Hepatitis C virus (HCV) is a major human pathogen that chronically infects 2-3% of the global population. In the United States it is the most common blood-borne illness with approximately 3.9 million carriers. Most patients infected with HCV progress to chronic disease and are at increased risk of liver cirrhosis and hepatocellular carcinoma. The standard of care for chronic hepatitis C is combination therapy with pegylated interferon and ribavirin, supplemented with an antiviral compound that inactivates the viral NS3/4A protease. The recent inclusion of protease inhibitors in combination therapy has led to an improvement in sustained viral response rates in many patients, but certain factors may limit the overall success of treatment. These include potential of HCV to acquire resistance to these antivirals, their high cost and the role of host factors in response to therapy. The development of an effective vaccine to control the global HCV epidemic is therefore highly desirable. New evidence strongly suggests that neutralizing antibodies play a more protective role in viral clearance than previously appreciated. A caveat is that such protective antibody responses are isolate-specific given the high sequence diversity of HCV. A prophylactic or therapeutic vaccine against HCV would therefore have to target conserved epitopes in the natural HCV antigens. This proposal focuses on linear, highly conserved epitopes in the viral glycoproteins E1 and E2 targeted by broadly neutralizing antibodies IGH526 and HCV1, respectively. It outlines a novel strategy for presenting these epitopes on chimeric virus-like particles engineered to present specific structures on their surfaces as a highly immunogenic particulate array. This strategy offers a wide selection of properties needed to mimic the cognate epitopes of IGH526 and HCV1, including the ability to orient and expose key residues and structural features for antibody recognition, in order to re- elicit broad neutralization activity.
Aim 1 outlines design, synthesis and characterization of VLPs displaying the highly conserved E1 and E2 epitopes and aim 2 investigates the immunogenic properties of the VLPs in mice. Their ability to induce antibodies that bind to full- length E1E2 heterodimer and their capacity to neutralize HCV particles will be evaluated. If successful, the work proposed could lead to a significant advance in HCV vaccine development.
We propose a new approach to generate broadly neutralizing antibodies against Hepatitis C virus (HCV), a major human pathogen that chronically infects 2-3% of the world population. We will combine structure-based design with display of conserved, linear epitopes of natural HCV antigens on virus-like particles, which are known to induce a strong immune response. The long term goal is to develop a prophylactic and therapeutic vaccine to prevent or resolve HCV infection.
