Global immuno-epidemiology and the persistence of mpox clade IIb in MSM

In 2022, mpox clade IIb spread globally in men who have sex with men (MSM) via sexual contact. By summer 2022, case numbers declined in Europe and Norther America due to behavior change and immunization, with almost no reported cases in 2023, followed by low-level transmission. By autumn 2022, many susceptible individuals at high risk of transmission may have become immunized. Moreover, because individuals with mpox are infectious for only 2--4 weeks, sustaining transmission chains requires considerable infection throughput. This raises the question: How did mpox persist and transition to endemic circulation? We developed an agent-based model of mpox transmission on the Berlin MSM sexual contact network that incorporates viral shedding kinetics, vaccination, infection-derived immunity, immune waning, and case importations. After calibrating the model, we estimated that the probability of mpox extinction in Berlin exceeded $80\%$ in 2023, when acquired immunity fragmented the transmission network. Extending the analysis to a European MSM metapopulation reduced the extinction probability to less than $60\%$, whereas incorporating global metapopulation dynamics reduced it to nearly zero. We find that mpox persistence was enabled by epidemic asynchrony: When transmission declined in Europe/the Americas, mpox transmission continued in Asia, long enough for immune waning to partially restore transmission potential in Europe, thereby enabling subsequent re-importation and endemic circulation. These model-based findings are supported by phylogenetic evidence indicating that all active German transmission clusters are either linked to (i) re-importation of clade F from the Americas, or (ii) the emergence of clades C and E linked to Asia. Our findings on asynchronous transmission across connected global MSM networks highlight the role of global immuno-epidemiology in enabling mpox persistence and emphasize the importance of coordinated international surveillance and control efforts.