Adeno-associated virus serotype 9 antibodies in neonates and young children: Seroprevalence and kinetics

Gene therapies such as onasemnogene abeparvovec for spinal muscular atrophy (SMA) utilize adeno-associated virus 9 (AAV9) for targeted gene delivery, which requires an AAV9 antibody (AAV9-Ab) immunoglobulin G (IgG) ≤1:50 titer threshold. This retrospective cohort study evaluated age-related AAV9-Ab IgG seroprevalence for patients with SMA (part 1) and AAV9-Ab IgG kinetics and time to 1:50 titer threshold in newborns with elevated AAV9-Ab IgG titers (≥1:100) (part 2). A semi-quantitative ELISA assay was used in part 1 (<i>N</i> = 1,323 patients). For patients aged <12 months, 3.9% (<i>n</i>/<i>N</i> = 31/795) had elevated AAV9-Ab IgG titers (≥1:100); prevalence declined with age. In part 2, a new quantitative ELISA (linear mixed effects model) described continuous AAV9-Ab IgG concentrations for patients with initial titers ≥1:100. AAV9-Ab IgG concentrations waned according to first-order kinetics (58 samples; <i>N</i> = 18 patients). The model-based estimation of the AAV9-Ab IgG average half-life was 41 (95% CI, 38-44) days. Based on visualization, 200 ELISA units/mL was a reasonable approximate for the 1:50 titer threshold. In conclusion, initially elevated titers ≥1:100 in newborn patients declined with age. The new quantitative ELISA may allow for quantification of time to threshold for AAV9-Ab IgG retesting for onasemnogene abeparvovec treatment, leading to treatment as early as possible for patients with SMA.