Euroasian Journal of Hepato-Gastroenterology

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VOLUME 4 , ISSUE 1 ( January-June, 2014 ) > List of Articles

ORIGINAL ARTICLE

Impact of the Immunogen Nature on the Immune Response against the Major HBV Antigens in an HBsAg and HLA-humanized Transgenic Mouse Model

M Mancini-Bourgine, G Guillen, ML Michel, JC Aguilar

Citation Information : Mancini-Bourgine M, Guillen G, Michel M, Aguilar J. Impact of the Immunogen Nature on the Immune Response against the Major HBV Antigens in an HBsAg and HLA-humanized Transgenic Mouse Model. Euroasian J Hepatogastroenterol 2014; 4 (1):36-44.

DOI: 10.5005/jp-journals-10018-1094

License: CC BY-NC 4.0

Published Online: 01-01-2014


Abstract

Hepatitis B chronic carriage remains as a major public health problem. Protein and DNA vaccines are now widely used in therapeutic vaccine candidates. Although, the hepatitis B surface antigen (HBsAg) based vaccines have been largely studied, candidates comprising both HBsAg and core (HBcAg) either protein- or DNA-based approaches deserve further immunological characterization. In the present study, a repeated dose administration schedule for protein or DNA immunogens was conducted in order to characterize the resulting immune response in a humanized and HBsAg-tolerized setting. A novel transgenic (Tg) mice that express the HBsAg, human MHC class I (HLA-A*0201) and MHC class II (HLA-DRB1*01) molecules and devoid of endogenous murine class I and II molecules was used as a model of HBV chronic carrier. Mice were immunized by subcutaneous (protein) or intramuscular (DNA) routes and the humoral and cellular responses were evaluated. Protein or DNA immunization induced humoral immune responses against both HBsAg and HBcAg. The systematic analysis of epitopes that activate CD4+ and CD8+ T lymphocytes confirmed the accuracy of the model. Cellular immune responses were detected differing in their nature. CD8 T-cell responses were induced mostly after DNA immunization while CD4 T-cell responses were predominant in protein based immunizations. In addition, the intensity of HLA-A2-restricted CD8+ T cell responses was reduced in Tg mice expressing HBsAg when compared to control Tg mice. In conclusion, our results indicate that cellular immune responses necessary for the development of protective immunity can be achieved by DNA or protein immunization. However, important differences in their nature arise when immunogens are administered several times.


