# Maternal Antibody-Mediated Enhancement of Dengue Pathogenesis

> **NIH NIH R01** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2022 · $725,399

## Abstract

ABSTRACT
Dengue virus (DENV) represents a major threat to global health. However, the precise role of the immune
system in protecting against and pathogenesis of the four DENV serotypes, which share antigenic similarities
and geographic ranges with each other and other closely related flaviviruses are poorly understood. In particular,
antibodies can contribute to DENV pathogenesis by mediating antibody (Ab)-dependent enhancement of
infection (ADE). This project focuses on defining the features of the anti-flavivirus Ab response that contributes
to ADE vs protection using epidemiologically relevant mouse models in which DENV infection of mouse pups is
enhanced by maternally acquired flavivirus Abs. Our published and new data demonstrate that flavivirus
vaccination-infection combinations can promote either pathogenesis or protection. Our preliminary data also
show that mice lacking T follicular helper (Tfh) cell responses are unable to induce DENV IgG response, and
that mice treated with an agonistic Ab that stimulates OX40, a T cell costimulatory molecule belonging to the
TNF receptor superfamily, exhibit a boosted DENV IgG response, suggesting that the magnitude of the Tfh
response correlates with the level of Ab response to DENV. Therefore, we hypothesize that promoting Tfh
responses will increase the production of broadly-neutralizing Ab (bnAb) responses that mediate protection and
minimize ADE during DENV infection. We will test this hypothesis by using an RNA replicon-based vaccine
platform that induces robust T cell and Ab responses in the following Specific Aims: (1) Determine how
vaccination with different flavivirus antigens affects Tfh cell and Ab responses in maternal mice and susceptibility
to DENV ADE in their offspring. (2) Test whether manipulation of immunization variables and candidate T cell
costimulatory pathways boosts maternal Tfh cell and Ab responses and induces a protective response to DENV2
infection in offspring. These studies will provide critical insights into the factors and mechanisms that regulate
ADE vs protective immunity to DENV2 infection. This knowledge is urgently needed to inform development of
DENV vaccines that protect infants and young children, the highly vulnerable populations, and other flaviviral
vaccines that are safe and effective worldwide, including in countries with co-circulation of 2 or more flaviviruses.
The proposed work is based on our strong track record in investigating humoral and cellular immune mechanisms
during flavivirus infections using state-of-the-art mouse models. The project will also benefit from our
collaborators’ expertise in Tfh cells, T cell costimulatory molecules, flaviviral Ab response in humans,
development of novel vaccine platforms, and genomics assays.

## Key facts

- **NIH application ID:** 10366012
- **Project number:** 5R01AI153500-02
- **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:** $725,399
- **Award type:** 5
- **Project period:** 2021-03-05 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366012

## Citation

> US National Institutes of Health, RePORTER application 10366012, Maternal Antibody-Mediated Enhancement of Dengue Pathogenesis (5R01AI153500-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10366012. Licensed CC0.

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