Co-Prevalence of Pre-Existing Immunity to Different Serotypes of Adeno-Associated Virus (AAV) in Adults with Hemophilia

Background: Recombinant and synthetic adeno-associated virus (AAV) vectors are in development for gene transfer in patients with hemophilia A (HA) or hemophilia B (HB). These include liver-directed recombinant AAV8 vectors BAX 888/SHP654/TAK-754 factor VIII (FVIII) gene therapy (GT) for severe HA, and SHP648/TAK-748 factor IX (FIX) GT for HB (Baxalta US Inc., a Takeda company, Lexington, MA, USA). However, environmental exposure to wild-type AAVs can result in individuals developing antibodies and cell-mediated immune responses to the naturally occurring AAV. While natural exposure to AAV does not result in any known disease in humans, presence of preexisting immunity can block delivery and prevent sustained expression of the transgene by an AAV-based vector in a gene therapy setting. Of the AAV serotypes, AAV2 is the most frequently encountered natural human infection and AAV5 and AAV8 have been the most commonly used vectors for hemophilia GT. Therefore, it is important to assess the prevalence and co-prevalence of antibody and T cell-mediated responses against each of these AAV serotypes and to better characterize the association between humoral and cellular immunity in people with hemophilia. Aims: To determine the prevalence of preexisting antibody-mediated immunity against AAV2, AAV5 and AAV8 and the association between AAV8-specific humoral and cell-mediated responses in adult patients with HA and HB in an international prospective, epidemiological study. Methods: This ongoing seroprevalence study involved adult male patients (18-75 years of age) with severe HA (