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Global Seroprevalence of Pre-existing Immunity against AAV Serotypes in People with Hemophilia A

1Comprehensive Care Haemophilia Treatment Center, Vivantes Klinikum im Friedrichshain, Berlin, Germany, 2BioMarin Pharmaceutical Inc., Novato, United States, 3Municipal Center of Hemophilia Therapy, St. Petersburg, Russian Federation, 4Ogikubo Hospital, Tokyo, Japan, 5Indiana Hemophilia and Thrombosis Center, Indianapolis, United States, 6Nara Medical University, Kashihara, Japan, 7ARUP Laboratories, Salt Lake City, United States, 8Universitätsklinikum Bonn, Bonn, Germany, 9Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil, 10Centre de Ressources et de Compétence des Maladies Hémorragiques Constitutionnelles, CHU de Bordeaux, Bordeaux, France, 11Haemophilia Comprehensive Care Centre, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa, 12Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy, 13Department of Haematology, Southampton University Hospital, Southampton, United Kingdom, 14Departments of Medicine and Laboratory Medicine, University of California San Francisco, San Francisco, United States, 15Division of Pediatric Hematology/Oncology, Central Michigan University, Detroit, United States, 16Centre Hospitalier Régional Universitaire de Brest, Hôpital A. Morvan, Brest, France, 17The Orthopedic Hemophilia Treatment Center, Los Angeles, United States

Abstract Number: LPB0022

Meeting: ISTH 2021 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia Gene Therapy

Background: Adeno‐associated virus (AAV)‐mediated gene therapy may provide durable protection from bleeding events and reduced treatment burden to people with hemophilia A (PwHA). However, pre-existing immunity against AAV may limit treatment success. Global data on the prevalence of AAV serotypes are limited.

Aims: We determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and rh10 capsids among PwHA from 9 countries.

Methods: BMN 270-901 was a prospective study conducted in PwHA in Brazil, France, Germany, Italy, Japan, Russia, South Africa, the UK, and the USA. Plasma samples were collected from participants who provided informed consent. 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.

Results: The study enrolled 546 participants: 478 adults (aged ≥18 years) and 68 adolescents (<18 years). Global seroprevalence of antibodies on day 1 are displayed in Table 1.

AAV Serotype Global Brazil France Germany Italy Japan Russia South Africa UK USA
AAV2 +/total (%) 300/513 (58.5%) N/A 52/86 (60.5%) 43/89 (48.3%) 9/20 (45.0%) 36/83 (43.4%) 58/91 (63.7%) 53/56 (94.6%) 11/17 (64.7%) 38/71 (53.5%)
AAV5 +/total (%) 188/540 (34.8%) 7/26 (26.9%) 32/86 (37.2%) 25/89 (28.1%) 8/20 (40.0%) 25/84 (29.8%) 42/91 (46.2%) 29/56 (51.8%) 1/17
(5.9%)		 19/71 (26.8%)
AAV6 +/total (%) 250/513 (48.7%) N/A 47/86 (54.7%) 39/89 (43.8%) 8/20 (40.0%) 26/83 (31.3%) 51/91 (56.0%) 45/56 (80.4%) 7/17 (41.2%) 27/71 (38.0%)
AAV8 +/total (%) 234/513 (45.6%) N/A 39/86 (45.3%) 38/89 (42.7%) 8/20 (40.0%) 32/83 (38.6%) 49/91 (53.8%) 39/56 (69.6%) 7/17 (41.2%) 22/71 (31.0%)
rh10 +/total (%) 236/513 (46.0%) N/A 45/86 (52.3%) 33/89 (37.1%) 10/20 (50.0%) 25/83 (30.1%) 48/91 (52.7%) 41/56 (73.2%) 9/17 (52.9%) 25/71 (35.2%)
Data are shown for participants with non-missing assessments.
+, positive; AAV, adeno‐associated virus; N/A, not available.

Table 1: Global seroprevalence of antibodies on day 1
Considerable geographic variability was observed in the prevalence of pre‐existing antibodies against each serotype, but the percentage of participants positive for AAV5 was consistently the lowest among serotypes and across the countries studied. A greater percentage of adult participants were positive for AAV5 antibodies (36%) when compared with adolescents (29%). Comparative analyses of AAV serostatus in non-hemophilic individuals in select countries showed similar rates of seropositivity, as would be expected for viruses endemic to the human population. Serostatus and antibody titer were generally stable over the 6-month sampling period.

Conclusions: Among PwHA, pre-existing immunity against AAV serotypes varied across serotypes and regions, but global seropositivity was lowest for AAV5 and highest for AAV2. As clinical trials of AAV-mediated gene therapies progress, the presence of antibodies against the various AAV serotypes may become an increasingly important eligibility consideration.

To cite this abstract in AMA style:

Klamroth R, Hayes G, Andreeva T, Suzuki T, Hardesty B, Shima M, Pollock T, Slev P, Oldenburg J, C Ozelo M, Castet S-, Mahlangu J, Peyvandi F, Kazmi R, D Leavitt A, Callaghan M, Pan-Petesch B, Quon D, Li M, Wong WY. Global Seroprevalence of Pre-existing Immunity against AAV Serotypes in People with Hemophilia A [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/global-seroprevalence-of-pre-existing-immunity-against-aav-serotypes-in-people-with-hemophilia-a/. Accessed December 3, 2021.

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