Gastroenteritis Norovirus
Conditions
Keywords
NoV, CIN-1, GII4. Norovirus, challenge, FUT-2 gene, HBGA-blocking Ab
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALNorovirus GII.4 Challenge Pool CIN-1
Norovirus Challenge GII.4 Strain 031693. Cohort 1: receive single oral dose of GII.4 CIN-1 at 10\^3 RT-PCR units. Cohort 2: single oral dose of GII.4 CIN-1 either at 10\^2 or 5x10\^3 RT-PCR units. Cohort 3: single oral dose of GII.4 CIN-1 at either 10\^4, 10\^3, 5x10\^2 or 5x10\^1 RT-PCR units. Cohort 4: single oral dose of GII.4 CIN-1 at either 5x10\^4 or 5x10\^3 or 10\^3 or 10\^2 or 10\^4 or 5x10\^2 or 5x10\^1RT-PCR units.
OTHERPlacebo
Placebo: 80 ml of sterile water for oral administration
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 49 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Determine Infectious Dose50 based on infection rate after challenge with various doses. | Day 1 to Day 180 |
| Number of serious adverse events related to virus challenge reported at any point during the study | Day 1 to Day 180 |
| Number of subjects experiencing Grade 3 adverse events after virus challenge throughout the study to day 30 | Day 1 to Day 30 |
| Number of subjects experiencing any mild, moderate or severe reactogenicity outcomes. | Day 1 to Day 180 |
| Proportion of subjects with Norovirus-GII.4 Challenge Stock (CIN-1; 031693) associated illness following norovirus GII.4 challenge | Day 1 to Day 5 |
Secondary
| Measure | Time frame |
|---|---|
| Mean duration (hours) of vomiting and/or diarrhea related to the challenge strain | Day 1 to Day 5 |
| At any time after challenge Proportion of subjects with >/= 4 fold rise from the baseline in virus-specific antibody titers in serum(IgA, IgG Blockade), or salivary IgA | Day 1 to Day 45 |
| Infection rate within each dose defined as proportion of subjects showing a > /=4 fold rise in virus specific serum IgG from baseline to Day 30 | Day 1 to Day 30 |
| Magnitude and duration of virus shedding in stool reported as qRT-PCR units for each challenge dose | Day 1 to Day 60 |
| Correlation of challenge outcome (infection) and preexisting serum immunoglobulins. | Day 1 to Day 45 |
| Time-to-cessation of virus shedding in stool in hours for each challenge dose. | Day 1 to Day 60 |
| Proportion of subjects with norovirus specific IgA- ASC / 10^6 PBMC (freshly isolated PBMCs) | Day 1 to Day 45 |
| Infection rate within each dose, defined as proportion of subjects excreting challenge virus in stool 24 hours after challenge | 24 hours after challenge |
| Proportion of subjects with norovirus specific IgG-ASC / 10^6 PBMC (freshly isolated PBMCs) | Day 1 to Day 45 |
| Clinical Severity Score of vomiting and/or diarrhea related to the challenge strain using the Modified Vesikari Scale | Day 1 to Day 5 |
| 95% confidence intervals of vomiting and/or diarrhea related to the challenge strain | Day 1 to Day 5 |
Countries
United States
Outcome results
None listed