# Molecular Basis of Flavivirus Cross-Neutralization by Human Antibodies

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $571,637

## Abstract

Abstract
Zika virus (ZIKV) and the four-dengue virus (DENV) serotypes are emerging mosquito-borne flaviviruses that
pose serious threats to human health. People exposed to primary DENV infections develop long-term serotype-
specific neutralizing and protective antibodies (Abs). Individuals exposed to secondary DENV infections with a
new serotype develop a novel class of cross neutralizing and protective Abs that are even effective against
serotypes not previously encountered by the individual. While the molecular properties of type-specific human
neutralizing Abs have been well-defined, little is known about the origin and properties of DENV cross-
neutralizing Abs induced after secondary infection. In this project, we will use an established human challenge
model of secondary DENV infection to test the hypothesis that secondary infections activate and expand memory
B cells from primary infections to generate somatically mutated Abs that bind with high affinity to epitopes that
are conserved between DENV serotypes (Specific Aim 1). We will also define the molecular specificity and
functional properties of neutralizing Abs induced in US travelers with laboratory confirmed ZIKV infections.
Building on our discoveries about primary Ab responses to DENVs, we propose that people exposed to ZIKV as
a primary flavivirus infection develop type-specific neutralizing Abs that target quaternary structure envelope (E)
protein epitopes displayed on the viral surface (Specific Aim 2). While repeat infections with different DENV
serotypes induce durable cross DENV neutralizing Abs, it is unclear if this response can expand to neutralize
ZIKV. By analyzing Ab responses in people exposed to secondary DENV infections and DENV immune
individuals infected with ZIKV, we will determine the molecular mechanisms and structural features that promote
or restrict the breadth of Ab cross-neutralization between the DENV sero-complex and ZIKV (Specific Aim 3).
The importance of our studies is underscored by the disappointing results recently reported with tetravalent live
attenuated DENV vaccines to induce balanced cross-protective immunity to the 4 DENV serotypes. Our studies
are relevant to the successful design and evaluation of the next generation of safe and effective vaccines against
emerging flaviviruses. Moreover, patterns of cross-neutralizing and protective immunity between dengue and
Zika viruses may explain the explosive spread of ZIKVs in Latin America compared to Asia.

## Key facts

- **NIH application ID:** 10245040
- **Project number:** 5R01AI107731-08
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Aravinda M. DeSilva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $571,637
- **Award type:** 5
- **Project period:** 2013-08-05 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245040

## Citation

> US National Institutes of Health, RePORTER application 10245040, Molecular Basis of Flavivirus Cross-Neutralization by Human Antibodies (5R01AI107731-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245040. Licensed CC0.

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