# Molecular and structural characterization of broadly neutralizing anti-HCV antibodies

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $804,923

## Abstract

Summary
More than 70 million people worldwide are infected with hepatitis C virus (HCV), and development of a vaccine
for HCV is essential for disease eradication. Although direct-acting antivirals are highly effective for treatment,
the majority of countries surveyed are not on track to reach the WHO goal of eliminating HCV as a public health
problem by 2030, with most countries seeing rising incidence of HCV. Fortunately, there is strong evidence that
vaccine-induction of high titers of broadly neutralizing antibodies (bNAbs; antibodies capable of neutralizing
diverse HCV variants) could provide protection against human HCV infection. However, we are unable to
stimulate bNAbs against HCV with a vaccine because we have not defined the full spectrum of anti-HCV
antibodies that are critical for neutralizing breadth or characterized the HCV envelope glycoprotein (E1 and E2)
genetic and structural features that favor bNAb selection and maturation. The overarching goal of this proposal
is to isolate a large and representative set of E1E2-specific bNAbs, bNAb unmutated ancestors, and bNAb
intermediates from Elite Neutralizers (EN), individuals with broadly neutralizing plasma and spontaneous
clearance of HCV infection. In Aim 1, we will isolate monoclonal antibodies (mAbs) from E1E2-specific B cells
isolated from EN and from controls with chronic, persistent infection (CP). We will infer unmutated germline bNAb
ancestors and use B cell receptor-sequencing of longitudinal E1E2-specific B cells to identify bNAb genetic
intermediates. We will compare neutralizing breadth, potency, epitopes, and genetic features for EN vs. CP
mAbs. In Aim 2, we will use X-ray crystallography or cryo-EM techniques to compare structures of EN bNAbs or
CP mAbs in complex with soluble E2 or E1E2 heterodimers. By comparing mAb-E1E2 interactions among CP
mAbs, bNAb unmutated ancestors, bNAb intermediates, and mature bNAbs, we will define structural and genetic
features of E1E2 necessary for the development of neutralizing breadth. Together, these studies will identify a
large, representative set of bNAbs associated with spontaneous clearance of HCV, defining key epitope residues
and structural features in E1E2 that could be stabilized to optimize vaccine antigens. These studies will inform
structure-based design efforts to improve E1E2-based vaccine candidates, which is an urgent challenge with
global public health implications.

## Key facts

- **NIH application ID:** 10786129
- **Project number:** 5R01AI127469-07
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Justin Richard Bailey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $804,923
- **Award type:** 5
- **Project period:** 2023-02-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786129

## Citation

> US National Institutes of Health, RePORTER application 10786129, Molecular and structural characterization of broadly neutralizing anti-HCV antibodies (5R01AI127469-07). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10786129. Licensed CC0.

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