Global seroprevalence of neutralizing antibodies against adeno-associated virus serotypes used for human gene therapies

Amit Chhabra; George Bashirians; Christos J Petropoulos; Terri Wrin; Yuvika Paliwal; Peter V Henstock; Suryanarayan Somanathan; Candida da Fonseca Pereira; Ian Winburn; John E J Rasko

doi:10.1016/j.omtm.2024.101273

Global seroprevalence of neutralizing antibodies against adeno-associated virus serotypes used for human gene therapies

Mol Ther Methods Clin Dev. 2024 May 29;32(3):101273. doi: 10.1016/j.omtm.2024.101273. eCollection 2024 Sep 12.

Authors

Affiliations

¹ Pfizer Inc., New York, NY, USA.
² Pfizer Inc., Cambridge, MA, USA.
³ Labcorp-Monogram Biosciences, South San Francisco, CA, USA.
⁴ Pfizer Inc., Collegeville, PA, USA.
⁵ Pfizer Inc., Andover, MA, USA.
⁶ Pfizer Australia, Sydney, NSW, Australia.
⁷ Pfizer Ltd., Walton on the Hill, Surrey, UK.
⁸ University of Sydney, Central Clinical School, Faculty of Medicine & Health, Sydney, NSW, Australia.
⁹ Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
¹⁰ Gene and Stem Cell Therapy Program, Centenary Institute University of Sydney, Sydney, NSW, Australia.

Abstract

Adeno-associated virus (AAV) vectors are promising gene therapy candidates, but pre-existing anti-AAV neutralizing antibodies (NAbs) pose a significant challenge to successful gene delivery. Knowledge of NAb seroprevalence remains limited and inconsistent. We measured activity of NAbs against six clinically relevant AAV serotypes across 10 countries in adults (n = 502) and children (n = 50) using a highly sensitive transduction inhibition assay. NAb prevalence was generally highest for AAV1 and lowest for AAV5. There was considerable variability across countries and geographical regions. NAb prevalence increased with age and was higher in females, participants of Asian ethnicity, and participants in cancer trials. Co-prevalence was most frequently observed between AAV1 and AAV6 and less frequently between AAV5 and other AAVs. Machine learning analyses revealed a unique clustering of AAVs that differed from previous phylogenetic classifications. These results offer insights into the biological relationships between the immunogenicity of AAVs in humans beyond that observed previously using standard clades, which are based on linear capsid sequences. Our findings may inform improved vector design and facilitate the development of AAV vector-mediated clinical gene therapies.

Keywords: AAV1; AAV5; AAV6; AAV8; AAV9; AAVRh74var; biotechnology; clinical trials; genetic diseases; rare disease.