# PRECLINICAL ASSAYS TO PREDICT TETRAVALENT DENGUE VACCINE EFFICACY

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $1,075,722

## Abstract

Program Summary
Dengue is the most common arthropod borne viral disease of humans. Vaccines are urgently needed to
prevent dengue yet vaccine development is complicated by the presence of four dengue virus (DENV)
serotypes and the possibility of immune enhanced dengue disease. The leading vaccine candidates contain 4
live attenuated viruses to cover the 4 serotypes. The most advanced vaccine candidate, a chimeric Yellow
Fever-Dengue tetravalent live virus vaccine (CYD-TDV) developed by Sanofi Pasteur, was recently evaluated
in human efficacy studies conducted in Asia and Latin America. Overall, CYD-TDV was efficacious at reducing
the burden of dengue disease in the vaccinated populations. However, the vaccine had unexpectedly low
efficacy against DENV serotype 2 (DENV2) and in dengue naïve subjects compared to dengue exposed
subjects who were vaccinated. The lower efficacy in these groups was unexpected because the vaccine
induced neutralizing antibodies (Abs) in these subjects. The central hypothesis of this proposal is that the
quality (Ab epitope specificity) rather than total quantity of cell-culture neutralizing Abs is a better predictor of
DENV vaccine performance in human populations. Moreover, as the DENV complex has 4 serotypes and
vaccines will be used in populations with a mix of naïve and partially immune individuals, immune assays
based on a single epitope are unlikely to predict efficacy against the 4 serotypes.
 This project is grounded on studies in our laboratories to understand protective and pathogenic Ab
responses in people exposed to natural DENV infections. We have discovered new quaternary structure Ab
epitopes linked to protection and developed reagents (human monoclonal Abs, recombinant DENVs) and
assays that precisely measure Ab epitope-specific responses in human sera. In collaboration with Sanofi
Pasture, we will use samples from the CYD-TDV efficacy trials, including several hundred samples from
people who experienced vaccine breakthrough infections, to identify Ab epitope based correlates of protective
immunity. Currently we are the only group capable of doing this study because no other dengue vaccine has
been tested in efficacy studies.
 As DENV vaccines have 4 attenuated replicating viruses, it has been difficult to obtain balanced
replication and immunity to all 4 serotypes. Currently there are no reliable models to optimize the formulation
of multi-component live dengue vaccine formulations. Investigators at Sanofi Pasteur's VaxDesign campus
have developed a fully automated human Peripheral Tissue Equivalent (PTE) biomimetic model for preclinical
evaluation of vaccines. As DENVs initially replicate in peripheral tissues after mosquito transmission or
vaccination, we will test if the PTE biomimetic model has utility for predicting and optimizing the replication of
single and multicomponent live-attenuated dengue vaccines.
 Within the time frame of this study, we will establish novel standardized assays for suppor...

## Key facts

- **NIH application ID:** 9901414
- **Project number:** 5R01AI125198-05
- **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:** 2020
- **Award amount:** $1,075,722
- **Award type:** 5
- **Project period:** 2016-05-08 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901414

## Citation

> US National Institutes of Health, RePORTER application 9901414, PRECLINICAL ASSAYS TO PREDICT TETRAVALENT DENGUE VACCINE EFFICACY (5R01AI125198-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9901414. Licensed CC0.

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