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Viral vector-based prime-boost immunization regimens: a possible involvement of T-cell competition

Gene Therapy volume 15, pages 393–403 (2008)Cite this article

Abstract

Vaccination with recombinant viral vectors may be impeded by preexisting vector-specific immunity or by vector-specific immunity induced during the priming immunization. It is assumed that virus-neutralizing antibodies represent the principal effector mechanism of vector-specific immunity, while killing of infected cells by vector-specific cytotoxic T lymphocytes (CTLs) has also been suggested. Using recombinant Semliki Forest virus (rSFV) expressing E6E7 antigen from human papillomavirus, we demonstrate that secondary immune responses against E6E7 are neither affected by vector-specific antibodies nor by CTL-mediated killing of infected cells. Instead, the presence of the antigen during the prime immunization appeared to be the main determinant for the boosting efficacy. After priming with rSFVeE6,7, a homologous booster stimulated the primed E6E7-specific CTL response and induced long-lasting memory. Passively transferred SFV-neutralizing antibodies did not inhibit E6E7-specific CTL responses, although transgene expression was strongly reduced under these conditions. Conversely, in mice primed with irrelevant rSFV, induction of E6E7-specific CTLs was inhibited presumably due to vector-specific responses induced by the priming immunization. When during the priming with irrelevant rSFV, E7-protein was co-administered, the inhibitory effect of vector-specific immunity was abolished. These results suggest that, apart from vector-specific antibodies or killing of infected cells, T-cell competition may be involved in determining the efficacy of viral vector-based prime-boost immunization regimens.

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Abbreviations

rSFV:

recombinant Semliki Forest virus

HPV:

human papillomavirus.

References

  1. Bessis N, GarciaCozar FJ, Boissier MC . Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene Therapy 2004; 11 (Suppl 1): S10–S17.

    Article  CAS  PubMed  Google Scholar 

  2. Franchini G, Gurunathan S, Baglyos L, Plotkin S, Tartaglia J . Poxvirus-based vaccine candidates for HIV: two decades of experience with special emphasis on canarypox vectors. Expert Rev Vaccines 2004; 3: S75–S88.

    Article  CAS  PubMed  Google Scholar 

  3. Cohen P . Immunity's yin and yang. A successful vaccine must first avoid being eliminated by pre-existing immunity before it can promote a protective immune response. IAVI Rep 2006; 10: 1–5.

    PubMed  Google Scholar 

  4. Sumida SM, Truitt DM, Kishko MG, Arthur JC, Jackson SS, Gorgone DA et al. Neutralizing antibodies and CD8+ T lymphocytes both contribute to immunity to adenovirus serotype 5 vaccine vectors. J Virol 2004; 78: 2666–2673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tsai V, Johnson DE, Rahman A, Wen SF, LaFace D, Philopena J et al. Impact of human neutralizing antibodies on antitumor efficacy of an oncolytic adenovirus in a murine model. Clin Cancer Res 2004; 10: 7199–7206.

    Article  CAS  PubMed  Google Scholar 

  6. Lauterbach H, Ried C, Epstein AL, Marconi P, Brocker T . Reduced immune responses after vaccination with a recombinant herpes simplex virus type 1 vector in the presence of antiviral immunity. J Gen Virol 2005; 86: 2401–2410.

    Article  CAS  PubMed  Google Scholar 

  7. Cichon G, Boeckh-Herwig S, Schmidt HH, Wehnes E, Muller T, Pring-Akerblom P et al. Complement activation by recombinant adenoviruses. Gene Therapy 2001; 8: 1794–1800.

    Article  CAS  PubMed  Google Scholar 

  8. Harrington LE, Most Rv R, Whitton JL, Ahmed R . Recombinant vaccinia virus-induced T-cell immunity: quantitation of the response to the virus vector and the foreign epitope. J Virol 2002; 76: 3329–3337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Molinier-Frenkel V, Gahery-Segard H, Mehtali M, Le Boulaire C, Ribault S, Boulanger P et al. Immune response to recombinant adenovirus in humans: capsid components from viral input are targets for vector-specific cytotoxic T lymphocytes. J Virol 2000; 74: 7678–7682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lowenstein PR . Input virion proteins: cryptic targets of antivector immune responses in preimmunized subjects. Mol Ther 2004; 9: 771–774.

