Seroprevalence and Half-life of Pre-existing Anti–adeno-associated Virus Serotype 9 (AAV9) Antibodies in Neonates


Clinical Management

Poster Number: 45


Rudolf Walther van Olden, MD, PhD, Novartis Gene Therapies Switzerland GmbH, Christophe Lo Bianco, PhD, Novartis Gene Therapies Switzerland GmbH, Keith Dilly, PhD, Novartis Gene Therapies, Aloys Tijsma, MSc, PhD, Viroclinics Biosciences BV, Carel van Baalen, PhD, Viroclinics Biosciences BV

Background: Onasemnogene abeparvovec is a one-time AAV9 vector-based gene replacement therapy for the treatment of spinal muscular atrophy. Safety and efficacy of onasemnogene abeparvovec for patients with elevated anti-AAV9 antibody titers (>1:50) are not established. Neonates may have elevated anti-AAV9 antibody concentrations because of transplacental maternal transfer, but titers generally decrease after birth. The seroprevalence and half-life of passively acquired anti-AAV9 antibodies in newborns are unknown.
Objective: We aimed to establish the seroprevalence and half-life of maternally transferred anti-AAV9 antibodies in neonates.
Methods: AAV9 IgG titers were measured with an enzyme-linked immunosorbent assay (ELISA) in 795 patients aged 0–12 months. AAV9 IgG concentrations of 13 neonates with at least two longitudinal samples and initial titers ≥1:100 were measured with a novel, more quantitative ELISA assay (Viroclinics Biosciences) to express AAV9 IgG concentrations in EU/mL and to calculate half-lives. Additional samples were tested to express IgG concentrations relative to AAV9 IgG titers.
Results: For neonates aged 0–1 month, the prevalence of elevated antibody titers was 14% (n=22/160). The prevalence was 2% for patients aged 2–3 months (n=4/178), and this continued to decrease during the first year of life. For the 13 patients with multiple samples, antibody concentrations waned for all patients according to first-order kinetics. The half-life of the antibodies was estimated to be 18–59 days. An AAV9 IgG titer of ≤1:50 was equivalent to a concentration of <203 EU/mL. Conclusions: Concentrations of anti-AAV9 antibodies acquired via transplacental maternal transfer decrease in newborns following first-order kinetics. To follow the decline of elevated anti-AAV9 antibody titers to concentrations that permit onasemnogene abeparvovec dosing, retesting should be considered at 4 weeks for patients with initial titers ≥1:200, and at 8 weeks for initial titers ≥1:400. Initially elevated anti-AAV9 antibodies in newborns do not preclude onasemnogene abeparvovec administration.