Center for rational HCV vaccine design & evaluation - overall project summary hepatitis c virus (HCV) infects over 50 million people worldwide and remains a leading cause of liver cirrhosis,…

The National Institute of Allergy and Infectious Diseases awarded the Scripps Research Institute a cooperative agreement valued at $3,282,170 on September 2, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to design and evaluate hepatitis C virus vaccine candidates.

The center will develop innovative, clinically translatable HCV vaccine candidates capable of eliciting potent broadly neutralizing antibody and multifunctional T cell responses. Project 1 will define the structural basis of conserved neutralizing epitopes and determine their presentation on HCV virions, virus-like particles, and vaccine immunogens using X-ray crystallography, cryo-EM, and cryo-ET to reveal E1E2 complex organization and how decoy regions affect epitope exposure. Project 2 will design and evaluate optimized immunogens targeting the E1E2 neutralizing face and bridging domain through structure-guided engineering, conformation stabilization, glycan modulation, germline targeting, nanoparticle and nucleic acid lipid nanoparticle platforms, with candidates benchmarked against Chiron E1E2 in mice and nonhuman primates to identify top designs for GMP translation. A Virology Immunology Data Core will standardize reagents, assays, and data integration for AI-assisted immune analysis, and an Animal Model Core will provide human immunoglobulin knock-in support.

Work is performed at Scripps Research Institute in La Jolla, California, with a period of performance through July 31, 2031. The award supports fundamental research addressing the extreme viral genetic diversity that has impeded HCV vaccine development, focusing immune responses on conserved viral epitopes recognized by broadly neutralizing antibodies and cross-reactive T cells.

Center for rational HCV vaccine design & evaluation - overall project summary hepatitis c virus (HCV) infects over 50 million people worldwide and remains a leading cause of liver cirrhosis, hepatocellular carcinoma, and autoimmune disorders. Despite curative antivirals, reinfection and ongoing transmission underscore the urgent need for a prophylactic vaccine. Extreme viral genetic diversity has long impeded HCV vaccine development, demanding approaches that focus immune responses on conserved viral epitopes recognized by broadly neutralizing antibodies (bnabs) and cross-reactive t cells. The U19 cooperative center for rational HCV vaccine design & evaluation aims to develop innovative and clinically translatable vaccine candidates capable of eliciting potent bnab and multifunctional t cell responses. Our central hypothesis is that understanding and optimizing the presentation of conserved epitopes will enable rationally designed vaccines to elicit stronger and broader protection than first-generation E1E2- or t cell-based candidates. Project 1 will define the structural basis of conserved neutralizing epitopes and determine their presentation on HCV virions, virus-like particles, and vaccine immunogens using x-RAY crystallography, cryo-EM, and cryo-ET. These studies will reveal the organization of E1E2 complexes and how decoy regions such as HVR1 affect epitope exposure. Project 2 will design and evaluate optimized immunogens targeting the E1E2 neutralizing face and bridging domain using structure-guided engineering, conformation stabilization, glycan modulation, germline targeting, nanoparticle and nucleic acid lipid nanoparticle platforms. Candidates will be benchmarked against chiron E1E2 in mice and nonhuman primates to identify top designs for GMP translation. The virology immunology data core will standardize reagents, assays, and data integration for AI-assisted immune analysis, while the animal model core will provide human immunoglobulin knock-in (IG-KI) mice and rhesus models for vaccine evaluation. This highly synergistic center will define HCV vulnerability mechanisms and deliver optimized vaccine prototypes ready for clinical development.