Highly efficient anogenital transmission of clade Ia monkeypox virus associated with increased shedding.

The transmission pattern of mpox has shifted from sporadic zoonotic outbreaks to sustained human-to-human spread. Epidemiological data indicate sexual contact as a crucial driver for efficient transmission and the associated devastating mpox outbreaks in recent years. However, our understanding of exact driving factors and transmission determinants is still limited. Here, we investigate MPXV clade Ia virus pathogenesis, shedding kinetics, and transmission potential in a prairie dog model (Cynomys ludovicianus). Mucosal inoculation via all routes (penile/preputial, vaginal, rectal, intranasal) results in a productive, systemic infection. Inoculation via urogenital routes generate the highest virus shedding and most severe clinical disease. Simulated sexual contact transmission results in 100% transmission efficiency with high virus shedding in sentinels on day 1, even before the onset of visible clinical signs. Our findings provide experimental support for the importance of anogenital mucosal infection and transmission and establish a model for studying these in vivo. These results advocate for a stronger focus on mucosal infection when evaluating countermeasures.