Induction of Gut Permeability by an Oral Vaccine

Study Overview
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Brief Summary
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This study evaluates the effect of an oral typhoid vaccine on disruption of the intestinal barrier and response of the immune system. Intestinal and whole-body responses will be measured in all participants before and after the vaccine.

Detailed Description
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The licensed Ty21a vaccine strain of S. enterica Typhi is routinely used by travelers to countries where typhoid is common. It is not known whether the vaccine causes measurable changes in intestinal permeability and whether changes in permeability are correlated with the magnitude of the vaccine response. In the current study, gut permeability will be measured in participants at baseline and after an aspirin challenge, which is known to disrupt intestinal permeability, and after the first, second, and fourth doses of a the Ty21a vaccine. Intestinal permeability will be measured using a three-sugar absorption test composed of lactulose, mannitol, and sucralose and by several plasma markers. Vaccine response will be measured by quantitating T cells and newly developed IgG-or IgA-secreting plasma cells specific for Ty21a.

Official Title
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Induction of Gut Permeability by an Oral Vaccine

Conditions
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Intestinal Permeability, Inflammation, Vaccine, Typhoid Fever

Intervention / Treatment
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* Biological: Vivotif Typhoid Oral Vaccine
* Drug: Aspirin (Positive Control)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body Mass Index (BMI) 18.5 - 29.9 kg/m2 Exclusion Criteria: Has HIV/AIDS or another disease that affects the immune system Has any kind of cancer Decline to take an HIV blood test Blood pressure greater than or equal to 140/90 mmhg Pregnant or lactating women Refusal to take a pregnancy test prior to the study Refusal to use a method of birth control during the study Allergy to vaccine components, i.e. Thimerosal and enteric-coated capsules Allergy to oral typhoid vaccine Allergy to aspirin Daily use of blood thinners Use of anti-inflammatory medications, i.e. nonsteroidal anti-inflammatory drugs (NSAID), aspirin, 3 or more times per month Use of sulfonamides or antibiotics in the past 30 days Use of anti-hypertensive drugs, i.e. beta blockers, diuretics, calcium channel blockers Use of anti-malaria drugs, i.e. Mefloquine, chloroquine, and proguanil Use of drugs that affect the immune system, i.e. immunosuppressants, immune-modifying drugs, corticosteroids, i.e. cortisone, prednisone, methylprednisolone, for 2 weeks or longer Is taking cancer treatment with radiation or drugs Greater than ten years residence in a typhoid-endemic area Receipt of typhoid vaccine in the last 5 years Receipt of any vaccine two weeks prior to receipt of Ty21a vaccine Individuals at increased risk of developing complications from a live, bacterial vaccine History of typhoid fever History of primary immune deficiency or autoimmune disease History of acute or chronic gastrointestinal (GI) disorder, i.e. Crohn's disease, irritable bowel syndrome, gastric ulcer Diarrheal illness (defined as passing 3 or more abnormally loose or watery stool in a 24 hour period) or persistent vomiting 2 weeks prior to the study History of bleeding disorder, including bleeding from the GI tract History of chronic illnesses, i.e. diabetes, cardiovascular disease, cancer, gastrointestinal malabsorption or inflammatory diseases, kidney disease, autoimmune disorders, HIV, liver disease, including hepatitis B and C. Asthma if taking medication on a daily basis Recent surgery (within 3 months) History of GI surgery Recent hospitalization (within 3 months) Acute febrile illness (within 2 weeks) Unwillingness to discontinue consumption of artificial sweeteners in foods or drinks, i.e. sport drinks, coconut water, diet drinks and foods (possibly containing sucralose) Not having at least one arm vein suitable for blood drawing Unwilling or uncomfortable with blood draws seven times in 29 days Regular blood or blood product donation and refusal to suspend donation Current participation in another research study Unable to fast for 12-16 hours

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single group<br>All participants will receive the vaccine and aspirin. | Biological: Vivotif Typhoid Oral Vaccine<br>* One capsule is swallowed on alternate days, e.g. days 15, 17, 19, and 21, for a total of 4 capsules.<br>* Other names: Ty21a Typhoid Oral Vaccine;Drug: Aspirin (Positive Control)<br>* Three tablets (325 mg aspirin in each tablet or 975 mg total) are swallowed on days 2 and 3.<br>* Other names: Aspirin Challenge;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in intestinal permeability | Measurement of sugar (lactulose, D-mannitol, and sucralose) excretion in urine. | Day 1, 3, 16, 18, and 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody response to typhoid vaccination | Measurement of Typhi-specific immunoglobulin G (IgG) and immunoglobulin A (IgA) plasma cells in peripheral blood using the antibody in lymphocyte supernatant assay. | Day 1, 18, 22, 24, and 29 | 
| T-cell response to typhoid vaccination | Measurement of vaccine-specific cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) T-cells in peripheral blood mononuclear cells. | Day 1, 22, and 29 | 
| Change in markers of inflammation | Measurement of plasma cytokines, chemokines, and acute phase proteins by a multiplex immunoassay. | Day 1, 3, 16, 18, 22, and 24 | 
| Change in intestinal fatty acid binding protein (iFABP) | Measurement of plasma iFABP. | Day 1, 3, 16, 18, and 22 | 
| Change in D-lactate | Measurement of plasma D-lactate. | Day 1, 3, 16, 18, and 22 | 
| Change in diamine oxidase | Measurement of plasma diamine oxidase. | Day 1, 3, 16, 18, and 22 | 
| Change in lipopolysaccharide binding protein (LBP) | Measurement of plasma LBP. | Day 1, 3, 16, 18, and 22 | 
| Change in citrulline | Measurement of plasma citrulline. | Day 1, 3, 16, 18, and 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastrointestinal Health, Intestinal Permeability, Inflammation, Vaccine Response, Ty21a Typhoid Vaccine, Typhoid Fever