Optimal Human Dose for GII.2 Norovirus (Snow Mountain) Challenge Studies

This is a phase I, randomized, double blind, as well as partially blinded (for Cohort 4),
placebo-controlled safety, illness, and infection study of a new experimental human challenge
stock of the Norovirus genogroup II, genotype 2 (GII.2) isolate designated Snow Mountain
virus (SMV), administered to healthy adults 18-49 years of age. Groups of 11 subjects each
will be admitted to the inpatient hospital research unit, challenged with live SMV or placebo
by oral administration, and remain in isolation in the unit for at least 4 days following
challenge. The study duration is 24 - 36 months. Subjects will be followed post-challenge for
safety, reactogenicity, and illness (primary objectives), and secondary or exploratory
objectives including infection and immune responses. There will be multiple clinical
assessments and collection of blood, emesis, saliva, and stool specimens. The primary
objectives are to: 1) evaluate the safety and reactogenicity of the GII.2 Snow Mountain
norovirus challenge stock and 2) determine a safe and optimal challenge dose of GII.2 Snow
Mountain norovirus to achieve illness in a high proportion (= / > 75%) of subjects. The
secondary objectives are to: 1) determine the rate of infection in study participants after
norovirus GII.2 challenge, 2) determine the quantity and duration of virus shedding in stool
by RT-qPCR, 3) estimate the median time to cessation of shedding, 4) determine the modified
Vesikari score as a measure of gastroenteritis severity, 5) determine GII.2 Snow Mountain
norovirus-specific Immunoglobulin titers by ELISA before and after the challenge, 6)
determine the effect of pre-existing GII.2 Snow Mountain norovirus-specific immunoglobulin in
serum and saliva on the rate of infection, 7) determine total and GII.2 Snow Mountain
norovirus-specific IgA- and IgG-Secreting Cells in circulation by ELISpot assay, 8) once the
optimal challenge dose is determined in secretor positive subjects: investigate the safety
and illness rate using that dose of the GII.2 challenge stock in secretor negative subjects.

Inclusion Criteria:

1. Subject able to provide written informed consent

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

3. 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

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

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

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

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

8. Demonstrated to be H type I secretor positive for HBGA binding by assay of saliva
(this applies to all cohorts except the SN cohort, which will include secretor
negative subjects only)

Exclusion Criteria:

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

2. 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). Individuals who provide any child day
care services (in-home or non-residential facility) are also excluded

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

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

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

6. 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

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

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

9. 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

10. Have moderate or severe illness and/or an oral temperature >/=100.4 degrees F and/or
diarrhea or vomiting within seven days prior to challenge

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

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

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

14. 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

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

16. Have HIV, hepatitis B, hepatitis C infection or untreated latent syphilis

17. Have a seizure disorder

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

19. 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

20. Have abnormal screening laboratory test results per laboratory reported normal values
for white blood cells (WBCs), hemoglobin (Hgb), platelets, absolute neutrophil count
(ANC), elevated total bilirubin, potassium, sodium and hemoglobin A1c (HbA1c) and
urine protein

21. Have a serum creatinine greater than 1.1 x ULN

22. Have an ALT (SGPT) greater than 1.1 x ULN

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

25. Have ongoing drug abuse/dependence (including alcohol), or a history of these issues
within 5 years of enrollment 26. Have a positive urine test for opiates 27. 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 28. Are unwilling to
comply with study procedures including abstaining from smoking for the duration of the
inpatient portion of the study 29. Have participated in a previous NoV challenge study or
NoV vaccine study 30. Have received experimental products within 30 days before study entry
or plan to receive experimental products at any time during the study 31. 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 32. Plan to donate blood during the course of the study
33. 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 34. 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 35. 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 36. Use of antibiotics within 7 days prior to entry into
the inpatient facility 37. Use of any H2 receptor antagonists (e.g., Tagamet, Zantac, and
Pepcid), proton pump inhibitors (e.g., Prilosec, Protonix, and Prevacid), or prescription
acid suppression medication or over-the-counter (OTC) antacids in the 72 hours prior to NoV
challenge 38. Use of prescription and OTC medications containing acetaminophen, aspirin,
ibuprofen, and other non-steroidal anti-inflammatory drugs within 48 hours prior to NoV
challenge 39. Regular use of laxatives or anti-motility agents 40. Have a history of
allergy to sodium bicarbonate 40. Have a history of allergy to sodium bicarbonate