Monkeypox: Comparison
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In 1958, several monkeys in a Copenhagen laboratory developed a skin rash from which an orthopoxvirus could be isolated, which was named monkeypox virus (MPXV). However, the natural animal reservoir for MPXV is thought to be a rodent. The first human case occurred in 1970, and the incidence has increased progressively throughout the years. 

  • monkeypox
  • animals
  • epidemiology
  • transmission

1. Introduction

Viruses are submicroscopic entities, with great simplicity, which have only either DNA or RNA, and for that reason, they must infect specific live cells in order to use their biosynthetic machinery to have more viral particles or virions made. Once this is accomplished, the new virions infect new cells. Some viruses are specific to their host and are said to have a narrow host range; on the contrary, others have a broad host range and can infect several species. Throughout history, viruses have produced many epidemics and pandemics in humans, animals, and plants [1,2][1][2]. One of such viruses has been smallpox virus, which originated in India or Egypt and spread throughout Africa, Asia, and Europe, leaving a trail of deaths behind. In the 20th century alone, a total of 300 million deaths have been attributed to this virus [3,4][3][4]. The mortality rate due to this virus has been an average of 30%, depending on the regions, the period, and the genetic conformation of the prevailing virus. Thanks to the geniality of a British doctor, Edward Jenner, the infection could be controlled to the point that it has been eradicated from Earth. He associated the lack of pock scars in the skin of milkmaids with the presence of pustules in the udder of cows and hypothesized that the latter could protect those in contact from contracting the disease. In 1797, he performed an experiment (which nowadays would not have passed any ethics committee) in which he practiced a scarification with the contents of the lesions in cows in a 12-year-old boy who did not contract smallpox when in close contact with infected persons [5]. This opened the door to the golden age of vaccinology, not lacking difficulties, such as how to bring the vaccine to other territories besides contiguous Europe, Asia, and Africa. This was solved by the Royal Philanthropic Expedition of the Vaccine, by which the Spanish doctor Balmis introduced the smallpox vaccine to these territories in 1803 [6], a first step to allow the WHO in 1979 to certify that the disease had been eradicated, a fact that was refrained in the WHO World Health Assembly in May 1980 [7]. Though undeniably a milestone in the history of mankind, its eradication has left an empty niche that might be filled by other viruses, such as the close relative monkeypox virus (MPXV), which produces a similar disease to smallpox, but a lower mortality rate.

2. Animal Hosts

The first known episode of monkeypox happened in 1958 in laboratory cynomolgus and rhesus monkeys imported to Copenhagen, Denmark, mostly from Singapore. Once in Denmark, they developed a vesicular disease from which a double-stranded DNA virus belonging to the genus Orthopoxvirus was isolated [8]. The virus was related to but distinct from smallpox virus (another orthopoxvirus) and was named monkeypox virus. Several similar outbreaks happened in 1959 and 1962 in different research facilities in the US [8]. A 1964 outbreak in a Rotterdam zoo sickened an array of animals, several of which died. Affected species included giant anteaters, orangutan, gorilla, chimpanzees, a gibbon, and a marmoset [8,9][8][9].
With respect to wild animals, only six trapped in Africa so far have yielded the virus: three rope squirrels, a Gambian rat, a shrew, and a sooty mangabey monkey. Most of these animals were apparently healthy except for a squirrel (Funisciurus anerythrus) that was diseased [10]. Though viral presence in wild animals has been elusive, antibodies have been detected in more specimens, mostly in African squirrels, but also in Cercopithecus [9,11][9][11]. Thus, non-human primates seem to be only accidental hosts, and the natural host is likely a rodent or rodent related [12,13][12][13]. Several rodent species may be infected experimentally by MPXV, including rope squirrels (Funisciurus spp.), Gambian squirrel (Heliosciurus spp.), African dormice (Graphiurus spp.), Gambian giant pouched rat (Cricetomys spp.), and prairie dogs (Cynomis spp.) (Figure 1) [8]. In several of these species, the infection is asymptomatic, and more studies are needed to elucidate which is the natural reservoir and how the virus circulates in nature [8,14][8][14]. The ample variety of species that MPXV may affect confirms that, unlike smallpox virus, which only infected humans, MPXV has a broad host range, and no species should be overlooked as possibly involved in its epidemiological cycle.
Figure 1. Species that have been found to be positive, either by virus isolation or presence of antibodies, and area of origin. Rodents are written in pink boxes; non-human primates in orange boxes and the species that were affected at the Rotterdam Zoo in a blue box.

