Monkeypox is a zoonotic viral disease caused by the monkeypox virus (MPXV), an orthopoxvirus belonging to the Poxviridae family of viruses. MPXV was first identified in 1958 in research monkeys that were shipped from Singapore, which is the likely reason for the disease being called ‘monkeypox’. However, the natural hosts of MPXV are more likely to be rodents and other small mammals. The Orthopoxvirus genus also includes variola virus (VARV), the causative agent of lethal smallpox disease. The symptoms of monkeypox in humans are relatively similar to those of smallpox, but with a lower mortality rate.

Sporadic cases of MPXV in humans were first identified in the 1970s in several African countries, but the virus became more widespread within the African continent over the past 20 years. Since May 2022, there has been a drastic increase in the number of MPXV cases worldwide, leading the World Health Organization (WHO) to declare the monkeypox outbreak a global health emergency.

Possible reasons for this current outbreak could be attributed to waning smallpox immunity in the general population and termination of the smallpox vaccination regime. Vaccination against smallpox has been shown to offer protection against monkeypox. An early study from Zaire in 1988 reported that individuals vaccinated against smallpox (during a national smallpox vaccination campaign beginning 12 years before the start of data collection) were approximately 85% less likely to contract monkeypox than those who were not vaccinated. In another study, severe complications and long-term effects of MPXV infection were found to be less common (39.5% versus 74%) with lower death rates in patients vaccinated against smallpox. Recently, a study on 528 infections diagnosed during this current outbreak reported that only 9% of the individuals who were infected received prior smallpox vaccination. Interestingly, one characteristic of the recent outbreaks is a disproportionate number of infections in men who have sex with men (MSM).

Phylogenetically, MPXV can be divided into two distinct clades — Central African (also commonly known as Congo Basin) and West African. Depending on the source of the West African MPXV, sequence similarity of ~95% or >99% between the two clades was reported. The Central African clade is generally considered to be more virulent, with an average fatality rate of 10.6% (95% CI 8.4–13.3%) compared with the 3.6% (95% CI 1.7–6.8%) reported for the West African clade. MPXV of the Central African clade has been identified in cases appearing in the Democratic Republic of the Congo (DRC) and South Sudan, whereas cases in Nigeria between 2010 and 2019 appeared to be due to the West African clade. Cases reported outside Africa, including those currently in circulation, have all been caused by the West African clade. Whether genetic changes in the MPXV genome could be responsible for this current outbreak is currently being investigated.

Here, we discuss our current understanding of the transmission and immunopathogenesis of MPXV and the unique epidemiological and pathological characteristics observed in this outbreak. Specifically, we examine the potential mechanisms of host immunity against MPXV, drawing parallels from other poxviruses where necessary. We also discuss vaccines and therapeutics and highlight remaining critical gaps in our knowledge. Of note, nomenclature for- orthopoxviruses gene/protein orthologues is very complex. In this Review, we refer to orthopoxvirus genes and proteins according to publicly available reference genomes: NC_063383 for the West African MPXV strain, NC_003310.1 for the Central African MPXV Zaire strain and NC_006998 for the vaccinia virus (VACV) Western Reserve strain. MPXV genes/proteins are referenced to the Central African MPXV Zaire strain, unless otherwise stated.

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