Protein-prime/modified vaccinia virus Ankara vector-boost vaccination overcomes tolerance in high-antigenemic HBV-transgenic mice

被引:54
作者
Backes, Simone [1 ,9 ]
Jaeger, Clemens [1 ]
Dembek, Claudia J. [1 ,2 ]
Kosinska, Anna D. [1 ]
Bauer, Tanja [1 ,2 ]
Stephan, Ann-Sophie [1 ]
Dislers, Andris [3 ]
Mutwiri, George [4 ,5 ]
Busch, Dirk H. [2 ,6 ,7 ]
Babiuk, Lorne A. [8 ]
Gasteiger, Georg [1 ,7 ,9 ]
Protzer, Ulrike [1 ,2 ,7 ]
机构
[1] Tech Univ Munich, Inst Virol, Helmholtz Zentrum Munchen, Trogerstr 30, D-81675 Munich, Germany
[2] German Ctr Infect Res DZIF, Munich Site, D-81675 Munich, Germany
[3] Univ Latvia, Biomed Res & Study Ctr, 1 Ratsupites St, LV-1067 Riga, Latvia
[4] Univ Saskatchewan, Sch Publ Hlth, Vaccinol & Immunotherapeut, 107 Wiggins Rd, Saskatoon, SK S7N 5E3, Canada
[5] Univ Saskatchewan, Vaccine & Infect Dis Org, Int Vaccine Ctr, 120 Vet Rd, Saskatoon, SK S7N 5E3, Canada
[6] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, Trogerstr 30, D-81675 Munich, Germany
[7] Helmholtz Zentrum Munchen, Clin Cooperat Grp Antigen Specif Immunotherapy &, Munich, Germany
[8] Univ Alberta, 3-7 Univ Hall, Edmonton, AB T6G 2J9, Canada
[9] Johannes Gutenberg Univ Mainz, Med Ctr, Inst Med Microbiol & Hyg, D-55131 Mainz, Germany
关键词
Hepatitis B virus; Therapeutic vaccination; Tolerance; Heterologous prime/boost strategy; Recombinant MVA; HEPATITIS-B-VIRUS; CYTOTOXIC T-LYMPHOCYTES; SURFACE-ANTIGEN; IN-VIVO; IMMUNE-RESPONSES; DENDRITIC CELLS; INFECTION; LAMIVUDINE; IMMUNIZATION; REPLICATION;
D O I
10.1016/j.vaccine.2015.12.060
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background: Therapeutic vaccination is a novel treatment approach for chronic hepatitis B, but only had limited success so far. We hypothesized that optimized vaccination schemes have increased immunogenicity, and aimed at increasing therapeutic hepatitis B vaccine efficacy. Methods: Modified Vaccinia virus Ankara (MVA) expressing hepatitis B virus (HBV) antigens was used to boost protein-prime vaccinations in wildtype and HBV-transgenic (HBVtg) mice. Results: Protein-prime/MVA-boost vaccination was able to overcome HBV-specific tolerance in HBVtg mice with low and medium but not with high antigenemia. HBV-specific antibody titers, CD8+ T-cell frequencies and polyfunctionality inversely correlated with HBV antigen levels. However, optimization of the adjuvant formulation, increasing the level of antigen expression and utilization of HBsAg of heterologous subtype induced HBV-specific CD8+ and CD4+ T-cells and neutralizing antibodies even in high-antigenemic HBVtg mice. Conclusions: Our results indicate that high HBV antigen levels limit the immunological responsiveness to therapeutic vaccination but optimization of the vaccine formulation can overcome tolerance even in the presence of high antigenemia. These findings have important implications for the development of future therapeutic hepatitis B vaccination strategies and potentially also for the stratification of chronic hepatitis B patients for therapeutic vaccination. (C) 2016 Elsevier Ltd. All rights reserved.
引用
收藏
页码:923 / 932
页数:10
相关论文
共 39 条
[1]   The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection [J].
Asabe, Shinichi ;
Wieland, Stefan F. ;
Chattopadhyay, Pratip K. ;
Roederer, Mario ;
Engle, Ronald E. ;
Purcell, Robert H. ;
Chisari, Francis V. .
JOURNAL OF VIROLOGY, 2009, 83 (19) :9652-9662
[2]   Activation of adjuvant core response genes by the novel adjuvant PCEP [J].
Awate, Sunita ;
Wilson, Heather L. ;
Lai, Ken ;
Babiuk, Lorne A. ;
Mutwiri, George .
MOLECULAR IMMUNOLOGY, 2012, 51 (3-4) :292-303
[3]   Restoring function in exhausted CD8 T cells during chronic viral infection [J].
Barber, DL ;
Wherry, EJ ;
Masopust, D ;
Zhu, BG ;
Allison, JP ;
Sharpe, AH ;
Freeman, GJ ;
Ahmed, R .
NATURE, 2006, 439 (7077) :682-687
[4]  
Bertoletti Antonio, 2009, Expert Rev Gastroenterol Hepatol, V3, P561, DOI 10.1586/egh.09.48
[5]   A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic mice [J].
Buchmann, Pascale ;
Dembek, Claudia ;
Kuklick, Larissa ;
Jaeger, Clemens ;
Tedjokusumo, Raindy ;
von Freyend, Miriam John ;
Drebber, Uta ;
Janowicz, Zbigniew ;
Melber, Karl ;
Protzer, Ulrike .
VACCINE, 2013, 31 (08) :1197-1203
[6]   Partially Randomized, Non-Blinded Trial of DNA and MVA Therapeutic Vaccines Based on Hepatitis B Virus Surface Protein for Chronic HBV Infection [J].
Cavenaugh, James S. ;
Awi, Dorka ;
Mendy, Maimuna ;
Hill, Adrian V. S. ;
Whittle, Hilton ;
McConkey, Samuel J. .
PLOS ONE, 2011, 6 (02)
[7]   Clinical and immunological efficacy of intradermal vaccine plus lamivudine with or without interleukin-2 in patients with chronic hepatitis B [J].
Dahmen, A ;
Herzog-Hauff, S ;
Böcher, WO ;
Galle, PR ;
Löhr, HF .
JOURNAL OF MEDICAL VIROLOGY, 2002, 66 (04) :452-460
[8]   Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus [J].
den Brouw, Marjoleine L. Op ;
Binda, Rekha S. ;
van Roosmalen, Mark H. ;
Protzer, Ulrike ;
Janssen, Harry L. A. ;
van der Molen, Renate G. ;
Woltman, Andrea M. .
IMMUNOLOGY, 2009, 126 (02) :280-289
[9]   Immune tolerance against HBV can be overcome in HBV transgenic mice by immunization with dendritic cells pulsed by HBVsvp [J].
Farag, Mohamed M. S. ;
Tedjokusumo, Raindy ;
Flechtenmacher, Christa ;
Asen, Theresa ;
Stremmel, Wolfgang ;
Mueller, Martina ;
Protzer, Ulrike ;
Weigand, Kilian .
VACCINE, 2012, 30 (42) :6034-6039
[10]  
FERRARI C, 1990, J IMMUNOL, V145, P3442