# Novel HCV vaccine antigens and nanoparticles

> **NIH NIH P01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $580,936

## Abstract

Project Summary
Hepatitis C virus (HCV) infects 1-2% of the world population and poses a significant threat to public health.
Recent studies have identified a panel of broadly neutralizing antibodies (bnAbs) and their genetic preferences.
The crystal structures of various HCV E2 constructs in complex with bnAbs and non-nAbs provide a structural
basis for rational vaccine design. In Project 2 of this P01 proposal, we will combine structural optimization of
HCV antigens, nanoparticle engineering, in vivo assessment, and next-generation sequencing (NGS) of B-cell
repertoires to assist in rational design of HCV vaccines that can elicit a bnAb response. The Specific Aims in
this project are: (1) To develop vaccine antigens to target multidonor class antibody responses. The
major virus neutralizing site, the E2 neutralizing face (E2 NF), is a well-known multidonor class antibody target
on HCV. E2 NF is conformationally flexible and is surrounded and protected by immunodominant variable
loops and N-glycans. The antigenic surface at and around E2 NF will be optimized by computational modeling
and mutagenesis scanning to “lock” E2 NF into desired neutralizing conformations. A rigid E2 NF, together with
modifications to improve protein folding and to minimize the decoy effect of immunodominant epitopes, should
improve the immunogenicity of vaccine antigens and as a result elicit multidonor class bnAbs to the conserved
neutralizing epitopes. (2) To develop E1E2-based vaccine antigens. In addition to E2 NF, the native E1E2
complex also present other conserved bnAb epitopes. We will apply scanning mutagenesis to the interface of
E1 and E2 ectodomains and design novel E1 and E2 fusion constructs to improve the stability and production
of the soluble E1E2 complex for the elicitation of bnAbs targeting the quaternary structure of the complex. (3)
To develop self-assembling antigen-presenting nanoparticle vaccines. The engineered E2 and E1E2
complex will be fused with the scaffold proteins of different nanoparticle platforms to identify a platform optimal
for the multimeric display of HCV antigens to the immune system. Based on our preliminary data, this strategy
will greatly improve the immunogenicity of vaccine antigens and elicit a rapid and potent nAb response. (4) To
evaluate immunogenicity and antibody responses of vaccine candidates in the mouse and non-human
primate (NHP) rhesus macaque models. The engineered E2, E1E2 antigens and nanoparticles will first be
studied in mice to confirm their immunogenicity in vivo and their ability to elicit antibodies that can bind and
neutralize HCV. The antigens and nanoparticles with the best properties in vitro and in mice will be studied
further using the NHP model. We have recently shown that rhesus macaques react to E1E2 immunization in a
manner highly reminiscent to that used by humans and develop bnAbs against E2 NF with genetic similarity to
human bnAbs. Here, we will immunize NHPs, identify bnAbs, and perform r...

## Key facts

- **NIH application ID:** 10428301
- **Project number:** 1P01AI168251-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Jiang Zhu
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $580,936
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428301

## Citation

> US National Institutes of Health, RePORTER application 10428301, Novel HCV vaccine antigens and nanoparticles (1P01AI168251-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10428301. Licensed CC0.

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