Induction of Gut Permeability by an Oral Vaccine

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Inflammation; Typhoid Fever; Vaccine; Intestinal Permeability
• Intervention / Treatment: Biological: Vivotif Typhoid Oral Vaccine; Drug: Aspirin (Positive Control)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Davis, California, United States, 95616
      • USDA, ARS, Western Human Nutrition Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: USDA, Western Human Nutrition Research Center
• Investigators: Principal Investigator: Danielle Lemay, PhD, USDA, ARS, Western Human Nutrition Research Center

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2019
• Primary Completion (Actual): January 31, 2022
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: September 5, 2019
• First Submitted That Met QC Criteria: September 5, 2019
• First Posted (Actual): September 10, 2019

Study Record Updates

• Last Update Posted (Estimated): January 8, 2024
• Last Update Submitted That Met QC Criteria: January 5, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation; Vaccine Response; Intestinal Permeability; Gastrointestinal Health; Ty21a Typhoid Vaccine; Typhoid Fever
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Enterobacteriaceae Infections; Salmonella Infections; Inflammation; Typhoid Fever; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Immunologic Factors; Aspirin; Vaccines
• Other Study ID Numbers: FL109

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No