TY - JOUR
T1 - Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A
AU - Klamroth, Robert
AU - Hayes, Gregory
AU - Andreeva, Tatiana
AU - Gregg, Keith
AU - Suzuki, Takashi
AU - Mitha, Ismail Haroon
AU - Hardesty, Brandon
AU - Shima, Midori
AU - Pollock, Toni
AU - Slev, Patricia
AU - Oldenburg, Johannes
AU - Ozelo, Margareth C.
AU - Stieltjes, Natalie
AU - Castet, Sabine Marie
AU - Mahlangu, Johnny
AU - Peyvandi, Flora
AU - Kazmi, Rashid
AU - Schved, Jean François
AU - Leavitt, Andrew D.
AU - Callaghan, Michael
AU - Pan-Petesch, Brigitte
AU - Quon, Doris V.
AU - Andrews, Jayson
AU - Trinh, Alex
AU - Li, Mingjin
AU - Wong, Wing Yen
N1 - Funding Information:
We thank the study participants, study site personnel, and investigators contributing to the 270–901 study. We thank Vikram Pansare, Emanuela Izzo, Greg de Hart, Brian Long, and Theresa Seitel of BioMarin Pharmaceu- tical for their contributions to this study and article. Adam Harris of BioMarin Pharmaceutical managed the biobank and oversaw all sample logistics. Medical writing support was provided by Meryl Gersh, PhD, and Kathleen Pieper, PhD, of AlphaBioCom and funded by BioMarin Pharmaceutical. Project management was provided by Micah Robinson, PhD, of BioMarin Pharmaceutical. A portion of the results in this article was previously presented at the International Society on Thrombosis and Haemostasis 2021 Virtual Congress.
Funding Information:
T.S. has received consulting fees from Chugai, Takeda, and CSL Behring; has received research grants from Bayer; has participated as a clinical trial investigator for Chugai, BioMarin Pharmaceutical, Inc., CSL Behring, and Novo Nordisk; and has received speaker honoraria for Chugai, BioMarin Pharmaceutical, Inc., Bayer, Takeda, Baxalta, CSL Behring, Japan Blood Product Organization, Welfen, KM Biologics, Sekisui Medical, and Novo Nordisk.
Publisher Copyright:
© Robert Klamroth et al. 2022.
PY - 2022/4
Y1 - 2022/4
N2 - Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (n = 56), 46.2% in Russia (n = 91), 40% in Italy (n = 20), 37.2% in France (n = 86), 26.8% in the United States (n = 71), 26.9% in Brazil (n = 26), 28.1% in Germany (n = 89), 29.8% in Japan (n = 84), and 5.9% in the United Kingdom (n = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.
AB - Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (n = 56), 46.2% in Russia (n = 91), 40% in Italy (n = 20), 37.2% in France (n = 86), 26.8% in the United States (n = 71), 26.9% in Brazil (n = 26), 28.1% in Germany (n = 89), 29.8% in Japan (n = 84), and 5.9% in the United Kingdom (n = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.
KW - adeno-associated virus
KW - antibody
KW - gene therapy
KW - hemophilia A
KW - seropositivity
UR - http://www.scopus.com/inward/record.url?scp=85128773941&partnerID=8YFLogxK
U2 - 10.1089/hum.2021.287
DO - 10.1089/hum.2021.287
M3 - Article
C2 - 35156839
AN - SCOPUS:85128773941
SN - 1043-0342
VL - 33
SP - 432
EP - 441
JO - Human Gene Therapy
JF - Human Gene Therapy
IS - 7-8
ER -