# Antibody-based Protection against Flavivirses

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $953,281

## Abstract

PROJET SUMMARY/ABSTRACT
Globally, the four serotypes of DENV cause an estimated 390 million new cases of dengue fever and 500,000
cases of dengue hemorrhagic fever (DHF) per year. Zika virus (ZIKV) is a related emerging virus linked to
Guillain-Barre syndrome in adults, and microcephaly, congenital malformations, and spontaneous abortion of
the fetus during pregnancy. Currently, no antiviral therapy is available for either virus. In the first two cycles of
this collaborative and inter-disciplinary R01, we developed panels of monoclonal antibodies (Abs) against the E
proteins of all four DENV serotypes and analyzed their structural, biophysical, and cellular mechanisms of
neutralization. These studies defined novel epitopes on DENV E proteins recognized by inhibitory Abs, some
of which are not solvent-accessible according to existing atomic models of the virus particle. We also defined
the dynamic state of DENV and related flaviviruses, determined the atomic structure of mature and immature
ZIKV, characterized atomic interactions between DENV and ZIKV virions, E protein, and new highly
neutralizing mouse and human Abs, and identified how different maturation states influence epitope
accessibility and Ab neutralization. Our studies revealed that flavivirus structure is more complex than
anticipated and is likely a heterogeneous and dynamic ensemble of different states, each of which may interact
differentially with Abs. In this renewal, our collaborative and inter-disciplinary team hopes to gain insight into
questions about the antigenicity of flavivirus virions and subviral particles (SVPs) as well as the cross-reactivity
that limits vaccine and diagnostic development and may affect pathogenesis. Our group will define new states
of DENV and ZIKV particle structure and determine how these states influence epitope exposure and
interaction with specific neutralizing Abs available in our laboratories. We also will compare the atomic
structure of SVPs with infectious virions, determine how these differences affect binding and induction of
neutralization Abs, and characterize further the structural basis of cross-reactivity of DENV and ZIKV. Our
studies may facilitate the generation of novel antigens and immunogens with improved capacity to detect and
elicit specific protective Ab responses against DENV, ZIKV, and likely other emerging flaviviruses.

## Key facts

- **NIH application ID:** 10172827
- **Project number:** 5R01AI073755-14
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Michael S Diamond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $953,281
- **Award type:** 5
- **Project period:** 2007-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172827

## Citation

> US National Institutes of Health, RePORTER application 10172827, Antibody-based Protection against Flavivirses (5R01AI073755-14). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10172827. Licensed CC0.

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