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.
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. Subjects susceptible to the human norovirus GII.4 challenge strain. The challenge study will be conducted in 2-3 cohorts of approximately 20 subjects each.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. 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.