Safety & Immunogenicity Study of Ad5 Based Oral Norovirus Vaccines

Study Overview
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Brief Summary
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VXA-NVV-103 is a phase 1B Randomized, Double-Blind, Placebo-Controlled, Multi-Center Safety and Immunogenicity Study of Adenoviral-vector Based Oral Norovirus Vaccines Expressing GI.1 or GII.4 VP1 with Monovalent or Bivalent Dosing in Healthy Adult Volunteers. The study consists of 2 parts: Part 1 is the double-blinded portion where subjects will be randomized to one of two monovalent vaccine groups, bivalent vaccine group or placebo. Subjects will be followed for  4 weeks post vaccination for safety and immunogenicity. Part 2 will consist of an open label booster vaccination for the bivalent treatment group  4 months post initial vaccination. All subjects will be followed for long term safety for 1 year post initial vaccination.

Detailed Description
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VXA-NVV-103 is a phase 1B Randomized, Double-Blind, Placebo-Controlled, Multi-Center Safety and Immunogenicity Study of Adenoviral-vector Based Oral Norovirus Vaccines Expressing GI.1 or GII.4 VP1 with Monovalent or Bivalent Dosing in Healthy Adult Volunteers. The study consists of 2 parts with will enroll 86 subjects: Part 1 - Double Blind Period: Post confirmation of eligibility subjects will be randomized in a double-blinded manner to one of four treatment arms. Treatment Group 1 will contain an open-label sentinel group of 6 subjects to be enrolled prior to initiation of subsequent treatment groups. After review of the safety data and confirmation the dose is well tolerated through Study Day 8, the rest of the study will proceed in a double-blinded, randomized fashion. The 6 sentinel subjects will not be part of the 16 subjects in Treatment Group 1 to be enrolled in the double-blinded placebo-controlled cohort; randomization will be 1:1:2:1 for Treatment Groups 1 through 4 respectively. Study Design and Vaccine Groups Monovalent GII.4 VXA-G2.4-NS (6 sentinels / 16 randomized) Monovalent GI.1 VXA-G1.1-NN (16 randomized) Bivalent GII.4/GI.1 VXA-G2.4-NS + VXA-G1.1-NN (32 randomized) Placebo Tablets no vaccine (16 randomized) Subjects will be followed for  4 weeks post vaccination for safety and immunogenicity. The study database will be locked post completion of Day 29 visits. Part 2 will consist of an open label booster vaccination for the bivalent treatment group  4 months post initial vaccination. Subjects will be followed for safety and immunogenicity for  4 weeks post the boost. All subjects will be followed for long term safety for 1 year post initial vaccination.

Official Title
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A Ph 1b, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Safety and Immunogenicity Study of Adenoviral-vector Based Oral Norovirus Vaccines Expressing GI.1 or GII.4 VP1 With Monovalent or Bivalent Dosing

Conditions
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Norovirus Infection

Intervention / Treatment
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* Biological: VXA-G1.1-NN
* Biological: VXA-G2.4-NS
* Biological: Placebo Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between the ages of 18 to 49 years, inclusive General good health, without significant medical illness, based on medical history, physical examination, vital signs, and clinical laboratories Demonstrate comprehension of the protocol procedures and willingness to adhere to all visits and assessments Body mass index between 17 and 35 at screening Female subjects must have a negative pregnancy test at screening and before each vaccination and fulfill protocol specified criteria for adequate birth control. Exclusion Criteria: Presence of a significant medical condition which in the opinion of the investigator precludes participation in the study History of cancer or cancer treatment within past 3 years Presence of immunosuppression or medical condition possibly associated with impaired immune responsiveness, including diabetes mellitus or angioedema Donation or use of blood/blood products within 4 weeks prior to vaccination 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 Positive HIV, HBsAg or HCV tests at the screening visit Use of antibiotics, proton pump inhibitors, H2 blockers or antacids within 7 days of vaccination Use of medications known to affect the immune function within 14 days of vaccination Use of NSAIDs, sulfonylureas, and angiotensin II blockers within 7 days of vaccination Evidence of recent or of current nonbacterial gastroenteritis suggestive of NV infection to any gastroenteritis within 2 weeks of vaccination History of drug, alcohol or chemical abuse within 1 year of screening or positive urine drug test at screening Consistent/habitual smoking within 2 months as per medical history History of hypersensitivity or allergic reaction to any component of the investigational vaccine or placebo Use of any investigational vaccine, drug or device within 8 weeks preceding vaccination, or planned use of the above stated for the duration of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label sentinel followed by Randomized, double-blind, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monovalent GI.1<br>Monovalent GI.1 tableted vaccine group | Biological: VXA-G1.1-NN<br>* Monovalent GI.1 tableted vaccine<br>* Other names: GI.1 oral vaccine tablet;Biological: Placebo Tablets<br>* Tablets matching in number and appearance to active vaccine doses<br>* Other names: Oral tablets for control arm;|
| Experimental: Monovalent GII.4<br>Monovalent GII.4 tableted vaccine group | Biological: VXA-G2.4-NS<br>* Monovalent GII.4 tableted vaccine<br>* Other names: GII.4 oral vaccine tablet;Biological: Placebo Tablets<br>* Tablets matching in number and appearance to active vaccine doses<br>* Other names: Oral tablets for control arm;|
| Experimental: Bivalent GI.1 and GII.4 vaccine group<br>Bivalent vaccine group consisting of co-administration of GI.1 and GII.4 vaccine | Biological: VXA-G1.1-NN<br>* Monovalent GI.1 tableted vaccine<br>* Other names: GI.1 oral vaccine tablet;Biological: VXA-G2.4-NS<br>* Monovalent GII.4 tableted vaccine<br>* Other names: GII.4 oral vaccine tablet;|
| Placebo Comparator: Placebo<br>Placebo tablets | Biological: Placebo Tablets<br>* Tablets matching in number and appearance to active vaccine doses<br>* Other names: Oral tablets for control arm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Solicited Adverse Events | Comparison of rate of occurance and severity of Solicited Adverse Events observed between treatment groups | Day 1 (Vaccination) to 7 days post vaccination | 
| Rate of Unsolicited Adverse Events | Comparison of the rate of occurrence and severity of unsolicited Adverse Events observed between treatment groups | Day 1 (Vaccination) to 28 days post vaccination | 
| Immunogenicity - VP1 Specific IgA ASC | LS Mean difference in VP1 specific IgA ASC between vaccine and placebo group | Day 1 (vaccination) to 7 days post-vaccination | 
| Immunogenicity - BT50 Assay | Difference in HBGA blocking antibodies (by blocking titer fifty assay [BT50]) between vaccine and placebo groups | Day 1 (vaccination) to 28 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity - VP1 specific serum IgG | LS Mean difference in VP1 specific serum IgG between vaccine and placebo groups | Day 1 (vaccination) to 7 days post-vaccination |