# Structure-Based Vaccine Design for Hepatits C Virus

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2020 · $1,128,779

## Abstract

Hepatitis C virus (HCV) is a highly variable RNA virus that has infected 185 million worldwide and is associated
with severe liver diseases and cancer. While a successful vaccine may require robust T and B cell responses,
the focus of this application is on a B cell-based vaccine. The vaccine must overcome the high diversity of HCV
isolates and its potential for viral escape, and the vaccine must induce sterilizing immunity despite the low
immunogenicity of epitopes that mediate broad virus neutralization (Vn). We have developed a unique
database on the E2 glycoprotein, the natural target of the majority of broadly neutralizing (Vn) antibodies. The
database outlines the immunogenic regions on E2 that segregate into five clusters of overlapping epitopes,
designated antigenic domains A-E, and hypervariable region 1 (HVR1). Domain A elicits non-virus-neutralizing
(non-Vn) antibodies and HVR1 elicits isolate-specific antibodies from which HCV can easily escape. By
contrast, epitopes within domains B, D and E elicit broad Vn antibodies. We will exploit this database, as well
as evidence that epitope conformational stability is a key determinant of immunogenicity and that Vn epitopes
can be grafted onto heterologous protein scaffolds, to address the following questions: Does increasing the
conformational stability of Vn B, D and E epitopes, or grafting them onto heterologous scaffolds, increase their
antigenicity? Can E2 be glycoengineered to silence domain A decoy epitopes and up-modulate Vn epitopes?
How can this information be employed to design an effective preventive vaccine? Our Aims are: 1. Structure-
guided computational redesign of the E2 glycoprotein. We will use X-ray crystallographic information on
human monoclonal antibodies (HMAbs) bound to B, D and E epitopes to computationally redesign E2 to
stabilize these broadly Vn epitopes and thereby increase their immunogenicity. Conversely, we will silence
domain A epitopes by strategic introduction of N-glycans. We will evaluate our most promising combinations of
designed E2 mutants in the context of the E1E2 heterodimer. 2. Design of scaffolded E2 immunogens to
optimize presentation of Vn epitopes. As a complementary approach to E2 redesign, we will engineer small
scaffolded immunogens to elicit Vn antibodies to B, D and E epitopes. 3. Self-assembling polyphosphazene
nanoparticles for multimeric E2 and E1E2 presentation. To achieve more effective presentation of
designed immunogens from Aims 1 and 2, we will develop biodegradable synthetic nanoparticles to display
them in multimeric mode. This will include self-assembling polyphosphazene macromolecules that have been
tested clinically. 4. Immunological characterization of candidate E2 and E1E2 vaccines from Aims 1-3.
Immunogenicity testing in mice will identify optimal combinations of HCV envelope immunogens, protein
expression system, and immunoadjuvant formulations. Leading candidates will be tested for immunogenicity in
macaques. These studi...

## Key facts

- **NIH application ID:** 9932343
- **Project number:** 5R01AI132213-04
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Alexander Andrianov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,128,779
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932343

## Citation

> US National Institutes of Health, RePORTER application 9932343, Structure-Based Vaccine Design for Hepatits C Virus (5R01AI132213-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932343. Licensed CC0.

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