Novel DNA-launched Venezuelan equine encephalitis virus vaccine with rearranged genome

Tretyakova, Irina; Tibbens, Alexander; Jokinen, Jenny D.; Johnson, Dylan M.; Lukashevich, Igor S.; Pushko, Peter

doi:10.1016/j.vaccine.2019.04.072

Cited by 27 publications

(37 citation statements)

References 48 publications

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“…VEEV TC-83 was obtained from U.S. Army Medical Research and Materiel Command (Fort Detrick, MD, USA), and amplified once in Vero cells. The pMG4020 plasmid for launching was previously described [33]. VEEV V4020 virus was prepared by electroporation of pMG4020 into Vero cells and the generated virus particles were concentrated by ultracentrifugation [33].…”

Section: Virusesmentioning

confidence: 99%

“…The pMG4020 plasmid for launching was previously described [33]. VEEV V4020 virus was prepared by electroporation of pMG4020 into Vero cells and the generated virus particles were concentrated by ultracentrifugation [33]. Virus titers were determined by infecting monolayers of Vero cells in 24-well tissue culture plates with serial dilutions of virus stocks for 1 h, followed by methylcellulose overlay.…”

Section: Virusesmentioning

confidence: 99%

“…Mice were weighted daily and assessed for signs of clinical disease on a 16-point scale as previously described [33]. Briefly, observation was based on grooming, adjusted grimace scale score, activity, and neurological responses including tail strength, hind leg strength, abdominal curl reflexes, and righting reflexes.…”

Section: Vaccine Replication Kinetics In Brain Tissuesmentioning

confidence: 99%

“…Substantial progress in alphavirus molecular virology and VEEV pathogenesis has provided a variety of powerful tools to address the safety and immunogenicity of the VEEV TC-83 vaccine. Recently, we have used several approaches to further improve the VEEV TC-83 vaccine: (i) infectious DNA (iDNA) technology to launch a live-attenuated vaccine in vivo [32]; (ii) rearrangement of alphavirus structural genes; and (iii) genetic stabilization of the TC-83-attenuated phenotype [33]. The novel V4020 experimental vaccine was rationally designed by securing the key TC-83 attenuating mutation (E2-T120A), along with a further improvement of attenuation by rearrangement of TC-83 structural genes [33].…”

Section: Introductionmentioning

confidence: 99%

“…In proof-of-concept studies, V4020 provided complete protection against wild-type VEEV TrD challenge, inducing sterilizing immunity in mice [33]. After a single dose of either subcutaneous live V4020 or electroporation with V4020 iDNA, one month later, BALB/c mice were protected from lethal challenge with VEEV-TrD [33]. Cynomolgus macaques, vaccinated with either a single dose or two doses of V4020, were aviremic following an aerosol challenge with VEEV TrD [34].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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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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Section: Virusesmentioning

confidence: 99%

Section: Virusesmentioning

confidence: 99%

Section: Vaccine Replication Kinetics In Brain Tissuesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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Use of Optical In Vivo Imaging to Monitor and Optimize Delivery of Novel Plasmid-Launched Live-Attenuated Vaccines

Sharma

Dallmeier

2021

Vaccine Design

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Plasmid-launched live-attenuated vaccines (PLLAV) are a modality of next-generation vaccines with the promise to combine the benefits of both (1) the potency of live vaccines and (2) the ease of production, quality control, and thermal stability of classical DNA vaccines. Using the live yellow fever 17D (YF17D) vaccine as paradigm, we establish a bioluminescence-based in vivo imaging approach that allows to rapidly monitor and optimize the dose and route of delivery of such PLLAV in a mouse model of YF17D immunization. Vaccine virus replication thus launched in the skin of vaccinated mice can be quantified by the light emitted, benchmarked to signals originating from a YF17D reporter virus and finally correlated to the induction of humoral immune responses to the yellow fever virus.

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Viruses as tools in gene therapy, vaccine development, and cancer treatment

et al. 2022

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Using viruses to our advantage has been a huge leap for humanity. Their ability to mediate horizontal gene transfer has made them useful tools for gene therapy, vaccine development, and cancer treatment. Adenoviruses, adeno-associated viruses, retroviruses, lentiviruses, alphaviruses, and herpesviruses are a few of the most common candidates for use as therapeutic agents or efficient gene delivery systems. Efforts are being made to improve and perfect viral-vector-based therapies to overcome potential or reported drawbacks. Some preclinical trials of viral vector vaccines have yielded positive results, indicating their potential as prophylactic or therapeutic vaccine candidates. Utilization of the oncolytic activity of viruses is the future of cancer therapy, as patients will then be free from the harmful effects of chemo- or radiotherapy. This review discusses in vitro and in vivo studies showing the brilliant therapeutic potential of viruses.

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Novel DNA-launched Venezuelan equine encephalitis virus vaccine with rearranged genome

Cited by 27 publications

References 48 publications

Advanced Safety and Genetic Stability in Mice of a Novel DNA-Launched Venezuelan Equine Encephalitis Virus Vaccine with Rearranged Structural Genes

Advanced Safety and Genetic Stability in Mice of a Novel DNA-Launched Venezuelan Equine Encephalitis Virus Vaccine with Rearranged Structural Genes

Use of Optical In Vivo Imaging to Monitor and Optimize Delivery of Novel Plasmid-Launched Live-Attenuated Vaccines

Viruses as tools in gene therapy, vaccine development, and cancer treatment

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