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Published on: May 6, 2015
Antigen design enhances the immunogenicity of Semliki Forest virus-based therapeutic human papillomavirus vaccines
P P Ip1, A Boerma1, M Walczak1
1Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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 10(5) 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.
Insights
Improving cancer vaccines, this study enhanced recombinant Semliki Forest virus (rSFV) vaccines by incorporating endoplasmic reticulum (ER) targeting and helper T-cell epitopes. This novel antigen format boosted T-cell responses, leading to tumor regression and protection against cancer.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- Cancer vaccines, including viral vector and DNA-based types, show promise in preclinical settings but often underperform in clinical trials.
- Enhancing the immunogenicity of cancer vaccines is crucial for clinical success.
- Previous work demonstrated that optimizing DNA vaccine antigen format with ER targeting and helper epitopes improves efficacy.
Purpose of the Study:
- To evaluate if an optimal antigen format, previously defined for DNA vaccines, can enhance the effectiveness of recombinant Semliki Forest virus (rSFV) vaccines.
- To investigate the impact of including helper T-cell epitopes and ER targeting signals on rSFV vaccine performance against cancer.
Main Methods:
- Generation and characterization of rSFV replicon particles expressing human papillomavirus (HPV) E6 and/or E7 proteins.
- Fusion of HPV antigens with helper T-cell epitopes and an ER targeting signal within the rSFV vaccine construct.
- Evaluation of vaccine efficacy in preclinical cancer models, assessing T-cell responses and tumor outcomes.
Main Results:
- The inclusion of a helper cassette and ER targeting signal significantly enhanced the stability of the expressed viral antigens.
- A marked augmentation in the frequencies of human papillomavirus (HPV)-specific T cells was observed following vaccination.
- The novel rSFV vaccine achieved significant tumor regression and protection, even at a low immunization dose of 10^5 replicon particles.
Conclusions:
- An optimized antigen format, incorporating helper epitopes and ER targeting, can significantly improve the efficacy of even highly effective viral vector vaccines like rSFV.
- This strategy enhances protein stability and boosts antigen-specific T-cell responses, translating to improved anti-cancer outcomes.
- The findings support the rational design of improved cancer vaccines by focusing on antigen presentation and T-cell epitope inclusion.
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