3. Natural History of Monkeypox: Reported Outbreaks in Africa

The first human case was recorded on 1 September, 1970, in the town of Bukenda in the equatorial region of the Democratic Republic of Congo (DRC). It happened in a 9-month-old baby boy admitted to the Basankusu Hospital who had a vesicular eruption. The lesions would have passed unnoticed were it not that the WHO had established an intense surveillance of most of Africa to eradicate smallpox. In the DRC, the last smallpox case was diagnosed in 1971 [15], and smallpox vaccination had been interrupted nine months before the monkeypox episode. When the infection by MPXV was recognized, studies showed cases between October 1970 and May 1971 in Ivory Coast, Liberia, Sierra Leona, and Nigeria [16]. Since 1970 and throughout that decade sporadic cases were reported in the previous countries and in most of Equatorial Africa, including Cameroon, Gabon, Republic of Congo, Central African Republic, and South Sudan [17]. Very recently, Ghana has also been added to this list [18]. Studies show an escalation of monkeypox cases, especially in the highly endemic DRC, a spread to other countries, and a growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which may have provided some cross-protection against monkeypox, leading to increased human-to-human transmission. As most cases have been happening in rural Africa, suspected underreporting may translate to an underestimation of the prevalence of MPXV [19].
The African countries that have reported the largest number of cases are the DRC (around 6000 cases), where it is considered to be endemic, and Nigeria (around 3000 cases). The number of cases has been gradually increasing since monkeypox was first reported in humans in 1970 [17]. Earlier epidemiological studies suggested that transmission of the virus between humans was not efficient and that most cases in Africa have happened due to repeated spillovers from animals [16,20,21][16][20][21]. Some of the reasons that favor an increased frequency of contact between animals and humans are deforestation, which exposes animals that are usually in the jungle; violence in the regions, which forces human groups to move to the more protected environment of the jungle; and lack of conventional food, so humans are compelled to consume other available sources, such as rodents, which might be infected [8]. The synanthropic rodent population, which increased in recent years in Africa, has led to more human-to-rodent interactions and thus increased transmission of MPXV [22]. All these factors are combined with the increase in human population in the affected areas and land shifts [2].
The number of cases in Nigeria has soared since September 2017, when an 11-year-old boy was diagnosed with monkeypox, starting an outbreak that is still ongoing [16,23][16][23]. Before 2017, the last confirmed case had been diagnosed in 1978. The WHO recognizes over 500 suspected cases and over 200 confirmed cases in this country, with an associated mortality rate of 3%. Epidemiological data suggest that the cases are not linked but that the virus has jumped several times from an animal host to humans [16]. The potential for accelerated adaptation to humans should be monitored through improved surveillance [20], and it has proven to be essential in view of the number of cases in Nigeria. Nearly 45 years after the end of routine smallpox vaccination, the larger and more interconnected immune-naïve population has crossed a threshold resulting in more sustainable human-to-human transmission of MPXV.

