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Advanced Safety and Genetic Stability in Mice of a Novel DNA-Launched Venezuelan Equine Encephalitis Virus Vaccine with Rearranged Structural Genes.
Johnson, Dylan M; Sokoloski, Kevin J; Jokinen, Jenny D; Pfeffer, Tia L; Chu, Yong-Kyu; Adcock, Robert S; Chung, Donghoon; Tretyakova, Irina; Pushko, Peter; Lukashevich, Igor S.
Afiliação
  • Johnson DM; Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
  • Sokoloski KJ; Center for Predictive Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
  • Jokinen JD; Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
  • Pfeffer TL; Center for Predictive Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
  • Chu YK; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
  • Adcock RS; Center for Predictive Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
  • Chung D; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
  • Tretyakova I; Center for Predictive Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
  • Pushko P; Center for Predictive Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
  • Lukashevich IS; Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Vaccines (Basel) ; 8(1)2020 Mar 02.
Article em En | MEDLINE | ID: mdl-32121666
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies País/Região como assunto: America do sul / Venezuela Idioma: En Revista: Vaccines (Basel) Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Suíça
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies País/Região como assunto: America do sul / Venezuela Idioma: En Revista: Vaccines (Basel) Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Suíça