# Correlates of protective immunity to HCV and rational vaccine design

> **NIH NIH U19** · EMORY UNIVERSITY · 2024 · $2,010,344

## Abstract

Abstract
Prevention of HCV infection remains an important public health objective even with the recent adoption
of highly effective antiviral therapies. Importantly, treatment with direct acting antivirals (DAAs) does
not prevent reinfection in those who have successfully been treated. A vaccine to prevent HCV
persistence is needed to stem an emerging epidemic of infection in adolescents and young adults who
inject drugs that have limited access to screening and treatment. Only twenty five percent of acute
HCV infections resolve spontaneously. Resolution does, however, sharply reduce the risk of persistent
infection upon re-exposure to the virus. Memory CD4+ T helper and CD8+ cytotoxic T cell responses
contribute to accelerated clearance of a second infection. However, the role of neutralizing antibodies
during reinfection is less clear. Importantly, vaccines to generate an equivalent T cell response failed to
thwart off the rate of persistence in naïve recipients. Here, we will test the central hypothesis that
memory CD4+ T cells contribute significantly to HCV reinfection outcome by promoting expansion of
HCV-specific B cells and production of broadly neutralizing antibodies that contribute to viral clearance.
Unique features of this proposal are (i) the use of longitudinal samples from the Montreal cohort of high-
risk people who inject drugs. Participants are monitored prior to, during, and after HCV infection and
then subsequently followed again when they have been re-exposed to HCV a second time after
resolving their primary infection. (ii) We have assembled a team of investigators in Cairo, Egypt who
will assist us with recruiting and treating subjects undergoing DAA treatment. Egypt has the highest
prevalence of HCV infection in the world. In 2014, Egypt's government has made DAA treatment
affordable and 2.5 million subjects have started treatment. Understanding the immune responses in
these two cohorts will provide us with valuable information to develop an efficacious vaccine regimen
that would emulate the successful responses generated during a natural challenge with HCV.
Three highly interactive Projects are proposed. Project 1 (N. Shoukry, PI) will compare the frequency,
breadth, function, and phenotype of CD4+ T cells in HCV reinfections that either resolve or become
persistent. Project 2 (A. Grakoui, PI) will use new state of the art technology to isolate and
characterize antigen-specific B cells during HCV reinfection and post DAA treatment. Project 3 (R.
Amara, PI) will develop vaccine modalities to induce both a CD4+ T helper response and a robust
antigen-specific antibody response in blood and liver using DNA, modified vaccinia Ankara (MVA) and
protein-based vaccines against HCV proteins in non-human primates.

## Key facts

- **NIH application ID:** 10835022
- **Project number:** 5U19AI159819-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Arash Grakoui
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,010,344
- **Award type:** 5
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10835022

## Citation

> US National Institutes of Health, RePORTER application 10835022, Correlates of protective immunity to HCV and rational vaccine design (5U19AI159819-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10835022. Licensed CC0.

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