This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The following is an amended submission for GCRC Protocol #2027 that incorporates changes requested by DMID/NIAID/NIH to meet FDA IND submission needs and limitations imposed by the subcontract expiration date of January 2003. Norwalk virus (NV) is the cuase of most acute , epidemic, non-bacterial gastroenteritis (24-hour intestinal flu). 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 for 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 second open reading frame (ORF) of NV was expressed in the baculovirus expression system and it produced recombinant, non-infectious virus-like particles (rNV-VLPs) or protein shells that do NOT contain viral nucleic acids. A recent study by this group demonstrate that rNV-VLP preparation (a prototype vaccine), when given by mouth to human volunteers, appeared safe and universally produce an IgG immune response. It is unknown if the immune response from the prospective vaccine is protective against disease and a method to test vaccine efficacy using live virus challenge is needed. 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 10 years ago with NV (NIH-8fIIa), a new pool (filtrate) was developed under GMP conditions. The subject produced relatively high amounts of viral antigen and RT-PCR analysis (viral-RNA titer) of the new challenge pool (lot 42399), which was submitted by the DMID/NIAID/NIH. The safety and infectivity of the new NV challenge pool will be established by this protocol. The clinical illness rate of lot 42399 will be determined. Initally, 20 subjects will be challenged with a dose of NV (lot 42399) which approximates the dose used in previous challenge studies. The predicted rate of infection, defined by fecal viral shedding, is 80% of those who receive oral challenge. Approximately two-thirds of infected subjects are expected to become symptomatic. Subsequently, another gorup of 20 subjects will be challenged with an escalated dose to determine if the attack rate can be increased. Smaller groups of subjects will then be challenged with lower dosages to determine the Human Infectious Dose 50% (HID-50). If the initial clinical illness rate is 80% or greater, the dose escalation phase (second group of 20 subjects) will be omitted and the protocol will immediate progress to the third phase (determination of HID-50). Under this revised submission, only 42 of the orignally requested 108 subjects will be studied under method phases I and II or phases I and III, but not all three phases will be performed at this time. HYPOTHESIS A new Norwald Virus (NV) challenge pool (Lot 42399) developed and processed at Baylor College of Medicine (BCM) is safe and predictably causes a acute, self-limiting symptomatic gastroenteritis when given to healthy volunteers. The overall goal of this study is to develop a challenge pool/inoculum of Norwalk virus (NV).
The specific aims and objectives of this clinical study of healthy adult subjects are: 1. To determine the safety and acute toxicity of a new NV challenge pool (Lot 42399) developed and processed at Baylor College of Medicine (BCM) in a certified Good Manufacturing Practice (cGMP) facility using Good Manufacturing Practices (GMP) 2. To determine the NV clinical attack rate induced by NV Lot 42399 3. To determine the infection rate and Human Infectious Dose 50% of NV Lot 42399. 4. To measure specific immunoglobulin responses to NV Lot 42399 inoculation/infection in blood, saliva and intestinal excretions;and 5. To examine peripheral blood mononuclear cells for the presence of NV
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