Advanced safety and genetic stability in mice of a novel dna-launched venezuelan equine encephalitis virus vaccine with rearranged structural genes

Dylan M. Johnson, Kevin J. Sokoloski, Jenny D. Jokinen, Tia L. Pfeffer, Yong Kyu Chu, Robert S. Adcock, Donghoon Chung, Irina Tretyakova, Peter Pushko, Igor S. Lukashevich

Research output: Contribution to journalArticle

Abstract

The safety and genetic stability of V4020, a novel Venezuelan Equine Encephalitis Virus (VEEV) vaccine based on the investigational VEEV TC-83 strain, was evaluated in mice. V4020 was generated from infectious DNA, contains a stabilizing mutation in the E2-120 glycoprotein, and includes rearrangement of structural genes. After intracranial inoculation (IC), replication of V4020 was more attenuated than TC-83, as documented by low clinical scores, inflammation, viral load in brain, and earlier viral clearance. During the first 9 days post-inoculation (DPI), genes involved in inflammation, cytokine signaling, adaptive immune responses, and apoptosis were upregulated in both groups. However, the magnitude of upregulation was greater in TC-83 than V4020 mice, and this pattern persisted till 13 DPI, while V4020 gene expression profiles declined to mock-infected levels. In addition, genetic markers of macrophages, DCs, and microglia were strongly upregulated in TC-83 mice. During five serial passages in the brain, less severe clinical manifestations and a lower viral load were observed in V4020 mice and all animals survived. In contrast, 13.3% of mice met euthanasia criteria during the passages in TC-83 group. At 2 DPI, RNA-Seq analysis of brain tissues revealed that V4020 mice had lower rates of mutations throughout five passages. A higher synonymous mutation ratio was observed in the nsP4 (RdRP) gene of TC-83 compared to V4020 mice. At 2 DPI, both viruses induced different expression profiles of host genes involved in neuro-regeneration. Taken together, these results provide evidence for the improved safety and genetic stability of the experimental V4020 VEEV vaccine in a murine model.

Original languageEnglish (US)
Article number114
JournalVaccines
Volume8
Issue number1
DOIs
StatePublished - Mar 2020
Externally publishedYes

Keywords

  • DNA vaccine
  • Gene rearrangement
  • Genetic stability
  • Live-attenuated vaccine
  • Reversion
  • Safety
  • Venezuelan equine encephalitis virus

ASJC Scopus subject areas

  • Immunology
  • Pharmacology
  • Drug Discovery
  • Infectious Diseases
  • Pharmacology (medical)

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  • Cite this

    Johnson, D. M., Sokoloski, K. J., Jokinen, J. D., Pfeffer, T. L., Chu, Y. K., Adcock, R. S., Chung, D., Tretyakova, I., Pushko, P., & Lukashevich, I. S. (2020). Advanced safety and genetic stability in mice of a novel dna-launched venezuelan equine encephalitis virus vaccine with rearranged structural genes. Vaccines, 8(1), [114]. https://doi.org/10.3390/vaccines8010114