥ 26 or Mild Cognitive Impairment (MCI) as defined by the National Institute of Health Alzheimer's Association (NIA-AA) Workgroup (2011) and MoCA score between 18 and 25 (inclusive);

- 4. Education level, English language skills, and literacy indicates subject will be able to complete all assessments;

- 5. Ability to provide informed consent;

- 6. Willing and able to complete all assessment and study procedures, including blood draws, lumbar punctures, and clinical assessments;

- 7. If on cholinesterase inhibitor and/or memantine, doses are stable for 3 months prior to baseline;

- 8. Negative test results for Human Immunodeficiency Virus (HIV) antibody and Tuberculosis (TB) (QuantiFERON) at screening;

- 9. No prior Bacillus Calmette-Guérin (BCG) exposure either through birth vaccinations (born in North American) or BCG bladder cancer treatment.

- 10. Documentation of current flu season vaccination dated at least 60 days prior to baseline visit.
Exclusion Criteria:
Study subjects meeting any of the following criteria will not be allowed to enroll in the study:
1. History of chronic infectious disease, such as HIV or untreated or active hepatitis;

- 2. History of tuberculosis, positive interferon-gamma release assay (IGRA, also known as the QuantiFERON-TB test), including a test with a high reactivity to mycobacteria of non-tuberculosis variety;

- 3. Prior BCG vaccination, positive T-spot tuberculosis test or a T-spot test showing significant Mycobacteria exposure;

- 4. A positive Severe acute respiratory syndrome coronavirus, Polymerase Chain Reaction (PCR) result within 3 months of screening, or known close contact with a confirmed Coronavirus 19 (COVID-19) positive person or symptoms highly suspicious for COVID-19 (per Center for Disease Control (CDC) guidelines) within 1 month of screening, including fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea, and/or sore throat, based on clinician's judgment;

- 5. History of treatment with metformin within the past one year;

- 6. Previous participation (ever) in active immunization research for Alzheimer's Disease (AD) or passive immunotherapy or other disease-modifying treatments for AD within the past three months;

- 7. Current treatment with immunosuppressants (calcineurin inhibitors, corticosteroids, or biological or cytotoxic immunosuppressants, or disease or condition likely to require high dose steroid or immunosuppressive therapy);

- 8. Other conditions or treatments associated with increased risk of infections or treatment with immunosuppressive medications for any reason;

- 9. Current treatment with aspirin > 160 mg/day or chronic, daily nonsteroidal anti-inflammatory drugs (NSAIDs);

- 10. Chronic use of antibiotics;

- 11. History of keloid formation;

- 12. Living with someone who is immunosuppressed and/or at high risk for infectious diseases (for example, HIV+ or taking immunosuppressive medications for any reason), or in a job (e.g. healthcare) in which the subject works with immunosuppressed populations;

- 13. Other/confounding neurological or psychiatric condition, unstable medical or psychiatric conditions, contraindications to BCG use and lab abnormalities or concurrent medication use posing risk for BCG or study procedures;

- 14. Laboratory abnormalities in B12, Folate, thyroid stimulating hormone (TSH), or other common laboratory parameters that may contribute to cognitive dysfunction;

- 15. Laboratory abnormalities in Complete Blood Count (CBC), electrolytes, Liver Function Tests (LFTs), Blood Urea Nitrogen (BUN), Creatinine (Cr), total serum immunoglobulins, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), or urinalysis posing risk to treatment with BCG per clinician judgment;

- 16. Laboratory abnormalities in prothrombin time /international normalized ratio (PT-INR), which would pose a risk to performing the lumbar puncture procedure;

- 17. Discontinuation of cholinesterase inhibitor or memantine within one month (28 days) prior to baseline visit;

- 18. Females who are pregnant, lactating or of child-bearing potential;

- 19. If male with female partner(s) of childbearing potential, unwilling or unable to adhere to contraception requirements specified in the protocol.

- 20. Administration of live vaccine <60 days prior to Baseline. - 21. Increased intracranial pressure as determined on a fundoscopy/neurological examination performed within 30 days of Lumbar Puncture (LP); - 22. COVID-19 vaccination < 60 days prior to baseline or within 14 days of BCG immunizations.

Gender: All

Minimum Age: 55 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Steven E Arnold, MD, Denise Faustman, MD, PhD

Role: Principal Investigator, Principal Investigator

Affiliation: Massachusetts General Hospital, Massachusetts General Hospital

Overall Contact

Name: N/A

Phone: N/A

Email: N/A

LOCATION