# Correlates of protective immunity to HCV and rational vaccine design: Project 2

> **NIH NIH U19** · EMORY UNIVERSITY · 2022 · $408,061

## Abstract

Project 2. B Cell-Mediated Protection Against HCV Reinfection
Prevention of HCV infection remains an important public health objective even with the recent adoption of highly
effective antiviral therapies. A vaccine to prevent HCV persistence is needed to stem an emerging epidemic in
susceptible populations. Recall responses to secondary viral infections naturally emulate the protective immune
mechanisms associated with vaccination against viral antigens. Our findings suggest that spontaneous resolvers
may possess antigen-specific B cells that become readily activated by T follicular helper (Tfh) cells and expand
rapidly following HCV antigenic exposure. However, resolution of secondary HCV infection is low in individuals
cured of persistent HCV infection by DAAs, despite an initial burst of HCV-specific CD4+ T cells at the start of
DAA treatment. Such contrasting recall responses between these two scenarios implicate profound phenotypic
and functional differences in antigen-specific memory T and B cell responses between DAA-treated versus
untreated, resolving individuals.
We propose to elucidate the differences in antibody recall responses between individuals who spontaneously
resolve primary infection and subsequently either clear their secondary HCV reinfection (SR/SR) or develop
persistent infection (SR/CI). We will also compare these responses to those of DAA-treated individuals who are
cured of persistent HCV infection. We will analyze longitudinal samples from two separate cohorts of HCV
infected individuals for these studies. One cohort consists of people who inject drugs (PWIDs) recruited from
Montreal, Canada, who spontaneously resolve primary HCV infection but have different secondary reinfection
outcomes. The other cohort consists of individuals from Egypt who cleared persistent HCV infection following
DAA treatment (HCV-cured). We hypothesize that SR/SR PWID mount a more accelerated and sustained
memory B cell response that produces early, broadly neutralizing antibodies (bNAbs) that contribute to faster
clearance, while delayed antibody responses from SR/CI PWID or HCV-cured individuals fail to suppress viremia
early, facilitating viral escape from neutralization. We propose the following aims:
Aim 1. Determine the phenotypic and transcriptional profiles of bulk and antigen-specific memory B cells from
primary resolvers who were reinfected but experienced divergent infection sequelae.
Aim 2. Evaluate neutralizing efficacy and breadth of HCV-specific antibodies from resolvers with contrasting HCV
reinfection outcomes.
Aim 3. Determine phenotypic and functional changes in B cells of DAA-treated individuals before and after viral
clearance.

## Key facts

- **NIH application ID:** 10393618
- **Project number:** 5U19AI159819-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Arash Grakoui
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $408,061
- **Award type:** 5
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393618

## Citation

> US National Institutes of Health, RePORTER application 10393618, Correlates of protective immunity to HCV and rational vaccine design: Project 2 (5U19AI159819-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10393618. Licensed CC0.

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