# An Informed Approach to Live Attenuated Vaccines against Encephalitis Alphaviruses

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $472,242

## Abstract

ABSTRACT
Eastern (EEEV), Venezuelan (VEEV), and Western (WEEV) equine encephalitis viruses
are mosquito-transmitted alphaviruses with the potential to cause fatal neuroinvasive
disease in humans and domesticated animals. These viruses also can be spread by the
aerosol route and thus, have significant potential as biowarfare/bioterrorism agents. In
2019, EEEV human infections increased to levels not seen since the 1950s. Currently,
there are no antiviral therapies or vaccines licensed for these alphaviruses. The existing
investigational live-attenuated VEEV vaccine (LAV; TC-83) was generated >40 years
ago, is highly reactogenic, poorly immunogenic, and causes disease in up to 20% of
recipients. For EEEV and WEEV, investigational formalin-inactivated vaccines have
been given to at-risk workers. While both elicit antibody responses, they provide
uncertain protection and require multiple booster injections. A trivalent veterinary vaccine
against VEEV, EEEV and WEEV is available but is so poorly immunogenic that domestic
animals must be boosted annually and disease is seen in vaccinated animals. Here, we
propose to develop safe and effective LAVs vaccine against these alphaviruses using
recent advances in understanding of the virulence mechanisms of each. These
advances will allow mutagenesis of pathogenicity domains that specifically reduce
virulence, increase cytokine induction and antigen presentation and provide long-lasting
protection. Furthermore, the mechanism of action of each mutation will be known and
each will be specifically designed to resist reversion. We will combine mutations to
create an optimal vaccine strain for each virus and then investigate their use in
multivalent formulations, critical to veterinary vaccine development and highly desired for
human formulations. We will identify correlates of protection for each vaccine and
address the extent of cross-protection versus encephalitic viruses. For the first time with
alphaviruses, the individual and combined effects of mutations with known mechanisms
of action will be tested for effects on virus replication, disease and immunogenicity in
animals.

## Key facts

- **NIH application ID:** 10027464
- **Project number:** 1R01AI153209-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** WILLIAM B KLIMSTRA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $472,242
- **Award type:** 1
- **Project period:** 2020-06-12 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10027464

## Citation

> US National Institutes of Health, RePORTER application 10027464, An Informed Approach to Live Attenuated Vaccines against Encephalitis Alphaviruses (1R01AI153209-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10027464. Licensed CC0.

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