AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer

Mol Ther. 2020 Mar 4;28(3):723-746. doi: 10.1016/j.ymthe.2019.12.010. Epub 2020 Jan 10.


Gene therapy with adeno-associated virus (AAV) vectors has demonstrated safety and long-term efficacy in a number of trials across target organs, including eye, liver, skeletal muscle, and the central nervous system. Since the initial evidence that AAV vectors can elicit capsid T cell responses in humans, which can affect the duration of transgene expression, much progress has been made in understanding and modulating AAV vector immunogenicity. It is now well established that exposure to wild-type AAV results in priming of the immune system against the virus, with development of both humoral and T cell immunity. Aside from the neutralizing effect of antibodies, the impact of pre-existing immunity to AAV on gene transfer is still poorly understood. Herein, we review data emerging from clinical trials across a broad range of gene therapy applications. Common features of immune responses to AAV can be found, suggesting, for example, that vector immunogenicity is dose-dependent, and that innate immunity plays an important role in the outcome of gene transfer. A range of host-specific factors are also likely to be important, and a comprehensive understanding of the mechanisms driving AAV vector immunogenicity in humans will be key to unlocking the full potential of in vivo gene therapy.

Keywords: AAV vectors; T cells; antibody responses; gene therapy; immune responses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Clinical Trials as Topic
  • Dependovirus / genetics
  • Dependovirus / immunology*
  • Drug Evaluation, Preclinical
  • Gene Transfer Techniques
  • Genetic Therapy / adverse effects
  • Genetic Therapy / methods
  • Genetic Vectors / adverse effects*
  • Genetic Vectors / genetics
  • Genetic Vectors / immunology
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity*
  • Immunity, Cellular
  • Immunity, Humoral
  • Immunity, Innate
  • Organ Specificity
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism