Norovirus Challenge Study

Phase 1

Completed

Conditions: Norovirus Infections

Interventions: Biological: VXA-G1.1-NN
Other: Placebo Tablets
Biological: Norovirus GI.1 Norwalk Virus Inoculum

Registration Number: NCT05212168

Lead Sponsor: Vaxart

Brief Summary: 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: 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 185 (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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 165

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:
1. At least one year post-menopausal;
2. Surgically sterile;
3. 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:
1. Family or personal history of bleeding or thrombosis
2. History of heparin-related thrombotic events, and/or receiving heparin treatments
3. History of autoimmune or inflammatory disease
4. 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:
1. QTc F (interval duration > 450 msec (male) or > 470 msec (female)
2. QRS interval greater than 120 msec
3. PR interval greater than 220 msec
4. 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:
1. Esophageal Motility Disorder
2. Malignancy
3. Malabsorption (e.g. Celiac disease, gluten intolerance)
4. Pancreaticobiliary disorders
5. Irritable bowel syndrome
6. Inflammatory Bowel Disease
7. Surgical Resection with the exception of appendectomy or a minor resection that is deemed acceptable by investigator and sponsor
8. Gastroesophageal reflux disease (GERD)
9. Hiatal Hernia
10. 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Active Vaccine Arm	VXA-G1.1-NN	Subjects receiving Norovirus GI.1 Norwalk VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant
Active Vaccine Arm	Norovirus GI.1 Norwalk Virus Inoculum	Subjects receiving Norovirus GI.1 Norwalk VP1 Vaccine, Oral E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant
Placebo Arm	Placebo Tablets	Subject receiving Placebo oral tablets similar in appearance and number to active vaccine tablets
Placebo Arm	Norovirus GI.1 Norwalk Virus Inoculum	Subject receiving Placebo oral tablets similar in appearance and number to active vaccine tablets

