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Antigen design enhances the immunogenicity of Semliki Forest virus-based therapeutic human papillomavirus vaccines

Gene Therapy volume 22, pages 560–567 (2015)Cite this article

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Abstract

Cellular immunity against cancer can be achieved with viral vector- and DNA-based immunizations. In preclinical studies, cancer vaccines are very potent, but in clinical trials these potencies are not achieved yet. Thus, a rational approach to improve cancer vaccines is warranted. We previously demonstrated that the relatively low intrinsic immunogenicity of DNA vaccines could be enhanced by inclusion of endoplasmic reticulum (ER) targeting and universal helper epitopes within the vaccine. We now evaluated whether an optimal antigen format, as defined in DNA vaccines, can further enhance the effectiveness of recombinant Semliki Forest virus (rSFV) vaccines. To this purpose, we generated, characterized and evaluated the efficacy of rSFV replicon particles expressing human papillomavirus E6 and/or E7 proteins fused to several helper T-cell epitopes and an ER targeting signal. Here, we show that inclusion of a helper cassette and an ER targeting signal enhanced protein stability and markedly augmented the frequencies of human papillomavirus-specific T cells. Even at an immunization dose of as low as 105 replicon particles, this novel vaccine achieved tumor regression and protection. Thus, even highly effective viral vector vaccines can benefit from an improved antigen format, based on the inclusion of defined helper epitopes and ER targeting.

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Acknowledgements

We thank Oana Draghiciu and Tjarko Meijerhof for animal technical support and Stephanie van de Wall for carefully reading the manuscript. This study is funded by an Ubbo Emmius grant.

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Authors and Affiliations

  1. Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    P P Ip, A Boerma, M Walczak & T Daemen

  2. Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    K Oosterhuis, J B Haanen & T N Schumacher

  3. Department of Gynecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    H W Nijman

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  1. P P Ip
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  2. A Boerma
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  3. M Walczak
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Correspondence to T Daemen.

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Competing interests

T Daemen and HW Nijman are co-founders of ViciniVax, a spin-off company from the University Medical Center Groningen developing therapeutic cancer vaccines. TN Schumacher, JB Haanen and K Oosterhuis are inventors on a patent application covering vaccine formats and are as such entitled to a fraction of possible future royalty income, as per NKI-AVL regulations.

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Ip, P., Boerma, A., Walczak, M. et al. Antigen design enhances the immunogenicity of Semliki Forest virus-based therapeutic human papillomavirus vaccines. Gene Ther 22, 560–567 (2015). https://doi.org/10.1038/gt.2015.24

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