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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 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

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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 6

Protection from EBNA1-induced B cell lymphoma challenge by heterologous vaccination.

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Protection from EBNA1-induced B cell lymphoma challenge by heterologous ...
(A) huDEC205-Tg mice were immunized with different combinations of vaccines for the prime and the boost, scheduled 10 days apart. Mice were challenged with 3 × 106 to 5 × 106 EBNA1+ B cell tumor cells (BL-E1) i.v. 14 days after the boost in a preventive setting. Mice were monitored every second day, including measurement of weight, observation of general behavior, and assessment using the mouse grimace scale. (B) At sacrifice, bulk single-cell suspensions of cells from LNs, spleen, liver, and blood were harvested and analyzed by EBNA1 qPCR. Abundance of the EBNA1 gene was normalized to the UBC gene as the tumor load. Data are shown as the mean ± SD from 2 independent experiments with at least 5 mice per group. (C) A tumor load cutoff of 0.005 or higher was set, and results of all analyzed organs from each mouse were pooled. The percentage of mice per condition without tumor burden and with tumor burden in 1 to 4 organs is depicted. *P < 0.05; Mantel-Cox test. (D) At sacrifice, splenic tissue from treated mice with EBNA1-induced B cell lymphoma were fixed in PFA and embedded in paraffin. Splenic tissues from PBS-treated mice without tumor treatment were used. Splenic tissue samples were stained with H&E, αCD19, αPCNA, and αXIAP Abs. One representative staining for each group is shown. Scale bar: 20 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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