Human monkeypox was first recognized outside Africa in 2003 during an outbreak in the USA that was traced to imported monkeypox virus (MPXV)-infected West African rodents. Unlike the smallpox-like disease described in the Democratic Republic of the Congo (DRC; a Congo Basin country), disease in the USA appeared milder. Here, analyses compared clinical, laboratory and epidemiological features of confirmed human monkeypox case-patients, using data from outbreaks in the USA and the Congo Basin, and the results suggested that human disease pathogenicity was associated with the viral strain. Genomic sequencing of USA, Western and Central African MPXV isolates confirmed the existence of two MPXV clades. A comparison of open reading frames between MPXV clades permitted prediction of viral proteins that could cause the observed differences in human pathogenicity between these two clades. Understanding the molecular pathogenesis and clinical and epidemiological properties of MPXV can improve monkeypox prevention and control.

Comparative genomics of 45 epidemiologically varied variola virus isolates from the past 30 years of the smallpox era indicate low sequence diversity, suggesting that there is probably little difference in the isolates' functional gene content. Phylogenetic clustering inferred three clades coincident with their geographical origin and case-fatality rate; the latter implicated putative proteins that mediate viral virulence differences. Analysis of the viral linear DNA genome suggests that its evolution involved direct descent and DNA end-region recombination events. Knowing the sequences will help understand the viral proteome and improve diagnostic test precision, therapeutics, and systems for their assessment.