Human adenoviruses rendered defective by deletion of E1 sequences have been used as vectors for gene transfer. In vivo administration of these vectors results in activation of B and T cells to the input capsid proteins and transgene products, which is due, in part, to the ability of this group of vectors to efficiently transduce dendritic cells. We have explored the application of adenoviral vectors as vaccine carriers with encouraging results. One problem with the use of vectors based on human adenoviruses is that a significant proportion of the population has neutralizing antibodies to the vector as a result of a naturally acquired infections; these antibodies substantially diminish the effectiveness of the vector as a vaccine. In order to overcome this problem, we propose to develop novel adenoviral vectors, derived from species other then humans, which elicit antigen specific immune responses but are not inhibited by sera generated to human adenoviruses. The approach described in this proposal is to characterize and develop as vectors adenoviruses previously isolated from chimpanzees. In preliminary studies we sequenced the chimp adenovirus called C68 and showed that an E1 deleted version of C68 can grow in cell lines expressing E1 from human Ad 5. The C68 vector efficiently transduces human dendritic cells and activates T and B ceils in mice, and C68 is not neutralized by human sera. The goals of this project are to expand our characterization of C68 and evaluate three additional chimp Ad isolates, called pan5, pan6 and pan7, as potential vectors for vaccines.
Specific Aim #1 will define the complete sequence of the additional chimp Ads and generate E1 deleted versions.
Specific Aim #2 will evaluate all four chimp Ads for gene transfer and toxicity when injected into mice and evaluate serologic similarity in terms of cross neutralization.
Specific Aim #3 will characterize the interaction of the chimp Ads with human lendritic cells.
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