The viral agent causing mpox was first isolated in 1958, following a pox-like disease outbreak among captive monkeys housed within the State Serum Institute in Copenhagen, Denmark [2]. The first recognized human case of mpox was reported in 1970; however, sporadic cases likely occurred well before then but were mistaken for mild cases of smallpox. It soon became apparent that smallpox vaccination protects against mpox, as most reported cases involved unvaccinated children younger than 10 years of age. Secondary spread to close contacts was distinctly uncommon (5%), unlike that encountered during outbreaks of smallpox (25% to 40%) [3]. Cases of mpox remained sporadic, and reports of secondary infection among susceptible contacts were limited, indicating insufficient transmissibility for sustaining propagation of MPXV infection within population groups. Thus, mpox disease was not considered a serious threat to public health [3].

MPXV is a large, double-stranded DNA viral agent within the genus Orthopoxvirus, family Poxviridae. Orthopoxviruses include Variola virus, Vaccinia virus, Monkeypox virus, and Cowpox virus. Infection with one orthopoxvirus or immunization with an orthopoxvirus vaccine induces immunologic cross-protection against other species of virus in the genus [6]. The source of MPXV in nature is unknown, though African rodents, including squirrels, are considered likely reservoirs. A variety of animals have been identified as susceptible to MPXV infection, including squirrels, Gambian pouched rats, dormice, non-human primates, and other species [1]. The pattern of MPVX circulation in nature and human behaviors that facilitate zoonotic transmission are not entirely clear.

Multiple factors are thought to account for the increasing incidence of reported MPXV infection, including rain forest exploitation, climate change, armed conflicts in disease areas, and waning herd immunity. [6]. Using ecological niche modeling techniques in conjunction with climate predictions and remote sensing variables, investigators were able to forecast animal reservoir distribution and the spread of MPXV in Africa's Congo Basin. Results show that forest clearing, and climate change are major factors driving the transmission of MPXV from wildlife to humans under current climate conditions [8]. As deforestation and urbanization has gradually enhanced incidental human contact with infected rodents, populations have also become more susceptible to MPXV because of waning herd immunity following cessation of smallpox vaccination in 1980. Previously, vaccination against smallpox with first-generation vaccinia-based vaccine was shown to be 85% effective in preventing mpox [1]. An analysis of data collected on 91 human mpox cases during the 1980s found that the secondary attack rate among contacts having no vaccination scar (4.3%) differed significantly from those who had been vaccinated in the past (0.7%) [3].

Unlike sporadic mpox cases previously reported in central Africa, human-to-human transmission is the predominant mode of transmission observed in the current global outbreak and accounts for the scope and rapidity of spread. Human-to-human transmission of MPXV requires close, sustained physical contact that results in direct exposure to body fluids or material emanating from open skin and mucosal lesions. Examples of intermediate- and high-risk exposures associated with the 2022 mpox outbreak include [10]:

The incubation period of mpox is 5 to 21 days [1]. Illness usually begins with a prodromal phase, including fever, malaise, headache, myalgias, and lymphadenopathy, followed in one to five days by onset of a maculopapular skin eruption and/or mucosal lesions, most pronounced on the face and extremities. According to WHO 2022 outbreak data, the most common sites for skin and mucosal lesions are face (95%), palms and soles (75%), oral mucus membranes (70%), genitalia (30%), and conjunctivae (20%) [1]. Skin lesions progress in stages from maculopapular to papulovesicular to umbilicated pustules before crusting over and desquamating within a period of two to four weeks. Several unusual features of the mpox rash have been observed in patients from the current outbreak: mucosal lesions more numerous than previously described; lesions confined to atypical locations, such as the genital or perineal/perianal area, as well as the mouth and eyes; and development of rash or mucosal lesions prior to onset of constitutional symptoms [1].

The incubation period of mpox is 5 to 21 days [1]. Illness usually begins with a prodromal phase, including fever, malaise, headache, myalgias, and lymphadenopathy, followed in one to five days by onset of a maculopapular skin eruption and/or mucosal lesions, most pronounced on the face and extremities. According to WHO 2022 outbreak data, the most common sites for skin and mucosal lesions are face (95%), palms and soles (75%), oral mucus membranes (70%), genitalia (30%), and conjunctivae (20%) [1]. Skin lesions progress in stages from maculopapular to papulovesicular to umbilicated pustules before crusting over and desquamating within a period of two to four weeks. Several unusual features of the mpox rash have been observed in patients from the current outbreak: mucosal lesions more numerous than previously described; lesions confined to atypical locations, such as the genital or perineal/perianal area, as well as the mouth and eyes; and development of rash or mucosal lesions prior to onset of constitutional symptoms [1].

The possibility of mpox should be considered in any patient with compatible clinical syndrome (e.g., fever, rash, lymphadenopathy) combined with epidemiologic risk factors for MPXV exposure such as travel or animal exposure connected to endemic areas of virus circulation or recent history of sexual activity involving persons known or suspected of mpox disease. The differential diagnosis includes other infections that present with generalized or focal skin lesions (e.g., herpes, varicella zoster, secondary syphilis, acute streptococcal or meningococcal infection). The presence of lymphadenopathy helps distinguish mpox from other, similar viral exanthems (e.g., varicella zoster, chickenpox). The laboratory diagnosis of MPXV infection relies on DNA PCR testing of specimens (scrapings) obtained from skin or mucosal lesions. PCR testing of blood samples are usually inconclusive because of the short duration of viremia relative to the timing of specimen collection [1]. Serologic testing is unreliable for mpox-specific confirmation because of common cross-reactivity with other orthopoxviruses and vaccination.

The characteristic skin eruption of mpox disease exhibits the following features: deep-seated, firm or rubbery, well-circumscribed lesions, that often develop central umbilication (Image 1) [14]. The lesions progress through sequential stages—macules, papules, vesicles, pustules, and scabs. The skin lesions are sometimes confused with those seen in other infections more commonly encountered in clinical practice (e.g., secondary syphilis, herpes, varicella zoster). Historically, sporadic accounts of patients co-infected with MPXV and other infectious agents (e.g., varicella zoster, syphilis) have been reported, so patients with skin lesions typical for mpox should be considered for testing, even if diagnostic testing for other conditions has returned positive [13]. Key characteristics for identifying mpox rash, including instructive photographic images of skin lesions in sequential stages, are provided at the CDC website, accessible at https://www.cdc.gov/mpox/hcp/clinical-signs [14].

VIG can be considered for prophylaxis against monkeypox in an exposed person with severe immunodeficiency in T-cell function for which smallpox vaccination following exposure to mpox virus is contraindicated [16].

In the context of the current national Public Health Emergency (PHE), an alternative regimen to subcutaneous JYNNEOS vaccine administration may be used. The authorized alternative regimen involves an intradermal route of administration with an injection volume of 0.1 mL. This approach could increase the number of available JYNNEOS vaccine doses by up to five-fold. Results from a clinical study showed that the lower intradermal dose was immunologically non-inferior to the standard subcutaneous dose [21].