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). The study duration is 24 - 36 months. 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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
DOUBLE
Enrollment
44
GII.2 Snow Mountain Norovirus Filtrate. Cohort 1: 1.2x10\^4 Genome Equivalent Copies (GEC) oral dose on Day 1. Cohort 2: either 1.2 x 10\^2 GEC or 1.2 x10\^6 GEC oral dose on Day 1, depending on the results of prior Cohort 1. Cohort 3: either 1GEC, 1.2 x 10\^1 GEC, 1.2 x 10\^2 GEC, 1.2 x 10\^3 GEC, 1.2 x 10\^5 GEC, or 1.2 x 10\^6 GEC, or 1.2 GEC x 10\^7 oral dose on Day 1, depending on the percentage of subjects with illness from Cohorts 1 and 2. Cohort 4: optimal dose of GEC as determined by the results of cohorts 1-3
Placebo: 80 ml of sterile water for oral administration
Emory Vaccine Center - The Hope Clinic
Decatur, Georgia, United States
Infectious Dose-50 based on infection rate after challenge with various doses
Time frame: Day 2 to Day 5
Number of serious adverse events related to virus challenge
Time frame: Day 1 to Day 180
Number of subjects experiencing any mild reactogenicity outcomes
Time frame: Day 1 to Day 10
Number of subjects experiencing any moderate reactogenicity outcomes
Time frame: Day 1 to Day 10
Number of subjects experiencing any severe reactogenicity outcomes
Time frame: Day 1 to Day 10
Number of subjects experiencing Grade 3 adverse events
Time frame: Day 1 to Day 30
Proportion of subjects with GII.2 Snow Mountain norovirus-associated illness following GII.2 challenge
Time frame: Day 1 to Day 5
Duration of diarrhea related to the challenge strain
Time frame: Day 1 to Day 5
Duration of virus shedding in PCR-positive stool for each challenge dose
Time frame: Day -60 to Day 75
Duration of vomiting related to the challenge strain
Time frame: Day 1 to Day 5
Levels of pre-existing serum blockage IgG prior to challenge
Time frame: Inpatient Admission
Levels of pre-existing serum IgA prior to challenge
Time frame: Inpatient Admission
Levels of pre-existing serum IgG prior to challenge
Time frame: Inpatient Admission
Levels of pre-existing serum salivary IgA prior to challenge
Time frame: Inpatient Admission
Magnitude of virus shedding in PCR-positive stools, reported as GEC/ml
Time frame: Day -60 to Day 75
Proportion of subjects excreting challenge virus in stool
Time frame: Day 1 to Day 30
Proportion of subjects showing a >/= 4 fold rise in virus-specific serum IgG
Time frame: Day 1 to Day 30
Proportion of subjects with =/> 4 fold rise in virus-specific salivary IgA
Time frame: Day 1 to Day 45
Proportion of subjects with =/> 4 fold rise in virus-specific serum blockage IgG
Time frame: Day 1 to Day 45
Proportion of subjects with =/> 4 fold rise in virus-specific serum IgG
Time frame: Day 1 to Day 45
Proportion of subjects with >/= 4 fold rise in virus-specific serum IgA
Time frame: Day 1 to Day 45
Proportion of subjects with norovirus specific IgA-ASC/10^6 PBMC (freshly isolated PBMCs)
Time frame: Day 1 to Day 45
Proportion of subjects with norovirus specific IgG-ASC/10^6 PBMC (freshly isolated PBMCs)
Time frame: Day 1 to Day 45
Severity of diarrhea related to the challenge strain, determined using the Vesikari Score
Time frame: Day 1 to Day 5
Severity of vomiting related to the challenge strain, determined using the Vesikari Score
Time frame: Day 1 to Day 5
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