1887

Abstract

Vectors based on vaccinia virus (VACV), the vaccine used to eradicate smallpox, are currently popular candidates for the vaccination against numerous infectious diseases including malaria and AIDS. Although VACV induces robust cellular and humoral responses, enhancing the safety and efficacy of these vectors remains an important area of research. Here, we describe the enhanced immunogenicity of a recombinant VACV Western Reserve (WR) strain lacking the immunomodulatory protein C6 (vΔC6). Intradermal infection of mice with vΔC6 was shown previously to induce smaller lesions, indicating viral attenuation, and this was confirmed here using a different inoculation dose. In addition, data presented show that vaccination with vΔC6 provided better protection against challenge with a lethal dose of VACV WR, indicating this virus is a better vaccine. Increased protection was not due to improved humoral responses, but instead enhanced cytotoxic activity of T-cells 1 month post-inoculation in the spleens of vΔC6-vaccinated mice.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.049700-0
2013-05-01
2020-01-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/94/5/1121.html?itemId=/content/journal/jgv/10.1099/vir.0.049700-0&mimeType=html&fmt=ahah

References

  1. Assarsson E. , Greenbaum J. A. , Sundström M. , Schaffer L. , Hammond J. A. , Pasquetto V. , Oseroff C. , Hendrickson R. C. , Lefkowitz E. J. . & other authors ( 2008; ). Kinetic analysis of a complete poxvirus transcriptome reveals an immediate-early class of genes. . Proc Natl Acad Sci U S A 105:, 2140–2145. [CrossRef] [PubMed]
    [Google Scholar]
  2. Bennink J. R. , Yewdell J. W. , Smith G. L. , Moller C. , Moss B. . ( 1984; ). Recombinant vaccinia virus primes and stimulates influenza haemagglutinin-specific cytotoxic T cells. . Nature 311:, 578–579. [CrossRef] [PubMed]
    [Google Scholar]
  3. Blanchard T. J. , Alcami A. , Andrea P. , Smith G. L. . ( 1998; ). Modified vaccinia virus Ankara undergoes limited replication in human cells and lacks several immunomodulatory proteins: implications for use as a human vaccine. . J Gen Virol 79:, 1159–1167.[PubMed]
    [Google Scholar]
  4. Clark R. H. , Kenyon J. C. , Bartlett N. W. , Tscharke D. C. , Smith G. L. . ( 2006; ). Deletion of gene A41L enhances vaccinia virus immunogenicity and vaccine efficacy. . J Gen Virol 87:, 29–38. [CrossRef] [PubMed]
    [Google Scholar]
  5. Cottingham M. G. , Andersen R. F. , Spencer A. J. , Saurya S. , Furze J. , Hill A. V. , Gilbert S. C. . ( 2008; ). Recombination-mediated genetic engineering of a bacterial artificial chromosome clone of modified vaccinia virus Ankara (MVA). . PLoS ONE 3:, e1638. [CrossRef] [PubMed]
    [Google Scholar]
  6. Delaloye J. , Roger T. , Steiner-Tardivel Q. G. , Le Roy D. , Knaup Reymond M. , Akira S. , Petrilli V. , Gomez C. E. , Perdiguero B. . & other authors ( 2009; ). Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. . PLoS Pathog 5:, e1000480. [CrossRef] [PubMed]
    [Google Scholar]
  7. Fahy A. S. , Clark R. H. , Glyde E. F. , Smith G. L. . ( 2008; ). Vaccinia virus protein C16 acts intracellularly to modulate the host response and promote virulence. . J Gen Virol 89:, 2377–2387. [CrossRef] [PubMed]
    [Google Scholar]
  8. Falivene J. , Del Médico Zajac M. P. , Pascutti M. F. , Rodríguez A. M. , Maeto C. , Perdiguero B. , Gómez C. E. , Esteban M. , Calamante G. , Gherardi M. M. . ( 2012; ). Improving the MVA vaccine potential by deleting the viral gene coding for the IL-18 binding protein. . PLoS ONE 7:, e32220. [CrossRef] [PubMed]
    [Google Scholar]
  9. Fenner F. , Anderson D. A. , Arita I. , Jezek Z. , Ladnyi I. D. . ( 1988; ). Smallpox and its Eradication. Geneva:: World Health Organisation;.
    [Google Scholar]
  10. Fujita F. , Taniguchi Y. , Kato T. , Narita Y. , Furuya A. , Ogawa T. , Sakurai H. , Joh T. , Itoh M. . & other authors ( 2003; ). Identification of NAP1, a regulatory subunit of IκB kinase-related kinases that potentiates NF-κB signaling. . Mol Cell Biol 23:, 7780–7793. [CrossRef] [PubMed]
