Human monoclonal antibodies targeting A35 protect from death against mpox 2296

Abstract Description The mpox disease, caused by the monkeypox virus (MPXV), has re-emerged as a significant global health threat, leading the World Health Organization (WHO) to declare it a Public Health Emergency of International Concern. Recent global outbreaks, particularly in non-endemic regions, and the new sustained human-to-human transmission pattern highlight the urgent need for effective therapeutic and prophylactic measures. One key tool in developing vaccines and therapeutic models against orthopoxviruses, including MPXV, is the vaccinia virus (VACV), closely related to MPXV and widely used in research and vaccine development due to its safety profile and ability to induce cross-protective immunity within this viral family. In our study, we isolated three human monoclonal antibodies (mAbs)—EV35-2, EV35-6, and EV35-7—from a mpox-convalescent individual. These antibodies target both A35 (MPXV) and its VACV ortholog A33, a crucial glycoprotein involved in viral attachment and entry. These mAbs were characterized for their binding specificity and affinity using ELISA and biolayer interferometry (BLI) against both viruses, followed by in vitro and in vivo neutralization and protection assays. All mAbs exhibited binding activity in the nanomolar range, with EV35-2 showing superior neutralizing efficacy in vitro. All mAbs provided 100% protection in a BALB/c mouse model, suggesting that targeting A35 could help develop potent antibody-based therapies or vaccines against orthopoxviruses. Funding Sources This project has been funded in whole or in part with federal funds from the National Institutes of Health (U19 AI142737, U19 AI168631). Topic Categories Vaccines and Immunotherapy (VAC)