Effects of shielding adenoviral vectors with polyethylene glycol on vector-specific and vaccine-mediated immune responses

Many individuals have been previously exposed to human adenovirus serotype 5 (Ad5). This prior immunity has long been known to hinder its use for gene therapy and as a gene-based vaccine. Given these immunogenicity problems, we have tested whether polyethylene glycol (PEG) can blunt immune effects against Ad5 during systemic and mucosal vaccination. Ad5 vectors were covalently modified with 5-, 20-, and 35-kDa linear PEG polymers and evaluated for their ability to produce immune responses against transgene antigen products and the vector itself. We show that shielding Ad5 with different-sized PEGs generally reduces transduction and primary antibody responses by the intramuscular or intranasal route. In contrast, PEGylated vectors generally appear better at boosting antibody responses in Ad-immune animals. Displaying either glucose or galactose on PEG mediated increased transduction and antibody responses by the intranasal, but not the intramuscular, route. In naive animals, PEGylated vectors generated T cell responses that were equal to or better than those by unmodified Ad. Priming by PEGylated vectors generally enabled better subsequent T cell responses after boost. Priming and boosting by PEGylated vectors produced T cell responses after boost that were equal to or higher than those produced by unmodified vectors. These data indicate that PEGylation can enable more effective application of Ad5 and perhaps other Ad serotype vaccines during prime-boost vaccination.