Immunogenicity in Approved Adeno-Associated Virus-Based Gene Therapies: A Framework for a Tailored Assessment Strategy

Abstract Adeno-associated virus (AAV)-based gene therapy has emerged as a promising approach for treating a variety of genetic disorders by delivering therapeutic genes to target tissues. There have been numerous publications reporting nonclinical assessments of immune responses to various AAV-based gene therapy products (GTPs). However, the immune response data from approved GTPs in humans have not been systematically reviewed, and the utility of the data generated in these clinical studies has not been evaluated. This manuscript is intended as a comprehensive review of the nonclinical and clinical immunogenicity data, with focus on adaptive immunity, from nine AAV-based GTPs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2017 and early 2026. It also offers science-based recommendations to inform the future development of GTPs. The accumulated experience from these approved GTPs support a tailored, risk-based approach to immunogenicity monitoring: pre-existing anti-vector antibodies show limited association to clinical response and cellular immune response measurement via ELISpot have practical limitations in clinical studies. These findings advocate for simplified analytical strategies — tailored to the drug development stage and informed by nonclinical data — that incorporate clinical safety markers such as liver function tests, cardiac damage markers, and transgene protein expression as indicators of clinically meaningful immune responses.