Pathogenicity and antiviral treatment of clade Ib Monkeypox virus infection in mice

Monkeypox virus (MPXV) has demonstrated significant variability regarding its virulence and transmission dynamics across different clades, particularly between those originating from Central Africa, referred to as clade I, and those from West Africa, known as clade II. The emergence of new subclades has triggered two public health emergencies of international concerns since 2022. The 2022 global mpox outbreak caused by clade IIb MPXV has lead to over 150,000 infections, while the most recent outbreak caused by clade Ib MPXV, initially detected in the Democratic Republic of the Congo (DRC) in late 2023, has reported more than 40,000 confirmed cases worldwide. Unlike historical clade Ia and IIa strains which are largely associated with zoonotic transmission events, clade IIb and Ib MPXV have demonstrated sustained human-to-human transmission, including sexual, household, and vertical transmission. Currently available therapeutics for Orthopoxvirus infections, namely tecovirimat, cidofovir, and brincidofovir, have been shown to be effective in treating animals infected with MPXV from clades Ia, IIa, and IIb, but not Ib. Here we describe the development of a lethal mouse model for clade Ib MPXV infection and its successful treatment using approved antivirals. Our results suggest that tecovirimat, cidofovir and brincidofovir remain suitable therapeutic options to treat clade Ib MPXV infection.