# Mechanisms of Protection and Durability for a Live Attenuated Tetravalent Dengue Vaccine

> **NIH NIH U01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2024 · $635,890

## Abstract

Project Summary
The four serotypes of dengue virus pose a significant and increasing disease risk to endemic areas (40% of the
world) and (via mosquito vector spread or travel) to areas not yet endemic. Tetravalent dengue vaccines are
critical to prevent dengue illness. They must generate concurrent and durable protection against all serotypes
without increasing risk of severe disease via imbalanced immunity leading to antibody-dependent enhancement
of infection. Given concerns with imbalanced dengue vaccine candidates, it is critical to define components and
mechanisms of durable four-serotype protection following vaccination, particularly in people (especially children)
who have not established protective immunity via sequential natural exposures. This proposal builds on the work
of long-standing collaborative investigators involved in developing the NIH live-attenuated tetravalent dengue
vaccine TetraVax (TV) in studies in the U.S. and in dengue-endemic Bangladesh. TV protected dengue-naïve
individuals from experimental infection six months later with dengue virus serotype 2 challenge and induced
robust dengue serotype-specific B cell and CD4+ and CD8+ T cell responses. Key questions include: the
durability of protective responses, whether similar protective mechanisms are at play in individuals in dengue-
endemic areas and in individuals previously exposed to dengue prior to vaccination. In Aim 1 we will evaluate
the development of serotype-specific B cells producing antibodies with neutralizing and Fc effector functions as
well as virus-specific CD4+ and CD8+ T cell responses throughout a 6–12-year period after TV vaccination and
assess whether these responses correlate with protection from subsequent DENV2 challenge. In Aim 2 we will
demonstrate the importance, persistence, and function of serotype-specific neutralizing vs. enhancing antibodies
following TV of dengue-naïve adults. In Aim 3 we will investigate whether TV vaccination contributes to protection
in dengue-exposed individuals via potent cross-reactive neutralizing antibodies. Overall, these insights into
immune mechanisms of durable protection will help answer persistent questions about dengue vaccine risk and
efficacy. Leveraged with highly controlled clinical studies these data should be broadly generalizable to the
understanding of safe and durable immunity following any tetravalent dengue vaccine.

## Key facts

- **NIH application ID:** 10764545
- **Project number:** 2U01AI141997-06
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Sean A. Diehl
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $635,890
- **Award type:** 2
- **Project period:** 2019-02-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764545

## Citation

> US National Institutes of Health, RePORTER application 10764545, Mechanisms of Protection and Durability for a Live Attenuated Tetravalent Dengue Vaccine (2U01AI141997-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10764545. Licensed CC0.

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