A recent study identifies two noncompeting human neutralizing antibodies, hMB621 and hMB668, targeting the B6 protein of the monkeypox virus (MPXV), which show protective effects against orthopoxvirus infections. The research evaluated preexisting antibody levels to MPXV B6 in individuals born before 1981, who had received smallpox vaccination. Two monoclonal antibodies were isolated from a vaccinee with high binding antibody levels to B6. Both antibodies exhibited broad binding abilities to B6 and its orthologs in vaccinia (VACV), variola (VARV), and cowpox viruses (CPXV). Neutralizing assays showed potent neutralization against VACV. Animal experiments using a BALB/c mouse model indicated effective protection against VACV via intraperitoneal injection. Structural analysis of the B6-hMB668 complex revealed the structural features of B6 and the epitope of hMB668. The study provides two promising antibody candidates for the treatment of orthopoxvirus infections, including mpox. The genus Orthopoxvirus includes four human pathogenic species: MPXV, VARV, VACV, and CPXV. MPXV is the causative agent of the recent mpox epidemic, which was declared a Public Health Emergency of International Concern by the WHO. The study highlights the need for effective countermeasures against mpox, as current vaccines and therapeutics have limitations. The research demonstrates the potential of these antibodies for broad-spectrum antiviral therapy against orthopoxviruses.A recent study identifies two noncompeting human neutralizing antibodies, hMB621 and hMB668, targeting the B6 protein of the monkeypox virus (MPXV), which show protective effects against orthopoxvirus infections. The research evaluated preexisting antibody levels to MPXV B6 in individuals born before 1981, who had received smallpox vaccination. Two monoclonal antibodies were isolated from a vaccinee with high binding antibody levels to B6. Both antibodies exhibited broad binding abilities to B6 and its orthologs in vaccinia (VACV), variola (VARV), and cowpox viruses (CPXV). Neutralizing assays showed potent neutralization against VACV. Animal experiments using a BALB/c mouse model indicated effective protection against VACV via intraperitoneal injection. Structural analysis of the B6-hMB668 complex revealed the structural features of B6 and the epitope of hMB668. The study provides two promising antibody candidates for the treatment of orthopoxvirus infections, including mpox. The genus Orthopoxvirus includes four human pathogenic species: MPXV, VARV, VACV, and CPXV. MPXV is the causative agent of the recent mpox epidemic, which was declared a Public Health Emergency of International Concern by the WHO. The study highlights the need for effective countermeasures against mpox, as current vaccines and therapeutics have limitations. The research demonstrates the potential of these antibodies for broad-spectrum antiviral therapy against orthopoxviruses.