Heterologous prime-boost vaccination protects against EBV antigen–expressing lymphomas
Julia Rühl, … , Carol S. Leung, Christian Münz
Julia Rühl, … , Carol S. Leung, Christian Münz
Published May 1, 2019; First published March 12, 2019
Citation Information: J Clin Invest. 2019;129(5):2071-2087. https://doi.org/10.1172/JCI125364.
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Research Article Immunology

Heterologous prime-boost vaccination protects against EBV antigen–expressing lymphomas

Abstract

The Epstein-Barr virus (EBV) is one of the predominant tumor viruses in humans, but so far no therapeutic or prophylactic vaccination against this transforming pathogen is available. We demonstrated that heterologous prime-boost vaccination with the nuclear antigen 1 of EBV (EBNA1), either targeted to the DEC205 receptor on DCs or expressed from a recombinant modified vaccinia virus Ankara (MVA) vector, improved priming of antigen-specific CD4+ T cell help. This help supported the expansion and maintenance of EBNA1-specific CD8+ T cells that are most efficiently primed by recombinant adenoviruses that encode EBNA1. These combined CD4+ and CD8+ T cell responses protected against EBNA1-expressing T and B cell lymphomas, including lymphoproliferations that emerged spontaneously after EBNA1 expression. In particular, the heterologous EBNA1-expressing adenovirus, boosted by EBNA1-encoding MVA vaccination, demonstrated protection as a prophylactic and therapeutic treatment for the respective lymphoma challenges. Our study shows that such heterologous prime-boost vaccinations against EBV-associated malignancies as well as symptomatic primary EBV infection should be further explored for clinical development.

Authors

Julia Rühl, Carmen Citterio, Christine Engelmann, Tracey Haigh, Andrzej Dzionek, Johannes Dreyer, Rajiv Khanna, Graham S. Taylor, Joanna B. Wilson, Carol S. Leung, Christian Münz

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Figure 2

Comprehensive priming of mouse CD4+ and CD8+ T cell responses against EBNA1 by heterologous vaccination in huDEC205-Tg mice.

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Comprehensive priming of mouse CD4+ and CD8+ T cell responses against EB...
huDEC205-Tg mice were immunized with different combinations of vaccines for the prime and the boost, which were scheduled 4 weeks apart. Mice were sacrificed 2 weeks after the boost. Bulk splenocytes were harvested and stimulated either with 1 μg/ml EBNA1 or control HCMV pp65 peptide pools. (A) Representative dot plots of ICS of restimulated splenocytes, gated for CD4 or CD8 expression and IFN-γ. One dot plot is shown for the PBS-treated and vaccination groups αDEC-E1 plus αDEC-E1, αDEC-E1 plus Lenti-IiE1, αDEC-E1 plus Adeno–E1-LMP, αDEC-E1 plus MVA-IiE1, and Adeno–E1-LMP plus MVA-IiE1 as representative examples for the data summarized in B. (B) Frequency of IFN-γ+CD4+ and IFN-γ+CD8+ cells from total splenocytes. Data are shown as the mean ± SEM from 4 independent experiments with at least 3 mice per group. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 versus PBS-treated mice; Kruskal-Wallis test with Dunn’s multiple comparison post test. (C) Cytokine profile of total splenic CD4+ or CD8+ T cells in mice vaccinated with αDEC-E1 plus αDEC-E1, αDEC-E1 plus Lenti-IiE1, αDEC-E1 plus Adeno–E1-LMP, αDEC-E1 plus MVA-IiE1, or Adeno–E1-LMP plus MVA-IiE1. Pie charts show the mean of percentage of each cytokine-secreting subset. (D) Serum obtained from mice from prime-boost experiments was analyzed for α–EBNA1 IgG by ELISA. Each data point represents 1 individually analyzed mouse. A negative control that contained no serum was included. **P < 0.01, versus PBS-treated mice; Kruskal-Wallis test with Dunn’s multiple comparisons post test. Error bars indicate the SEM.