Gene Expression Driven by a Strong Viral Promoter in MVA Increases Vaccination Efficiency by Enhancing Antibody Responses and Unmasking CD8⁺ T Cell Epitopes.
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.
Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany. pablo.becker@kcl.ac.uk.
Pablo D
PD
Becker
Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany. noerder@clinical-trial-center.de.
Miriam
M
Nörder
Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany. sebastian.weissmann@helmholtz-hzi.de.
Sebastian
S
Weissmann
Institute of Virology, Technische Universität München, D-81675 Munich, Germany. ronny.ljapoci@med.uni-duesseldorf.de.|Laboratory for Molecular Virology, Institute for Virology, Düsseldorf University Hospital, Heinrich-Heine-University, D-40225 Düsseldorf, Germany. ronny.ljapoci@med.uni-duesseldorf.de.
Ronny
R
Ljapoci
Institute of Virology, Technische Universität München, D-81675 Munich, Germany. volker.erfle@googlemail.com.|Clinical Cooperation Groups "Antigen Specific Immunotherapy" and "Immune-Monitoring" Helmholtz Centre Munich, D-81675 Munich, Germany. volker.erfle@googlemail.com.
Volker
V
Erfle
Institute of Virology, Technische Universität München, D-81675 Munich, Germany. ingo.drexler@med.uni-duesseldorf.de.|Laboratory for Molecular Virology, Institute for Virology, Düsseldorf University Hospital, Heinrich-Heine-University, D-40225 Düsseldorf, Germany. ingo.drexler@med.uni-duesseldorf.de.|Clinical Cooperation Groups "Antigen Specific Immunotherapy" and "Immune-Monitoring" Helmholtz Centre Munich, D-81675 Munich, Germany. ingo.drexler@med.uni-duesseldorf.de.
Ingo
I
Drexler
Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany. carlos.guzman@helmholtz-hzi.de.
Carlos A
CA
Guzmán
delivery  system; modified vaccinia virus Ankara; promoter; vaccine; vaccine vector