Antibodies to distinct epitopes on MPXV enveloped virion provide additive and complete protection
The continuing evolution of monkeypox virus (MPXV) clades capable of sustained human-to-human transmission poses an escalating global health risk, yet no effective therapy exists for poxvirus infection. Here, we investigate a panel of human monoclonal antibodies (mAbs), derived from an antibody library, which targets A35 and B6 antigens located on the extracellular enveloped virion (EV). Four high-affinity mAbs target the central groove of the A35 dimer, whereas one targets a previously unidentified epitope on the A35 protruding loop. Three other mAbs recognize distinct, previously unmapped epitopes on the multidomain B6 antigen. Those epitopes are conserved across most orthopoxviruses. A combination of an anti-A35 and an anti-B6 antibody provides additive and complete protection from both morbidity and mortality in a lethal VACV mouse model, challenging the previous assumption that targeting both the EV and mature virion (MV) forms is required for full protection. These studies uncover critical information for next-generation therapeutics and vaccines against emerging MPXV as well as other Orthopoxvirus threats.
Authors
- Ding Zhang (ORCID: https://orcid.org/0009-0001-1057-0256)
- Raianna Farhat Fantin (ORCID: https://orcid.org/0000-0003-0184-8612)
- Michael Schotsaert (ORCID: https://orcid.org/0000-0003-3156-3132)
- Ian A. Wilson (ORCID: https://orcid.org/0000-0002-6469-2419)
- Meng Yuan (ORCID: https://orcid.org/0000-0001-9754-4503)
- Marie I. Samanovic (ORCID: https://orcid.org/0000-0002-6987-2232)
- Jean K. Lim (ORCID: https://orcid.org/0000-0002-4572-6417)
- Seok‐Chan Park (ORCID: https://orcid.org/0000-0003-2489-2202)
- Guilherme de Moraes Nobrega (ORCID: https://orcid.org/0000-0001-9406-4256)
- Jordan J. Clark (ORCID: https://orcid.org/0000-0003-1790-7883)
- Angelica C Kottkamp (ORCID: https://orcid.org/0000-0003-4103-1666)
- Mark J. Mulligan (ORCID: https://orcid.org/0000-0001-7262-9746)
- Gabriel Laghlali (ORCID: https://orcid.org/0009-0009-7928-984X)
- Ziqi Feng (ORCID: https://orcid.org/0000-0001-5046-9788)
- Xueyong Zhu (ORCID: https://orcid.org/0000-0002-6021-3740)
- Camila H. Coelho (ORCID: https://orcid.org/0000-0002-7885-9996)
Institutions
- Scripps Research Institute (US)
- NYU Langone Health (US)
- New York University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1126/sciimmunol.aee7011
- Primary Topic
- Poxvirus research and outbreaks
- Type
- article
- Field-Weighted Citation Impact
- 0.00