Phase I Study to Determine the Optimal Human Challenge Dose for a Norovirus GII.4 Challenge Stock (CIN-1)

This is phase I, double blind, placebo-controlled safety and infectivity study of
experimental human Norovirus genogroup GII.4 administered to healthy adults 18-49 years of
age. The unblinded pharmacist will assign treatments. Subjects will be admitted to an
inpatient nursing unit, challenged with live GII.4 Norovirus strain by oral administration,
remain in the unit for at least 4 days following challenge and then followed for
post-challenge safety and efficacy with multiple clinical assessments and collection of
blood and stool specimens.

Subjects susceptible to the human norovirus GII.4 challenge strain, CIN-1 (i.e. presence of
a functional FUT-2 gene), regardless of ABO blood type, will be housed in the Cincinnati
Center for Clinical Research (CCCR) inpatient facility and challenged orally with different
doses of the virus. The challenge study will be conducted in 2-3 cohorts of approximately 20
subjects each, with the initial cohort receiving 103 RT-PCR units or placebo (9 "challenge"
and 1 "placebo" per 10 subjects). Based on the illness rate of acute gastroenteritis (AGE)
in the initial cohort, the second cohort will be enrolled to receive a challenge dose based
on the results of the previous studies. Additional cohorts may be necessary. Illness is
defined as infection accompanied by vomiting and/or diarrhea during the inpatient stay.Two
to three additional subjects per cohort will serve as alternates in the event that any of
the study subjects are unavailable or become ineligible at the time of the inpatient
study.Subjects will remain in the inpatient facility for at least four days following
challenge and assessed daily for clinical and virologic evidence of norovirus infection.
Subjects will return to the investigational site for evaluation on Day 6 (6-8 days) and
about 15 (14-16 days) and 30 days (28-35 days), and 45 (40-45 days), and (55-65) post
challenge.

The primary objectives are to evaluate the safety and reactogenicity of the norovirus GII.4
(CIN-1; 031693) challenge stock and to determine a safe and optimal challenge dose of
Norovirus GII.4 Challenge Stock norovirus to achieve illness in > /=50% of subjects. Illness
is defined as: diarrhea (>3 loose or liquid stools or >300 gm of loose or liquid stool
/24h), and/or vomiting during the inpatient period, in a participant with evidence of
infection. The secondary objectives are to determine the rate of infection in study
participants by; virus detection in stool by Norovirus GII.4 Challenge Stock-specific
qRT-PCR and anti- Norovirus GII.4 Challenge Stock serum IgG by ELISA (> /=4 fold rise from
baseline to Day 30), determine the quantity and duration of virus shedding in stool by
qRT-PCR, conduct Time-to-event analysis to estimate the median time to cessation of shedding
using Kaplan-Meier methods, determine the modified Vesikari score as a measure of
gastroenteritis severity, determine Norovirus GII.4 Challenge Stock-specific immunoglobulin
titers by ELISA before and after the challenge; Serum IgA and IgG, Serum Blockade IgG,
Salivary IgA, determine the effect of preexisting Norovirus GII.4 Challenge Stock-specific
Immunoglobulin in serum and saliva on the rate of infection, determine total and Norovirus
GII.4 Challenge Stock-specific IgA- and IgG-Secreting Cells in circulation by ELISpot assay.

Inclusion Criteria:

Subjects must meet all of the following inclusion criteria:

- Subject able to provide written informed consent.

- Male or non-pregnant females between the ages of 18 and 49 years, inclusive.

- Women of childbearing potential must be practicing abstinence or using an acceptable
method of birth control for at least 30 days prior to enrollment through day 45 after
receipt of the challenge virus. Male subjects must agree not to father a child prior
to day 45 after receipt of the challenge virus.

- A woman is considered of childbearing potential unless post-menopausal (absence
of menses for >/= 1 year) or surgically sterilized (tubal ligation, bilateral
oophorectomy or hysterectomy).

- Acceptable contraception methods for women include but are not limited to:
sexual abstinence from intercourse with men, monogamous relationship with
vasectomized partner who has been vasectomized for 6 months or more prior to the
subject enrolling in the study, barrier methods such as condoms or diaphragms
with spermicide or foam, effective devices (IUDs, NuvaRing®) or licensed
hormonal products such as implants, injectables or oral contraceptives.

- For women of childbearing potential, must have a negative serum or urine pregnancy
test at screening and negative urine or serum pregnancy test within 24 hours prior to
challenge.

- Are in good general health, as determined by the study investigator within 60 days of
challenge.

- Demonstrate knowledge and comprehension of the study by scoring >/=70 procent on a
quiz of the study protocol and policies.

- Willing and able to participate in all study visits, including an inpatient stay of
at least 96 hours.

- Demonstrated to be secretor positive for HBGA binding.

Exclusion Criteria:

Subjects who meet any of the following exclusion criteria will be excluded from study
participation:

- Have household contact with or have daily contact with children less than 2 years of
age or persons older than 70 years of age.

- Have expected occupational or social contact with immunocompromised individuals in
the 8 weeks after challenge, including persons with HIV infection or active cancer,
children < 2 years of age, pregnant women or persons who are immunosuppressed (e.g.
history of stem cell or organ transplantation) and/or provide any child day care
services (in-home or non-residential facility).

