Approximately 170 million people are infected by hepatitis C virus (HCV) worldwide and many of these will go on to develop disease, primarily cirrhosis of the liver and hepatoma. A vaccine is required to help limit spread of the disease. Most effective vaccines developed to date elicit neutralizing antibodies (NAbs). There have been at least two major roadblocks en route to developing a component that elicits NAbs to HCV. The first is the lack of a conventional neutralization assay because of an inability to culture HCV in vitro. This roadblock has recently been at least partly dismantled by the development of systems for culturing HCV, albeit currently with certain limitations. The second roadblock is the great sequence variation of HCV found in infected donors that suggests a vaccine should elicit NAbs effective against a wide variety of different viruses, i.e. the vaccine should elicit broadly neutralizing antibodies. We propose a program to investigate the necessary conditions to induce a strong neutralizing antibody response against multiple HCV isolates and use the knowledge gained to design a NAb-inducing component of an HCV vaccine. We will systematically dissect NAb responses to HCV in natural infection, and isolate mAbs that are most potent and broad against neutralizing diverse isolates of HCV (Aim 1). These prototype mAbs will help us to identify neutralizing epitopes on HCV and we will explore the interaction between these epitopes and NAbs at the molecular level (Aim 2). We will apply knowledge gained from these molecular studies to the design of immunogens in order to produce NAb responses in animals (Aim 3). The prototype broadly neutralizing mAbs and Abs from animals immunized with the novel immunogens will be tested in a small animal model (Aim 4).
Hepatitis C virus infection is a major health problem worldwide and a vaccine is urgently needed to protect at-risk populations. We propose to develop antibody-inducing vaccine candidates against HCV. A key feature of our work is the rational design of vaccine candidates based on countering some of the tricks that this virus uses to evade antibodies.
|O'Shea, Daire; Law, John; Egli, Adrian et al. (2016) Prevention of hepatitis C virus infection using a broad cross-neutralizing monoclonal antibody (AR4A) and epigallocatechin gallate. Liver Transpl 22:324-32|
|Ruwona, Tinashe B; Mcbride, Ryan; Chappel, Rebecca et al. (2014) Optimization of peptide arrays for studying antibodies to hepatitis C virus continuous epitopes. J Immunol Methods 402:35-42|
|de Jong, Ype P; Dorner, Marcus; Mommersteeg, Michiel C et al. (2014) Broadly neutralizing antibodies abrogate established hepatitis C virus infection. Sci Transl Med 6:254ra129|
|Kong, Leopold; Giang, Erick; Nieusma, Travis et al. (2013) Hepatitis C virus E2 envelope glycoprotein core structure. Science 342:1090-4|
|Roughan, Jill E; Reardon, Kathryn M; Cogburn, Kristin E et al. (2012) Chronic hepatitis C virus infection breaks tolerance and drives polyclonal expansion of autoreactive B cells. Clin Vaccine Immunol 19:1027-37|
|Giang, Erick; Dorner, Marcus; Prentoe, Jannick C et al. (2012) Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Proc Natl Acad Sci U S A 109:6205-10|
|Kong, Leopold; Giang, Erick; Robbins, Justin B et al. (2012) Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1. Proc Natl Acad Sci U S A 109:9499-504|
|Dorner, Marcus; Horwitz, Joshua A; Robbins, Justin B et al. (2011) A genetically humanized mouse model for hepatitis C virus infection. Nature 474:208-11|