Venezuelan equine encephalitis vaccine with rearranged genome resists reversion and protects non-human primates from viremia after aerosol challenge

Tretyakova, Irina; Plante, Kenneth S.; Rossi, Shannan L.; Horowitz, Lawrence; Peel, Jennifer E; Gudjohnsen, Sif; Wang, Eryu; Mirchandani, Divya; Tibbens, Alexander; Lamichhane, Tek N.; Lukashevich, Igor S.; Comer, Jason E.; Weaver, Scott C.; Pushko, Peter

doi:10.1016/j.vaccine.2020.02.007

Cited by 22 publications

(21 citation statements)

References 65 publications

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“…Taken together, these results indicate that V4020 is a safer and genetically more stable alternative to TC-83. Successful testing of V4020 in a non-human primate aerosol challenge model provides an additional argument for the clinical development of this experimental vaccine [34].…”

Section: Discussionmentioning

confidence: 99%

“…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]. Here, we compared the safety and genetic stability of V4020 and TC-83 in viral replication kinetics studies in brain tissues, and then assessed the potential to revert to a pathogenic phenotype during passages of the vaccines in mice.…”

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Data curated from literature reported through February 2021. Numbers in superscript refer to reference numbers (See Reference list [ 23 , 73 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 ,…”

Section: Figurementioning

confidence: 99%

Insights into Antibody-Mediated Alphavirus Immunity and Vaccine Development Landscape

Torres‐Ruesta

Chee

2021

Microorganisms

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Alphaviruses are mosquito-borne pathogens distributed worldwide in tropical and temperate areas causing a wide range of symptoms ranging from inflammatory arthritis-like manifestations to the induction of encephalitis in humans. Historically, large outbreaks in susceptible populations have been recorded followed by the development of protective long-lasting antibody responses suggesting a potential advantageous role for a vaccine. Although the current understanding of alphavirus antibody-mediated immunity has been mainly gathered in natural and experimental settings of chikungunya virus (CHIKV) infection, little is known about the humoral responses triggered by other emerging alphaviruses. This knowledge is needed to improve serology-based diagnostic tests and the development of highly effective cross-protective vaccines. Here, we review the role of antibody-mediated immunity upon arthritogenic and neurotropic alphavirus infections, and the current research efforts for the development of vaccines as a tool to control future alphavirus outbreaks.

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“…Vaccinated mice were protected against challenges with wildtype VEE, while all control mice died. The VEE V4020 vaccine was also evaluated in intramuscularly immunized cynomolgus macaques showing high levels of virus-neutralizing antibodies and protection against aerosol challenges with wildtype VEE [86].…”

Section: Lundstrommentioning

confidence: 99%

The Potential of Self-amplifying RNA Vaccines for Infectious Diseases and COVID-19

Lundström

2020

vacres

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In addition to conventional vaccine development for infectious diseases, nucleic acidbased vaccine approaches have recently been presented as serious alternatives to previously used strategies based on live attenuated virus particles and subunit vaccines. Particularly, RNA-based vaccines have proven attractive. In this context, immunization with messenger RNA (mRNA) has provided strong immune responses and protection against challenges with lethal doses of pathogenic viruses in vaccinated animals. Alternatively, the efficient RNA replication mechanism provided by self-amplifying RNA (saRNA) viruses has been utilized. Enhanced immune responses with reduced doses required for immunization has been obtained in comparison to conventional mRNA administration. The rapid spread and destruction caused by the COVID-19 pandemic has substantially accelerated the demand for the development of robust and efficient vaccines against SARS-CoV-2. Both mRNA-and saRNA-based COVID-19 vaccine candidates are currently in human clinical trials.

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Venezuelan equine encephalitis vaccine with rearranged genome resists reversion and protects non-human primates from viremia after aerosol challenge

Cited by 22 publications

References 65 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

Insights into Antibody-Mediated Alphavirus Immunity and Vaccine Development Landscape

The Potential of Self-amplifying RNA Vaccines for Infectious Diseases and COVID-19

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