4. Monkeypox Outside Africa

The first time that monkeypox was detected outside Africa was in May 2003 in the USA. The first person outside of Africa to be diagnosed to have monkeypox was a 3-year-old girl bitten by one of her pet prairie dogs [9]. In two months’ time, 72 people attended the medical services because they had developed fever, vesicular eruption, respiratory distress, and lymphadenopathy (42 cases were confirmed [24]). The cases happened mostly in the Midwest and included the states of Illinois, Indiana, Kansas, Missouri, Ohio, Wisconsin, and New Jersey. No human deaths were registered due to this outbreak. The survey conducted on the first 53 cases showed that 50 had been in contact with prairie dogs (Cynomis spp.) kept as pets. The prairie dogs were traced back to an animal distributor in Texas, to which a number of African rodents had been imported from Ghana in April 2003. Upon analysis, 22 animals tested positive for MPXV, including Gambian pouched rats (Cricetomys gambianus), Funisciurus spp., Heliosciurus spp., Cricetomys spp., Atherurus spp., Graphiurus spp., and Hybomys spp. [25]. The genomic analysis of the virus from one person, a prairie dog, a rope squirrel (Funisciurus sp.), and a Gambian giant rat (Cricetomys sp.) showed that all four sequences were identical, confirming the epidemiological link. All prairie dogs were embargoed, and a ban on the import and breeding of African rodents was put into effect. This ban was partly modified in 2008 allowing US-born African rodents to be bred, but not imported [26]. The possibility of MPXV taking up permanent residence in wildlife outside of Africa, forming a reservoir that could lead to repeated human outbreaks is frightening [9], since this could imply recurring outbreaks in humans and the development of more dangerous virus variants. However, surveys of wild animals in Wisconsin and Illinois never found MPXV, none of the infected humans passed on the disease to other people, and worries about this exotic outbreak subsided [9].
In September 2018, the first human monkeypox cases exported from Africa were seen in the United Kingdom (n = 2) and Israel (n = 1) [27]. The case in the UK had a related nosocomial (health care worker) and a family home (an adult and a child in a household cluster) transmission events, becoming the first confirmed human-to-human monkeypox transmission events outside of Africa [28,29][28][29]. In May 2019, one case was detected in Singapore [30,31][30][31] and in December of the same year another case in the UK. They all corresponded to travelers who had been to Nigeria and developed the typical rash once back in their countries, and except for the nosocomial and household transmissions, all were unrelated. Isolates from all travelers and a Nigerian case shared a most recent common ancestor. Genetic variation for this cluster was lower than would be expected from a random sampling of genomes from this outbreak, but data did not support direct links between travelers [32]. Isolated cases were detected in 2021 in the UK and in Dallas (TX, Dallas, USA), as well as in travelers to Nigeria. The whole-genome sequencing of the Dallas case showed that the virus was consistent with a strain of MPXV known to circulate in Nigeria, but the specific source of the patient’s infection was not identified [33]. With the appearance of outbreaks beyond Africa, the global potential of the disease became evident [17].
Starting from 6 May, 2022, a large number of monkeypox cases not linked to travel to endemic countries was reported in at least 80 different countries (https://ourworldindata.org/monkeypox, accessed on 20 August 2022), mostly in Western Europe, but also in Central Europe, North America, in Australia. As of 18 August 2022, the total number of cases has been 44,500 cases, with a total of 5 deaths in non-endemic countries (https://www.cdc.gov/poxvirus/monkeypox/response/2022/world-map.html, accessed on 20 August 2022). The situation is evolving rapidly, and the majority of cases have been detected in Spain (with two deaths out of the 5792 cases), Germany, the UK, France, and Portugal, while numbers are also increasing fast in some other European countries, as well as in the USA and Brazil. Epidemiological data suggest person-to-person community transmission [34]. In addition, investigations into the early cases based on genomic data [35] suggest that the outbreak in Europe was certainly underway as early as mid-April and most likely earlier on [36].

