Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A

Abstract

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.

Testing preexisting antibodies prior to AAV gene transfer therapy: rationale, lessons and future considerations

“… 41 In the hemophilia A population, 47% of patients in Russia were seropositive for anti-AAV5 antibodies compared with 21% in the United States. 42 …”

Gene therapy in haemophilia: literature review and regional perspectives for Turkey

“… 56 , 57 Global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10 in haemophilia A patients ⩾ 12 years of age. 58 A study from the UK reported the prevalence of neutralizing antibodies as 23%, 35% and 18% for AAV-LK03, AAV3B and AAV8, respectively, with the lowest seroprevalence between 3 and 17 years of age for all serotypes. 59 Most of the studies showed that the presence of anti-AAV antibodies, even at low titers, can significantly diminish AAV vector delivery.…”

Haemophilia gene therapy—Update on new country initiatives

“…To this end, South Africa participates in several gene therapy development programs for haemophilia A and B (NCT03370913; NCT03520712; NCT04272554; NCT03432520). However, an emerging finding in South African participants is the high prevalence of antibodies to specific AAV serotypes used in gene therapy (Haemophilia A seroprevalence: AAV2 94%, AAV5 51%, AAV6 80%, AAV8 70% 36 ; Haemophilia B seroprevalence: AAV5 95%, AAV8 38% 37 ). It is in this context that we have embarked on an extensive screening program for anti‐AAV antibodies in both patients and the general population.…”