Studies of the Infectivity of Norwalk and Norwalk-like Viruses

EPA Grant Number: R826139
Title: Studies of the Infectivity of Norwalk and Norwalk-like Viruses
Investigators: Moe, Christine L. , Frelinger, Jeffrey A. , Heizer, William , Stewart, Paul
Institution: University of North Carolina at Chapel Hill
EPA Project Officer: Hiscock, Michael
Project Period: January 16, 1998 through January 15, 2001 (Extended to January 15, 2002)
Project Amount: $587,842
RFA: Drinking Water (1997) RFA Text |  Recipients Lists
Research Category: Water , Drinking Water

Description:

The overall objective of this research is to develop our understanding of the risks associated with exposure to waterborne human caliciviruses as a function of dose and host susceptibility factors. This study will determine the infectious dose of two important human caliciviruses (HuCVs), a prototype Genogroup I virus (Norwalk virus (NV)), and a prototype Genogroup II virus (Snow Mountain Agent (SMA)), which are recognized as major waterborne pathogens. The specific objectives are: 1) to identify the dose range of NV and SMA (ID10, ID50 and ID90) in human volunteers with various levels of preexisting antibodies, 2) examine the immune response (serum and secretory antibodies) and determine the characteristics of volunteers that are susceptible to infection, and 3) evaluate the fit of several mathematical models of dose-infectivity to the data.

Approach:

Two double-blinded human challenge studies are proposed to determine the dose-infectivity relationships for NV and SMA. These studies will build upon a pilot NV dose-ranging study currently supported by the USEPA. The proposed NV study, with 40 subjects, will focus on infectivity in the critical low-dose region of the dose response curve and will provide more accurate information on the risks of NV infection associated with low levels of virus typical of the concentrations in water. Twenty subjects will be dosed at the lowest dose that gives infection in the pilot NV dose-ranging study. The other 20 subjects will be randomized to doses spaced at equal intervals (determined from the dose-infectivity curve generated in the NV pilot study) above the lowest dose. The SMA dose-ranging study, with 45 subjects, will be conducted in 3 rounds. Each round will have 15 subjects randomized to one of 3 doses that approximate the ID10, ID50 and ID90. In both studies, subjects will be monitored for gastrointestinal symptoms for 5 days and will return for Day 8, 14 and 21 follow-up visits. Stool specimens will be assayed for NV or SMA RNA by reverse transcription-polymerase chain reaction (RT-PCR). NV and SMA serum antibodies and secretory antibodies will be measured by enzyme immunoassay. Infection will be defined as excretion of NV or SMA or seroconversion. The outcomes of interest in these studies are both symptomatic and asymptomatic NV and SMA infection. Symptomatic infection is of concern because of the disease burden on the population, the effect on absenteeism and the impact on the health care system. In terms of public health protection, asymptomatic infection is also of concern because of the potential for secondary transmission and the consequences of these infections for the immuno-compromised population, including infants and the elderly. Several mathematical models of dose-infectivity (probit, log-linear and beta-distribution) will be evaluated.

Expected Results:

The infectivity of NV and SMA in humans will be defined in terms of RT-PCR detectable units since this is the only available method that can measure HuCVs in both clinical and environmental samples. This study will provide the USEPA with important data on the relationship between viral dose and susceptibility to infection (as measured by preexisting serum antibody levels and other host factors), clinical symptoms and immune response. The results of these studies will be valuable for estimating the risk of NV and SMA infection and gastroenteritis associated with exposure to contaminated water and to establish safe exposure limits for HuCVs in water to reduce waterborne disease.

Publications and Presentations:

Publications have been submitted on this project: View all 38 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 13 journal articles for this project

Supplemental Keywords:

drinking water, risk assessment, health effects, human health, epidemiology., RFA, Health, Scientific Discipline, Water, Environmental Chemistry, Chemistry, Epidemiology, Risk Assessments, Analytical Chemistry, Susceptibility/Sensitive Population/Genetic Susceptibility, genetic susceptability, Drinking Water, microbial contamination, pathogens, public water systems, risk factors, sensitive populations, microbial risk assessment, Norwalk, waterborne disease, human health effects, exposure and effects, infants, chemical byproducts, disinfection byproducts (DPBs), dose response, exposure, calciviruses, community water system, gastroenteritis, children, immuno-compromised population, human exposure, susceptibility, immune system response, treatment, emerging pathogens, elderly, drinking water contaminants, infectivity, water treatment, age dependent response, drinking water system, environmental hazard exposures

Progress and Final Reports:

  • 1998
  • 1999
  • 2000 Progress Report
  • Final Report