New Challenge Pool of Norwalk Virus Inoculum
New Challenge Pool of Norwalk Virus Inoculum
The main objective of this study is to see the number of volunteers that get sick from a
 Norwalk virus (NV) inoculation with typical symptoms of nausea, vomiting, and diarrhea. If
 this NV preparation is shown to cause Norwalk illness, then it can be used to test new
 vaccines in the future. Additionally, researchers hope to determine the lowest dose of NV
 inoculum that can be given to volunteers and cause illness. Study participants will include
 57 healthy adults, ages 18-50. Participants will either be given the NV inoculum or placebo
 (water without virus). Participants will be hospitalized for a maximum of 7 days and a
 minimum of 4 days following the NV challenge. Study procedures include physical exam, blood
 testing, and collection of saliva, urine, and stool samples. Participants will be involved in
 study related procedures for up to 180 days.
Noroviruses are the cause of most acute, epidemic, non-bacterial gastroenteritis (24-hour
 intestinal flu) and Norwalk virus (NV) is the prototype strain of this group of viruses.
 Although NV was identified some 30 years ago, progress in understanding its molecular
 characteristics has been slow due to the inability to grow the virus in cell culture and the
 lack of an animal model. As such, most work must be performed in human volunteers. The
 principal source of virus for research has been stool samples obtained from human volunteers
 who were experimentally infected with NV (NIH-8fIIa) obtained from the National Institutes
 for Health (NIH). The quantities of NV were sufficient to characterize the entire genome and
 significant advances have been made. The original NV challenge pool, obtained from the
 NIAID/NIH, is no longer available. Using stored stool specimens obtained from an otherwise
 healthy subject who was infected approximately 14 years ago with NV (NIH-8fIIa), a new pool
 (filtrate) was produced. This study has been designed to support an IND application, for NV
 challenge pool Lot 42399, to be submitted by the DMID/NIAID/NIH. The safety and infectivity
 of the new NV challenge pool will be established by this protocol. The clinical attack rate
 of Lot 42399 will be determined. Initially, 20 subjects will be challenged with a dose of NV
 (Lot 42399) that approximates the dose used in previous challenge studies. The predicted rate
 of infection in this study, defined by fecal viral shedding or seroresponse, is at least 90%
 of those who receive inoculation. Approximately two-thirds of infected subjects are expected
 to become symptomatic. Subsequently, smaller groups of subjects will be challenged with lower
 dosages to determine the Human Infectious Dose 50 percent (HID50). The overall objective of
 this study is to develop a challenge pool/inoculum of NV. The specific objectives of this
 clinical study are: to determine the safety and acute toxicity of a new NV challenge pool; to
 determine the NV clinical attack rate; to determine the infection rate and HID50 of NV Lot
 42399; to measure specific immunoglobulin responses to NV Lot 42399 inoculation/infection in
 blood, saliva and intestinal excretions; and examine peripheral blood mononuclear cells for
 the presence of NV. Study participants will include 57 healthy adults, ages 18-50. This
 double-blind study consists of informed consent, a screening and enrollment period, the NV
 challenge (inpatient NV inoculation phase), and a post challenge follow-up period. Many
 subjects participating in this study are expected to become ill with typical symptoms and
 signs of viral gastroenteritis. Subjects will be hospitalized, for up to a maximum of 7 days
 and minimum of 4 days. Participants will be involved in study related procedures for up to
 180 days.
Inclusion Criteria:

 -  Subjects must be 18 to 50 years of age and in good health as determined by medical
 history and physical examination.

 -  Subjects must sign informed consent prior to study initiation.

 -  All screening clinical laboratory test results within the protocol-defined normal
 range. Subjects with a history of positive Hepatitis A antibody or vaccination and
 normal liver transaminases (serum) may be accepted.

 -  If the subject is a woman, a negative serum pregnancy test within 3 days of
 inoculation and negative urine or blood pregnancy test on day of inoculation.

 -  Subjects must be able to demonstrate a sufficient understanding of the study protocol
 and the ability to follow all required study procedures, including measures to prevent
 Norwalk Virus (NV) contamination of the environment and spread of NV infection and
 illness to the community. The prospective subjects must pass (> 75 percent correct
 responses, or 21 of 27 questions answered correctly) a written examination before
 enrollment. The exam will contain 27 multiple choice or true/false questions on all
 aspects of the study protocol. Subjects will be re-instructed about any question they
 may have answered incorrectly.

 -  Subjects must be available to return for follow-up visits following discharge from the
 General Clinical Research Center (GCRC) and deliver specimens to the investigator
 promptly.

 -  Agree to storage of unused, identifiable clinical specimens for an indefinite period
 at Baylor College of Medicine for use in future research.

 -  Subject must express the H type-1 oligosaccharide (as measured by positive salivary
 secretor status).

 -  Must use acceptable form of birth control, if female. The only acceptable birth
 control methods are oral contraceptives, intrauterine devices (IUDs), contraceptive
 implants under the skin, or contraceptive injections, and condoms with foam.

