title: Fully detargeted polyethylene glycol-coated adenovirus vectors are potent genetic vaccines and escape from pre-existing anti-adenovirus antibodies.
abstract: Genetic vaccination with adenoviral (Ad) gene transfer vectors requires transduction of professional antigen-presenting cells. However, because the natural Ad receptors are expressed on many cell types, the Ad vectors currently in use are characterized by high promiscuity. In fact, the majority of injected Ad vector particles are likely to transduce non-target cells. We have analyzed various sizes of polyethylene glycol (PEG) molecules for vector particle detargeting, and our data provide evidence that the size of the PEG determines detargeting efficiency. With the use of appropriately large PEG molecules, vector particles were detargeted from muscle after local delivery and from liver after systemic delivery in mouse models. Surprisingly, fully detargeted PEGylated Ad vectors still induced strong cellular and humoral immune responses to vector-encoded transgene products. Also, injection of PEGylated and non-PEGylated vector particles resulted in similar kinetics of transgene product-specific cytotoxic immune responses, thereby suggesting that the same cell types were involved in their induction. Furthermore, we showed that PEGylated vectors evade neutralizing anti-Ad antibodies in vivo. This feature might help circumvent the recognized limitation imposed by the widespread occurrence of anti-Ad immunity in the human population. We suggest that PEGylated Ad particles with significantly reduced promiscuity may qualify as a novel and safe vector format for genetic vaccination.
authors.affiliation: Division of Gene Therapy, University of Ulm, Ulm, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wortmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Vöhringer
authors.forename: Tatjana
authors.initials: T
authors.lastname: Engler
authors.forename: Stephanie
authors.initials: S
authors.lastname: Corjon
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schirmbeck
authors.forename: Jörg
authors.initials: J
authors.lastname: Reimann
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
authors.forename: Florian
authors.initials: F
authors.lastname: Kreppel
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood*; D045744:Cell Line, Tumor; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000378:metabolism*; D014161:Transduction, Genetic; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D019444:Vaccines, DNA; D014765:Viral Vaccines; D011092:Polyethylene Glycols