Norovirus Challenge Study

Study Overview
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Brief Summary
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This is a Phase 2b randomized, double-blind, placebo-controlled vaccination and challenge study to assess the protective efficacy of the Vaxart Norovirus vaccine (VXA-G1.1-NN). Healthy adults will be randomized in a 1:1 ratio to receive one oral dose of vaccine or placebo. Arm 1: VXA-G1.1-NN oral vaccine tablets [1x1011 IU±0.5 log] Arm 2: Placebo tablets similar in appearance and number to active vaccine tablets Approximately 28 days post-vaccination, subjects will be admitted to an isolation ward and challenged with the NV GI.1 Norwalk challenge strain. After challenge, subjects will be monitored for signs and symptoms of acute gastroenteritis (AGE) from Day 29 to discharge. At 4 days post challenge (Day 33) asymptomatic subjects will be discharged from the isolation ward and will be followed in a series of outpatient visits and telephone calls. Symptomatic subjects may be kept in the isolation ward for up to an additional 3 days.

Detailed Description
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Study Population Healthy male and female adult volunteers age 18 to 49 years inclusive with blood type O or A and who are confirmed H type-1 antigen secretory positive Investigational Product Active Vaccine: Norovirus GI.1 Norwalk VP1 Vaccine (VXA-G1.1-NN), an Oral E1/E3-Deleted Replication-Defective Recombinant Adenovirus serotype 5 with double-stranded ribonucleic acid (dsRNA) Adjuvant. The vaccine vector encodes for a full-length VP1 gene from Norwalk virus (NV). The adjuvant is a short hairpin RNA, expressed as a 21 nucleotide sequence (GAAACGA TATGGGCTGAATAC) as a tandem sequence in forward and reverse orientations separated by 6 nucleotides that comprise the loop of the RNA. The final drug product (DP) is formulated into enteric-coated tablet. Dose: 1x10E11 IU±0.5 log Placebo Control: • Oral tablets similar in appearance and number to active vaccine tablets Multiple tablets of study drug will be dispensed to allow delivery of the intended vaccine dose (1x10E11 IU). A matching number of placebo tablets will be dispensed to maintain the study blinding. Viral Challenge Inoculum Norovirus GI.1 (Norwalk Virus Inoculum Lot 001-09NV, IND 14697) Dose: 1x10E6 Genomic Copies (GC). A dose which allows 50% - 65% infectivity in the healthy adult population (per NV infection rate observed in the GI.1 viral titration study Study Hypothesis Norovirus vaccine (VXA-G1.1-NN) will protect against Norovirus Gastroenteritis (NVG) related to norovirus (NoV) infection in the challenge model Approximately 120 subjects will be dosed in the vaccination phase to ensure at least 100 subjects (  50 VXA-G1.1-NN vaccine and 50 placebo) are available to participate in the challenge phase. Approximately 28 days post-vaccination, subjects will be admitted to an isolation ward and challenged with the NV GI.1 Norwalk challenge strain. After challenge, subjects will be monitored for signs and symptoms of acute gastroenteritis (AGE) from Day 29 to discharge. NV illness lasts 2-4 days and is self-limited. At 4 days post challenge (Day 33) asymptomatic subjects will be discharged from the isolation ward and will be followed in a series of outpatient visits and telephone calls. Symptomatic subjects may be kept in the isolation ward for up to an additional 3 days. The following study visits and remote contacts will be conducted during the study Vaccination Phase: Pre-Screening Period (Days -90 to Screening) may be utilized for purposes of ascertaining subjects' H type-1 antigen secretory status and blood type Screening Period (Days -45 to -1) Day 1 Visit (Baseline assessments; day of randomization and vaccination) Day 8 Visit (safety and evaluation of immune response) Day 28 (evaluation of immune response; 1 day prior to challenge, start inpatient stay) Challenge Phase: Day 29 (viral challenge, sequestration) Days 30 to 33 (sequestration - discharge; +3 days) Day 36 Visit (evaluation of immune response and safety assessment) Day 57 Visit (end of active period) Safety Follow-Up: Day 120, Day 180, Day 240 and Day 300 (follow-up contact) Day 365 (follow-up phone call): Study completion An independent Safety Monitoring Committee (SMC) will convene at pre-defined intervals during the norovirus challenge period, and also ad hoc as needed during the vaccination and challenge periods, to oversee the safety of the study.

