Vaccinia virus (VV) has many attractive characteristics as a potential cancer therapeutic. There are several strains of VV. The nonvaccine strain Western Reserve VV with deletion of both the thymidine kinase and the viral growth factor genes (known as WRDD) has been reported as the most potent tumor-targeted oncolytic VV. Other strains, such as the European vaccine Lister strain, are largely untested. This study evaluated the antitumor potency and biodistribution of different VV strains using in vitro and in vivo models of cancer. Lister strain virus with thymidine kinase gene deletion (VVΔTK) demonstrated superior antitumor potency and cancer-selective replication in vitro and in vivo, compared with WRDD, especially in human cancer cell lines and immune-competent hosts. Further investigation of functional mechanisms revealed that Lister VVΔTK presented favorable viral biodistribution within the tumors, with lower levels of proinflammatory cytokines compared with WRDD, suggesting that Lister strain may induce a diminished host inflammatory response. This study indicates that the Lister strain VVΔTK may be a particularly promising VV strain for the development of the next generation of tumor-targeted oncolytic therapeutics.

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Immunogenicity and relative attenuation were examined for the following Tian Tan strain vaccinia-rabies recombinant viruses: 1) NGc-1, which coexpresses the glycoprotein (G) and nucleocapsid protein (N) of the rabies virus Challenge Virus Standard (CVS) strain; 2) Nc-1, which expresses the CVS N; 3) Gc-2, Gc-3, Gc-4, and Gc-5, which express CVS G via promoters from different vaccinia strains or from different vaccinia genome loci; 4) Ga-1, which expresses the G of rabies virus strain aG; and 5) Gas-1; which expresses the carboxyltruncated G ectodomain (Gs) of strain aG. All but Nc-1 and Gas-1 induced rabies virus neutralizing antibodies (VNAs) and protected groups of mice at very high frequencies from intramuscular (IM) or intracranial (IC) challenge with CVS or SW1 Shanghai dog street rabies virus (SRV); Nc-1 and Gas-1 were partly protective, more frequently against IM challenge. NGc-1 and Gc-5 appeared to induce high levels of VNAs sooner after immunization than the other constructs in mice. Relative attenuation assessed by IM infection of neonatal mice, IC infection of adult mice, and intradermal infection of rabbits with varying doses was best for NGc-1. All the recombinants were at least 100-fold more attenuated than the parent, Tian Tan vaccinia virus. Gc-2, Gc-3, Gc-4, Gc-5, and NGc-1 induced VNAs after immunization of dogs, and a subset of VNA-positive animals vaccinated with NGc-1 or Gc-3 were protected against an otherwise lethal IM injection of SRV at 21 days after vaccination.

Several temporal genes, including TGFβ2, TGFβ3, ALDH2, ALDH3A2, ARG1 and NOS3, might be involved in SCI.