# Determine if a candidate dengue vaccine in advanced trials induces antigen-specific cellular immunity that mimics immunity after multiple infections and controls antibody-enhanced viral replication

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2020 · —

## Abstract

Dengue (DV) disease is a major and spreading global health problem. Transmission is now endemic in
at least one U.S. state; hundreds of veterans were affected by a DV outbreak in 2007-10. Most severe DV
disease is mediated by antibody-mediated enhancement of infection (ADE) inwhich antibodies from a prior
infection with another DV serotype or maternal-infant transmission facilitate viral entry and replication. A 7.5-
fold increased risk of severe DV disease is seen in DV-naïve recipients of the YF-vectored DV vaccine (CYD),
indicating this vaccine is inducing ADE in those subjects. As neither vaccination nor repeated infection induce
durable high titer neutralizing antibodies in sufficient numbers of people at risk, it is vital to determine how CMI
blocks ADE-mediated DV replication in primary host cells so these responses can be targeted in vaccines. The
macrophage is both the primary DV replication-permissive cell and a key contributor to the exaggerated
inflammatory response seen in severe DV. Blocking DV replication in macrophages will both lower viremia and
inflammation. It is therefore critical to identify people with CMI that can mediate cross-serotypic control of
ADE-mediated DV replication in autologous macrophages. These people can then be further studied to
identify cellular mechanisms/effector molecules which mediate control of ADE-enhanced DV replication. We
hypothesize that a safe protective DV vaccine must induce effective durable CMI which blocks ADE-enhanced
DV replication in the primary host cell.  A Key Gap in knowledge is the CMI cells and phenotypes which inhibit
DV replication in primary human cells are inadequately defined.
 We have optimized an ex vivo protection assay which measures DV-specific memory CMI inhibition of
ADE-enhanced DV replication. Using samples collected from a TDV dengue vaccine trial at Saint Louis
University, we have shown that TDV vaccination of flavivirus-naives can induce cross-serotype CMI capable of
inhibiting ADE-mediated DV replication in macrophages. Using this assay, we will:
 1.Determine whether TDV vaccination induces durable cross-protective CMI in DV naives which inhibits
 ADE-enhanced DV replication.
 2.Determine if CMI after TDV vaccination is comparable to CMI after sequential natural infections.
 3.Identify key CMI functions associated with control of ADE-enhanced DV replication in MDMs.
 4.Determine the durability of DV replication-inhibitory memory CMI after TDV vaccination of DV-naives.
 5.Determine the prevalence of prior DV infection in a representative cohort of DV-exposed veterans and
 measure the prevalence of cross-serotype protective CMI years after exposure.
Our data will answer the following questions: 1. Does TDV vaccination induce durable CMI able to control
ADE-enhanced DV replication in primary cells in flavivirus-naives? DV-naives cannot receive the CYD vaccine
so it is vital to identify a safe vaccine for this population. 2. Since repeated DV infections induce protect...

## Key facts

- **NIH application ID:** 9932279
- **Project number:** 5I01BX003714-04
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Sarah George
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932279

## Citation

> US National Institutes of Health, RePORTER application 9932279, Determine if a candidate dengue vaccine in advanced trials induces antigen-specific cellular immunity that mimics immunity after multiple infections and controls antibody-enhanced viral replication (5I01BX003714-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9932279. Licensed CC0.

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