Venezuelan Equine Encephalitis Virus V3526 Vaccine RNA-Dependent RNA Polymerase Mutants Increase Vaccine Safety Through Restricted Tissue Tropism in a Mouse Model

Clint A. Haines, Rafael K. Campos, Sasha Azar, K. Lane Warmbrod, Tiffany F. Kautz, Naomi Forrester, Shannan Rossi

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: Venezuelan equine encephalitis virus (VEEV) is an arbovirus endemic to the Americas, for which no vaccines or antiviral agents have been approved. TC-83 and V3526 are the best-characterized vaccine candidates for VEEV. Both are live-attenuated vaccines and have been associated with safety concerns, although fewer concerns exist for V3526. A previous attempt to improve the TC-83 vaccine focused on further attenuating the vaccine by adding mutations that alter the error-incorporation rate of the RNA-dependent RNA polymerase (RdRp). Methods: The research herein examined the effects of these RdRp mutations in V3526 by cloning the 3X and 4X strains, assessing vaccine efficacy against challenge in adult female CD-1 mice, examining neutralizing-antibody titers, investigating vaccine tissue tropism, and testing the stability of the mutant strains. Results: The V3526 RdRp mutants exhibited less tissue tropism in the spleen and kidney than the wild-type V3526, while maintaining vaccine efficacy. Illumina sequencing indicated that the RdRp mutations reverted to wild-type V3526 after five passages in murine pup brains. Conclusions: The observed genotypic reversion is likely to be of limited concern, because wild-type V3526 remains an effective vaccine capable of providing protection. Our results indicate that the V3526 RdRp mutants may be a safer vaccine design than the original V3526.

Original languageEnglish (US)
Article number2
JournalZoonoses (Ireland)
Volume2
Issue number1
DOIs
StatePublished - Jan 6 2022

Keywords

  • fidelity
  • TC-83
  • V3526
  • vaccine
  • Venezuelan equine encephalitis virus

ASJC Scopus subject areas

  • Infectious Diseases
  • veterinary (miscalleneous)

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