    Article  CAS  PubMed  Google Scholar 

  11. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12: 342–347.

    Article  CAS  PubMed  Google Scholar 

  12. Chen J, Wu Q, Yang P, Hsu HC, Mountz JD . Determination of specific CD4 and CD8 T cell epitopes after. Mol Ther 2006; 13: 260–269.

    Article  PubMed  Google Scholar 

  13. Liljestrom P, Garoff H . A new generation of animal cell expression vectors based on the Semliki Forest virus replicon. Biotechnology (NY) 1991; 9: 1356–1361.

    Article  CAS  Google Scholar 

  14. Berglund P, Sjoberg M, Garoff H, Atkins GJ, Sheahan BJ, Liljestrom P . Semliki Forest virus expression system: production of conditionally infectious recombinant particles. Biotechnology (NY) 1993; 11: 916–920.

    CAS  Google Scholar 

  15. Berglund P, Fleeton MN, Smerdou C, Liljestrom P . Immunization with recombinant Semliki Forest virus induces protection against influenza challenge in mice. Vaccine 1999; 17: 497–507.

    Article  CAS  PubMed  Google Scholar 

  16. Daemen T, Regts J, Holtrop M, Wilschut J . Immunization strategy against cervical cancer involving an alphavirus vector expressing high levels of a stable fusion protein of human papillomavirus 16 E6 and E7. Gene Therapy 2002; 9: 85–94.

    Article  CAS  PubMed  Google Scholar 

  17. Sundback M, Douagi I, Dayaraj C, Forsell MN, Nordstrom EK, McInerney GM . Efficient expansion of HIV-1-specific T cell responses by homologous immunization with recombinant Semliki Forest virus particles. Virology 2005; 341: 190–202.

    Article  PubMed  Google Scholar 

  18. Zhou X, Berglund P, Zhao H, Liljestrom P, Jondal M . Generation of cytotoxic and humoral immune responses by nonreplicative recombinant Semliki Forest virus. Proc Natl Acad Sci USA 1995; 92: 3009–3013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Daemen T, Pries F, Bungener L, Kraak M, Regts J, Wilschut J . Genetic immunization against cervical carcinoma: induction of cytotoxic T lymphocyte activity with a recombinant alphavirus vector expressing human papillomavirus type 16 E6 and E7. Gene Therapy 2000; 7: 1859–1866.

    Article  CAS  PubMed  Google Scholar 

  20. Daemen T, Riezebos-Brilman A, Bungener L, Regts J, Dontje B, Wilschut J . Eradication of established HPV16-transformed tumours after immunisation with recombinant Semliki Forest virus expressing a fusion protein of E6 and E7. Vaccine 2003; 21: 1082–1088.

    Article  CAS  PubMed  Google Scholar 

  21. Huckriede A, Bungener L, Holtrop M, de Vries J, Waarts BL, Daemen T et al. Induction of cytotoxic T lymphocyte activity by immunization with recombinant Semliki Forest virus: indications for cross-priming. Vaccine 2004; 22: 1104–1113.

    Article  CAS  PubMed  Google Scholar 

  22. Daemen T, Riezebos-Brilman A, Regts J, Dontje B, van der Zee A, Wilschut J . Superior therapeutic efficacy of alphavirus-mediated immunization against human papilloma virus type 16 antigens in a murine tumour model: effects of the route of immunization. Antivir Ther 2004; 9: 733–742.

    PubMed  Google Scholar 

  23. Riezebos-Brilman A, Regts J, Freyschmidt EJ, Dontje B, Wilschut J, Daemen T . Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice. Gene Therapy 2005; 12: 1410–1414.

