Cytolytic Perforin as an Adjuvant to Enhance the Immunogenicity of DNA Vaccines

Shrestha, Ashish C.; Wijesundara, Danushka K.; Masavuli, Makutiro G.; Mekonnen, Zelalem A.; Gowans, Eric J.; Grubor-Bauk, Branka

DNA vaccines are still a promising option in the development of novel vaccination strategies. Although they have many advantages, the ability to induce effective immune responses in humans required for protection has been challenging. These challenges include ineffective delivery and poor uptake of DNA. Consequently, a recent focus has been in the development of delivery methods and/or inclusion of genetic adjuvants. Such genetic adjuvants are generally coexpressed with the antigen of interest or delivered through different plasmids. In the quest to develop and identify effective genetic adjuvants, a range of adjuvants was tested (HSP70, VSVG, IMX313, DTa, and PRF) and a novel and promising cytolytic DNA vaccine strategy has been developed. This cytolytic DNA vaccine is unique as it is based on a bicistronic plasmid with the ability to coexpress antigen and PRF in a balanced mechanism causing necrosis of vaccine-transduced cells, followed by increased activation of immune cells and cross presentation of vaccine immunogen. Cytolytic DNA vaccines encoding nonstructural proteins of HCV have been tested to enhance immunogenicity of vaccine antigen in mice [57, 107] and in a large preclinical animal model, the pig [56] . Likewise, increased immunogenicity and improved protection against EcoHIV challenge in mice with HIV Gag PRF [60] demonstrate the effectiveness of cytolytic DNA vaccines.