Primary Outcome Measures

Name	Time	Method
Geometric Mean Titer (GMT) of Histo-blood Group Antigen (HBGA) Blocking Antibodies Against NV by Blocking Titer 50 (BT50) at Day 28	Day 28	Blood samples were collected at different timepoints throughout the study. A positive change indicates an increase in titers.
VP1-specific Serum Immunoglobulin G (IgG) Response at Day 28	Day 28	Blood samples were collected at different timepoints throughout the study.
VP1-specific Serum IgA at Day 28	Day 28	Blood samples were collected at different timepoints throughout the study.
Number of Participants Who Experienced Norovirus Gastroenteritis (NVG)	Up to approximately Day 57	NVG is a composite endpoint defined as meeting both the definition of AGE and NV. AGE was defined as meeting any one of 3 criteria (diarrhea, vomiting, or diarrhea and vomiting) in any 24-hr rolling period. The individual criteria for diarrhea, vomiting, or diarrhea and vomiting were as follows: 1. Diarrhea: i. ≥ 3 loose or liquid stools in any 24-hr rolling period, or ii. 400 g of loose or liquid stools in any 24-hr rolling period 2. Vomiting: ≥ 2 vomiting episodes in any 24-hr rolling period, or 3. Diarrhea and vomiting: i. one vomiting episode plus any loose or liquid stool in any 24-hr rolling period ii. one vomiting episode plus ≥ 2 of the following events in any 24-hr rolling period: 1. nausea 2. fever (oral temperature ≥ 37.6°C) 3. abdominal cramps or pains 4. abdominal gurgling or bloating 5. myalgia NV infection was defined as having 1 or more positive results in stool or urine by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR).
Levels of Viral Protein 1, Major Capsid, or Surface Protein of Viruses (VP1)-Specific Immunoglobulin A (IgA) Antibody-Secreting Cell (ASC) Against Norwalk at Day 8	Day 8	Blood samples were collected at different timepoints throughout the study.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Solicited Symptoms of Reactogenicity	Up to Day 8	Solicited symptoms of reactogenicity included: * Gastrointestinal reactions: nausea, vomiting, diarrhea and abdominal pain * Systemic reactogenicity: malaise/fatigue, anorexia, fever, headache and myalgia
Number of Participants Who Experienced Unsolicited Adverse Events (AEs) During the Vaccination Phase	Up to Day 28 of Vaccination Phase (28-days phase)	Unsolicited AEs referred to any AEs that occurred during a clinical trial but were not specifically pre-defined or actively sought by the study protocol. Unsolicited AEs could include any medical condition or symptom, whether or not it was related to the intervention being studied.
Number of Participants Who Experienced Serious AEs (SAEs), AEs of Specific Interest (AESIs), and New Onsets of Chronic Illness (NOCIs)	Up to approximately 12 months post vaccination	A SAE was any AE that resulted in one or more of the following outcomes: death, a life-threatening event where the subject was at immediate risk of death (not hypothetically), inpatient hospitalization or the prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of normal life functions, congenital abnormality or birth defect, or an important medical event that, that jeopardized the participant's health or required medical or surgical intervention to prevent a serious outcome. A NOCI was defined as the diagnosis post-study drug administration of a new medical condition, which was chronic in nature, including those potentially controllable by medication (e.g., diabetes, asthma).
Duration of AGE	Up to approximately Day 57	Time to onset of AGE was calculated as the time from challenge administration to the first recorded instance of an event satisfying the criteria for AGE. AGE was defined as meeting any of the 3 criteria: 1. Diarrhea: i. ≥ 3 loose or liquid stools in any 24-hr rolling period, or ii. 400 g of loose or liquid stools in any 24-hr rolling period 2. Vomiting: ≥ 2 vomiting episodes in any 24-hr rolling period, or 3. Diarrhea and vomiting: i. one vomiting episode plus any loose or liquid stool in any 24-hr rolling period ii. one vomiting episode plus ≥ 2 of the following events in any 24-hr rolling period: 1. nausea 2. fever (oral temperature ≥ 37.6°C) 3. abdominal cramps or pains 4. abdominal gurgling or bloating 5. myalgia
Number of Participants Who Experienced Incidences of Diarrhea or Emesis	Up to approximately Day 57	Classification of diarrhea was done through grading stools with Grade 3 (thick liquid stool) to Grade 5 (clear water diarrheal stool) being considered diarrhea.
Number of Participants Who Experienced Unsolicited AEs During the Challenge Phase	Up to Day 29 of Challenge Phase (28-days phase)	Unsolicited AEs referred to any AEs that occurred during a clinical trial but were not specifically pre-defined or actively sought by the study protocol. Unsolicited AEs could include any medical condition or symptom, whether or not it was related to the intervention being studied.
Number of Participants With AGE During the Inpatient Challenge Phase	Day 28 of Challenge Phase (28-days phase)	AGE was defined as meeting any one of 3 criteria (diarrhea, vomiting, or diarrhea and vomiting) in any 24-hr rolling period. The individual criteria for diarrhea, vomiting, or diarrhea and vomiting were as follows: 1. Diarrhea: i. ≥ 3 loose or liquid stools produced in any 24-hr rolling period, or ii. 400 g of loose or liquid stools produced in any 24-hr rolling period 2. Vomiting: ≥ 2 vomiting episodes in any 24-hr rolling period, or 3. Diarrhea and vomiting: i. one vomiting episode plus any loose or liquid stool in any 24-hr rolling period ii. one vomiting episode plus ≥ 2 of the following events in any 24-hr rolling period: 1. nausea 2. fever (oral temperature ≥ 37.6°C) 3. abdominal cramps or pains 4. abdominal gurgling or bloating 5. myalgia
Severity of AGE Assessed Using the Modified Vesikari Scale	Up to approximately Day 36	The Modified Vesikari Scale is a tool used to assess the severity of AGE by evaluating symptoms such as diarrhea, vomiting, fever, and dehydration. It scores these symptoms based on their frequency and severity, with a minimum score of 0 and a maximum score of 20, where higher scores indicate more severe symptoms and lower scores suggest milder or no symptoms and severity.
Number of Participants Who Experienced Moderate or Severe Gastroenteritis	Up to approximately Day 57	Moderate or severe gastroenteritis was defined by cumulative loose stools ≥ 1000gr during the inpatient period.
Number of Participants With Norovirus (NoV) Infection up to Challenge Period Day 8	Challenge Phase Day 8 (equal to Study Day 36)	NoV infection was defined as a positive qRT-PCR in stool or emesis up to Challenge Period Day 8, and the presence of NV antigen in stool.
Geometric Mean Genome Copies (GCs) of NoV Shedding in Stool Measured by qRT-PCR	Pre-challenge up to Day 8 of Challenge Phase (equal to Study Day 36)	NoV shedding was assessed by qRT-PCR. Stool samples were reported on 10\^3 copies/gm. If a participant produced multiple results for a given study day, the result with the largest shedding response was used for analysis. Samples that were reported as "Not Quantifiable" or as lower than the limit of detection (LOD) were analyzed as ½2\*LOD (76.2).
Geometric Mean GCs of NoV Shedding in Emesis Measured by qRT-PCR	Pre-challenge up to Day 8 of Challenge Phase (equal to Study Day 36)	NoV shedding was assessed by qRT-PCR. Emesis samples were reported in 10\^3 copies/mL. If a participant produced multiple results for a given study day, the result with the largest shedding response was used for analysis. Samples that were reported as "Not Quantifiable" or as lower than the limit of detection (LOD) were analyzed as ½2\*LOD (15.3).
Duration of NoV Infection	Up to approximately Day 57	Duration of NoV Infection was defined as the time from NoV infection to the time of resolution of infection, defined as a negative qRT-PCR result not followed by a positive qRT-PCR result.