Enhancement of Antitumor Immunity Using a DNA-Based Replicon Vaccine Derived from Semliki Forest Virus

Liang Zhang,Yu Wang,Yuanji Xu,Kun Gao,Yan Gao,Jinqi Yan,Yi Xiao,Jinkai Dong,Xi Wang,Wei Zhang,Yue Wang,Jiyun Yu,Jean Kanellopoulos

doi:10.1371/journal.pone.0090551

Abstract

A DNA-based replicon vaccine derived from Semliki Forest virus, PSVK-shFcG-GM/B7.1 ( Fig. 1a ) was designed for tumor immunotherapy as previously constructed. The expression of the fusion tumor antigen (survivin and hCGβ-CTP37) and adjuvant molecular protein (Granulocyte-Macrophage Colony-Stimulating Factor/ GM-CSF/B7.1) genes was confirmed by Immunofluorescence assay in vitro, and immunohistochemistry assay in vivo. In this paper, the immunological effect of this vaccine was determined using immunological assays as well as animal models. The results showed that this DNA vaccine induced both humoral and cellular immune responses in C57BL/6 mice after immunization, as evaluated by the ratio of CD4+/CD8+ cells and the release of IFN-γ. Furthermore, the vaccination of C57BL/6 mice with PSVK-shFcG-GM/B7.1 significantly delayed the in vivo growth of tumors in animal models (survivin+ and hCGβ+ murine melanoma, B16) when compared to vaccination with the empty vector or the other control constructs ( Fig. 1b ). These data indicate that this type of replicative DNA vaccine could be developed as a promising approach for tumor immunotherapy. Meanwhile, these results provide a basis for further study in vaccine pharmacodynamics and pharmacology, and lay a solid foundation for clinical application.

Highlights

Over the past few years, tremendous progress has been achieved in tumor therapy by using antigen-encoded plasmid DNA as a vaccine
The utilization of traditional DNA vaccines is determined by many factors such as the carrier system, the target genes, and the microenvironment
There is great concern that the DNA vaccine may integrate into the host cell genome

Summary

Introduction

Over the past few years, tremendous progress has been achieved in tumor therapy by using antigen-encoded plasmid DNA as a vaccine. Self-replication and transcription of the replicon DNA vaccine occurs in the cytoplasm and eventually eliminates the risk of integration into the host cell genome and greatly improves the safety [7]. Members of this family have served as a basis for viral vector and DNA plasmid vaccines for infectious diseases and cancer [8]. The application of alphavirus vectors as vaccines has included the administration of SFV, SIN and VEE virus as layered DNA-RNA vectors [9,10,11,12,13]. The expression of the murine VEGFR-2 from SFV vectors led to the inhibition of angiogenesis, which reduced tumor growth and metastasis in mice [15]

Methods

Results

Conclusion