Ovine adenovirus vectors overcome preexisting humoral immunity against human adenoviruses in vivo

Recombinant human adenoviruses (hAd) have become widely used as tools to ac hieve efficient gene transfer. However, successful application of hAd-deriv ed vectors in clinical trials is limited due to immunological and potential safety problems inherent in their human origin. In this study, we describe a recombinant ovine adenovirus (OAV) as an alternative vector for gene tra nsfer in vivo. In contrast to an hAd vector, the OAV vector was not neutral ized by human sera. An OAV vector which contained the cDNA of the human alp ha(1)-antitrypsin (hAAT) gene Linked to the Rous sarcoma virus promoter was generated and administered systemically to mice. The level and duration of hAAT gene expression was similar to that achieved with an hAd counterpart in both immunocompetent and immunodeficient mice. However, the tissue distr ibution of the OAV vector differed from that observed for hAd vectors in th at the liver was not the dominant target. Significantly, we demonstrated ef ficient gene transfer with the OAV vector into mice immunized with hAd vect ors and vice versa. We also confirm that the immune response to a transgene product can prevent its functional expression following sequential applica tion of a vector. Our results suggest a possible solution to endemic humora l immunity against currently used hAd vectors and should therefore have an impact on the design of improved gene therapy protocols utilizing adenoviru s vectors.