# Project 3: Peribunyaviridae Pathogenesis and Vaccine Testing

> **NIH NIH U19** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $3,842,980

## Abstract

Project Summary/Abstract – Project 3: Peribunyaviridae Pathogenesis and Vaccine Testing
The orthobunyaviruses (OBVs) of Peribunyviridae cause disease in humans manifesting with fever, nausea,
fatigue, and viral encephalitis, as well as long-term neurological complications. Identifying receptors and immune
factors mediating infection will highlight additional avenues of therapeutic development to work in tandem with
vaccination efficacy approaches. As these viruses are increasing in prevalence and vector range, their emergent
potential is high, and there is a critical need to better understand their pathogenesis and develop safe and
effective vaccines against OBVs. As part of this U19, this project will focus on identifying additional vaccine
targets while validating protein-adjuvant and mRNA vaccines developed in Projects 1 and 2. Importantly, these
studies will define both acute and long-term correlates of protection. The long-term goals are to 1) validate
immunogenic, multi-platform vaccines for OBVs, targeting LACV, OROV, and CVV as representative viruses; 2)
delineate mechanisms of OBV pathogenesis; and 3), define the role vaccines play in preventing sequelae. This
will test the hypothesis that 1) differential cytokine expression drives early and late stage OBV disease, 2)
vaccination prevents both acute and long-term effects of infection, and 3) OBVs exploit conserved receptors for
entry into the CNS. The first aim will define host immune responses to OBV infection in vivo. To determine
early and late-stage host immune responses to OBV infection, we will assess innate and adaptive immunity in
humanized immuno-competent and -compromised mouse models after infection with LACV, OROV, or CVV.
Serum cytokine levels, regulation of immune signaling genes, and histopathology will be assessed. This will
define key immunological mechanisms of protection against OBV infection and highlight avenues for additional
therapeutic development. The second aim will assess short and long-term protection against OBV infection
with adjuvanted subunit and mRNA vaccines in vivo. Adjuvanted subunit vaccines and mRNA vaccines
targeting Gc/Gn and NP antigens will be tested for protection against short- and long-term OBV outcomes in
animal models to identify lead vaccine candidates. MRI and behavioral analyses will be applied to understand
vaccine protection against disease sequelae. The third aim will identify conserved host cell receptors for
OBV attachment and entry mediating CNS tropism. The Antibody Generation, Epitope Mapping, and Machine
Learning Core will provide computational interaction screening, after which candidates will be verified in
permissive CNS cells and mouse models. Promising receptors will be blocked with inhibitors and knocked out
by CRISPR/Cas9 with subsequent infectivity measured in mouse and brain co-culture systems. Receptor
deficient mice will also be evaluated for changes in viral replication. Mouse models of severe infection will be
treate...

## Key facts

- **NIH application ID:** 10863344
- **Project number:** 1U19AI181968-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Shannon Ronca
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $3,842,980
- **Award type:** 1
- **Project period:** 2024-08-20 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863344

## Citation

> US National Institutes of Health, RePORTER application 10863344, Project 3: Peribunyaviridae Pathogenesis and Vaccine Testing (1U19AI181968-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10863344. Licensed CC0.

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