Immunogenicity & Safety Study of Adenovirus Type 5 (AD5) Based Oral Norovirus Vaccines

Study Overview
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Brief Summary
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To evaluate the immunogenicity of VXA-G1.1-NN with repeat-dose administration at Day 1 and varying boost schedules (Week 4, 8 or 12 post initial dose) in healthy adults aged 18-55, inclusive, and to assess the safety and tolerability of VXA- G1.1-NN with repeat-dose administration at varying boost schedules (Week 4, 8 or 12) in healthy adults aged 18-55, inclusive

Official Title
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A Phase 1b, Open-label, Boost-optimization Study of an Adenoviral- Vector Based Oral Norovirus Vaccine (VXA-G1.1-NN) Expressing GI.1 VP1 Administered Orally to Healthy Adult Volunteers

Conditions
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Norovirus Infections

Intervention / Treatment
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* Biological: VXA-G1.1-NN


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for this study, participants must meet all the following: Age 18 to 55 years old inclusive at the time of signing the Informed Consent Form (ICF). Type of Participants General good health, without significant medical illness, based on medical history, physical examination, vital signs, and clinical laboratories (CBC, chemistry, and urinalysis) as determined by the investigator in consultation with the Research Monitor and Sponsor Body mass index (BMI) between 17 and 35 kg/m2 at screening Available for all planned visits and phone calls, and willing to complete all protocol- defined procedures and assessments (including ability and willingness to swallow multiple small enteric-coated tablets per study dose). Gender and Reproductive Considerations Male or female participants Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a. Female participants must provide a negative pregnancy test at each required visit and fulfill one of the following criteria: At least 1 year post-menopausal (defined as amenorrhea for ≥12 consecutive months prior to Screening without an alternative medical cause). Women under 60 years will need to verify post-menopausal status via a follicle-stimulating hormone (FSH) test if another option to prevent potential pregnancy will not be utilized for 30 days prior to baseline vaccination and until 60 days after the last vaccination. Surgically sterile Use of oral, implantable, transdermal or injectable contraceptives for 30 days prior to initial vaccination and until 60 days after the last vaccination. The form of contraception must be approved by the Investigator A reliable form of contraception must be approved by the Investigator (e.g., double barrier method, Depo-Provera, intrauterine device, Norplant, oral contraceptives, contraceptive patches). Not be sexually active (abstinent) or be in a relationship with partner who is sterile (must be discussed with site staff and documented). Informed Consent Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Exclusion Criteria: The participants must be excluded from participating in the study if they meet any of the following: Medical Conditions Presence of significant uncontrolled medical or psychiatric illness (acute or chronic) including institution of new medical/surgical treatment or significant dose alteration for uncontrolled symptoms or drug toxicity within 3 months of screening and reconfirmed at baseline Cancer, or received treatment for cancer, within past 3 years (excluding basal cell carcinoma or squamous cell carcinoma) Presence of immunosuppression or medical condition possibly associated with impaired immune responsiveness, including diabetes mellitus 1 and 2 History of irritable bowel disease or other inflammatory digestive or gastrointestinal condition that could affect the distribution/safety evaluation of an orally administered vaccine targeting the mucosa of the small intestine. Such conditions may include but are not limited to: Esophageal Motility Disorder Malignancy Malabsorption Pancreaticobiliary disorders Irritable bowel syndrome Inflammatory Bowel Disease Surgical Resection GERD Hiatal Hernia Peptic Ulcer (History of cholecystectomy is not exclusionary) History of any form of angioedema History of serious reactions to any vaccination such as anaphylaxis, respiratory problems, hives or abdominal pain Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could make blood draws problematic Any condition that resulted in the absence or removal of the spleen Acute disease within 72 hours prior to vaccination defined as the presence of a moderate or severe illness (as determined by the Investigator through medical history and physical exam). (Assessment may be repeated during screening period.) Presence of a fever ≥ 38oC measured orally at baseline (Assessment may be repeated during screening period) Any significant hospitalization within the last year which in the opinion of the Investigator or Sponsor could interfere with study participation. Any other condition that in the clinical judgment of the investigator would jeopardize the safety or rights of a participant taking in the study, would render the participant unable to comply with the protocol or would interfere with the evaluation of the study endpoints Diagnostic Assessments Positive human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) tests at the screening visit Positive urine drug screen for drugs of abuse at screening Positive breath or urine alcohol test at screening and baseline Prior/Concurrent Therapy Receipt of a licensed vaccine within 14 days prior to baseline vaccination or planned administration during the study active period (4 weeks post each study vaccination). Use of antibiotics, proton pump inhibitors, H2 blockers or antacids within 7 days prior to study drug administration or planned use during the active study period Use of medications known to affect the immune function (e.g., systemic corticosteroids and others) within 2 weeks before study drug administration or planned use during the active study period Daily use of nonsteroidal anti-inflammatory drugs within 7 days prior to study drug administration or planned use during the active study period Administration of any investigational vaccine, drug or device within 8 weeks preceding study drug administration (Day 1), or planned use within the duration of the study Other Exclusions Donation or use of blood or blood products within 30 days prior to study drug administration or planned donation during the active study period History of drug, alcohol or chemical abuse within 1 year of screening History of hypersensitivity or allergic reaction to any component of the investigational vaccine, including but not limited to fish gelatin

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Prevention
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1 (4-week boost vaccination)<br>(4-week boost vaccination) 10 subjects will receive two doses of 1x10 log10 IU ± 0.5 log at Day 1 and Week 4 | Biological: VXA-G1.1-NN<br>* Norovirus GI.1 Norwalk VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with double-stranded RNA Adjuvant<br>|
| Active Comparator: Cohort 2 (8-week boost vaccination)<br>(8-week boost vaccination) 10 subjects will receive two doses of 1x10 log10 IU± 0.5 log at Day 1 and Week 8 | Biological: VXA-G1.1-NN<br>* Norovirus GI.1 Norwalk VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with double-stranded RNA Adjuvant<br>|
| Active Comparator: Cohort 3 (12-week boost vaccination)<br>(12-week boost vaccination) 10 subjects will receive two doses of 1x10 log10 IU± 0.5 log at Day 1 and Week 12 | Biological: VXA-G1.1-NN<br>* Norovirus GI.1 Norwalk VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with double-stranded RNA Adjuvant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral-capsid protein 1 (VP1)-specific antibody secreting cells (ASC) by enzyme-linked immunospot (ELISpot) assay | Comparison of VPI specific immunoglobin A (IgA) ASC levels between the 3 study cohorts | Day 1 (Initial Vaccination) through Day 8 post boost (Second Vaccination) | 
| Norovirus G1.1 histo-blood group antigen (HBGA) blocking antibodies (BT50) Assay | Comparison of GI.1 BT50 levels between the 3 study cohorts | Day 1 (Initial Vaccination) through Day 29 post boost (Second Vaccination) | 
| VP1 serum immunoglobin G (IgG) by ELISA | Comparison of VPI specific immunoglobin A (IgA) ASC levels between the 3 study cohorts | Day 1 (Initial Vaccination) through Day 29 post boost (Second Vaccination) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Solicited symptoms of Reactogenicity | Comparison of frequency, duration, and severity of solicited symptoms | Day 1 (Vaccination) to Day 8 post each vaccination |