    Article  CAS  PubMed  Google Scholar 

  24. Riezebos-Brilman A, de Mare A, Bungener L, Huckriede A, Wilschut J, Daemen T . Recombinant alphaviruses as vectors for anti-tumour and anti-microbial immunotherapy. J Clin Virol 2006; 35: 233–243.

    Article  CAS  PubMed  Google Scholar 

  25. Byers AM, Kemball CC, Moser JM, Lukacher AE . Cutting edge: rapid in vivo CTL activity by polyoma virus-specific effector and memory CD8+ T cells. J Immunol 2003; 171: 17–21.

    Article  CAS  PubMed  Google Scholar 

  26. Barber DL, Wherry EJ, Ahmed R . Cutting edge: rapid in vivo killing by memory CD8T cells. J Immunol 2003; 171: 27–31.

    Article  CAS  PubMed  Google Scholar 

  27. Kedl RM, Kappler JW, Marrack P . Epitope dominance, competition and T cell affinity maturation. Curr Opin Immunol 2003; 15: 120–127.

    Article  CAS  PubMed  Google Scholar 

  28. Kedl RM, Rees WA, Hildeman DA, Schaefer B, Mitchell T, Kappler J et al. T cells compete for access to antigen-bearing antigen-presenting cells. J Exp Med 2000; 192: 1105–1113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Daemen T, de Mare A, Bungener L, de Jonge J, Huckriede A, Wilschut J . Virosomes for antigen and DNA delivery. Adv Drug Deliv Rev 2005; 57: 451–463.

    Article  CAS  PubMed  Google Scholar 

  30. Bungener L, de Mare A, de Vries-Idema J, Sehr P, van der Zee A, Wilschut J et al. A virosomal immunization strategy against cervical cancer and pre-malignant cervical disease. Antivir Ther 2006; 11: 717–727.

    CAS  PubMed  Google Scholar 

  31. von Andrian UH, Mackay CR . T-cell function and migration. Two sides of the same coin. N Engl J Med 2000; 343: 1020–1034.

    Article  CAS  PubMed  Google Scholar 

  32. Colmenero P, Berglund P, Kambayashi T, Biberfeld P, Liljestrom P, Jondal M . Recombinant Semliki Forest virus vaccine vectors: the route of injection determines the localization of vector RNA and subsequent T cell response. Gene Therapy 2001; 8: 1307–1314.

    Article  CAS  PubMed  Google Scholar 

  33. Iparraguirre A, Weninger W . Visualizing T cell migration in vivo. Int Arch Allergy Immunol 2003; 132: 277–293.

    Article  PubMed  Google Scholar 

  34. Willis RA, Kappler JW, Marrack PC . CD8T cell competition for dendritic cells in vivo is an early event in activation. Proc Natl Acad Sci USA 2006; 103: 12063–12068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wolpert EZ, Grufman P, Sandberg JK, Tegnesjo A, Karre K . Immunodominance in the CTL response against minor histocompatibility antigens: interference between responding T cells, rather than with presentation of epitopes. J Immunol 1998; 161: 4499–4505.

    CAS  PubMed  Google Scholar 

  36. Grufman P, Wolpert EZ, Sandberg JK, Karre K . T cell competition for the antigen-presenting cell as a model for immunodominance in the cytotoxic T lymphocyte response against minor histocompatibility antigens. Eur J Immunol 1999; 29: 2197–2204.

    Article  CAS  PubMed  Google Scholar 

  37. Kedl RM, Schaefer BC, Kappler JW, Marrack P . T cells down-modulate peptide-MHC complexes on APCs in vivo. Nat Immunol 2002; 3: 27–32.

    Article  CAS  PubMed  Google Scholar 

  38. Ge Q, Bai A, Jones B, Eisen HN, Chen J . Competition for self-peptide-MHC complexes and cytokines between naive and memory CD8+ T cells expressing the same or different T cell receptors. Proc Natl Acad Sci USA 2004; 101: 3041–3046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rechtsteiner G, Warger T, Hofmann M, Rammensee HG, Schild H, Radsak MP . Precursor frequency can compensate for lower TCR expression in T cell competition during priming in vivo. Eur J Immunol 2006; 36: 2613–2623.

