Safety of Lactobacillus Rhamnosus GG Versus Placebo in Elderly Subjects Receiving Live Attenuated Influenza Vaccine

Double Blind Randomized Controlled Trial to Evaluate the Safety of Lactobacillus Rhamnosus GG ATCC 53103 (LGG) Versus Placebo in Elderly Subjects Receiving Live Attenuated Influenza Vaccine

This is a Phase I, randomized controlled trial to evaluate the safety of Lactobacillus rhamnosus GG (LGG) versus placebo in elderly subjects receiving the live attenuated influenza vaccine. Lactobacilli are part of the normal flora of the intestine. LGG is one of several strains of Lactobacilli that is used as a probiotic or microorganism administered to confer "health benefits". Our research is focused on studying the possible therapeutic effects of LGG. The study hypotheses are:

1. LGG or placebo administered twice daily will be safe and well tolerated in elderly subjects who have just received the live attenuated influenza vaccine,
2. The immune response to the influenza vaccine at day 21, 28, and 56 will be higher in the LGG group than the placebo group,
3. The diversity of the microbiota in nasopharyngeal and stool specimens at day 21, 28, and 56 will be greater in the LGG group than the placebo group.

Inclusion Criteria:

1. Age 65-80 years

2. Willing to complete the informed consent process

3. Able and willing to participate for the planned duration of the study, including availability for follow-up telephone contact

4. Is community dwelling for the past two years

5. Has received routine physical in the past two years

6. Has no new chronic conditions in the past two years

7. Identifies a primary care clinician

8. Has received recommended preventive services (Task Force for Clinical Preventive Services) for vaccination and cancer prevention/detection, e.g.:

   • Pneumococcal vaccination
   • Mammography
   • Screening colonoscopy for colon cancer

9. Willing to comply with protocol and report on compliance and side effects during the study period

10. Informed consent obtained and signed prior to screening

Exclusion Criteria:

1. Vaccination with any vaccine within the one month period prior to study enrollment or intent to receive any other vaccine during the study period, other than TIV in fall 2012

2. History of hypersensitivity to any influenza vaccine components including eggs, egg proteins, gentamicin, gelatin or arginine

3. History of avoidance of egg and/or egg-based products for any reason, unless they have previously received TIV or LAIV without hypersensitivity

4. History of Guillain-Barre syndrome

5. Acute febrile illness within the week prior to LAIV immunization - immunization deferred until illness resolved

6. Consumption of supplements or food products containing LGG or probiotics for 28 days prior to the start of the study or consumption of yogurt that has the "live and active" cultures seal

7. Known or suspected allergies to probiotics, Lactobacillus, microcrystalline cellulose, gelatin or antibiotics that may be used to treat LGG bacteremia or infection (i.e., subject able to tolerate at least 2 of the following regimens - Ampicillin or other beta lactam antibiotic, and Clindamycin, and Moxifloxacin)

8. Received oral or parenteral antibiotics within 4 weeks of enrollment or prescribed antibiotics on the day or enrollment

9. Drug or alcohol abuse, defined as the continued use of alcohol despite the development of social, legal, or health problems, within the previous 12 months

10. Hospitalization, major surgery or endoscopy within the last 3 months

11. Scheduled hospital admission or surgery within 3 months of enrollment

12. Resident of a nursing home or rehabilitation center

13. Close and/or household contact with severely immunocompromised persons (e.g., transplant recipients, cancer patients)

14. Receipt of any of the following medications within the specified time frame:

    • Antiviral agents for influenza A and B in the prior 2 weeks (anti-influenza medications are unlikely to be needed after LAIV immunization since LAIV will be administered at the end of the influenza season, but should be prescribed if clinically indicated)
    • Immune Globulin within the prior 6 months
    • Immune modulating drugs such as Belimumab, azathioprine, mercaptopurine, methotrexate, hydroxychloroquine or leflunomide at any time or any oral or parenteral corticosteroid in the prior 12 months
    • Fingolimod at any time
    • Salicylates at doses higher than 163 mg/day for primary prevention of myocardial infarction. (Reye's Syndrome in adults is extremely rare - to our knowledge the oldest reported patient was aged 61 and as of 1989 when Reye Syndrome was more common, it had only been reported in 25 adults. In addition, increasing numbers of adults are being placed on low dose aspirin for primary and secondary prevention of cardiovascular disease, some of whom may also have influenza, but there has been no increase in reports or Reye's Syndrome in adults.)

15. Presence of any of the following:

    • Grade 2 or higher abnormal vital signs or abnormalities on physical exam during screening or presence of any wheezing on physical exam at baseline
    • Indwelling catheter or implanted hardware/prosthetic device or feeding tube
    • Current or within the last 2 years, any episode of bowel leak, acute abdomen, diverticulitis, colitis, bloody bowel movements or peptic ulcer disease, including any surgical procedure or current prescription medications for any of these conditions
    • Current or within the last four weeks, active bowel disease such as an episode of infectious or non-infectious diarrhea, constipation or vomiting lasting more than 12 hours or current prescription medications for any of these conditions
    • Any history of gastric or intestinal dysmotility, slowed transit time, variable small intestinal permeability, pancreatitis, history of gastrointestinal tract cancer or metastasis or inflammatory bowel disease or current prescription medication for any of these conditions
    • Any history of Hepatitis B or Hepatitis C infections, cirrhosis, or chronic liver disease
    • Underlying structural heart disease such as abnormal native heart valve or congenital abnormality, previous history of endocarditis or valve replacement, Stage IV congestive heart failure or chronic cardiovascular conditions (except hypertension)
    • History of peripheral vascular disease or stroke
    • Immunosuppression including HIV positive, solid organ or stem cell transplant recipient, receiving any oral or parenteral immunosuppressive therapy, neutrophil count < 500/mm3, or an anticipated drop in the neutrophil count to < 500/mm3 during the 56 days post LAIV vaccination or active or planned chemotherapy or radiotherapy
    • History of collagen vascular or autoimmune disease
    • History of renal disease
    • History of chronic obstructive pulmonary disease or asthma
    • History of neurologic or neuromuscular diseases
    • History of hematologic diseases
    • Diabetes or thyroid disease or metabolic disorder
    • Active tuberculosis (TB), defined as undergoing a work up for suspected active TB infection or currently on treatment for active TB or scheduled for tuberculin test in the next 4 weeks
    • Fever or acute illness or nasal congestion during the baseline visit (LAIV administration)

16. Positive drug or alcohol testing at screening or positive breathalyzer at baseline or an unwillingness to undergo drug and alcohol testing

17. Abnormal laboratory tests defined as any of the following:

    • White blood cell (WBC)< 3.3 or > 12.0 K/microliters
    • Neutrophil < 500/mm3
    • Platelets < 125 K/microliter
    • Hemoglobin males: < 12.0 g/dL; females: < 11.0 g/dL
    • Creatinine > 1.8 mg/dL
    • Blood urea nitrogen (BUN) > 27 mg/dL
    • Aspartate aminotransferase (AST) > 1.25 ULN
    • Alanine aminotransferase (ALT) > 1.25 ULN
    • Alkaline phosphatase > 1.25 ULN
    • Bilirubin (total) > 1.5 ULN
    • Glucose (non-fasting) > 126 mg/dL
    • Positive HIV, Hepatitis B surface antigen or Hepatitis C antibody

18. Any other condition that in the opinion of the investigator would jeopardize the safety or rights of the subject participating in the study or would make it unlikely the subject could complete the study