    [Google Scholar]
  11. García-Arriaza J. , Nájera J. L. , Gómez C. E. , Tewabe N. , Sorzano C. O. , Calandra T. , Roger T. , Esteban M. . ( 2011; ). A candidate HIV/AIDS vaccine (MVA-B) lacking vaccinia virus gene C6L enhances memory HIV-1-specific T-cell responses. . PLoS ONE 6:, e24244. [CrossRef] [PubMed]
    [Google Scholar]
  12. Gómez C. E. , Nájera J. L. , Krupa M. , Esteban M. . ( 2008; ). The poxvirus vectors MVA and NYVAC as gene delivery systems for vaccination against infectious diseases and cancer. . Curr Gene Ther 8:, 97–120. [CrossRef] [PubMed]
    [Google Scholar]
  13. Gómez C. E. , Perdiguero B. , Nájera J. L. , Sorzano C. O. , Jiménez V. , González-Sanz R. , Esteban M. . ( 2012; ). Removal of vaccinia virus genes that block interferon type I and II pathways improves adaptive and memory responses of the HIV/AIDS vaccine candidate NYVAC-C in mice. . J Virol 86:, 5026–5038. [CrossRef] [PubMed]
    [Google Scholar]
  14. González J. M. , Esteban M. . ( 2010; ). A poxvirus Bcl-2-like gene family involved in regulation of host immune response: sequence similarity and evolutionary history. . Virol J 7:, 59. [CrossRef] [PubMed]
    [Google Scholar]
  15. Graham S. C. , Bahar M. W. , Cooray S. , Chen R. A. , Whalen D. M. , Abrescia N. G. , Alderton D. , Owens R. J. , Stuart D. I. . & other authors ( 2008; ). Vaccinia virus proteins A52 and B14 share a Bcl-2-like fold but have evolved to inhibit NF-κB rather than apoptosis. . PLoS Pathog 4:, e1000128. [CrossRef] [PubMed]
    [Google Scholar]
  16. Gubser C. , Hué S. , Kellam P. , Smith G. L. . ( 2004; ). Poxvirus genomes: a phylogenetic analysis. . J Gen Virol 85:, 105–117. [CrossRef] [PubMed]
    [Google Scholar]
  17. Lane J. M. , Ruben F. L. , Neff J. M. , Millar J. D. . ( 1969; ). Complications of smallpox vaccination, 1968. . N Engl J Med 281:, 1201–1208. [CrossRef] [PubMed]
    [Google Scholar]
  18. Law M. , Pütz M. M. , Smith G. L. . ( 2005; ). An investigation of the therapeutic value of vaccinia-immune IgG in a mouse pneumonia model. . J Gen Virol 86:, 991–1000. [CrossRef] [PubMed]
    [Google Scholar]
  19. Lefkowitz E. J. , Wang C. , Upton C. . ( 2006; ). Poxviruses: past, present and future. . Virus Res 117:, 105–118. [CrossRef] [PubMed]
    [Google Scholar]
  20. Mackett M. , Smith G. L. , Moss B. . ( 1982; ). Vaccinia virus: a selectable eukaryotic cloning and expression vector. . Proc Natl Acad Sci U S A 79:, 7415–7419. [CrossRef] [PubMed]
    [Google Scholar]
  21. Meyer H. , Sutter G. , Mayr A. . ( 1991; ). Mapping of deletions in the genome of the highly attenuated vaccinia virus MVA and their influence on virulence. . J Gen Virol 72:, 1031–1038. [CrossRef] [PubMed]
    [Google Scholar]
  22. Moore J. B. , Smith G. L. . ( 1992; ). Steroid hormone synthesis by a vaccinia enzyme: a new type of virus virulence factor. . EMBO J 11:, 1973–1980.[PubMed]
    [Google Scholar]
  23. Moss B. . ( 2007; ). Poxviridae: the viruses and their replication. . In Fields Virology, , 5th edn., pp. 2905–2946. Edited by Knipe D. M. . . Philadelphia:: Lippincott Williams & Wilkins;.
    [Google Scholar]
  24. Moss B. . ( 2011; ). Smallpox vaccines: targets of protective immunity. . Immunol Rev 239:, 8–26. [CrossRef] [PubMed]
    [Google Scholar]
  25. Panicali D. , Paoletti E. . ( 1982; ). Construction of poxviruses as cloning vectors: insertion of the thymidine kinase gene from herpes simplex virus into the DNA of infectious vaccinia virus. . Proc Natl Acad Sci U S A 79:, 4927–4931. [CrossRef] [PubMed]
    [Google Scholar]
  26. Panicali D. , Davis S. W. , Weinberg R. L. , Paoletti E. . ( 1983; ). Construction of live vaccines by using genetically engineered poxviruses: biological activity of recombinant vaccinia virus expressing influenza virus hemagglutinin. . Proc Natl Acad Sci U S A 80:, 5364–5368. [CrossRef] [PubMed]
    [Google Scholar]
  27. Pomerantz J. L. , Baltimore D. . ( 1999; ). NF-κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. . EMBO J 18:, 6694–6704. [CrossRef] [PubMed]
    [Google Scholar]
