Vaccination Efficacy With Metformin in Older Adults

Study Overview
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Brief Summary
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With aging the immune system gets weaker. This makes older adults more susceptible to influenza (flu). Vaccinations help to prevent infection from the flu virus, however the immune system of older adults do not respond as well to vaccines compared to young adults and thus, aren't as well protected from the complications from the flu. This research is being done to determine if Metformin, an FDA-approved diabetes medication, is effective at enhancing immune responses to flu vaccine in older men and women. Participants will be randomly assigned to either metformin or placebo treatment for a total of 22 weeks. Participants will be vaccinated with high-dose flu vaccine after 12 weeks of treatment. Immune responses will be evaluated throughout the study at 6 time points.

Official Title
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Vaccination Efficacy With Metformin in Older Adults: A Pilot Study

Conditions
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Aging, Age-Related Immunodeficiency, Vaccine Response Impaired

Intervention / Treatment
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* Drug: Metformin Hydrochloride Extended-Release Tablets
* Biological: Influenza Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women 65 years and older Willingness to provide consent and participate in all aspects of the trial including randomization to the intervention group and receiving this year's flu vaccine Received previous year's seasonal influenza vaccine Exclusion Criteria: History of severe renal impairment and/or eGFR ≤ 45 mL/min/1.73m2 Excessive alcohol use (more than 14 alcoholic drinks/week) or clinical/laboratory evidence of hepatic disease (via medical history and/or AST and/or ALT ≥ 3 times upper limit of normal at screening) Acute or chronic metabolic acidosis (via medical history and/or low serum bicarbonate (< 22mEq/L), increased anion gap (> 10 mEq/L)) History of B12 deficiency within the last 10 years Known type 2 diabetes or screening of prediabetic (HbA1c 5.7-6.4%) or diabetic (HbA1c ≥ 6.5%) Currently taking metformin or other diabetes medications Unwilling or unable (due to significant cognitive impairment) to provide informed consent Terminal illness with life expectancy less than 12 months Advanced neurological disorder (Parkinson's, ALS, MS, dementia) Cancer or history of cancer in the past 2 years (excluding non-melanoma skin cancer) or any history of metastatic (stage 4) cancer Significant co-morbid disease (severe chronic obstructive pulmonary disease, active rheumatologic diseases, chronic infection (HIV, tuberculosis), severe congestive heart failure (NYHA class 4), myocarditis, etc) Myocardial infarction, stroke or hospitalization for heart failure in the last 12 months Severe active psychiatric disorder (e.g. bipolar, schizophrenia) Unable to complete physical performance testing due to medical conditions (at discretion of the PI) Uncontrolled hypertension (systolic/diastolic blood pressure >150/90 mmHg) Unintentional weight loss >10% in past 12 months Allergy or history of adverse reaction to flu vaccine or any ingredients in flu vaccine, including eggs History of Guillain-Barre syndrome following vaccination Immunosuppressive disorders or taking immunosuppressive medications (including oral prednisone > 10mg/day) Current participation in another interventional study Refusal to receive flu vaccine

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin Hydrochloride Extended Release Tablets<br>Patients will consume 3 tablets of 500mg metformin hydrochloride extended-release tablets daily (1500mg/day (after 3 week dose gradation)). | Drug: Metformin Hydrochloride Extended-Release Tablets<br>* Subjects will ingest 1500mg/day of metformin hydrochloride extended release. Immune responses will be examined prior to treatment, prior to flu vaccination, and after flu vaccination.<br>* Other names: metformin ER;Biological: Influenza Vaccine<br>* All subjects will be vaccinated with high-dose influenza vaccine at the appropriate time of the year per current CDC and FDA recommendations<br>* Other names: Flu Vaccine;|
| Placebo Comparator: Placebo<br>Patients will consume 3 identical placebo tablets (after similar 3 week dose gradation). | Biological: Influenza Vaccine<br>* All subjects will be vaccinated with high-dose influenza vaccine at the appropriate time of the year per current CDC and FDA recommendations<br>* Other names: Flu Vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cell-mediated Flu Vaccine Responses - inducible Granzyme B | Change in inducible Granzyme B levels in peripheral blood mononuclear cells (PBMCs) stimulated ex vivo with live flu virus will be compared between the metformin and placebo group. | Prior to vaccination (week 12) and 5 weeks post vaccination (week 17) | 
| Change in Cell-mediated Flu Vaccine Responses - interferon(IFN)-γ/interleukin(IL)-10 ratio | Change in interferon(IFN)-γ/interleukin(IL)-10 ratio in culture supernatant of peripheral blood mononuclear cells (PBMCs) stimulated ex vivo with live flu virus will be compared between the metformin and placebo group. | Prior to vaccination (week 12) and 5 weeks post vaccination (week 17) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Influenza Antibody Titers | Serum antibody titers will be analyzed via hemagglutination inhibition assays (HI) via established Center for Disease Control (CDC) and World Health Organization (WHO) protocols for each vaccine strain. Change in antibody titer levels over time will be evaluated. | Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) | 
| Change in T Cell Metabolic Phenotype | T cells will be evaluated for phenotypic differences of glucose transporter expression via flow cytometry and reported as percent positive cells. Change in percent positive cells over time will be evaluated. | Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) | 
| Change in T Cell Oxygen Consumption Rate | T cells will be evaluated for oxygen consumption rate via Seahorse Agilent Technologies. Change in oxygen consumption rate over time will be evaluated. | Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) | 
| Change in Frailty Phenotype | Subjects will complete frailty testing via Fried Frailty Phenotype. Change in frailty phenotype over time will be evaluated. | Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) |