F8 and hemophilia A: Initial exposure to fVIII by persons with hemophilia A represents an immunologic challenge that can lead to the development of neutralizing humoral immunity in ~25% of persons with severe hemophilia A.5,30 Since rAAV gene therapies are designed to provide a continuous source of the exogenous protein in treated individuals, this response presents a considerable safety and efficacy concern as these vectors are translated into human trials.