  28. Pütz M. M. , Midgley C. M. , Law M. , Smith G. L. . ( 2006; ). Quantification of antibody responses against multiple antigens of the two infectious forms of vaccinia virus provides a benchmark for smallpox vaccination. . Nat Med 12:, 1310–1315. [CrossRef] [PubMed]
    [Google Scholar]
  29. Reading P. C. , Moore J. B. , Smith G. L. . ( 2003a; ). Steroid hormone synthesis by vaccinia virus suppresses the inflammatory response to infection. . J Exp Med 197:, 1269–1278. [CrossRef] [PubMed]
    [Google Scholar]
  30. Reading P. C. , Symons J. A. , Smith G. L. . ( 2003b; ). A soluble chemokine-binding protein from vaccinia virus reduces virus virulence and the inflammatory response to infection. . J Immunol 170:, 1435–1442.[PubMed] [CrossRef]
    [Google Scholar]
  31. Rehm K. E. , Roper R. L. . ( 2011; ). Deletion of the A35 gene from modified vaccinia virus Ankara increases immunogenicity and isotype switching. . Vaccine 29:, 3276–3283. [CrossRef] [PubMed]
    [Google Scholar]
  32. Ryzhakov G. , Randow F. . ( 2007; ). SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK. . EMBO J 26:, 3180–3190. [CrossRef] [PubMed]
    [Google Scholar]
  33. Schröder M. , Baran M. , Bowie A. G. . ( 2008; ). Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKε-mediated IRF activation. . EMBO J 27:, 2147–2157. [CrossRef] [PubMed]
    [Google Scholar]
  34. Smith G. L. , Mackett M. , Moss B. . ( 1983a; ). Infectious vaccinia virus recombinants that express hepatitis B virus surface antigen. . Nature 302:, 490–495. [CrossRef] [PubMed]
    [Google Scholar]
  35. Smith G. L. , Murphy B. R. , Moss B. . ( 1983b; ). Construction and characterization of an infectious vaccinia virus recombinant that expresses the influenza hemagglutinin gene and induces resistance to influenza virus infection in hamsters. . Proc Natl Acad Sci U S A 80:, 7155–7159. [CrossRef] [PubMed]
    [Google Scholar]
  36. Staib C. , Kisling S. , Erfle V. , Sutter G. . ( 2005; ). Inactivation of the viral interleukin 1beta receptor improves CD8+ T-cell memory responses elicited upon immunization with modified vaccinia virus Ankara. . J Gen Virol 86:, 1997–2006. [CrossRef] [PubMed]
    [Google Scholar]
  37. Tscharke D. C. , Smith G. L. . ( 1999; ). A model for vaccinia virus pathogenesis and immunity based on intradermal injection of mouse ear pinnae. . J Gen Virol 80:, 2751–2755.[PubMed]
    [Google Scholar]
  38. Tscharke D. C. , Reading P. C. , Smith G. L. . ( 2002; ). Dermal infection with vaccinia virus reveals roles for virus proteins not seen using other inoculation routes. . J Gen Virol 83:, 1977–1986.[PubMed]
    [Google Scholar]
  39. Tscharke D. C. , Karupiah G. , Zhou J. , Palmore T. , Irvine K. R. , Haeryfar S. M. , Williams S. , Sidney J. , Sette A. . & other authors ( 2005; ). Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines. . J Exp Med 201:, 95–104. [CrossRef] [PubMed]
    [Google Scholar]
  40. Tscharke D. C. , Woo W. P. , Sakala I. G. , Sidney J. , Sette A. , Moss D. J. , Bennink J. R. , Karupiah G. , Yewdell J. W. . ( 2006; ). Poxvirus CD8+ T-cell determinants and cross-reactivity in BALB/c mice. . J Virol 80:, 6318–6323. [CrossRef] [PubMed]
    [Google Scholar]
  41. Unterholzner L. , Sumner R. P. , Baran M. , Ren H. , Mansur D. S. , Bourke N. M. , Randow F. , Smith G. L. , Bowie A. G. . ( 2011; ). Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7. . PLoS Pathog 7:, e1002247. [CrossRef] [PubMed]
    [Google Scholar]
  42. Upton C. , Slack S. , Hunter A. L. , Ehlers A. , Roper R. L. . ( 2003; ). Poxvirus orthologous clusters: toward defining the minimum essential poxvirus genome. . J Virol 77:, 7590–7600. [CrossRef] [PubMed]
    [Google Scholar]
  43. Williamson J. D. , Reith R. W. , Jeffrey L. J. , Arrand J. R. , Mackett M. . ( 1990; ). Biological characterization of recombinant vaccinia viruses in mice infected by the respiratory route. . J Gen Virol 71:, 2761–2767. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.049700-0
Loading
/content/journal/jgv/10.1099/vir.0.049700-0
Loading

Data & Media loading...

Most cited articles

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error