Joint Fellowship Training Program
Mentor:
Stephen Feinstone, M.D.
Organizational Affiliation and Position:
Chief, Laboratory of Hepatitis Viruses, Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research (CBER), FDA
Email:
stephen.feinstone@fda.hhs.gov
Telephone:
301-827-1880
Co-mentor:
Mei-Ying W. Yu, Ph.D.
Organizational Affiliation and Position:
Supervisory Research Chemist, Laboratory of Plasma Derivatives Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research (CBER), FDA
Email:
mei-ying.yu@fda.hhs.gov
Telephone:
301-402-4634
Title of Research Program:
Hepatitis C infection and Oncogenesis
Research Project Summary (if applicable):
Chronic viral hepatitis is the leading cause of hepatocellular carcinoma (HCC) in the world. In some areas, hepatitis B virus (HBV) infections are the major cause of HCC while in other the hepatitis C virus is most often associated with liver cancer. While hepatitis B remains a serious problem, a very successful vaccine has been available for over two decades. Where the vaccine has been broadly used in infants and children, there has already been demonstrated a significant decrease in the incidence of HCC occurring in children. The hepatitis B vaccine is the first true anti-cancer vaccine. It is estimated that over 170 million people worldwide are persistently infected with HCV. In Japan, medical practices during and after the war as well as increased drug abuse resulted in an epidemic of HCV infections beginning in the late 1940's. As this cohort has now been infected for 30 to 50 years, they are experiencing a large number of new HCC cases related to the chronic HCV infections. The U.S. had a large increase in HCV infections in the late 1960's and 70's so that now we are just beginning to see a rapid rise in HCC here. While new infections with HCV have decreased lately, it remains imperative that we find ways to prevent them.
The major project in LHV addresses the problem of prevention of new HCV infections through the development of effective vaccine strategies. Ideally, prevention of HCV infection is the first goal of a vaccine. However, the most important aspect of HCV infection is that it becomes chronic in up to 85 percent of individuals infected. While acute HCV infections are often mild or even unapparent, chronic infections lead to chronic liver disease, cirrhosis and HCC. Patients with chronic infections are also the major source of spread of the infection. Therefore, a vaccine that could prevent chronic HCV infections would be an important tool to protect the public health. The vaccine project involves first developing a basic understanding of the pathogenesis of hepatitis C, understanding the control of HCV infections by both the innate and acquired immune systems, constructing vaccines and vaccine delivery systems that could induce effective immune responses and testing those vaccines in animal models including the chimpanzee. Chimpanzees are the only animal in which the effectiveness of a vaccine on actual prevention of hepatitis C can be evaluated as they can be infected with HCV and the develop disease, including chronic disease, similar to that seen in humans. The contributions of both humoral and cellular immune responses to prevention or resolution of HCV infections is being evaluated. New small animal models are being developed that will greatly facilitate our investigations. New delivery systems are being designed to produce improved specific immune responses as well as targeted responses that our earlier studies have indicated may be important for control of HCV infections.
Finally, in collaboration with the FDA/NCI genomics/proteomics program, we have initiated a study to develop early diagnostic for HCC based on proteomic analysis of plasma. It is hoped that the development of a simple blood-screening test will permit very early detection of HCC in high-risk patients at a time when therapy is potentially effective.
Proposed Project for IOTF Fellow:
We propose that the IOTF fellow would pursue studies of HCV pathogenesis in the newly developed transgenic mouse model with specific emphasis on effects of HCV infection on the biology of the hepatocyte in situ. Information from the mouse studies might be applied to infected chimpanzee hepatocytes.
Regulatory Activity:
The IOTF fellow would have the opportunity to participate in review activity on new HCV vaccines applications as well as diagnostics that are regulated by the OBRR.
Reference(s):
Major ME, Dahari H, Mihalik K, Puig M, Rice CM, Neumann AU, Feinstone SM. Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees. Hepatology. 2004 Jun;39(6):1709-20.
Puig M, Major ME, Mihalik K, Feinstone SM. Immunization of chimpanzees with an envelope protein-based vaccine enhancesspecific humoral and cellular immune responses that delay hepatitis C virus infection.. Vaccine. 2004 Feb 25;22(8):991-1000.
Research Project Summary of co-mentor:
One of our projects is to develop and/or evaluate specific therapeutic antibody preparations against both existing and emerging viral infectious diseases. In collaboration with NIH and FDA scientists, we recently demonstrated broadly reactive neutralizing antibodies to HCV present in plasma pools and the resulting immune globulins derived from anti-HCV-positive plasma by using chimpanzees and an in- vitro system based on neutralization of infectious HCV pseudoparticles. Our current efforts are to explore whether the extended profiles of HCV genotypes in starting plasma pools can correlate with the broad neutralizing capabilities in the resulting immune globulins. In addition, we are to identify and characterize potential HCV neutralization epitopes through various approaches including peptide-based phage display and peptide mapping, and to enrich neutralizing antibodies by means of affinity selection. Generation of these HCV specific neutralizing antibodies would be useful for preparing immunoprophylactic products to prevent hepatitis C infection.
In a separate project in collaboration with FDA/NCI scientists, we study and identify gene products affected by hepatitis C viral infection, especially by the HCV core protein in human B cells and macrophages. HCV core protein features many intriguing properties and plays roles in cell growth, apoptosis, cell transformation and eventually in tumor development. The study involves the uses of oligo microarray and proteomics to identify those early gene markers deregulated by HCV.
Proposed Project for IOTF Fellow:
We propose that the IOTF fellow would participate in both projects in LPD
Regulatory Activity:
The LPD has the primary regulatory responsibility for the safety and efficacy of immune globulins (from donors that are from the general population or from individuals with high titers against specific organisms/antigens, i.e., hyperimmune globulin) derived from human or animal origin. The IOTF fellow would participate in reviewing submissions related to hepatitis C Immune Globulin or other immune globulin products.
Reference(s):
Yu MW, Bartosch B, Zhang P, Guo ZP, Renzi PM, Shen L, Granier C, Feinstone SM, Cosset F, Purcell RH. Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from anti-HCV-positive plasma. Proc Natl Acad Sci USA 2004; 101: 7705-10.
Wu, CG, Forgues M, Shabina S, Valerie K, Wang XW. SAGE transcript Profiles deregulated by the Oncogenic Hepatitis B Virus X Protein. FASEB J 16(12): 1665-7, 2002 Arduino JM, Stuver SO, Spiegelman D, Okayama A, Tabor E, Yu MW, Kohara M, Tsubouchi H,
Mueller NE. Assessment of markers of hepatitis C virus infection in a Japanese adult population. J Inf Dis 2001; 184:1229-35.
