# Balancing protection versus immunopathology by RSV-specific memory CD8 T cells

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $376,900

## Abstract

ABSTRACT
Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease in children, the elderly and
immunocompromised individuals. There is currently no licensed RSV vaccine. High titers of RSV-specific
antibodies can provide protection against severe RSV-induced disease; however, even the highest antibody
titers fail to protect some individuals against RSV reinfection and disease. Thus, the correlates of protective
immunity against RSV remain unclear. Memory CD8 T cells can provide protective immunity against a wide
range of acute viral infections, including respiratory viruses such as influenza virus and the severe acute
respiratory syndrome (SARS) human coronavirus. In most virus infections, memory CD8 T cells mediate viral
clearance without causing substantial damage to the infected host. Because it is clear that antibodies alone
are not sufficient to provide complete protection against RSV infection, we hypothesized that induction of a
strong pre-existing RSV-specific memory CD8 T cell response in the absence of RSV-specific memory CD4 T
cells and antibodies would provide protective immunity against an RSV infection. In order to test our
hypothesis we modified an accelerated prime/boost approach to generate robust pre-existing memory CD8 T
cell populations specific to the immunodominant M282-90 epitope. Our preliminary data indicate that RSV-
specific memory CD8 T cells can significantly inhibit viral replication, but unexpectedly do so at the cost of
causing fatal immunopathology upon RSV challenge. Importantly, the immunopathology was not an inherent
property of the T cells, as RSV-specific memory CD8 T cells were capable of mediating protection without
immunopathology against a lethal challenge with a recombinant influenza virus expressing the RSV-derived
M282-90 epitope. Our data reveal that the design of a strictly T cell-based RSV vaccine could have severe
consequences. Thus, important knowledge gaps exist regarding how RSV-specific memory CD8 T cells
function to control RSV infection and the mechanisms that result in the development of immunopathology. The
goal of this proposal is to address these critical knowledge gaps and provide mechanistic insight into if memory
CD8 T cells can be manipulated to confer optimal protective immunity against RSV infection. We will achieve
these goals by pursuing the following three specific aims: Aim 1. Determine the mechanism of memory CD8 T
cell-mediated immunopathology following RSV infection. Aim 2. Investigate the characteristics of memory
CD8 T cells that enhance immunity and limit immunopathology after RSV challenge. Aim 3. Define the
optimal correlates of protection against RSV infection. The knowledge gained from these studies will provide
vital information regarding the correlates of protective immunity to RSV, information that will greatly impact the
design and evaluation of future RSV vaccine candidates.
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## Key facts

- **NIH application ID:** 9977905
- **Project number:** 5R01AI124093-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Steven M Varga
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,900
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977905

## Citation

> US National Institutes of Health, RePORTER application 9977905, Balancing protection versus immunopathology by RSV-specific memory CD8 T cells (5R01AI124093-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977905. Licensed CC0.

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