orthopoxviruses has waned, particularly in younger individuals lacking vaccinia-induced immunity, and the number of unvaccinated, susceptible individuals has grown worldwide. Indeed, these changes have been accompanied by an increased frequency and geographic distribution of human monkeypox cases in recent years. EPIDEMIOLOGY Discovery and Animal Reservoirs MPXV was first detected in 1958 in an outbreak of a vesicular disease among captive monkeys transported to Copenhagen, Denmark from Africa for research purposes. Hence the name “monkeypox.”20 The term is inappropriate because the largest animal reservoirs of the virus have been found in rodents, including squirrels and giant pouched rats, both of which are hunted for food.21 Rodents are the largest group of mammals with more than 1500 species. The extent of the wild animal reservoir, the natural history, and pathogenesis of monkeypox in Fig. 1. Map of Africa showing countries reporting human Monkeypox cases (1971–2019). Human Monkeypox 3 both animals and humans remains unknown, requiring characterization through ecologic and epidemiologic studies. Thus far, MPXV has been detected in diverse animal species: squirrels (rope and tree), rats, striped mice, dormice, and monkeys. In 1985, the virus was isolated from a rope squirrel in the Democratic Republic of Congo (DRC) and a dead infant mangabey monkey in Tai National Park, Cote d’Ivoire.22 During a large monkeypox outbreak following introduction of the virus through animals imported into an animal trading company, at least 14 species of rodents were found to be infected.23 Like humans, monkeys are considered disease hosts. Further studies are needed to understand how the virus persists in nature, and to explore pathogen-host associations and the effect of climatic and ecologic factors influencing the shifts between geographic areas and the virus as a cause of disease in humans.24 Transmission of Monkeypox Virus to Humans Not only the specific animal host reservoir of monkeypox but also the mode of transmission of MPXV from animals to humans remain unknown. Aerosol transmission has been demonstrated in animals,25,26 and may explain a nosocomial outbreak in the Central African Republic.27 However, indirect or direct contact with live or dead animals is assumed to be the driver of human monkeypox infections in humans.28,29 Poverty and continued civil unrest force people to hunt small mammals (bushmeat) to obtain protein-rich food, thus increasing exposure to wild rodents, which may carry monkeypox.30 In August 1970 the first human case of monkeypox was identified in a 9-year-old child with smallpox-like vesicular skin lesions in the village of Bukenda in the Equatorial region of Zaire (now DRC).31 This patient was found during a period of intensified smallpox surveillance conducted 9 months after the World Health Organization (WHO) the eradication of smallpox in the DRC had certified the eradication of smallpox in the DRC. Geographic Endemicity and Increase in Number of Cases Ever since its discovery, the disease has been endemic to Central and West Africa with intermittent, sporadic cases of monkeypox transmitted from local wildlife reported among humans. Retrospective studies indicated that similar cases had occurred in 1970 to 1971 in the Ivory Coast, Liberia, Nigeria, and Sierra Leone.32–35 Subsequent enhanced surveillance observed a steady increase in the rate of human monkeypox cases. The number of cases of human monkeypox has increased exponentially over the past 20 years, and has already exceeded that accumulated during the first 45 years since its first discovery.28,29,36–45 A comprehensive enhanced surveillance study in the DRC in 2004 to 2005 showed a steep increase in incidence compared with data from a WHO enhanced surveillance program carried out from 1970 to 1986 reporting 404 cases.46 The incidence was highest in forested regions, and in lower age groups not vaccinated as part of the smallpox eradication program.42 To date, human monkeypox cases have been reported from 10 African countries: DRC, Republic of the Congo, Cameroon, Central African Republic, Nigeria, Ivory Coast, Liberia, Sierra Leone, Gabon, and South Sudan.1,36,47 The growing incidence of human monkeypox cases in Central and West Africa is considered a consequence of waning crossprotective immunity among the population after smallpox vaccination was discontinued in the early 1980s, following the eradication of smallpox.28,42 The deteriorating immunologic status is not only related to waning vaccine-induced protection among those initially vaccinated, but probably—and even more—to 4 Petersen et al the increasing proportion of those never given the vaccine, that is, nonvaccinated younger age groups. Both mechanisms lead to a growing percentage of susceptible individuals in the endemic areas in Central and West Africa. Another central factor considered to contribute to the incidence of monkeypox is related to increasing contact between humans and small mammals potentially carrying MPXV. Humans invade jungles and forests, the natural environment of the reservoir species. Civil wars, refugee displacement, farming, deforestation, climate change, demographic changes, and population movement may have led to