Development of in vitro and in vivo Systems for the Evaluation of Products for the Prevention and Detection of Hepatitis C and SARS Viruses in the Blood Supply

Principal Investigator: Deborah R. Taylor, PhD
Office / Division / Lab: OBRR / DETTD / LHREA

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Overview

Public Health Issue: Nearly 2% of the world population has been infected with Hepatitis C virus (HCV). Nearly all who are exposed become chronically infected with the virus, which can lead to liver disease, including liver failure and cancer. Disease associated with HCV infection is the leading cause of liver transplant in the United States. Treatment for HCV is largely ineffective, expensive and not well-tolerated due to severe side effects. The blood supply is currently screened for HCV with very few cases of transfusion-related transmission. Because HCV is an RNA virus, the emergence of variants that may escape detection is a potential threat to the blood supply. SARS infections were first reported in China in the winter of 2003. By July of 2003, the outbreak had subsided leaving 774 people dead and having infected more than 8000 people in 29 countries. The United States must be prepared in the event of a future outbreak, either from natural disease emergence or from biowarfare release. There is currently no vaccine or effective treatment available.

Regulatory Contribution: Currently there are no FDA-licensed vaccines for HCV or SARS. There is a need for the development of cell culture systems for the growth of HCV. Growth of HCV, which may allow for the production of vaccines, the evaluation of products that may be contaminated with HCV, preparation of panels and also for the development of assays to detect HCV variants in the blood supply. The development of a vaccine for SARS has been hampered by the lack of an animal model that mimics human disease for the purpose of evaluating vaccine safety and efficacy. SARS virus has not been detected in blood during asymptomatic phase, and no known cases of transfusion-transmitted SARS occurred. However, natural mutation of the SARS virus could change that and the development of assays for its detection as well as virus inactivation protocols are being studied at the FDA.

Research Approach: This research program has established a system for the growth of infectious hepatitis C virus from human blood in culture. This system will be useful for the growth of viruses that may be used in vaccine preparations, for the study of viral pathogenesis, for growing viruses for use as panel members and for the evaluation of products that may be contaminated with HCV. An appropriate animal model would be useful to test the safety and efficacy of a vaccine for SARS coronavirus (SARS-CoV) and Dengue virus. SARS and dengue virus animal models do not demonstrate the severe clinical features seen in humans. Development of an animal model will be useful for the evaluation of vaccine safety and efficacy. These studies have included the serological and nucleic acid detection of virus and characterization of inactivation properties of SARS-CoV by several techniques, including those to establish inactivation methods in blood products.

Mission Relevance & Outcomes: The availability of cell lines susceptible to Hepatitis C infection and animal models of dengue and SARS viruses will allow the development and evaluation of vaccines, blood products, and screening assays to detect hepatitis C, dengue and SARS viruses and, thus, increase the safety of the US blood supply.

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Publications

Front Biosci 2008 May 1;13:4873-81
The role of programmed-1 ribosomal frameshifting in coronavirus propagation.
Plant EP, Dinman JD

J Infect Dis 2007 Nov 1;196(9):1329-38
Severe acute respiratory syndrome coronavirus infection in vaccinated ferrets.
Darnell ME, Plant EP, Watanabe H, Byrum R, St Claire M, Ward JM, Taylor DR

Transfusion 2006 Oct;46(10):1770-7
Evaluation of inactivation methods for severe acute respiratory syndrome coronavirus in noncellular blood products.
Darnell ME, Taylor DR

Vaccine 2006 Feb 13;24(7):863-71
Obstacles and advances in SARS vaccine development.
Taylor DR

J Virol 2005 May;79(10):6291-8
New Antiviral Pathway That Mediates Hepatitis C Virus Replicon Interferon Sensitivity through ADAR1.
Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM

J Virol Methods 2004 Oct;121(1):85-91
Inactivation of the coronavirus that induces severe acute respiratory syndrome, SARS-CoV.
Darnell ME, Subbarao K, Feinstone SM, Taylor DR

J Virol 2004 Sep;78(18):9782-9
Long-term persistence of infection in chimpanzees inoculated with an infectious hepatitis C virus clone is associated with a decrease in the viral amino Acid substitution rate and low levels of heterogeneity.
Fernandez J, Taylor D, Morhardt DR, Mihalik K, Puig M, Rice CM, Feinstone SM, Major ME