# Structure-guided vaccine design of HCV E1E2 to induce broadly neutralizing antibodies (bNAbs)

> **NIH NIH U19** · STANFORD UNIVERSITY · 2023 · $965,967

## Abstract

ABSTRACT - PROJECT 1
An effective HCV vaccine to prevent chronic infection will need to induce robust T and B cell responses shortly 
after exposure in the susceptible host, the overall goal of this U19. Project 1 focuses on a structure-guided approach to develop an immunogen that increases the neutralization potency/affinity of elicited 
broadly neutralizing antibodies (bNAbs) to conserved epitopes and particularly to those epitopes 
associated with neutralization synergy. It will be an optimized mutant (mt) E1E2 heterodimer that maintains 
native conformational structures for multiple bNAb epitopes to minimize viral escape. The increasing 
information on E2 crystal structures made possible by human monoclonal antibodies (HMAbs) that we 
and others have isolated and characterized as bNAbs, provides a strong foundation for the molecular 
approaches in rational design. A critical and complementary element is the availability of a high-resolution, 
functional map of both bNAb and non-neutralizing epitopes in E2 and E1E2. We have developed a large 
database on immunogenic domains on E2 that is derived from epitope mapping studies with a large panel of 
E2 bNAbs. We have also developed a large panel of bNAbs to E1E2 that will contribute to structural studies on 
E1E2 heterodimer in Project 4. In addition, Project 1 is built on substantial achievements with native 
recombinant wild-type (wt) E1E2 heterodimer as a vaccine against HCV. We have developed the necessary 
production and purification processes and tested to show that our wt E1E2 expresses many bNAbs 
epitopes and that antisera generated from vaccinated mice, guinea pigs, chimpanzees and humans contains 
bNAbs. However, there are gaps in the breadth of protection against some genotypes 2, 3 and 7 HCV isolates. 
Thus, a benchmark is to design a mt E1E2 that elicits antisera more able to neutralize these genotype isolates 
while maintaining a high level of neutralization towards the other genotype isolates achieved with wt E1E2. We 
propose to accomplish this goal by the following Specific Aims: Aim 1. Structure-guided modeling to redesign 
E1E2 structures to optimize presentation of E1E2 bNAb epitopes; Aim 2. Expression, purification, and 
characterization of modified/mutant E1E2 heterodimers; and Aim 3. Immunological characterization of 
candidate E1E2 vaccines to select optimized E1E2. Finally, we aim to combine optimized E1E2 with powerful 
adjuvants to enhance neutralizing antibody titers (Project 3). Aim 4 is then the immunological 
characterization of NHP receiving an HCV vaccine optimized for bNAbs and T cell responses

## Key facts

- **NIH application ID:** 10797240
- **Project number:** 5U19AI159840-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Steven Foung
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $965,967
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797240

## Citation

> US National Institutes of Health, RePORTER application 10797240, Structure-guided vaccine design of HCV E1E2 to induce broadly neutralizing antibodies (bNAbs) (5U19AI159840-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10797240. Licensed CC0.

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