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

> **NIH NIH U01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $615,445

## Abstract

PROJECT SUMMARY
Approximately 40% of the world's population is at risk for illness caused by the four serotypes of dengue virus.
Development of durable, safe, and efficacious tetravalent dengue vaccines is a global priority. Since incomplete
immunity may predispose individuals to more severe disease via antibody-dependent enhancement, the goal of
dengue vaccines is long-term simultaneous protection against all four serotypes. Given the weaknesses and
risks observed following use of the only currently licensed dengue vaccine, it is critical to clarify components and
mechanisms of durable four-serotype protection following vaccination. This proposal leverages the work of long-
standing collaborative investigators involved in the development of the NIH live-attenuated tetravalent dengue
vaccine. It builds on preliminary data from our monovalent and tetravalent vaccine studies, as well use of the
human dengue virus challenge model for early indications of vaccine efficacy. Preliminary work suggests that
protected vaccinees exhibit dengue-specific plasmablasts soon after vaccination, followed by neutralizing
antibody responses targeted to all serotypes and cellular responses-including CD8+ T cell responses targeting
dengue non-structural proteins. This proposal plans to evaluate data and specimens via four aims corresponding
to specifically-designed vaccine and/or human viral challenge trials to iteratively expand and refine these
observations for the immunologic characterization of durable protection. These trials include tetravalent
vaccinations followed by short term (30d) or long term (>3 years) viral challenge; an incompletely protective tri-
valent vaccine followed by missing-serotype challenge; and an endemic setting vaccine trial of naïve and
previous dengue-experienced subjects followed for several years post-vaccination. We hypothesize that if
homotypic antibodies all serotypes are not present, defined mechanisms may compensate for the missing
serotype and to maintain protection from illness. We hope to demonstrate that in settings of incomplete or waning
immunity, these mechanisms, such as cellular responses (CD8+ non-structural protein and CD4+ cytotoxic) or
heterotypic antibodies to conserved epitopes, are necessary and effective even in the presence of enhancing
antibodies. Overall, these immunologic evaluations will help answer critical and 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 tetravalent dengue vaccines.

## Key facts

- **NIH application ID:** 9856971
- **Project number:** 5U01AI141997-02
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Jason W. Botten
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $615,445
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856971

## Citation

> US National Institutes of Health, RePORTER application 9856971, Mechanisms of Protection and Durability for a Live Attenuated Tetravalent Dengue Vaccine (5U01AI141997-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856971. Licensed CC0.

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