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Vaccine Detail

dVV-L
Vaccine Information
  • Vaccine Name: dVV-L
  • Target Pathogen: Variola virus
  • Target Disease: Smallpox
  • Vaccine Ontology ID: VO_0004094
  • Type: Live, attenuated vaccine
  • p53 gene engineering:
    • Type: Protein
    • Description: Tumor suppressor protein p53, a nuclear protein, plays an essential role in the regulation of cell cycle, specifically in the transition from G0 to G1. It is found in very low levels in normal cells; however, in a variety of transformed cell lines, it is expressed in high amounts and is believed to contribute to transformation and malignancy. p53 is a DNA-binding protein containing DNA-binding, oligomerization, and transcription activation domains. It is postulated to bind as a tetramer to a p53-binding site and activate expression of downstream genes that inhibit growth and/or invasion and thus function as a tumor suppressor. Mutants of p53 that frequently occur in a number of different human cancers fail to bind the consensus DNA binding site and hence cause the loss of tumor suppressor activity. Alterations of the TP53 gene occur not only as somatic mutations in human malignancies, but also as germline mutations in some cancer-prone families with Li-Fraumeni syndrome (Ober et al., 2002).
    • Detailed Gene Information: Click Here.
  • Adjuvant: complete Freunds adjuvant
  • Adjuvant: incomplete Freunds adjuvant
  • Preparation: This vaccine strain was created from the Lister strain by deleting a gene necessary to encode the UDG enzyme, which is essential for a complete cycle of viral replication (Parrino et al., 2006).
  • Virulence: The vaccinia virus strain NYVAC was genetically attenuated by deletion of many nonessential genes, including virulence and host range genes, resulting in a strain growing only in primary cells. Passaging in mammalian cells increases virulence in mammals, resulting in new MVA-like strains with unknown safety profiles in humans. The resulting viruses grow exclusively in a complementing permanent cell line, excluding reversion to virulence and obviating the need for primary cells. The WR strain is a vaccinia virus laboratory strain passaged in mouse brain that has unfavorable properties, such as neurovirulence and gonadotropism, not suitable for clinical use. The large deletions characteristic for MVA seemed to suggest that the restriction in host range and virulence was mainly due to these deletions, including the loss of a host range gene and many immune modulatory genes. It will be interesting to see whether an MVA strain first adapted to growth in mammalian cells and then passaged in mouse brain also regains virulence. In contrast to MVA, dVVs with an essential gene deleted cannot regain replication and virulence functions upon passaging in a chosen host. Reversion to virulence can principally be excluded because the vector lacks an essential gene, which restricts its host range to a complementing cell line (Ober et al., 2002).
  • Description: dVV-L has been evaluated as a poxvirus vaccine. One great advantage of this approach is that the attenuated virus can be manufactured in a cell line that complements the uracil-DNA-glycosylase (UDG) deficiency, rather than in primary cells or eggs as is often needed for other replication-defective viruses, resulting in an improved safety profile and increased capacity for rapid production (Parrino et al., 2006).
Host Response

Mouse Response

  • Host Strain: Mice (BALB/c/SCID, 6 to 8 weeks old).
  • Vaccination Protocol: Groups of four immunodeficient mice were challenged subcutaneously (s.c.) with high doses of the wild-type Lister strain or the nonreplicating Lister- or MVA-based vectors (Ober et al., 2002).
  • Persistence: Using the wild-type Lister virus, doses of ≥106 PFU led to a progressive vaccinia virus infection within a 2-month observation period (Ober et al., 2002).
  • Side Effects: The defective Lister strain-based viruses did not induce any signs of progressive disease. The nonreplicating virus was tolerated without any visible signs of discomfort of the mice at doses of 107 and 108 PFU. The highest dose of 109 PFU was accompanied by mild signs of sickness in the first few days, which disappeared later. At 4 weeks after challenge a lesion was observed at the injection site, which subsequently healed. In summary, not only in the in vitro system but also in vivo in immunodeficient animals, dVVs based on the Lister strain are as well tolerated as the MVA-based viruses (Ober et al., 2002).
  • Efficacy: A more suitable smallpox prevaccine for immunocompromised subjects, dVV was highly protective in a preclinical challenge model, induced antibodies and CTLs similarly to MVA, and was as safe as MVA-based recombinants in immunodeficient mice. In addition, reversion to virulence can principally be excluded because the vector lacks an essential gene, which restricts its host range to a complementing cell line (Ober et al., 2002).
  • Description: The main concern about the use of replication-competent viruses in immunotherapy is that severe adverse effects may occur in immunocompromised patients. The mouse model was used to more thoroughly address the safety question in an in vivo model (Ober et al., 2002).
References
Ober et al., 2002: Ober BT, Bruhl P, Schmidt M, Wieser V, Gritschenberger W, Coulibaly S, Savidis-Dacho H, Gerencer M, Falkner FG. Immunogenicity and safety of defective vaccinia virus lister: comparison with modified vaccinia virus Ankara. Journal of virology. 2002 Aug; 76(15); 7713-23. [PubMed: 12097585].
Parrino et al., 2006: Parrino J, Graham BS. Smallpox vaccines: Past, present, and future. The Journal of allergy and clinical immunology. 2006 Dec; 118(6); 1320-6. [PubMed: 17157663 ].