# Improved RhCMV/SIV vaccine efficacy via IL-10 pathway modulation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $767,292

## Abstract

The goal of this project is to test if rhesus cytomegalovirus-based SIV vaccines (RhCMV/SIV) can be
improved via IL-10 pathway modulation to obtain significantly over 50% protective efficacy. We found
that second-generation RhCMVdIL10/SIV vaccines lacking the viral IL-10 gene protect non-human primate
infants, while first-generation (IL-10 intact) RhCMV/SIV vaccines do not. First-generation vaccines have been
proven effective only in wild-type RhCMV-seropositive macaques having neutralizing antibodies to viral IL-10.
The significance of this work is that if successful it will provide (i) new candidate HIV vaccines with greater
efficacy in some or all segments of the population, (ii) a coherent, mechanistic explanation for previously
obscure patterns of RhCMV/SIV vaccine protectiveness, (iii) new pharmacologic tools for control over IL-10
signaling, and (iv) immunologic insight into consequences of cellular and viral IL-10 pathway modulation.
Our preliminary data show that rhesus macaques infected by wild-type rhesus cytomegalovirus (wtRhCMV)
mount immune responses to viral interleukin-10 (vIL-10), which in most cases leads to generation of
neutralizing antibodies. RhCMV/SIV vaccine stringently protects ~50% of such wtRhCMV+ but not wtRhCMV-
seronegative monkeys against SIV challenge. A second-generation RhCMV/SIV vaccine lacking the viral IL-10
gene, however, can protect seronegative macaques.
We hypothesize that RhCMV/SIV vaccination in the context of inhibited host IL-10 signaling will achieve
superior efficacy (>50%) in infant and adult macaques. Our specific aims are:
Aim 1. Define the transcriptomic and immunologic signatures of increased or decreased IL-10
signaling using previously collected samples. Here we determine the true transcriptomic signature of host
IL-10 signaling using samples from animals receiving anti-IL-10 antibody or with forced IL-10 expression. We
then evaluate host responses to RhCMV/SIV vaccination in the presence of varying levels of viral IL-10
neutralization to determine how such neutralization affects (i) host IL-10 signaling, (ii) likelihood of generating a
transcriptomic signature associated with protection, and (iii) vaccine efficacy.
Aim 2. Test if cellular IL-10 inhibition augments vaccine efficacy in infant (RhCMV-negative) macaques.
Since viral IL-10 deletion presumably interferes with the host IL-10 response, we reason that further
interference (via administration of neutralizing anti-IL-10 antibody) will further augment vaccine efficacy. In this
aim we therefore administer RhCMVdIL10/SIVgag alone or in the presence of neutralizing anti-cIL-10 antibody.
Aim 3. Test if cellular and/or viral IL-10 inhibition augment vaccine efficacy in adult (RhCMV-positive)
macaques. Here we test if complete inhibition of viral and/or cellular IL-10 can substantially increase efficacy.
Together these studies will provide clear understanding of the role of IL-10 signaling in RhCMV/SIV vaccine
efficacy and may point the way to...

## Key facts

- **NIH application ID:** 9994824
- **Project number:** 5R01AI143554-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** DENNIS J. HARTIGAN-O'CONNOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $767,292
- **Award type:** 5
- **Project period:** 2018-09-24 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994824

## Citation

> US National Institutes of Health, RePORTER application 9994824, Improved RhCMV/SIV vaccine efficacy via IL-10 pathway modulation (5R01AI143554-03). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9994824. Licensed CC0.

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