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 3

Persistent and potent EBNA1-specific CD8+ T cell responses upon comprehensive CD4+ and CD8+ T cell priming by heterologous vaccination.

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Persistent and potent EBNA1-specific CD8+ T cell responses upon comprehe...
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 (A–C) or 21 weeks (E–G) after the boost. Bulk splenocytes were harvested and stimulated either with 1 μg/ml EBNA1 or control HCMV pp65 peptide pools. IFN-γ production by CD4+ (A and E) or CD8+ (B and F) T cells was monitored by ICS. α–EBNA1 IgG titers were determined by ELISA (C and G). Each data point represents 1 individual mouse. Data are shown as the mean ± SEM from 3 independent experiments (inverse regimen) or 1 long-term experiment. *P < 0.05, **P < 0.01, and ***P < 0.001; Kruskal-Wallis with Dunn’s multiple comparisons post test. (D) Mice from 1 long-term experiment were observed up to week 21 after the boost. Blood was withdrawn at weeks 7, 11, 15, and 21 after the boost. PBMCs were restimulated with 1 μg/ml EBNA1 peptide pool after vaccination. IFN-γ production was monitored by ICS in CD8+ cells. Data are shown as the mean ± SEM. *P < 0.05 versus PBS-treated mice; 2-way ANOVA with Tukey’s multiple comparisons test.