699. Effective AAV9 Vector Delivery to Nasal Mucosa for Protection Against Airborne Challenge with Influenza A and B

Abstract

To transition the AAV-mediated passive immunization strategy for protection against influenza A and B from mice to humans, an efficient vector delivery strategy is needed. Here, we demonstrate the ability of AAV9 expressing anti-influenza A and B antibodies (FI6 and CR8033, respectively) coupled with an intranasal mucosal atomization device (IMAD) to effectively protect mice against challenge with pandemic and seasonal influenza. First, we determined that an equimolar combination of AAV9.FI6 and AAV9.CR8033 vectors delivered intranasally at a dose of 5×1010 GC/KG per mouse effectively protected mice against lethal intranasal challenge with influenza A (PR8) or influenza B (B/Lee/40), respectively. In an effort to progress AAV9 into the clinic, we next determined vector compatibility with the IMAD for loss in volume, vector titer and vector potency. Groups of mice were intranasally administered a mixture of AAV9.FI6 and AAV9.CR8033 as well as a mixture of AAV9.FI6 and AAV9.CR8033 that was processed through the IMAD. Seven days later, the mice were challenged with 5LD50 of PR8 or B/Lee/40. No difference in effectiveness of protection against influenza A or B was observed when the vector mixture was processed through the IMAD. We next translated this approach to the nose of macaques, a model more closely related to the human nose that is the target tissue. In this model, we assessed the kinetics of the onset of transgene expression and stability of expression when vector was delivered via the IMAD compared with traditional, direct liquid delivery. At the conclusion of the study, vector biodistribution was also examined. Overall, no significant differences in the kinetics and profile of gene expression or vector biodistribution were observed between the two delivery methods. In conclusion, we demonstrate the safety and effectiveness of AAV-mediated prophylaxis against influenza A and B when vectors are delivered via the IMAD, an easy-to-use device that localizes transduction to the site of influenza infection, the nasal mucosa.