Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A

Mol Ther. 2021 Feb 3;29(2):597-610. doi: 10.1016/j.ymthe.2020.12.008. Epub 2020 Dec 10.


Evaluation of immune responses to adeno-associated virus (AAV)-mediated gene therapies prior to and following dose administration plays a key role in determining therapeutic safety and efficacy. This report describes up to 3 years of immunogenicity data following administration of valoctocogene roxaparvovec (BMN 270), an AAV5-mediated gene therapy encoding human B domain-deleted FVIII (hFVIII-SQ) in a phase 1/2 clinical study of adult males with severe hemophilia A. Patients with pre-existing humoral immunity to AAV5 or with a history of FVIII inhibitors were excluded from the trial. Blood plasma and peripheral blood mononuclear cell (PBMC) samples were collected at regular intervals following dose administration for assessment of humoral and cellular immune responses to both the AAV5 vector and transgene-expressed hFVIII-SQ. The predominant immune response elicited by BMN 270 administration was largely limited to the development of antibodies against the AAV5 capsid that were cross-reactive with other common AAV serotypes. No FVIII inhibitor responses were observed within 3 years following dose administration. In a context of prophylactic or on-demand corticosteroid immunosuppression given after vector infusion, AAV5 and hFVIII-SQ peptide-specific cellular immune responses were intermittently detected by an interferon (IFN)-γ and tumor necrosis factor (TNF)-α FluoroSpot assay, but they were not clearly associated with detrimental safety events or changes in efficacy measures.

Keywords: AAV; AAV antibody; adeno-associated virus vector; cellular immunity; clinical immunogenicity; clinical safety; cross-reactivity; gene therapy; hemophilia A; humoral immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cross Reactions / immunology
  • Dependovirus / genetics*
  • Dependovirus / immunology
  • Factor VIII / genetics
  • Genetic Therapy* / adverse effects
  • Genetic Therapy* / methods
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / adverse effects
  • Genetic Vectors / genetics*
  • Hemophilia A / genetics*
  • Hemophilia A / therapy*
  • Host Microbial Interactions / immunology
  • Humans
  • Immunity, Humoral
  • Male
  • Transgenes
  • Treatment Outcome


  • Factor VIII