# Hepacivirus control by vaccine-elicited T cells.

> **NIH NIH F30** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2021 · $51,036

## Abstract

PROJECT ABSTRACT/SUMMARY
The hepatitis C virus (HCV) is a human hepatotropic hepacivirus known for causing persistent infections that
often progress to fatal liver diseases. Although new antivirals cure >97% of infections, the vast majority of
infected patients are either undiagnosed or unable to receive therapy due to substantial socioeconomic
barriers. To achieve global eradication, a vaccine to prevent HCV persistence will be needed. Although the
immune factors that dictate whether an infection will be controlled are poorly defined, T cells are considered
key immunological determinants. Indeed, silencing of virus-specific CD8+ T cells is a classic feature of
infections that persist. Furthermore, the only vaccine to advance to phase II clinical testing in humans is based
on a T cell immunization strategy that showed signs of efficacy in the chimpanzee model. Despite this
promising momentum, it is not fully clear why this approach succeeded in chimps and whether similar results
can be expected in humans. Indeed, mechanisms of vaccine-induced immunity are incompletely known and
deciphering these in humans will be challenging and slow. Furthermore, due to the elimination of chimps from
research, there are no suitable animal models available to further evaluate vaccine-mediated protection
against HCV persistence. Recently, we developed a surrogate model for HCV using a homologous hepacivirus
found in feral rats. Several aspects of this model are significant. First, infection in lab rats is strictly hepatotropic
and highly persistent despite the activation of host adaptive immunity. Second, immune responses can be
readily analyzed in the infected liver, which is poorly accessible in humans. Finally, use of a rodent host
permits the expedited testing and mechanistic deconstruction of promising vaccination concepts, which was
not easily afforded by chimps. Our long-term goal in this proposal is to identify correlates of vaccine-induced
immunity to chronic hepacivirus infection and to translate this knowledge into rational HCV vaccine designs. As
the impetus for our studies, we show in our preliminary data that persistent infection in rats can be prevented
using an adenovirus-vectored vaccine encoding non-structural proteins, which primes cellular immunity in the
absence of neutralizing antibodies. How this approach leads to control of an otherwise highly persistent
infection is unclear. Our central hypothesis is that CD8+ T cell function is essential for hepacivirus clearance,
and pre-exposure priming of CD4+ T cell help via vaccine protects virus-specific CD8+ T cells from failure
during infection, resulting in effective antiviral control. Two specific aims are proposed. Aim 1 will provide a
detailed comparison of cellular immunity between vaccinated and unvaccinated animals after virus challenge;
functional responses will be comprehensively analyzed and minimal T cell epitopes will be mapped. Aim 2 will
test the requirement for CD4+ and CD8+ T cells...

## Key facts

- **NIH application ID:** 10065490
- **Project number:** 5F30AI143060-03
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Alex Stephen Hartlage
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2018-12-17 → 2022-12-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065490

## Citation

> US National Institutes of Health, RePORTER application 10065490, Hepacivirus control by vaccine-elicited T cells. (5F30AI143060-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10065490. Licensed CC0.

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