Studies of Efficacy, Safety and Potency Assay Development for Prophylactic and Therapeutic Vaccines against Hepatitis Viruses

Principal Investigator: Marian Major, PhD
Office / Division / Lab: OVRR / DVP / LHV

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Overview

Public Health Issue: HCV is a serious public health concern, there is no vaccine and 85% of people that become infected with the virus develop persistent infections that can, in later life, lead to severe liver problems such as cirrhosis or hepatocellular carcinoma (HCC). HCC is one of the few cancers increasing in frequency and mortality in the U.S., and studies show that ~50% of HCC cases occur as a result of chronic HCV infection. According to the CDC, there are 8,000-10,000 deaths each year due to HCV-associated cirrhosis and cancer. Understanding the pathogenesis of this disease is vital to the development of suitable therapeutics and prophylactic treatments.

Regulatory Contribution: Vaccine development for HCV has proven difficult. Increasingly new and innovative approaches are being employed such as nanotechnology and T lymphocyte cell (T-cell) based, rather than antibody based, prophylactic and therapeutic vaccines. To support vaccine development, we need to be able to evaluate the safety of these products and understand or provide guidance on development of assays for potency and biomarkers of efficacy to ensure consistent manufacturing and efficacy of candidate products.

Research Approach: The primary areas of investigation for this research program are targeted to the hepatitis C virus (HCV) and are focused on developing scientific tools to understand the immunobiology and pathogenesis of HCV. Studies include the development of a small animal model for HCV infection, identification of efficacy biomarkers (i.e., immunologic correlates of protection), development of neutralization tests for the virus, the use of nanotechnology for induction of protective immune responses and studies on the safety of therapeutic vaccines for this virus.

Mission Relevance and Outcomes: These studies will provide the ability to evaluate new technologies being applied to vaccine development. They will be pivotal in guiding and assessing the safety, efficacy and manufacturing issues associated with HCV vaccines.

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Publications

Hepatology 2006 Dec;44(6):1478-86
Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver.
Heo J, Factor VM, Uren T, Takahama Y, Lee JS, Major M, Feinstone SM, Thorgeirsson SS

Hepatology 2006 Aug 29;44(3):736-745
CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus.
Puig M, Mihalik K, Tilton JC, Williams O, Merchlinsky M, Connors M, Feinstone SM, Major ME

Proc Natl Acad Sci U S A 2006 Mar 7;103(10):3805-9
Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro.
Lindenbach BD, Meuleman P, Ploss A, Vanwolleghem T, Syder AJ, McKeating JA, Lanford RE, Feinstone SM, Major ME, Leroux-Roels G, Rice CM

Gastroenterology 2005 Apr;128(4):1056-66
Mathematical modeling of primary hepatitis C infection: noncytolytic clearance and early blockage of virion production.
Dahari H, Major M, Zhang X, Mihalik K, Rice CM, Perelson AS, Feinstone SM, Neumann AU

Virology 2004 Nov 10;329(1):53-67
The NS3 protein of hepatitis C virus induces caspase-8-mediated apoptosis independent of its protease or helicase activities.
Prikhod'ko EA, Prikhod'ko GG, Siegel RM, Thompson P, Major ME, Cohen JI

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

Proc Natl Acad Sci U S A 2004 Jul 6;101(27):10149-54
Neutralizing antibody response during acute and chronic hepatitis C virus infection.
Logvinoff C, Major ME, Oldach D, Heyward S, Talal A, Balfe P, Feinstone SM, Alter H, Rice CM, McKeating JA

Hepatology 2004 Jun;39(6):1709-20
Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees.
Major ME, Dahari H, Mihalik K, Puig M, Rice CM, Neumann AU, Feinstone SM

Vaccine 2004 Feb 25;22(8):991-1000
Immunization of chimpanzees with an envelope protein-based vaccine enhances specific humoral and cellular immune responses that delay hepatitis C virus infection.
Puig M, Major ME, Mihalik K, Feinstone SM