Extensive cryptic circulation sustains mpox among men who have sex with men

Sporadic cases of clade IIb mpox continue to be notified among men who have sex with men, with most lacking identifiable transmission links. To resolve underlying dynamics, we tested prospectively for evidence of monkeypox virus infection in anorectal swabs from a cohort of men who have sex with men in Los Angeles, whom we monitored concurrently for clinical mpox diagnoses during summer, 2024. Here we estimate that infections exceeded reported mpox cases by a 33-fold margin (95% confidence interval: 16-68). Independent estimates derived from phylogenetic reconstruction and a meta-analysis of surveillance studies corroborated this extensive under-reporting. We estimate that undiagnosed infections must cause at least 31-44% of all transmission to explain observed monkeypox virus phylogenies; under realistic modeling assumptions, this proportion rises to 61-97%. Contrary to current guidance, our findings suggest a substantial proportion of monkeypox virus circulation may be associated with subclinical infections, challenging the feasibility of current mpox elimination targets.