# Novel HCV vaccine antigens targeting conserved neutralizing epitopes

> **NIH NIH U19** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $256,885

## Abstract

Project Summary
It has been estimated that ~3% of the word population is infected with hepatitis C virus (HCV). Recent studies
have identified a number of neutralizing epitopes on the HCV E1 and E2 glycoproteins and demonstrated with
atomic structures how broadly neutralizing antibodies (bnAbs) interact with these epitopes. The 2.65Å crystal
structure of HCV E2 core (E2c) in complex with a bnAb (AR3C) revealed atomic details of this long-sought
target, providing a structural basis for rational design of HCV vaccines. In Project 2 of this U19 proposal, we
will combine the latest findings in HCV structural biology and cutting-edge technologies in computational
protein design and next-generation sequencing (NGS) of B-cell repertoire to facilitate HCV immunogen design
for the induction of bnAbs in vaccination. The specific aims are: (1) to develop epitope-focused immunogens
and E2 core-based immunogens. Crystal structures of E2 and E1 neutralizing epitopes in complex with bnAbs
have been determined recently. We hypothesize that heterologous protein scaffolds presenting a grafted HCV
epitope can induce cross-neutralizing antibodies to the epitope. We also hypothesize that the E2c domain can
be optimized as a subunit vaccine immunogen to induce cross-neutralizing antibodies to the conserved
epitopes presented on the E2 surface. Based on the crystal structure of E2c, we will shorten the variable loops,
engineer the surface N-linked glycans, and introduce space-filling mutations to the front layer region to stabilize
the E2c conformation. Successfully designed and expressed HCV antigens will be displayed multivalently on
ferritin particle and bacteriophage Qβ VLP. (2) to use NGS repertoire profiling to assess antibody response in
mouse and non-human primate immunization. Promising immunogen candidates will be first tested in mice. In
collaboration with the Law lab, an array of HCV-specific immunological assays will be available and performed
to map the serum antibody responses. A small set of designed immunogens that can induce cross-neutralizing
antibodies in mice will be tested in non-human primates (NHPs) at the Southwest National Primate Research
Center (SNPRC). Flow cytometry-based single B-cell sorting and microfluidics-based B-cell encapsulation will
be utilized to isolate HCV-neutralizing antibodies (nAbs). NGS-based repertoire profiling will be used to obtain
a quantitative readout of antibody response during immunization and to trace the lineage development of HCV
nAbs. The antibody repertoire profiles will be used to guide immunogen optimization and to compare different
immunogen candidates. The research proposed in Project 2 will therefore be complementary to and will benefit
from the human sample analysis, epitope mapping, and testing of the Novartis E1E2 vaccine in Project 1, and
together constitute the center for studying hepatitis C virus antibody responses and vaccine antigens.

## Key facts

- **NIH application ID:** 9903198
- **Project number:** 5U19AI123861-05
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Jiang Zhu
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $256,885
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903198

## Citation

> US National Institutes of Health, RePORTER application 9903198, Novel HCV vaccine antigens targeting conserved neutralizing epitopes (5U19AI123861-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9903198. Licensed CC0.

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