# Engineering high fidelity mutations to increase safety of live-attenuated alphavirus vaccines

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $538,306

## Abstract

Project Summary
Live-attenuated vaccines are the gold standard for preventing viral illness but they can
revert to virulence, sometimes causing severe or fatal disease. The mosquito-borne
alphaviruses chikungunya (CHIKV) and Venezuelan equine encephalitis (VEEV) are
RNA viruses that produce a debilitating arthritic syndrome or encephalitis, respectively.
Both have repeatedly emerged to produce millions of human cases worldwide and
CHIKV has expanded into the Americas since 2013, indicating increasing need for
vaccines. Although live-attenuated candidate human vaccines have been developed for
both viruses, no licensed vaccines currently exist, in part due to adverse events in
clinical trials caused by revertant mutations. There is therefore a need to increase the
genetic stability of live-attenuated virus vaccine candidates to improve safety. The goal
of this project is to develop safe and effective CHIKV and VEEV vaccines to
prevent millions of human infections globally each year. Virus variants that mutate
less frequently would accrue fewer mutations that confer virulence, and may therefore
serve as safer live-attenuated vaccine candidates. This project will use high fidelity
variants we already identified and characterized inserted into candidate CHIKV and
VEEV vaccines to understand: 1) stability, infectivity, and potential for reversion; 2)
whether incorporation of high fidelity mutations improves vaccine safety while
maintaining or increasing immunogenicity in established mouse models; and 3)
mechanism(s) of attenuation. This approach represents the first use of fidelity
modulation to increase safety of live alphavirus vaccine candidates. If successful, this
strategy will potentially lead to a broader application of fidelity variants in improving
vaccine safety that can be used for other live-attenuated alphavirus vaccine platforms
and possibly other RNA viruses.

## Key facts

- **NIH application ID:** 9925764
- **Project number:** 5R01AI125902-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Lark L Coffey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $538,306
- **Award type:** 5
- **Project period:** 2016-06-20 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925764

## Citation

> US National Institutes of Health, RePORTER application 9925764, Engineering high fidelity mutations to increase safety of live-attenuated alphavirus vaccines (5R01AI125902-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9925764. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*