Efficacy of a Broadly Neutralizing Monoclonal Antibody Against Mpox in Non-Human Primates

SUMMARY Mpox (Monkeypox virus, MPXV) has become a global health threat, yet current prevention and treatment tools remain inadequate. The JYNNEOS vaccine offers limited protection, and Tecovirimat, the only antiviral tested in humans, has failed in clinical trials. There are currently no approved monoclonal antibody (mAb) therapies for mpox or any orthopoxvirus. This project proposes to develop and evaluate EV35-6, a potent mAb targeting A35, a critical MPXV protein involved in viral dissemination and a promising antibody target not engaged by vaccination. Aim 1 will assess the efficacy and optimal delivery route (intravenous vs. subcutaneous) of EV35-6 in a rigorously validated non-human primate (NHP) model of mpox that mimics human disease. Outcomes include clinical protection, reduction in viral load, tissue-level pathology, and pharmacokinetic profiling. Aim 2 will evaluate whether the presence of EV35-6-like antibodies correlates with protection in NHPs and determine how broadly EV35-6 binds to A35 orthologs across multiple orthopoxviruses, including Variola, Vaccinia, Cowpox, and different MPXV clades. Techniques include competition ELISA, affinity binding assays, and in vitro neutralization. This is the first study to test a monoclonal antibody for mpox in NHPs. It will generate critical data for the clinical development of EV35-6 and set a foundation for rational, epitope-driven antibody therapies for mpox and other orthopoxvirus threats.