Enhancing DNA vaccine potency by co-administration of xenogenic MHC-class-I DNA

Intramuscular administration of DNA vaccines can lead to the generation of antigen-specific immune responses through cross-priming mechanisms. We propose a strategy that is capable of leading to local inflammation and enhancing cross-priming, thus resulting in improved antigen-specific immune responses. Therefore, in the current study, we evaluated immunologic responses elicited through electroporation mediated intramuscular administration of a DNA vaccine encoding calreticulin (CRT) linked to HPV-16 E7 (CRT/E7) in combination with DNA expressing HLA-A2 as compared to CRT/E7 DNA vaccination alone. We found that the co-administration of a DNA vaccine in conjunction with a DNA encoding an xenogenic MHC molecule could significantly enhance the E7-specific CD8+ T cell immune responses as well an antitumor effects against an E7-expressing tumor, TC-1 in C57BL/6 tumor-bearing mice. Furthermore, a similar enhancement in E7-specific immune responses was observed by co-administration of CRT/E7 DNA with DNA encoding other types of xenogenic MHC class I molecules. This strategy was also applicable to another antigenic system, ovalbumin. Further characterization of the injection site revealed that co-administration of HLA-A2 DNA led to a significant increase in the number of infiltrating CD8+ T lymphocytes as well as CD11b/c+ antigen presenting cells. Furthermore, the E7-specific immune responses generated by intramuscular co-administration of CRT/E7 with HLA-A2 DNA were reduced in HLA-A2 transgenic mice. Thus, our data suggest that intramuscular co-administration of DNA encoding xenogenic MHC class I can further improve the antigen-specific immune responses as well as antitumor effects generated by DNA vaccines through enhancement of cross-priming mechanisms.