title: Nonmethylated CG motifs packaged into virus-like particles induce protective cytotoxic T cell responses in the absence of systemic side effects.
abstract: DNA rich in nonmethylated CG motifs (CpGs) greatly facilitates induction of immune responses against coadministered Ags. CpGs are therefore among the most promising adjuvants known to date. Nevertheless, CpGs are characterized by two drawbacks. They have unfavorable pharmacokinetics and may exhibit systemic side effects, including splenomegaly. We show in this study that packaging CpGs into virus-like particles (VLPs) derived from the hepatitis B core Ag or the bacteriophage Qbeta is a simple and attractive method to reduce these two problems. CpGs packaged into VLPs are resistant to DNase I digestion, enhancing their stability. In addition, and in contrast to free CpGs, packaging CpGs prevents splenomegaly in mice, without affecting their immunostimulatory capacity. In fact, vaccination with CpG-loaded VLPs was able to induce high frequencies of peptide-specific CD8(+) T cells (4-14%), protected from infection with recombinant vaccinia viruses, and eradicated established solid fibrosarcoma tumors. Thus, packaging CpGs into VLPs improves both their immunogenicity and pharmacodynamics.
authors.affiliation: Cytos Biotechnology AG, Schlieren-Zürich, Switzerland.
authors.forename: Tazio
authors.initials: T
authors.lastname: Storni
authors.forename: Christiane
authors.initials: C
authors.lastname: Ruedl
authors.forename: Katrin
authors.initials: K
authors.lastname: Schwarz
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Renner
authors.forename: Martin F
authors.initials: MF
authors.lastname: Bachmann
mesh_terms: D017908:Allolevivirus / Q000235:genetics / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000956:Antigens, Viral / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D018899:CpG Islands / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D019175:DNA Methylation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D004306:Dose-Response Relationship, Immunologic; D005354:Fibrosarcoma / Q000276:immunology / Q000517:prevention & control; D006023:Glycoproteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D006512:Hepatitis B Core Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D008081:Liposomes / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D012367:RNA, Viral / Q000008:administration & dosage / Q000235:genetics; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D013873:Thionucleotides / Q000037:antagonists & inhibitors / Q000633:toxicity; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology; D014764:Viral Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014771:Virion / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019065:Virus Assembly / Q000235:genetics / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; C408982:CPG-oligonucleotide; D006023:Glycoproteins; D006512:Hepatitis B Core Antigens; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D012367:RNA, Viral; D013873:Thionucleotides; D019444:Vaccines, DNA; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus