Potent neutralization by antibodies targeting the MPXV A28 protein
- Ron Yefet
- Leandro Battini
- Mathieu Hubert
- Katya Rakayev
- Florence Guivel-Benhassine
- Noam Rattner
- Francoise Porrot
- Lilach Abramovitz
- Gilad Ostashinsky
- Noam Ben-Shalom
- Jeanne Postal
- Ksenia Polonsky
- Maya Ralph-Altman
- Sireen Sweed
- Tal Korner
- Nadav Friedel
- David Hagin
- Eli Sprecher
- Zvi Fishelson
- Oren Kobiler
- Lihi Adler-Abramovich
- Olivier Schwartz
- Pablo Guardado-Calvo
- Natalia T. Freund
2025-12-10
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.