engleski

Protection following intramuscular injection of replication-defective adenovirus vectored vaccines is linked to promoter efficiency in muscle representative cells

To investigate the respective role of transduced cells in the induction of immune response following intramuscular inoculation of adenovirus-based vaccines, we generated several replication-defective adenoviruses expressing the glycoprotein D gene of pseudorabies virus (PRV) under the control of four different promoters : major late promoter of adenovirus type 2, human cytomegalovirus immediate-early promoter/enhancer (CMV), Rous sarcoma virus - long terminal repeat promoter, and human desmin gene 5' regulatory region (DES). All the adenovirus constructs were able to fully protect mice against challenge with PRV. The far most effective adenovirus constructs, on the criterion of protective doses and specific antibody response induction, were those in which the foreign gene was driven by the DES or CMV promoter. Wide variations in promoter strength in vitro were evidenced in several cell types representative of putative target cells following muscular inoculation (myoblasts, myotubes, fibroblasts, macrophages and endothelial cells). We confirmed previous findings that due to the E1A enhancer, only partial regulation of tissue-specific cellular promoters (i.e. DES) can be conferred, after introduction of the foreign gene cassette in the E1A region of adenovirus. The level of efficacy in vivo, was not correlated with the level of expression in myotubes, but paralleled the level of expression in endothelial cells and in myoblasts. These results suggest that, following adenovirus injection, locally produced cytokines may induce myoblasts to act as local antigen presenting cells.

adenovirus-based vaccines; glycoprotein D; immune response

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