Ron Yefet, Leandro Battini, Mathieu Hubert, Katya Rakayev, Florence Guivel‐Benhassine, Noam Rattner, Françoise Porrot, Lilach Abramovitz, Gilad Ostashinsky, Noam Ben-Shalom, Jeanne Postal, Ksenia Polonsky, Maya Ralph-Altman, Sireen Sweed, T. W. Körner, Nadav Friedel, David Hagin, Eli Sprecher, Zvi Fishelson, Oren Kobiler, Lihi Adler‐Abramovich, Olivier Schwartz, Pablo Guardado‐Calvo, Natalia T. Freund
Monkeypox virus (MPXV) is the most pathogenic Poxvirus in circulation, yet key viral antigens remain immunologically unexplored. We isolate and characterize a panel of monoclonal antibodies (mAbs) targeting MPXV A28 (OPG153), an important membranal protein present on mature MPXV virions. From male convalescent individuals, we isolate anti-A28 mAbs alongside additional mAbs targeting the A35 and H3 proteins. Anti-A28 mAbs potently neutralize MPXV and Vaccinia virus (VACV) through complement-dependent mechanisms involving C1q and C3 deposition. High-resolution crystal structures of two anti-A28 mAbs, 10M2146 and 8M2110, in complex with VACV A26 reveal two distinct and highly conserved proximal epitopes within the N-terminal domain. Passive transfer of 8M2110 modestly attenuates disease in infected female mice. Moreover, immunization with A28 elicits antigen-specific B cells and robust neutralizing antibody responses and provides protection against lethal VACV challenge. These findings identify MPXV A28 as a promising central target for the induction of neutralizing antibodies and antiviral interventions.