# Human Monoclonal Antibodies for Encephalitic Alphaviruses

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $858,139

## Abstract

SUMMARY:
Eastern equine encephalitis virus (EEEV) is a re-emerging mosquito-borne alphavirus that causes a debilitating
encephalitic illness in humans. About a third of human cases of EEEV infection die and many survivors have
long-term, debilitating neurologic problems. The virus is maintained in an enzootic cycle between Culiseta
melanura mosquitoes and avian hosts but can be transmitted to humans and horses by
some Aedes, Coquillettidia, and Culex species. The infection is unusual in humans but increasing in frequency
in recent years, likely secondary to climate changes, vector expansion, and other uncharacterized factors. EEEV
also is regarded as a potential bioterrorism threat due to spread via aerosol route. Despite the highly pathogenic
nature of the virus, no specific treatment or vaccine for EEEV is available. A primary goal of this project is to
define the molecular, genetic, immunologic, and structural characteristics of ultra-potent neutralizing human
mAbs with broad activity in vivo against EEEV. Additional goals include defining the mechanistic correlates of
protection by these ultra-potent neutralizing mAbs and determining ways to optimize function and deliver to the
brain. In these studies, we will elucidate how antiviral Abs with exceptional inhibitory activity exert their action in
cell culture and in vivo. The approach will include high efficiency isolation of human mAbs, coupled with
innovative antibody gene repertoire studies based on next-gen sequencing. Several hypotheses will be tested,
including the concept that ultra-potent neutralizing activity results from features of both the antibodies (selection
of optimal V-D-J clonotypes and accumulation of critical somatic mutations) and the antigen (binding to
quaternary epitopes on multiple adjacent envelope proteins and blockade of structural transitions critical for virus
entry or release). We also will apply new technologies for receptor-mediated transfer of molecules across the
blood-brain barrier using engineered sequence changes in the Fc region. Although our focus is to understand
how and why ultra-potent human mAbs inhibit EEEV, the studies likely will be relevant to general principles of
antibody neutralization of many different encephalitic viruses. In addition to defining the molecular and structural
basis of Ab neutralization of EEEV and deploying new strategies for delivery of biologics to the brain, these
studies will generate a group of fully human mAbs that can prevent and treat EEEV infection, which could be
developed in the near future as a possible therapeutic for humans. Studies in this project, while targeted against
EEEV, likely will inform future Ab-based and/or vaccine efforts against other arboviruses that cause human brain
infections. We have assembled a unique group of investigators, including a human Ab expert, a molecular
virologist with experience in Ab-virus interactions, an animal model and pathogenesis expert with specific
expertise in encephali...

## Key facts

- **NIH application ID:** 10539155
- **Project number:** 1R01AI172156-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** James E Crowe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $858,139
- **Award type:** 1
- **Project period:** 2022-07-20 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539155

## Citation

> US National Institutes of Health, RePORTER application 10539155, Human Monoclonal Antibodies for Encephalitic Alphaviruses (1R01AI172156-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10539155. Licensed CC0.

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