Official Title
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A Phase 2b Double-Blinded, Randomized, Placebo-Controlled, Human Norovirus GI.1 (Norwalk Virus Inoculum) Challenge Study Following Administration of an Oral, Single-dose Norovirus Vaccine Expressing GI.1 VP1 and dsRNA Adjuvant to Protect Against Norovirus Gastroenteritis (NVG) in Healthy Adult Volunteers

Conditions
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Norovirus Infections

Intervention / Treatment
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* Biological: VXA-G1.1-NN
* Other: Placebo Tablets
* Biological: Norovirus GI.1 Norwalk Virus Inoculum


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between the ages of 18 - 49 years, inclusive Able to give written informed consent Healthy, as determined by the principal investigator (PI) or PI in consultation with the research monitor and Sponsor Healthy = No clinically significant health concerns or medical illness, as determined by medical history, physical examination, vital signs, electrocardiogram (ECG), and clinical laboratories (complete blood count (CBC), chemistry and urinalysis) Comprehension of the study requirements with ability and willingness to complete all assessments and comply with confinement period post viral challenge, and all scheduled visits and contacts Confirmed blood type (A or O) Demonstrated to be H type-1 antigen secretor positive (by saliva test) Body mass index between 17 and 35 kg/m2, inclusive, at Screening Female participants must have a negative pregnancy test at pre-vaccination and pre-challenge and fulfill one of the following Criteria: At least one year post-menopausal; Surgically sterile; Use of oral, implantable, transdermal or injectable contraceptives for 30 days prior to immunization and until 60 days after challenge; i. A reliable form of contraception must be approved by the Investigator (eg, double barrier method, Depo-Provera, intrauterine device, Norplant, oral contraceptives, contraceptive patches) d. Not be sexually active (abstinent) or in a same sex relationship (must be discussed with site staff and documented) Male subjects must agree not to father a child or donate sperm, as well as to use contraception/barrier (a male condom) or be abstinent from heterosexual intercourse, from vaccination through the active period (Day 57) Exclusion Criteria: Administration/use of any investigational drug or device 30 days prior to vaccination through the active period (Day 57) Administration of any licensed vaccine within 30 days prior to vaccination or planned use of the above stated during the active period (through Day 57) Presence of a significant medical condition, which, in the opinion of the investigator, precludes participation in the study. Significant medical condition = for example, psychiatric conditions, or gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active gastritis or gastroesophageal reflux disease, inflammatory bowel disease, alcohol or illicit drug abuse/dependency, or other laboratory abnormalities Laboratory values outside the range of normal for platelet counts and the following coagulation tests: prothromibin time test (PT/INR), activated partial thromboplastine time test (aPTT) and fibrinogen Any of the following history or conditions that may lead to higher risk of clotting events and/or thrombocytopenia: Family or personal history of bleeding or thrombosis History of heparin-related thrombotic events, and/or receiving heparin treatments History of autoimmune or inflammatory disease Presence of any of the following conditions known to increase risk of thrombosis within 6 months prior to screening: Recent surgery other than removal/biopsy of cutaneous lesions Immobility (confined to bed or wheelchair for 3 or more successive days) Head trauma with loss of consciousness or documented brain injury Receipt of anticoagulants for prophylaxis of thrombosis Recent clinically significant infection Any one of the following ECG findings within 45 days prior to vaccination: Exclusionary ECG findings: QTc F (interval duration > 450 msec (male) or > 470 msec (female) QRS interval greater than 120 msec PR interval greater than 220 msec Clinically significant ST-T wave changes or pathologic Q waves History of cancer or cancer treatment within past 3 years (excluding basal cell or squamous cell carcinomas) Presence of immunosuppression or medical condition possibly associated with impaired immune responsiveness, including diabetes mellitus or angioedema Donation or use of blood or blood products within 30 days prior to vaccination through the active period (Day 57) 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 Evidence of confirmed infection with human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) with confirmatory assays Abnormal stool pattern (fewer than 3 bowel movements per week or more than 3 per day) History of irritable bowel disease or 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 (e.g. Celiac disease, gluten intolerance) Pancreaticobiliary disorders Irritable bowel syndrome Inflammatory Bowel Disease Surgical Resection with the exception of appendectomy or a minor resection that is deemed acceptable by investigator and sponsor Gastroesophageal reflux disease (GERD) Hiatal Hernia Peptic Ulcer (History of cholecystectomy is not exclusionary) Use of proton pump inhibitors, H2 blockers or antacids within 7 days prior to vaccination through the active period (Day 57) Use of antibiotics within 30 days prior to vaccination through the active period (Day 57) Note: use of a brief (≤ 10 days) course of oral or topical antibiotic for minor upper respiratory infection (URI), urinary tract infection (UTI), dental work, or skin infection allowed within the screening period, but must be completed 7 days prior to first vaccination Use of medication known to affect the immune function (e.g. systemic corticosteroids and others) within 14 days prior to vaccination through the active period (Day 57) Regular use of nonsteroidal anti-inflammatory drugs within 7 days prior to vaccination through the active period (Day 57) Use of over-the-counter probiotics or antidiarrheals within 7 days prior to vaccination through the active period (Day 57) Evidence of recent (within 2 months of vaccination) or of current nonbacterial gastroenteritis suggestive of NV infection [vomiting or unformed or watery stools (> 2 during a 24-hour period)] Any gastroenteritis within the past 2 weeks prior to vaccination Acute disease within 72 hours prior to vaccination, defined as the presence of a moderate or severe illness with or without fever (as determined by the Investigator through medical history and physical examination). (Assessment may be repeated during screening period) Presence of a fever ≥ 38ºC measured orally at baseline History if hematochezia (blood in stool) or melena (black stool) Any significant hospitalization within the last year which in the opinion of the investigator or sponsor could interfere with study participation History of serious reactions to any vaccination such as anaphylaxis, respiratory problems, Guillain-Barre syndrome, hives or abdominal pain History of a hypersensitivity or allergic reaction to any component of the investigational vaccine or placebo, including but not limited to fish gelatin. Subjects with known fish allergies should be excluded. History of drug, alcohol or chemical abuse within 1 year prior to vaccination Positive test for drugs of abuse or alcohol at screening, vaccination baseline and pre-challenge (except for previous marijuana use; concurrent or ongoing use of marijuana during the active study period). Consistent/habitual smoking within 2 months prior to vaccination (defined as smoking ≥ 1 pack of cigarettes a day). Smoking is not permitted during the inpatient stay Other conditions, in the clinical judgment of the investigator, that would jeopardize the safety or rights of a subject or interfere with the evaluation of the study Social/Occupational: Living with or having daily contact with children < 5 years old or women known to be pregnant or nursing; this includes significant contact at home, school, day-care, or equivalent facilities Living with or having daily contact with elderly persons > 70 years of age or infirmed, diapered individuals, persons with disabilities or incontinence; this includes at work or visits to nursing homes and day-care or equivalent facilities Employment in the food service industry such as restaurant or cafeteria facilities; specifically, this includes persons whose employment requires food handling and processing in the 4 weeks following viral challenge Health-care workers with patient contact expected in the 4 weeks following viral challenge Expected contact, via employment or at home, with immunocompromised persons in the 4 weeks following viral challenge. Immunocompromised persons = HIV-positive, receiving immunosuppressive medications such as oral steroids, anti-neoplastic agents Presence of household members who have received the Ad4 or Ad7 vaccines within 2 months prior to vaccination Employment as an airline flight attendant or cruise ship crew, scheduled to work in the 4 weeks following challenge Persons planning to live in a confined environment (eg, a cruise, camp, etc.) in the 4 weeks following viral challenge

