Monkeypox virus (MPXV), which causes mpox disease in humans, comprises two clades: the Central African clade I (with a case fatality rate of about 11%) and the West African clade II (with a case fatality rate of about 4%). The differences in virulence among MPXV clades in humans warrant further investigation; however, a critical gap is the lack of small-animal models for comparing IIa vs. IIb clades.