- Are healthcare workers with patient contact in the 8 weeks after challenge.

- Are food service workers expected to prepare/handle food in the 8 weeks after
challenge.

- Plan to be living in a confined environment (e.g. ship, camp, or dormitory) within 8
weeks after receiving the challenge strain.

- For females, are pregnant or plan to become pregnant at any time between the
Screening Visit through 45 days after receipt of the challenge virus.

- Are breastfeeding or plan to breastfeed at any given time throughout the study.

- Have a history of gastroenteritis in the 4 weeks prior to challenge or any history of
chronic or recurrent diarrhea or vomiting.

- Have a history of malabsorption or maldigestion disorder (e.g. celiac sprue), major
gastrointestinal (GI) surgery, irritable bowel syndrome or any other chronic GI
disorders that would interfere with the study, including chronic constipation or
increased stool frequency.

- Have moderate or severe illness and/or an oral temperature >/=100.4 degre Fahrenheit
and/or diarrhea or vomiting within seven days prior to challenge.

- Have a pulse rate less than 55 bpm or greater than 100 bpm. If heart rate is <55
beats per minute and the investigator determines that this is not clinically
significant (e.g., athletes) and heart rate increases > 55 beats per minute on
moderate exercise (two flights of stairs), subject will not be excluded.

- Have a systolic blood pressure less than 90 mm Hg or greater than 140 mm Hg on two
separate measurements (screening and pre-challenge).

- Have a diastolic blood pressure less than 50 mm Hg or greater than 90 mmHg on two
separate measurements (screening and pre-challenge).

- Have long-term use (>/=2 weeks) of high-dose oral (>/= 20 mg per day prednisone or
equivalent) or parenteral glucocorticoids, or high-dose inhaled steroids for greater
than 7 days in the last 6 months.

- Have an autoimmune, inflammatory, vasculitic or rheumatic disease, including but not
limited to systemic lupus erythematosus, polymyalgia rheumatic, rheumatoid arthritis
or scleroderma.

- Have HIV, Hepatitis B, Hepatitis C infection or untreated latent syphilis.

- Have a seizure disorder.

- Have an active malignancy or history of malignancy (excluding nonmelanotic skin
cancer in remission without treatment for more than 5 years) or current use of
immunosuppressive or cytotoxic therapy.

- Have positive fecal culture for E. coli O157:H7, Salmonella, Campylobacter, Yersinia,
or Shigella, evidence of norovirus in the stool by RT-qPCR or pathogenic ova and
parasites detected on microscopic examination at screening.

- Have abnormal screening laboratory test results per laboratory reported normal values
and Section 18 Appendix B for white blood cells (WBCs), hemoglobin (Hgb), platelets,
absolute neutrophil count (ANC), bilirubin, potassium, sodium, Hemoglobin A1-c
(HgbA1-c) and urine protein.

- Serum creatinine greater than 1.1 x ULN

- Alanine aminotransferase (ALT), greater than 1.1 x ULN.

- Have a chronic condition that the study physician feels would pose a threat to
participating subjects, including, but not limited to solid organ or stem cell
transplantation, diabetes, clinically significant history of immunosuppressive
illness, gall bladder disease, heart disease, lung disease, pancreatic disease, renal
disease or neurological disease.

- Have abnormal findings on screening electrocardiogram deemed clinically significant
by study physician.

- Have ongoing drug abuse/dependence (including alcohol), or a history of these issues
within 5 years of enrollment.

- Have a positive urine test for opiates.

- Have any medical, psychiatric, occupational, or behavioral problems that make it
unlikely for the subject to comply with the protocol as determined by the
investigator.

- Are unwilling to comply with study procedures including abstaining from smoking for
the duration of the inpatient portion of the study.

- Have participated in a previous NoV challenge study or NoV vaccine study.

- Have received experimental products within 30 days before study entry or plan to
receive experimental products at any time during the study.

- Plans to enroll in another clinical trial that could interfere with safety assessment
of the investigational product at any time during the study period, including study
interventions such as drugs, biologics or devices.

- Plan to donate blood during the course of the study.

- Have received a live vaccine within 30 days before study entry or plan to receive a
live vaccine prior to Day 30 of the study.

- Have received an inactivated vaccine within 14 days before study entry or plan to
receive an inactivated vaccine prior to Day 14 of the study.

- Have received parenteral immunoglobulin or blood products within 3 months of the
study start, or plan to receive parenteral immunoglobulin or blood products within 3
months after receiving the study agent.

- Use of antibiotics within 7 days prior to entry into the inpatient facility.

- Use of any H2 receptor antagonists (e.g., Tagamet, Zantac, and Pepcid), proton pump
inhibitors (e.g., Prilosec, OTC, Protonix, and Prevacid), or prescription acid
suppression medication or over-the-counter (OTC) antacids in the 72 hours prior to
NoV challenge.

- Use of prescription and OTC medications containing acetaminophen, aspirin, ibuprofen,
and other non-steroidal anti-inflammatory drugs within 48 hours prior to NoV
challenge.

- Regular use of laxatives or anti-motility agents.

- Have a history of allergy to sodium bicarbonate.