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: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Vaccine Arm<br>Subjects receiving Norovirus GI.1 Norwalk VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant | Biological: VXA-G1.1-NN<br>* Norovirus GI.1 Norwalk VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant<br>Biological: Norovirus GI.1 Norwalk Virus Inoculum<br>* Norwalk Virus Inoculum Lot 01-09NV<br>|
| Placebo Comparator: Placebo Arm<br>Subject receiving Placebo oral tablets similar in appearance and number to active vaccine tablets | Other: Placebo Tablets<br>* Oral tablets similar in appearance and number to active vaccine tablets<br>Biological: Norovirus GI.1 Norwalk Virus Inoculum<br>* Norwalk Virus Inoculum Lot 01-09NV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of norovirus Norwalk virus infection post vaccine and post challenge | To assess the rate of norovirus infection as detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of stool or emesis sample collected through Day 8 post challenge | Change from baseline (Day 1 pre-vaccination and Day 28 pre-challenge) at Day 36 post-challenge through end of Active Phase (Day 57) | 
| To assess the rate of clinical norovirus acute gastroenteritis | Subject monitoring 2X/Day for diarrhea, vomiting, nausea, fever, myalgia, and abdominal cramps, pain, gurgling, or bloating | From Day 29 (challenge) through Day 36 | 
| To assess the induction of VP1-specific Immunoglobin A (IgA) antibody-secreting cells (ASC) by ELISpot assay | Change from baseline in VP1-specific Immunogolobin A (IgA) antibody-secreting cells (ASC) by ELISpot assay will be evaluated at Day 8 | Change from baseline (Day 1 pre-vaccination) at Day 8 | 
| To assess histo-blood group antigen (HBGA) blocking antibodies by blockade titer (BT50) | Change from baseline in histo-blood group antigen (HBGA) blocking antibodies evaluated | Change from baseline at Day 28 | 
| To assess VP1-specific serum Immunoglobin G (IgG) by Mesoscale Discovery (MSD) assay | Change from baseline in VP1-specific Immunoglobin G (IgG) by Mesoscale Discovery (MSD) assay will be evaluated at Day 28 | Change from baseline at Day 28 | 
| To assess the VP1-specific serum Immunoglobin A (IgA) by Mesoscale Discovery (MSD) assay | Change from baseline in VP1-specific serum IgG by Mesoscale Discovery (MSD) | Change from baseline at Day 28 |