 Exclusion Criteria:

 -  Living with or having daily contact with children age 10 years or less or a woman
 known to be pregnant. This includes contact at home, school, day-care, or equivalent
 facilities.

 -  Living with or having daily contact with childcare workers.

 -  Living with or having daily contact with elderly persons, aged 70 years or more, or
 the infirmed, diapered individuals, persons with disabilities or incontinent persons.
 This includes work or visits to nursing homes and day-care or equivalent facilities.

 -  Evidence of recent (within 3 months), or of current nonbacterial gastroenteritis
 suggestive of Norwalk Virus (NV) infection [vomiting or unformed or watery stools (>2
 during a 24 hour period)].

 -  History of chronic functional dyspepsia, chronic gastroesophageal reflux disease,
 peptic ulcer disease, gastrointestinal hemorrhage, gall bladder disease, inflammatory
 bowel disease, irritable bowel syndrome, frequent diarrhea, or diverticulitis anytime
 during the subject's lifetime.

 -  Positive serological tests for hepatitis viruses B (core and/or surface antigen
 serology) and/or C, human immunodeficiency virus (HIV)-1, or syphilis. Prior to HIV-1
 testing, subjects will be counseled by a qualified clinical investigator as to the
 purpose and meaning of such testing. Any subject with a positive test will be referred
 to the local HIV-1 clinic or his/her private practitioner.

 -  Pregnant or lactating woman.

 -  History of drug or alcohol dependence, or significant acute or chronic medical or
 psychiatric illness that could limit the subject's ability to complete the study
 and/or compromise the objectives of the study. One positive CAGE questionnaire
 response is exclusionary.

 -  Regular use of medication, such as, but not limited to, corticosteroids, anti-diarrhea
 medications, opioids, immunosuppressive agents, nonsteroidal anti-inflammatory drugs,
 antipyretics, and anticoagulants (e.g., warfarin or heparin or gold salts). Oral
 contraceptives are permitted.

 -  Use of antibiotics within 14 days of inoculation.

 -  Use of an investigational drug within 30 days prior to the start of study drug.

 -  Evidence of renal disease, as indicated by (any of the following) , serum sodium, or
 serum potassium outside normal laboratory range, or BUN or serum creatinine >upper
 limit of normal range, or uric acid >8.5 mg/dL.

 -  A baseline serum amylase value of 115 IU/L or greater or a baseline serum lipase value
 of 210 IU/L or greater.

 -  Evidence of cardiovascular disease, as indicated by (any of the following) blood
 pressure >150/90 mm HG in two measurements on different days, hospitalization for
 myocardial infarction, arrhythmia, syncope, or murmur (non-functional) detected on
 physical examination.

 -  Evidence of liver or other reticuloendothelial disease as indicated by (any of the
 following) serum alanine aminotransferase (ALT) > 1.25 times normal, aspartate
 aminotransferase (AST) > 1.25 times normal, alkaline phosphatase > 1.25 times normal,
 hepatosplenomegaly, jaundice, or lymphadenopathy on physical examination.

 -  Evidence of hematologic, rheumatologic, or immunologic disease, as indicated by (any
 of the following) white blood cell count <3.0 thous./cu.mm, white blood cell count
 >11.0 thousand/cu.mm, neutropenia (<1500/cu.mm), hemoglobin outside laboratory normal
 range, history of more than 3 hospitalizations for invasive bacterial infections
 (pneumonia, meningitis), acute or chronic dermatitis (e.g., eczema, seborrhea,
 psoriasis) or collagen vascular disease [e.g., systemic lupus erythematosus (SLE) or
 dermatomyositis].

 -  History or evidence of diabetes mellitus or hyperglycemia (e.g., random glucose >120
 mg/dL).

 -  The presence of other serious chronic illness (i.e., malignancy other than a resolved
 skin lesion, neurological condition or malnutrition).

 -  Bacterial gastroenteritis or positive fecal culture for salmonella, campylobacter, E.
 coli 0157:H7, and Shigella; positive fecal screen for ova and parasites with fecal
 white cell examination.

 -  Employment in the food service industry, such as restaurants, or cafeteria facilities.
 Specifically, this will include persons whose employment requires food processing in
 the 4 weeks following inoculation.

 -  Health-care workers with patient contact expected in the 4 weeks following
 inoculation.

 -  Expected contact (through employment or at home) with immunocompromised persons
 (HIV-positive, receiving immunosuppressive medications such as oral steroids,
 anti-neoplastic agents) in the 4 weeks following inoculation.

 -  Employment as an airline flight attendant scheduled to work in the 4 weeks following
 inoculation. Persons planning on taking a cruise in the 4 weeks following inoculation.

 -  Persons who have consumed or plan to consume raw shellfish (e.g., oysters) within 7
 days prior to enrollment or throughout the study.

 -  Other conditions that in the opinion of the investigator might jeopardize the safety
 or rights of a volunteer subject participating in the trial or would render the
 subject unable to comply with the study protocol.

 -  Expresses blood group B histoblood group antigen (blood group B or AB)