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

> **NIH NIH R01** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2022 · $712,699

## Abstract

ABSTRACT
The long-term goal of this project is to develop a dengue-Zika vaccine that provides protection against
the four serotypes of dengue (DENV1-4) and Zika (ZIKV) viruses with maximal safety and efficacy. To
date, flavivirus vaccine development has focused 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, DENV disease 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 an RNA replicon-based vaccine expressing
ZIKV nonstructural protein 3 elicits only T cell but not nAb responses and confers protection against ZIKV
challenge in mice. Thus, we hypothesize that our combinatorial DENV-ZIKV 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 efficacy of a DENV-ZIKV vaccine. 2) To
determine the durability and mechanistic underpinnings of DENV-ZIKV vaccine-induced protective
immunity.

## Key facts

- **NIH application ID:** 10413253
- **Project number:** 5R01AI163188-02
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Sujan Shresta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $712,699
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413253

## Citation

> US National Institutes of Health, RePORTER application 10413253, Development of a Replicon RNA-based Vaccine against Dengue and Zika (5R01AI163188-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10413253. Licensed CC0.

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