# Development of a Replicon RNA-based Universal Vaccine against Dengue and Zika

> **NIH NIH R56** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2020 · $761,992

## Abstract

ABSTRACT
The long-term goal of this project is to develop a mRNA replicon-based vaccine that provides long-lived
protection against the four serotypes of dengue (DENV1-4) and Zika (ZIKV) viruses. To date, flavivirus
vaccine development has focused almost exclusively on the induction of neutralizing antibodies (nAbs),
as they have been assumed to be the key mechanism for protection against natural infection. However,
DENV and perhaps ZIKV are unusual in that weak Ab responses to vaccination or prior infection can
induce antibody-dependent enhancement (ADE) of infection and pathogenesis during subsequent
reinfections. In fact, ADE with severe sequalae has been documented in children given the only currently
licensed DENV vaccine. Thus, the primary objective of this application is to develop an effective vaccine
against DENV and ZIKV that cannot mediate ADE. We hypothesize that this vaccine will need to elicit
both strong nAb responses and strong T cell effector responses that will counterbalance the presence of
any ADE-mediating Abs, based on our work investigating the interplay between Ab and T cell responses
to DENV and ZIKV. In particular, we have shown that CD8 T cells mediate cross-protection against
heterotypic DENV and ZIKV infections, and that DENV vaccine-elicited CD8 T cells can prevent ADE. In
addition, our preliminary data show that a mRNA replicon-based vaccine expressing ZIKV nonstructural
protein 3 elicits only T cell but not Ab responses and confers protection against ZIKV challenge in mice.
Thus, we hypothesize that our pan-flavivirus mRNA replicon-based vaccine expressing both Ab- and T
cell-targeting proteins of DENV1-4 and ZIKV will produce humoral and cellular immune responses that
provide robust, long-term protection against all five viruses. We will test this hypothesis by achieving the
following Specific Aims: 1: To evaluate immunogenicity and protective efficacy of a pan-flavivirus vaccine
against DENV1-4 and ZIKV designed to elicit CD8 T cell and Ab responses in wild-type mice. 2: To
assess durability and immune mechanisms underlying the pan-flavivirus vaccine-induced protective
immunity and ADE in mice. 3: To assess the immune response and protection induced by the pan-
flavivirus vaccine in nonhuman primates.

## Key facts

- **NIH application ID:** 10241044
- **Project number:** 1R56AI148635-01
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Sujan Shresta
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $761,992
- **Award type:** 1
- **Project period:** 2020-09-14 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241044

## Citation

> US National Institutes of Health, RePORTER application 10241044, Development of a Replicon RNA-based Universal Vaccine against Dengue and Zika (1R56AI148635-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241044. Licensed CC0.

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