# Structure based design of dengue subunit vaccines for inducing protective but not disease enhancing antibodies

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $723,184

## Abstract

ABSTRACT
Dengue virus (DENV) vaccine development has been challenging because of the presence of 4 serotypes
(DENV1-4) and the potential for vaccine enhanced severe disease. The leading live attenuated tetravalent DENV
vaccines have been plagued by poorly balanced replication of vaccine components leading to variable efficacy
and vaccine primed severe dengue disease in some children. The goal of this proposal is to develop novel
recombinant DENV envelope (E) protein and virus like particle (VLP) vaccines that overcome barriers faced by
live attenuated tetravalent vaccines. We have discovered that the DENV E protein produced as a secreted
protein is a poor vaccine because it is a monomer that does not display major quaternary epitopes targeted by
human neutralizing and protective antibodies (Abs). This proposal is based on new discoveries from our group
about how structure based, computational approaches can be used to produce highly stable and properly folded
DENV E dimers that are efficiently secreted from mammalian cells. We will use mouse models of DENV
vaccination and infection to test if artificially stabilized DENV E dimers stimulate Ab responses that are similar to
serotype-specific and serotype-cross-protective Ab responses in people exposed to primary and secondary wild
type DENV infections. The stabilized E dimers will be further modified to test if large-scale resurfacing of the E
dimer can be used to focus the immune response on epitopes recognized by potent neutralizing Abs, while
eliminating responses to off target, disease enhancing epitopes. Finally, we will design membrane anchored
variants of stabilized E dimers to promote the formation of dengue virus-like particle (VLP) vaccine candidates
that better resemble mature infectious virions than VLPs made with current techniques. Our studies, which
explore how to design and deliver recombinant E antigens to focus the host antibody response on important
quaternary structure neutralizing epitopes, will stimulate new research directions in the field of flavivirus subunit
vaccines.

## Key facts

- **NIH application ID:** 10813001
- **Project number:** 5R01AI161025-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Aravinda M. DeSilva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $723,184
- **Award type:** 5
- **Project period:** 2022-04-21 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813001

## Citation

> US National Institutes of Health, RePORTER application 10813001, Structure based design of dengue subunit vaccines for inducing protective but not disease enhancing antibodies (5R01AI161025-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10813001. Licensed CC0.

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