5. Etiology: Genetic Types of Monkeypox Virus (MPXV) and the Phylogenetic Relationship to other Poxviruses

Smallpox virus, vaccinia virus (the live virus component of vaccines against these viruses), and monkeypox virus are large double-stranded DNA. Like other poxviruses, MPXV is a brick-shaped particle of around 200 nm × 200 nm × 250 nm [27,37][27][37]. The virion is surrounded by a lipid envelope with distinct crests [38]. The genome is about 194 to 199 kbp and encodes about 200 proteins. It is a linear double-stranded DNA genome with covalently closed hairpin ends (no free 3′ or 5′ ends). Genes are closely packed and intergenic regions of more than 100 bp are rare. The central conserved region encodes “housekeeping” genes involved in transcription, replication, and virion assembly. The genes in the terminal regions encode proteins involved in host range and pathogenesis (Figure 2). Unlike other viruses that require cell receptors to infect a cell, some poxviruses have proteins on their surfaces that form a hydrophobic face, a water-repelling area that can bind nonspecifically to hydrophilic cell membranes and initiate the infection process [9]. This may be a reason for the broad host range of MPXV.
Figure 2. Open reading frames (ORF) identifiable in the monkeypox virus reference sequence (NC_063383; 197,209 bp) (above), and genomic sections in which they are organized (below). Adapted from GenBank and ViralZone.
The genome structure is challenging. There are three main reasons for this: (a) it has a 6.5 kb inverted terminal repeats (ITR) at each end hard to resolve into individual copies with short read approaches, (b) it has a low G/C content and high poly A/T homopolymeric tracts that are hard to sequence accurately, and (c) there are local tandem repeats scattered across the genome [39,40][39][40].
Phylogenetic analysis has shown that there are two main distinct clades (recently proposed to be called lineages [35]). One is centered in the Democratic Republic of Congo and is called Central or Congo Basin (CB) clade or Clade 1. The other, called West African (WA) clade or Clade 2, lies mostly between the Equator and South of the Sahara. Cameroon is the only country where both clades have been detected to co-exist. The CB clade produces more severe cases and is more contagious than the WA clade and is associated with 10.6% (95% CI: 8.4–13.3%) mortality vs. 3.6% (95% CI: 1.7–6.8%) estimated for the WA clade [17,23,41][17][23][41].
There is ongoing research to determine precisely which genes are responsible for the higher virulence and transmissibility of the CB clade, compared with the WA clade. This is proving difficult due to the large size of the genome and because relatively few sequences are available in Africa due to economic constraints [42]. The Portuguese researcher Palacios suggested that one of the differences between both clades might be the N2R and N3R deletion observed in the CB clade, not present in the WA clade, and which is associated with human-to-human transmission [20].
The recent MPXV outbreak has triggered intense studies. Shotgun metagenomics allowed the rapid reconstruction and phylogenomic characterization of the first genome sequences of the MPXV outbreak variants, placing them in Clade 3 (within the formerly designated West African clade, which also includes Clade 2) [35]. This Clade 3 comprises human MPXV (hMPXV)-1A, with newly classified lineages A.1 and B.1. Lineage B.1 includes all MPXV genomes from the 2022 outbreak. It was estimated that the B.1 lineage of this clade emerged in Europe in February 2022 [43].
Although researchers need more data to confirm their hypotheses, the sequences of the recent cases they have evaluated so far are nearly identical to each other, suggesting that a thorough epidemiological investigation might find that the recent outbreaks outside Africa all link back to a single origin. A second possibility is that the virus may have been introduced through earlier outbreaks and circulated unnoticed outside Africa in human or animal populations; an argument against this possibility is that monkeypox virus was known to produce visible local or generalized lesions in most infected humans and would hardly have passed unnoticed [42]. However, in the present outbreak, WHO has warned that the typical lesions may be absent or difficult to identify, which would have allowed the spread of the infection.
Regardless of the genomic uniformity, results show that the virus in the present outbreak is rapidly mutating, especially for a DNA virus [35], and which is a sign of MPXV microevolution during person-to-person transmission, suggesting an adaptation to the human host [44]. Around 50 single-nucleotide polymorphisms (SNPs) (or substitutions) have been identified scattered across the genome when compared to the closest relatives, those of the European cases of 2018 and 2019 [35], which likely represent a recent evolutionary jump. Up till now, only 1 or 2 substitutions/site/year had been detected [45], suggesting that 50 changes could represent an accelerated evolution of the virus [35]. Many of the mutations are silent, and they do not change the encoded amino acids, but at least 21 mutations are non-synonymous. Some affect proteins involved in human transmission, virulence, or interaction with antiviral drugs. It is difficult to recognize the impact of these substitutions, which would require structural modeling, but when compared to other orthopoxviruses, an approximation may be predicted. Of the non-silent mutations, there are three that are considered high priority, all in the B1/B2 proteins: D209N, P722S, and M1741I. This hypermutation signature suggests the potential action of host enzymes, such as Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC)-3 in viral evolution. APOBEC molecules form part of the innate immune system. These enzymes may edit the viral DNA and block viral replication [46,47][46][47]. They inhibit many viruses by introducing mutations. Occasionally, they do not completely inhibit viral replication, but allow the expansion of hypermutated variants, edited by the enzymes, but which are viable and with similar characteristics to the parental strains, which may escape the immune response [44]. This could be the case of these B1/B2 mutations, which could be an important target for antibodies, and they could allow escaping from the protection conferred by vaccines [48]. B1/B2 is a T-cell inhibitor also found in cowpox virus, camelpox virus, and horsepox virus. When the protein is knocked-in into non-virulent cowpox virus, the resulting virus increases disease severity and mortality in rats [39].

