# Project 1: Vaccine Design Neurotropic Flaviviruses

> **NIH NIH U19** · WASHINGTON UNIVERSITY · 2024 · $4,728,047

## Abstract

SUMMARY
Emerging and re-emerging arthropod-vectored viruses pose a significant threat to human health. Tick- and
mosquito-transmitted viruses can cause encephalitis and hemorrhagic fever leading to significant morbidity and
mortality. West Nile virus (WNV), tick-borne encephalitis virus (TBEV), and Zika virus (ZIKV) all have tropism for
neuronal cells, which can lead to infection and injury in the central nervous system. Several emerging and re-
emerging neurotropic flaviviruses represent a growing health concern due to their epidemic potential. New
rational immunogen design strategies are necessary to elicit protective responses that confer durable protection
against current and future flavivirus threats. Project 1 of our Flavivirus and Alphavirus ReVAMPP (FLARE)
Center uses iterative immunogen design cycles to develop, optimize, and advance next-generation vaccine
candidates using WNV and TBEV as prototype neurotropic flaviviruses. Our approaches focus on the major
surface envelope (E) glycoprotein, and we hypothesize that the structural conservation of the E glycoprotein will
enable a ‘plug and play’ modular workflow of immunogen and vaccine platform pairs that can be deployed for
other emerging or re-emerging neurotropic flaviviruses. In Aim 1, we design protein-based nanoparticles for
multivalent display of E-subdomains, E-DI and E-DIII. In Aim 2, we use protein engineering strategies to
covalently and non-covalently stabilize E dimers to display complex, conformation-specific epitopes present on
the virion that are the target of potently neutralizing and protective immune responses. In Aim 3, we implement
two immune-focusing strategies, epitope scaffolding and hyperglycosylation, to elicit responses to conserved E-
DIII epitopes. Initial down-selection will occur using protein-based immunogens with some candidates advancing
to mRNA-based delivery with our industry partner, Moderna. Vaccine candidates will be tested for
immunogenicity, antigenicity, and immune focusing with optimal candidates advancing to protection studies
using lethal WNV and TBEV murine challenge models in Aim 4. After down-selection and rigorous Go/No-Go
decision criteria, the top vaccine candidates will be transitioned to Animal Core D for further evaluation in mice
and non-human primates. Project 1 will work closely with Structural Core C to accomplish these objectives and
is conceptually and scientifically linked to FLARE Projects 2 and 3, which are focused on endemic flaviviruses
and alphaviruses, respectively.

## Key facts

- **NIH application ID:** 10863002
- **Project number:** 1U19AI181960-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Aaron Gregory Schmidt
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $4,728,047
- **Award type:** 1
- **Project period:** 2024-08-12 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863002

## Citation

> US National Institutes of Health, RePORTER application 10863002, Project 1: Vaccine Design Neurotropic Flaviviruses (1U19AI181960-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10863002. Licensed CC0.

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