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  1. Zuckerman JN. Protective efficacy, immunotherapeutic potential and safety of hepatitis B vaccines. J Med Virol 2006;78:169- 177
  2. Therapeutic vaccination in chronic hepatitis B virus carriers. Expert Rev Vaccines 2006;5:707-716
  3. Therapeutic HBV Vaccine group of investigators. Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, controlled study of coadministration of HBsAg/AS02 candidate vaccine and lamivudine. Vaccine 2007; 25(51):8585-8597
  4. In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B. J Clin Virol 2005;32(2):156-161
  5. Role of B cells in antigen presentation of the hepatitis B core. Proc Natl Acad Sci USA 1997;94:14648-14653
  6. Comparative immunogenicity of hepatitis B virus core and E antigens. J Immunol 1988;141:3617-3624
  7. Preferential recognition of hepatitis B nucleocapsid antigens by Th1 or Th2 cells is epitope and major histocompatibility complex dependent. J Virol 1995;69:2776-2785
  8. Antibody production to the nucleocapsid and envelope of the hepatitis B virus primed by a single synthetic T cell site. Nature 1987;329: 547-549
  9. The position of heterologous epitopes inserted in hepatitis B virus core particles determines their immunogenicity. J Virol 1992;66:106-114. M Mancini-Bourgine et al 44 10. Aguilar JC, Lobaina Y, Muzio V, et al. Development of a nasal vaccine for chronic hepatitis B infection that uses the ability of hepatitis B core antigen to stimulate a strong Th1 response against hepatitis B surface antigen. Immunol Cell Biol 2004; 82:539-546
  10. Coinoculation with hepatitis B surface and core antigen promotes a Th1 immune response to a multiepitopic protein of HIV-1. Immunol Cell Biol 2006;84(2):174-183
  11. Vaccine adjuvants revisited. Vaccine 2007;25:3752-3762
  12. Phase I clinical trial in healthy adults of a nasal vaccine candidate containing recombinant hepatitis B surface and core antigens. Int J Infect Dis 2007;11:394-401
  13. Therapeutic potential of a novel therapeutic vaccine containing both hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) administered through mucosal and parenteral route in patients with chronic hepatitis B. Hepatology 2010;52(Suppl):438A-439A
  14. Immunogenicity of a hepatitis B DNA vaccine administered to chronic HBV carriers. Vaccine 2006;24(21):4482-4489
  15. Induction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers. Hepatology 2004;40(4):874-882
  16. Identification of novel HLA-DR1-restricted epitopes from the hepatitis B virus envelope protein in mice expressing HLA-DR1 and vaccinated human subjects. Microbes Infect 2006;8(12-13):2783-2790
  17. HBsAg/HLA-A2 transgenic mice: a model for T cell tolerance to hepatitis B surface antigen in chronic hepatitis B virus infection. Int Immunol 2003;15(10):1125-1136
  18. DNA mediated immunization to the hepatitis B surface antigen in mice: aspects of the humoral response mimic hepatitis B viral infection in humans. Proc Natl Acad Sci USA 1995;92: 5307
  19. DNA-mediated immunization in a transgenic mouse model of the hepatitis B surface antigen chronic carrier state. Proc Natl Acad Sci USA 1996 Oct 29;93(22):12496-12501
  20. A mouse model of human adaptive immune functions: HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice. Eur J Immunol 2004 Nov; 34(11):3060-3069
  21. CpG oligodeoxynucleotydes with hepatitis B surface antigen (HBsAg) for vaccination in HBsAg-transgenic mice. J Virol 2001;75:6482
  22. Optimum culture conditions for specific and nonspecific activation of whole blood and PBMC for intracellular cytokine assessment by flow cytometry. J Immunol Methods 2004;292: 1-15
  23. Antiviral therapy for adults with chronic hepatitis B: a systemic review for a National Institutes of Health Consensus Development Conference. Ann Intern Med 2009;150:111-124
  24. Therapeutic vaccination in the immunotolerant phase of children with chronic hepatitis B infection. Pediatr Infect Dis J 2003;22:345-349
  25. Specific vaccine therapy in chronic hepatitis B: induction of T cell proliferative responses specific for envelope antigens. J Infect Dis 1999;180:15-26
  26. The effect of the parenteral route of administration on the immune response to simultaneous nasal and parenteral immunizations using a new HBV therapeutic vaccine candidate. Viral Immunol 2010;23:521-529
  27. Article in press 2011
  28. Revealing the potential of DNA-based vaccination: lessons learned from the hepatitis B virus surface antigen. Biol Chem 200;382:543-552
  29. Alternative processing of endogenous or exogenous antigens extends the immunogenic, H-2 class Irestricted peptide repertoire. Mol Immunol 2002 Oct;39 (3-4):249-259
  30. Alternative pathways for processing exogenous and endogenous antigens that can generate peptides for MHC class I-restricted presentation. Immunol Rev 1999; 172:131-152
  31. Prime-boost strategies for malaria vaccine development. J Exp Biol 2003;206:3771-3779
  32. A heterologous DNA priming- Mycobacterium bovis BCG boosting immunization strategy using mycobacterial Hsp70, Hsp65 and Apa antigens improves protection against tuberculosis in mice. Infect Immun 2004; 72:6945-6950
  33. Heterologous prime-boost vaccination strategies for HIV-1: augmenting cellular immune responses. Curr Opin Investig Drugs 2002;3:374-378
  34. DNA prime/protein boost vaccine strategy in neonatal macaques against simian human immunodeficiency virus. J Med Primatol 2002;31:40-60
  35. Enhanced immunogenicity of gp120 protein when combined with recombinant DNA priming to generate antibodies that neutralize the JR-FL primary isolate of human immunodeficiency virus type 1. Virology 2005; 79:7933-7937
  36. DNA electroporation prime and protein boost strategy enhances humoral immunity of tuberculosis DNA vaccines in mice and nonhuman primates. Vaccine 2006;24:4565-4568
  37. The successful immune response against hepatitis C nonstructural protein 5A (NS5A) requires heterologous DNA/protein immunization. Vaccine. 2010 Feb 23;28(8):1987-1996
  38. Resolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen. Gastroenterology 2002; 122:614-624
  39. Immune modulator and antiviral potential of dendritic cells pulsed with both hepatitis B surface antigen and core antigen for treating chronic HBV infection. Antivir Ther 2010;15:887-895.
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