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 old taylor whiskey 1933 price 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, 9002nc 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.