Hepatitis C virus (HCV) chronically infects 2-3% of the global population, predisposing the patients to chronic liver diseases and liver cancer. A broadly effective vaccine will be a cost- effective mean to solve this global problem. However, HCV is genetically varied and vaccines designed based on a single viral strain will not be effectively against genetically diverse circulating viruses. To overcome this scientific challenge, the vaccine candidates must target conserved regions on the virus. The goal of this application is to determine the molecular structure of virus neutralizing epitopes to aid the rational design of immunogens, that will focus antibody responses to the conserved epitopes in vaccination. This """"""""epitope vaccine"""""""" approach include: (1) Determination of crystal structures of HCV antibody epitopes in complex with the corresponding broadly neutralizing antibodies;(2) Design and synthesis of immunogens as biomimetics of the known epitope structures;(3) Testing of the novel immunogens in a small animal model of HCV infection to identify lead vaccine candidates. If successful, this proposal can result in novel HCV vaccine candidates for clinical trials, and also significantly advance the HCV and vaccine fields.

Public Health Relevance

Hepatitis C virus (HCV) is a leading cause of liver cirrhosis and cancer. A broadly effective vaccine will be vital for the eradication of this silent epidemic The goal of this project is to develop and evaluate vaccine candidates that target genetically conserved regions of the virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI106005-01A1
Application #
8632770
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Koshy, Rajen
Project Start
2014-03-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$175,312
Indirect Cost
$82,799
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Bazzill, Joseph D; Ochyl, Lukasz J; Giang, Erick et al. (2018) Interrogation of Antigen Display on Individual Vaccine Nanoparticles for Achieving Neutralizing Antibody Responses against Hepatitis C Virus. Nano Lett :
Tzarum, Netanel; Wilson, Ian A; Law, Mansun (2018) The Neutralizing Face of Hepatitis C Virus E2 Envelope Glycoprotein. Front Immunol 9:1315
Aleman, Fernando; Tzarum, Netanel; Kong, Leopold et al. (2018) Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors. Proc Natl Acad Sci U S A 115:7569-7574
Velázquez-Moctezuma, Rodrigo; Galli, Andrea; Law, Mansun et al. (2018) Hepatitis C virus escape studies for human antibody AR3A reveals a high barrier to resistance and novel insights on viral antibody evasion mechanisms. J Virol :
Gopal, Radhika; Jackson, Kelli; Tzarum, Netanel et al. (2017) Probing the antigenicity of hepatitis C virus envelope glycoprotein complex by high-throughput mutagenesis. PLoS Pathog 13:e1006735
Velázquez-Moctezuma, Rodrigo; Law, Mansun; Bukh, Jens et al. (2017) Applying antibody-sensitive hypervariable region 1-deleted hepatitis C virus to the study of escape pathways of neutralizing human monoclonal antibody AR5A. PLoS Pathog 13:e1006214
Kong, Leopold; Lee, David E; Kadam, Rameshwar U et al. (2016) Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen. Proc Natl Acad Sci U S A 113:12768-12773
McBride, Ryan; Head, Steven R; Ordoukhanian, Phillip et al. (2016) Low-Cost Peptide Microarrays for Mapping Continuous Antibody Epitopes. Methods Mol Biol 1352:67-83
Prentoe, Jannick; Velázquez-Moctezuma, Rodrigo; Foung, Steven K H et al. (2016) Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity. Hepatology 64:1881-1892
Winer, Benjamin Y; Ding, Qiang; Gaska, Jenna M et al. (2016) In vivo models of hepatitis B and C virus infection. FEBS Lett 590:1987-99

Showing the most recent 10 out of 21 publications