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

HSP70, a class of molecular chaperone, is known to induce maturation of DCs and activation of the Th1 pathway [78] [79] [80] . A fusion vaccine for multiple myeloma termed hDKK1-hHSP70 was shown to be effective in inhibiting the targeted tumor and increased survival of vaccinated mice by eliciting tumor-specific humoral and cellular immune responses [80] . However, a DNA vaccine encoding HPV16E7 fused with HSP70, targeting HPV16 and cervical intraepithelial neoplasia 2/3 failed to enhance significant T cell responses in a Phase I clinical trial [69] . A bicistronic DNA encoding HSP70 as a membrane bound or secreted protein has been used to improve the immunogenicity of a HIV Gag [60] . In this case, HSP70 expression was driven by a weaker SV40 promoter and HIV Gag by a stronger CMV promoter. Such a vaccine design enhanced Gag-specific T cell responses, providing greater protection in mice challenged with EcoHIV [60] . EcoHIV is a chimeric virus containing the envelope protein gp 80 of mouse leukemia virus rather than HIV gp 120 that can replicate in mouse leukocytes in vivo, thus representing a viable mouse challenge model for early assessment of HIV vaccines [81] . The proposed mechanism of HSP70 as an adjuvant is that TLR 2/4 on DCs interacts with secreted or bound HSP70, further attracting DCs to the site of antigen expression. This is followed by DC maturation, presentation of antigens by MHC molecules and secretion of cytokines and costimulatory molecules [82] , thus enhancing T cell immune responses against the vaccine antigen.