T-cell–mediated immunity to the capsid in the AAV8-F.IX trial. (A-B) Subject 5 received a vector dose of 2 × 10¹² vg/kg. At week 8 postinfusion, his F.IX levels (red line) began to decline and his liver enzymes increased (ALT, green line). Concomitantly, capsid-specific T cells became detectable in peripheral blood. A course of prednisolone was associated with resolution of the transaminitis and partial rescue of F.IX transgene expression levels. (C-D) Subject 6, dosed at 2 × 10¹² vg/kg, experienced an increase in liver enzymes and was promptly treated with steroids. In this subject, increase in liver enzymes and decrease in F.IX transgene expression levels was also associated with detection of capsid-reactive T cells in PBMCs. Reprinted from Nathwani et al.⁴