{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T03:27:40Z","timestamp":1788319660082,"version":"build-2803163510"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NIAID","award":["AI155406"],"award-info":[{"award-number":["AI155406"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>There is a need for safe and effective vaccines against the Venezuelan equine encephalitis virus that infects both humans and equines. However, development of a live-attenuated vaccine using the TC-83 strain has been hampered by substantial reactogenicity and the potential for neuroinvasion. In this study, we demonstrate that V4020, a new TC-83-based investigational VEEV vaccine with redundant safety features preventing neuroinvasion and reversion, exhibited no neuroinvasion potential in a murine model. Following subcutaneous or intramuscular administration, a subset of mice that received the TC-83 vaccine succumbed to central nervous system infection, with replicating virus detected in the CNS, demonstrating a low, yet detectable neuroinvasion potential of the TC-83 vaccine in vivo. Sequencing analysis of the TC-83 virus recovered from the brains identified a pseudoreversion of E2 R120I, as E2 R120 is known to confer attenuation for TC-83. In contrast, V4020 showed no evidence of virus in the CNS, highlighting one of the V4020 features, a new synonymous codon to minimize reversion to the wild-type residue. Overall, our study establishes V4020 as a rationally designed, safe vaccine candidate for VEEV with significantly reduced neuroinvasion risk.<\/jats:p>","DOI":"10.3390\/v17081136","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T13:08:51Z","timestamp":1755608931000},"page":"1136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["V4020 Venezuelan Equine Encephalitis Vaccine: Mitigating Neuroinvasion and Reversion Through Rational Design"],"prefix":"10.3390","volume":"17","author":[{"given":"Adrian","family":"Centers","sequence":"first","affiliation":[{"name":"School of Medicine, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2581-1591","authenticated-orcid":false,"given":"Koji","family":"Barnaby","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidney","family":"Goedeker","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9978-8744","authenticated-orcid":false,"given":"Ava","family":"Pignataro","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Tretyakova","sequence":"additional","affiliation":[{"name":"Medigen, Inc., 8420-S Gas House Pike, Frederick, MD 21701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6523-5116","authenticated-orcid":false,"given":"Igor","family":"Lukashevich","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1073-6981","authenticated-orcid":false,"given":"Peter","family":"Pushko","sequence":"additional","affiliation":[{"name":"Medigen, Inc., 8420-S Gas House Pike, Frederick, MD 21701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2626-172X","authenticated-orcid":false,"given":"Donghoon","family":"Chung","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Louisville, 505 S. 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