Grant: Project Grant

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 HIV. Our patented 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, Marburg virus, respiratory syncytial virus, and C. Difficile toxin challenge, among other infectious diseases. Here 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. We hypothesize that AAV-mAb expression can prevent clinical illness caused by viral infectious diseases in NHP animal models and strategies can be employed to evade pre-existing immunity, mitigate immune-mediated clearance of vector transduced cells, and lower vector doses resulting in long-term mAb expression. To address this hypothesis, we will execute the following aims: (1) Evaluate innovative strategies to enhance AAV-mAb expression in the presence of pre-existing immunity, and/or to facilitate repeat administration in rodents, (2) Analyze the efficacy of a pan-filovirus AAV VIP platform expressing a bispecific mAb in rodents, (3) Investigate mechanisms of ADA responses to AAV-mAb expression in a large animal sheep model and (4) Based on the optimization steps in Aims 1-3, characterize the AAV VIP platform, including evaluation of ADA response, in a MARV NHP challenge model Expertise: Dr. Wootton is expert in the field of AAV biology and vector design. Dr. Banadyga is an expert in high consequence pathogen animal model and CL4 containment challenge studies. Dr. Susta is an expert in animal models of infectious disease and anatomic pathology.