Gene Expression Driven by a Strong Viral Promoter in MVA Increases Vaccination Efficiency by Enhancing Antibody Responses and Unmasking CD8+ T Cell Epitopes

被引:9
作者
Becker, Pablo D. [1 ]
Noerder, Miriam [1 ,6 ]
Weissmann, Sebastian [1 ]
Ljapoci, Ronny [2 ,3 ]
Erfle, Volker [2 ,4 ]
Drexler, Ingo [2 ,3 ,4 ]
Guzman, Carlos A. [1 ,5 ]
机构
[1] Helmholtz Ctr Infect Res, Dept Vaccinol & Appl Microbiol, D-38124 Braunschweig, Germany
[2] Tech Univ Munich, Inst Virol, D-81675 Munich, Germany
[3] Heinrich Heine Univ, Dusseldorf Univ Hosp, Inst Virol, Mol Virol Lab, D-40225 Dusseldorf, Germany
[4] Antigen Specif Immunotherapy & Immune Monitoring, Clin Cooperat Grp, D-81675 Munich, Germany
[5] Kings Coll London, Dept Immunoregulat & Immune Intervent, London SE1 9RT, England
[6] Hannover Clin Trial Ctr GmbH, D-30625 Hannover, Germany
关键词
modified vaccinia virus Ankara; vaccine vector; promoter; delivery system; vaccine;
D O I
10.3390/vaccines2030581
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Viral vectors are promising tools for vaccination strategies and immunotherapies. However, CD8+ T cell responses against pathogen-derived epitopes are usually limited to dominant epitopes and antibody responses to recombinant encoded antigens (Ags) are mostly weak. We have previously demonstrated that the timing of viral Ag expression in infected professional Ag-presenting cells strongly shapes the epitope immunodominance hierarchy. T cells recognizing determinants derived from late viral proteins have a clear disadvantage to proliferate during secondary responses. In this work we evaluate the effect of overexpressing the recombinant Ag using the modified vaccinia virus early/late promoter H5 (mPH5). Although the Ag-expression from the natural promoter 7.5 (P7.5) and the mPH5 seemed similar, detailed analysis showed that mPH5 not only induces higher expression levels than P7.5 during early phase of infection, but also Ag turnover is enhanced. The strong overexpression during the early phase leads to broader CD8 T cell responses, while preserving the priming efficiency of stable Ags. Moreover, the increase in Ag-secretion favors the induction of strong antibody responses. Our findings provide the rationale to develop new strategies for fine-tuning the responses elicited by recombinant modified vaccinia virus Ankara by using selected promoters to improve the performance of this viral vector.
引用
收藏
页码:581 / 600
页数:20
相关论文
共 57 条
[1]  
[Anonymous], 2013, FLOWJ SOFTW VERS 9 6
[2]  
[Anonymous], 2013, GRAPHP PRISM SOFTW W
[3]   Immunobiology of dendritic cells [J].
Banchereau, J ;
Briere, F ;
Caux, C ;
Davoust, J ;
Lebecque, S ;
Liu, YT ;
Pulendran, B ;
Palucka, K .
ANNUAL REVIEW OF IMMUNOLOGY, 2000, 18 :767-+
[4]   Dendritic cells and the control of immunity [J].
Banchereau, J ;
Steinman, RM .
NATURE, 1998, 392 (6673) :245-252
[5]   Immune modulator adamantylamide dipeptide stimulates efficient major histocompatibility complex class I-restricted responses in mice [J].
Becker, Pablo D. ;
Noerder, Miriam ;
Guzman, Carlos A. ;
Grinstein, Saul .
CLINICAL AND VACCINE IMMUNOLOGY, 2007, 14 (05) :538-543
[6]   Immunogenicity of the candidate malaria vaccines FP9 and modified vaccinia virus Ankara encoding the pre-erythrocytic antigen ME-TRAP in 1-6 year old children in a malaria endemic area [J].
Bejon, P ;
Mwacharo, J ;
Kai, OK ;
Todryk, S ;
Keating, S ;
Lang, T ;
Gilbert, SC ;
Peshu, N ;
Marsh, K ;
Hill, AVS .
VACCINE, 2006, 24 (22) :4709-4715
[7]   Modified vaccinia virus Ankara undergoes limited replication in human cells and lacks several immunomodulatory proteins:: implications for use as a human vaccine [J].
Blanchard, TJ ;
Alcamí, A ;
Andrea, P ;
Smith, GL .
JOURNAL OF GENERAL VIROLOGY, 1998, 79 :1159-1167
[8]   Preclinical Studies of a Modified Vaccinia Virus Ankara-Based HIV Candidate Vaccine: Antigen Presentation and Antiviral Effect [J].
Brandler, Samantha ;
Lepelley, Alice ;
Desdouits, Marion ;
Guivel-Benhassine, Florence ;
Ceccaldi, Pierre-Emmanuel ;
Levy, Yves ;
Schwartz, Olivier ;
Moris, Arnaud .
JOURNAL OF VIROLOGY, 2010, 84 (10) :5314-5328
[9]   Construction, characterization, and immunogenicity of a multigene modified vaccinia Ankara (MVA) vaccine based on HIV type 1 subtype C [J].
Burgers, Wendy A. ;
Shephard, Enid ;
Monroe, James E. ;
Greenhalgh, Trish ;
Binder, Anke ;
Hurter, Etienne ;
Van Harmelen, Joanne H. ;
Williamson, Carolyn ;
Williamson, Anna-Lise .
AIDS RESEARCH AND HUMAN RETROVIRUSES, 2008, 24 (02) :195-206
[10]   Host range and cytopathogenicity of the highly attenuated MVA strain of vaccinia virus: Propagation and generation of recombinant viruses in a nonhuman mammalian cell line [J].
Carroll, MW ;
Moss, B .
VIROLOGY, 1997, 238 (02) :198-211