Project 456332

Adeno-associated virus (AAV)-mediated expression of pathogen specific, broadly protective monoclonal antibodies (mAb) has been demonstrated to provide protection against a variety of infectious diseases in a range of animal models and is now being tested in two human clinical trials for human immunodeficiency virus (HIV) (NCT03374202 and NCT01937455). Our patented (U.S. patent US 10,806,802) AAV-mAb expression platform utilizes a novel, rationally engineered AAV6 mutant capsid, termed AAV6.2FF, which has been shown to be highly efficacious as a prophylactic against Ebola virus and C. Difficile toxin challenge, among other infectious diseases. In this proposal we aim to optimize and expand our vectored immunoprophylaxis (VIP) platform to aid in the clinical translation of this promising alternative vaccine and therapeutic strategy. Specifically, we will investigate AAV-vectored mAb expression kinetics, anti-drug antibody development, effect of pre-existing immunity, and ways to modulate gene expression and in a range of larger animal models including guinea pigs, ferrets, sheep, and non-human primates. Finally, we will implement novel vector design improvements and explore new applications for AAV-vectored mAb expression.