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.