# Defining viral and immune mechanisms of Dengue virus serotype 2 immune evasion

> **NIH NIH F32** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $41,236

## Abstract

Project summary
Dengue virus (DENV) is one of the most significant arthropod-borne viruses currently leading to >390 million
human infections worldwide. DENV can cause severe disease and death in children and the elderly in endemic
regions such as Asia and Latin America. DENV is genetically and serotypically divided into four serotypes (1-4)
and each serotype can be further subdivided into distinct genotypes. Alarmingly, in the next 50-80 years,
DENV infections are projected to spread to new areas of the world, including the United States, putting millions
of additional individuals at risk for DENV disease. Moreover, the only licensed DENV vaccine does not perform
equally well against the existing four DENV serotypes. The vaccine efficacy against DENV serotype 2 (DENV2)
is remarkably low (39% efficacy), underlining the need to improve DENV vaccine design and strategies. While
it is known that DENV genetic diversity exists among the four serotypes, the role of DENV intraserotypic
diversity within the distinct genotypes in modulating neutralization resistance to vaccine-elicited antibodies is
not well understood. Therefore, this project aims to define the role of naturally occurring DENV2 genetic
variation on neutralizing antibody evasion. This project also aims to define IgG Fc characteristics, such as IgG
subclass and Fcγ receptor binding, of vaccine-elicited binding and neutralizing antibodies in NIH vaccinees. To
complete this project, I have generated a DENV2 genotype variant virus panel using reverse genetics.
Importantly, this genotype panel contains contemporary isolates from distinct regions in the world including:
Asian I, Asian II, Asian-American, Cosmopolitan, Sylvatic African, and Sylvatic Asian isolates. I discovered that
these DENV2 genotypic variants exhibit considerable amino acid residue variability within the prM and in E
domain I (EDI), II (EDII), and III (EDIII), which are key targets for neutralizing antibodies. Interestingly, my
preliminary data demonstrates that the genotypic genetic diversity observed in DENV2 modulates differential
neutralization sensitivity to both neutralizing monoclonal antibodies and polyclonal antibodies from DENV2-
infected individuals. I will therefore evaluate the role of DENV2 genetic diversity in modulating neutralization
resistance to vaccine-elicited neutralizing antibodies from NIH monovalent DENV human vaccinees and
tetravalent DENV human vaccinees. Moreover, I will define the Fc region characteristics, such as IgG subclass
and binding to Fcγ receptors, of these vaccine-elicited antibody responses that mediate protection in a human
challenge model of DENV infection. A better understanding of the mechanism(s) by which DENV evades
neutralizing antibodies will be critical to improve the existing DENV2 vaccine that performs poorly. These
project findings will provide crucial information on the strategies that DENV2 employs to subvert host-elicited
neutralizing antibodies, which will be important ...

## Key facts

- **NIH application ID:** 10066591
- **Project number:** 1F32AI152296-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** David R. Martinez
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $41,236
- **Award type:** 1
- **Project period:** 2020-08-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066591

## Citation

> US National Institutes of Health, RePORTER application 10066591, Defining viral and immune mechanisms of Dengue virus serotype 2 immune evasion (1F32AI152296-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10066591. Licensed CC0.

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