Germline incorporation of a replication-defective adenoviral vector in mice does not alter immune responses to adenoviral vectors

The utility of adenoviral vectors is limited by immune responses to adenovi ral antigens. We sought to develop immune-competent mice in which the immun e response to adenoviral antigens was selectively absent. To do so, we gene rated mice that were transgenic for a replicationdefective vector. Adenovir al antigens might be seen as self-antigens by these mice, and the mice coul d exhibit immunologic tolerance after postnatal exposure to adenoviral vect ors. In addition, characterization of these mice could reveal potential con sequences of germline transmission of an adenoviral vector, as might occur in a gene therapy trial. Injection of a "null" (not containing a transgene) E1, E3-deleted vector genome into mouse zygotes yielded five founders that were capable of transmitting the vector genome. Among offspring of these m ice, transgenic pups were significantly underrepresented: 108 of 255 pups ( 42%) were transgenic (P < 0.02 versus expected frequency of 50%). Postnatal transgenic mice, however, had no apparent abnormalities. Persistence of an adenoviral vector after intravenous injection was equivalent in livers of transgenic mice and their nontransgenic littermates. Transgenic and nontran sgenic mice also had equivalent humoral and cellular immune responses to ad enoviral vector injection. Mice that are transgenic for an E1, E3-deleted a denoviral genome can be easily generated; however, they are not tolerant of adenovirus. Moreover, germline transmission of an adenoviral vector genome does not prevent generation of a robust immune response after exposure to adenoviral antigens.