The Role of the Intestinal Microbiome in Enteric and Systemic Vaccine Immune Responses

Study Overview
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Brief Summary
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The purpose of this study is to evaluate if the intestinal microbiota influences rotavirus vaccine immune responses in healthy adult volunteers.

Detailed Description
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This study will alter the intestinal microbiota in healthy adults using antibiotics and subsequently measure immune reactions to the rotavirus vaccine (Rotarix), the tetanus vaccine and the pneumococcal vaccine (Pneumo23).

Official Title
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The Role of the Intestinal Microbiome in Enteric and Systemic Vaccine Immune Responses

Conditions
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Rotavirus Infections, Intestinal Bacteria Flora Disturbance, Reaction - Vaccine Nos, Tetanus, Streptococcal Pneumonia

Intervention / Treatment
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* Biological: Rotavirus vaccine, Tetanus vaccine and Pneumococcal vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, as determined by a responsible physician, based on a medical evaluation including medical history, physical examination and laboratory tests carried out within 28 days prior to starting antibiotics (day -98). A subject with a clinical abnormality or laboratory parameter outside the reference range may be included if the investigator agrees that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures Male between 18 and 35 years of age, inclusive at the time of signing the informed consent Capable of giving written informed consent and able to comply with the requirements and restrictions listed in the informed consent form Normal defecation pattern (defined as ≤3x/ day and ≥3x/week) Exclusion Criteria: Subject has had a major illness in the past 3 months or any significant chronic medical illness that the investigator would deem unfavorable for enrollment, including inflammatory diseases. Subject with any history of immunodeficiency Subjects with a history of any type of malignancy Subject with a history of thrombocytopenia or bleeding disorder Subject has a past or current gastrointestinal disease which may influence the gut microbiota Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) History of alcoholism and/or drinking more than an average of 5 units of alcohol per day The subject has received an investigational product within three months of day 0 of the current study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Control group - subjects will receive no antibiotics followed by Rotavirus vaccine, Tetanus vaccine and Pneumococcal vaccine | Biological: Rotavirus vaccine, Tetanus vaccine and Pneumococcal vaccine<br>* All subjects will be given an oral dose of the rotavirus vaccine, RotarixTM, and intramuscular injections of the Tetanus vaccine and Pneumococcal vaccine, Pneumo 23.<br>* Other names: RotarixTM, Pneumo 23;|
| Active Comparator: Broad-spectrum antibiotics<br>Subjects will receive 7 days of pre-treatment (days -9 to -3) with: Ciprofloxacin 500mg 2dd1 Vancomycin 250mg 3dd2 Metronidazole 500mg 3dd1 followed by Rotavirus vaccine, Tetanus vaccine and Pneumococcal vaccine | Biological: Rotavirus vaccine, Tetanus vaccine and Pneumococcal vaccine<br>* All subjects will be given an oral dose of the rotavirus vaccine, RotarixTM, and intramuscular injections of the Tetanus vaccine and Pneumococcal vaccine, Pneumo 23.<br>* Other names: RotarixTM, Pneumo 23;|
| Active Comparator: Narrow-spectrum antibiotics<br>Subjects will receive 7 days of pre-treatment (days -9 to -3) with: • Vancomycine 250mg 3dd2 followed by Rotavirus vaccine, Tetanus vaccine and Pneumococcal vaccine | Biological: Rotavirus vaccine, Tetanus vaccine and Pneumococcal vaccine<br>* All subjects will be given an oral dose of the rotavirus vaccine, RotarixTM, and intramuscular injections of the Tetanus vaccine and Pneumococcal vaccine, Pneumo 23.<br>* Other names: RotarixTM, Pneumo 23;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height of serum anti-rotavirus Immunoglobulin A (IgA) response | Geometric Mean Concentration (GMC) | 28 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to positivity for serum anti-rotavirus Immunoglobulin A (IgA) and G (IgG) response | (days) | day 0 through day 28 post vaccination | 
| Change in pre and post-vaccination anti-rotavirus (anti-RV) serum neutralizing antibodies measured by Geometric Mean Concentration (GMC) |  | 28 days post-vaccination | 
| Change in pre and post-vaccination anti-RV serum IgG response measured by Geometric Mean Concentration (GMC) |  | day 0 through day 28 post vaccination | 
| Change in serum tetanus toxoid IgG response, measured as pre and post vaccination titer (international units/mL) ratio |  | day 0 through day 28 post vaccination | 
| Change in serum pneumococcal poly-saccharide-specific IgG for all vaccine strains , measure in pre and post vaccination titer (micrograms/mL) ratio |  | day 0 through day 28 post vaccination | 
| Composition of the fecal micro biome before and after antibiotics and between groups measured by the HITChip and bacterial 16S rRNA sequencing |  | day -9 and day 0 pre vaccination |