Humoral immune response to recombinant adenovirus and adeno-associated virus after in utero administration of viral vectors in mice

Adenovirus and adeno-associated virus vector-mediated gene delivery is limited by the induction of a humoral immune response that prevents read mini strati on. To determine whether viral delivery in the "preimmune" fetus would produce dose- or time-dependent tolerance, we evaluated the humoral immune response after sequential pre- and postnatal virus administration. We evaluated six injection route and viral dose combinations of adenovirus (intra-amniotic, intrahepatic, and intramuscular injection at 4 x 10(8) and 2 x 10(9) particles/fetus) at d 15 postconception (p.c.); three route and dose combinations at d 13 p.c. (intramuscular injection at 1 x 10(8), 3 x 10(8), and 5 x 10(8) particles/fetus); and one route and dose combination of adenoassociated virus (intramuscular at 2.5 x 10(10) genome copies/ fetus) at d 15 p.c. In utero injection of either viral vector at any route and dose combination resulted in the production of low titers of neutralizing antivirus and antitransgene (beta-galactosidase) antibodies. This primary immune response only partially blocked transgene expression after the readministration of viral vectors postnatally. However, delivery of the virus postnatally triggered an immune response that completely blocked transgene expression after a third viral injection. Together, these results suggest that, for B6/129 F1 mice, in utero injection of recombinant adenovirus or adeno-associated virus between d13 and 15 p.c. does not induce tolerance to the viral vector or transgene product.