    Article  CAS  PubMed  Google Scholar 

  40. Gray PM, Reiner SL, Smith DF, Kaye PM, Scott P . Antigen-experienced T cells limit the priming of naive T cells during infection with Leishmania major. J Immunol 2006; 177: 925–933.

    Article  CAS  PubMed  Google Scholar 

  41. Liu XS, Dyer J, Leggatt GR, Fernando GJP, Zhong J, Thomas R et al. Overcoming Original Antigenic Sin to generate new CD8T cell IFN-gamma responses in an antigen-experienced host. J Immunol 2006; 177: 2873–2879.

    Article  CAS  PubMed  Google Scholar 

  42. Mueller S, Hosiawa-Meagher KA, Konieczny BT, Sullivan BM, Bachmann MF, Locksley RM et al. Regulation of homeostatic chemokine expression and cell trafficking during immune responses. Science 2007; 317: 670–674.

    Article  CAS  PubMed  Google Scholar 

  43. Veiga-Fernandes H, Walter U, Bourgeois C, McLean A, Rocha B . Response of naive and memory CD8+ T cells to antigen stimulation in vivo. Nat Immunol 2000; 1: 47–53.

    Article  CAS  PubMed  Google Scholar 

  44. Sharpe S, Polyanskaya N, Dennis M, Sutter G, Hanke T, Erfle V et al. Induction of simian immunodeficiency virus (SIV)-specific CTL in rhesus macaques by vaccination with modified vaccinia tor immunity. J Gen Virol 2001; 82: 2215–2223.

    Article  CAS  PubMed  Google Scholar 

  45. Sailaja G, HogenEsch H, North A, Hays J, Mittal SK . Encapsulation of recombinant adenovirus into alginate microspheres circumvents vector-specific immune response. Gene Therapy 2002; 9: 1722–1729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Scallan CD, Jiang H, Liu T, Patarroyo-White S, Sommer JM, Zhou S et al. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood 2006; 107: 1810–1817.

    Article  CAS  PubMed  Google Scholar 

  47. Boere WA, Benaissa-Trouw BJ, Harmsen M, Kraaijeveld CA, Snippe H . Neutralizing and non-neutralizing monoclonal antibodies to the E2 glycoprotein of Semliki Forest virus can protect mice from lethal encephalitis. J Gen Virol 1983; 64 (Part 6): 1405–1408.

    Article  CAS  PubMed  Google Scholar 

  48. Boere WA, Harmsen T, Vinje J, Benaissa-Trouw BJ, Kraaijeveld CA, Snippe H . Identification of distinct antigenic determinants on Semliki Forest virus by using monoclonal antibodies with different antiviral activities. J Virol 1984; 52: 575–582.

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

We thank B Dontje and BN Hoogeboom for (bio)technical assistance, Solvay Pharmaceuticals for generous supplies of Influenza virus, Professor C Melief and Dr JW Hesselink for constructive discussions and Dr M Fiedler and Dr P Jansen-Dürr for provision of purified E7 protein. This research was supported by the Dutch Cancer Society, grant RuG-2001-2361 (Arjan de Mare).

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Authors and Affiliations

  1. Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    A de Mare, A J A Lambeck, J Regts, J Wilschut & T Daemen

  2. Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    G M van Dam

  3. Department of Gynecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    H W Nijman

  4. Eijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, Section Vaccines, University Medical Center, Utrecht, The Netherlands

    H Snippe

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Correspondence to T Daemen.

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de Mare, A., Lambeck, A., Regts, J. et al. Viral vector-based prime-boost immunization regimens: a possible involvement of T-cell competition. Gene Ther 15, 393–403 (2008). https://doi.org/10.1038/sj.gt.3303060

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