title: Minicircle DNA is superior to plasmid DNA in eliciting antigen-specific CD8+ T-cell responses.
abstract: Clinical trials reveal that plasmid DNA (pDNA)-based gene delivery must be improved to realize its potential to treat human disease. Current pDNA platforms suffer from brief transgene expression, primarily due to the spread of transcriptionally repressive chromatin initially deposited on plasmid bacterial backbone sequences. Minicircle (MC) DNA lacks plasmid backbone sequences and correspondingly confers higher levels of sustained transgene expression upon delivery, accounting for its success in preclinical gene therapy models. In this study, we show for the first time that MC DNA also functions as a vaccine platform. We used a luciferase reporter transgene to demonstrate that intradermal delivery of MC DNA, relative to pDNA, resulted in significantly higher and persistent levels of luciferase expression in mouse skin. Next, we immunized mice intradermally with DNA encoding a peptide that, when presented by the appropriate major histocompatibility complex class I molecule, was recognized by endogenous CD8(+) T cells. Finally, immunization with peptide-encoding MC DNA, but not the corresponding full-length (FL) pDNA, conferred significant protection in mice challenged with Listeria monocytogenes expressing the model peptide. Together, our results suggest intradermal delivery of MC DNA may prove more efficacious for prophylaxis than traditional pDNA vaccines.
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology and Masonic Cancer Center, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA.
authors.forename: Wynette M
authors.initials: WM
authors.lastname: Dietz
authors.forename: Nicole E B
authors.initials: NE
authors.lastname: Skinner
authors.forename: Sara E
authors.initials: SE
authors.lastname: Hamilton
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Jund
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Heitfeld
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Litterman
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Chen
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.forename: John R
authors.initials: JR
authors.lastname: Ohlfest
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Pennell
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Osborn
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D004270:DNA, Circular / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008088:Listeriosis / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D010957:Plasmids / Q000235:genetics / Q000276:immunology*; D012867:Skin / Q000378:metabolism; D019076:Transgenes / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology
chemical_list: D004270:DNA, Circular; D018984:Epitopes, T-Lymphocyte; D019444:Vaccines, DNA