# Project 5: mAb Development Flaviviruses and Alphaviruses

> **NIH NIH U19** · WASHINGTON UNIVERSITY · 2024 · $5,594,501

## Abstract

SUMMARY
Flaviviruses and alphaviruses are insect-transmitted RNA viruses that globally cause severe
human syndromes, including acute and chronic musculoskeletal disease, hemorrhagic fever,
hepatitis, and encephalitis. Flaviviruses and alphaviruses are pathogens with pandemic potential
because of the geographical expansion of their vectors, urbanization and population density
increases, and their capacity for epidemic transmission. In Project 5 of the Flavivirus and
Alphavirus ReVAMPP (FLARE) Center, we propose to use multiple orthogonal antibody
discovery approaches to generate and validate best-in-class human monoclonal antibodies
(mAbs) against prototype flaviviruses (West Nile virus [WNV] and dengue virus [DENV]) and
alphaviruses (chikungunya virus [CHIKV]). Using these mAbs, we aim to determine the principles
that govern the design of optimal mAb combinations to elicit synergistic responses and create
barriers to genetic resistance in vitro and in vivo. In collaboration with the Structure,
Computational, and Protein Engineering Core C, we also will develop novel computational
methods to improve upon mAb neutralization potency and breadth. We will refine a high-efficiency
screening platform to rapidly discover human mAbs against prototype flaviviruses and
alphaviruses that then can be genetically modified to endow extended half-life properties,
enabling them as vaccine-like treatment options. Identification of key protective and neutralizing
epitopes of mAbs (with Core C) also can inform immunogen design in Projects 1-3 through
reverse vaccinology approaches. In Aim 1, we will perform structural and function synergy studies
to determine the principles governing the selection of optimal mAb combination therapies against
the alphavirus, CHIKV. In Aim 2, we will use innovative computational approaches (with Core C)
to functionally mature the paratope-epitope interactions of human mAbs against DENV to
enhance potency and breadth. In Aim 3, we will perform a new discovery screening campaign to
identify potently neutralizing anti-WNV mAbs that can be partnered with a computationally
modified version of WNV-86 to enhance inhibitory potency and prevent neutralization escape. In
Aim 4, as a proof-of-concept, we will demonstrate the efficiency and applicability of our workflow
by performing a ‘sprint’ to rapidly identify an optimal combination therapy of potently neutralizing
mAbs against Mayaro virus, an emerging alphavirus with pandemic potential. Overall,
experiments in Project 5 will refine our understanding of the correlates of mAb protection against
flaviviruses and alphaviruses to enable the design of a modular ‘
plug-and-play’ workflow
that can
respond to potential pandemics by rapidly generating optimized combinations of mAbs.

## Key facts

- **NIH application ID:** 10863006
- **Project number:** 1U19AI181960-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** James E Crowe
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $5,594,501
- **Award type:** 1
- **Project period:** 2024-08-12 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863006

## Citation

> US National Institutes of Health, RePORTER application 10863006, Project 5: mAb Development Flaviviruses and Alphaviruses (1U19AI181960-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10863006. Licensed CC0.

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