6. Epidemiology

In Africa, the median age at presentation has increased from 4 (in the 1970s) to 21 years (2010–2019) [17]. In the current 2022 outbreak in non-endemic countries, most of the cases have been detected in males between 18 and 50 years. As of 4 July 2022, 21 cases of the 7553 had been reported in women. The risk for children is considered low [49]. The ongoing epidemic differs from previous outbreaks in terms of age (more than half of the individuals have been in their thirties, which may be associated with a lack of smallpox vaccination in their childhood), sex/gender (most cases being males; for example, as for 24 June, of the 528 cases diagnosed by PCR by an international collaborative group of clinicians, 98% were men, with an average age of 38 years), risk factors, and transmission route, with sexual transmission being highly likely [50]. In addition, most cases have been neither part of identified transmission chains, nor linked to travel or had contact with symptomatic persons or with animals, suggesting the possible previously undetected spread of monkeypox [51], which may have gone undetected for quite a while [52], amplified by recent large social events and increased travel. According to WHO, up-till-now few cases required hospitalization (in Spain, as of 16 June, of the 497 cases, 11 required hospitalization), and as of 18 August, 5 deaths have been registered (2 in Spain, 1 in Brazil, 1 in Peru, and 1 in India) (https://www.cdc.gov/poxvirus/monkeypox/response/2022/world-map.html, accessed on 20 August 2022). As the data are evolving rapidly, the basic and effective reproduction rates (R0 and Re) in different populations have not been established [22].
Preliminary risk factors in the ongoing epidemic are: being a young male; having sex with other men; engaging in risky sexual behaviors and activities, including condomless sex, multiple sexual partners, and human immunodeficiency virus infection [53,54,55,56][53][54][55][56]; and a story of previous sexually transmitted infections, including syphilis [53,56][53][56]. In a Spanish study, 54% of the patients had had a positive diagnosis of sexually transmitted infections (STIs) in the previous months, 42% were positive for HIV, and 76% had a concomitant STI at the time of diagnosis of MPXV [56].

7. Transmission

The specific mechanism for transmission is not well established and still leaves many questions unanswered. However, the data from other poxviruses suggest that the virus is present both in the skin lesions and in droplets exhaled while breathing.
An infected animal may transmit MPXV to a human through direct or indirect contact with its blood, body fluids, or lesions, when the animal is managed or succeeds in biting or scratching the person. Within humans, the virus may be transmitted through respiratory droplets (>5 mm, which makes them heavy and thus cannot travel long distances, requiring close contact), direct or indirect contact with body fluids, content of the lesions, or recently contaminated surfaces or materials. The virus penetrates through the injured skin, respiratory tract, and mucous membranes, such as the eyes, nose, or mouth. It may cross the placenta and produce miscarriages in the first trimester and fetal death, with the stillborn showing typical skin lesions [57,58][57][58]. Newborns may also contract the infection during delivery or soon after birth [59].
The possibility of sexual transmission is raising big concern, as a large number of cases have happened in men who have sex with men (MSM) [34,36,50,54,56,60,61,62][34][36][50][54][56][60][61][62]. The development of skin lesions and eruptions in the genital and perianal regions suggests that direct physical contact with lesions during sexual contact is a likely route of transmission [52]. The temporal association observed between sexual intercourse, increased inguinal lymphadenopathy, and recurrence of rash suggests a possible genital reservoir for MPXV, which needs to be further studied. Though biological samples from the seminal fluid were positive for MPXV viral DNA in some studies [61,63[61][63][64],64], another study found no MPXV in semen [28]. However, it would be advisable to recommend men to use condoms for their sexual relationships up to 12 weeks after the complete recovery from the infection until more is known about levels of the virus and potential infectivity in semen during the period that follows recovery (https://www.who.int/news-room/questions-and-answers/item/monkeypox, accessed on 20 August 2022).

8. Pathogenesis

Like most other poxviruses, MPXV has a tropism for epithelial cells and, to a lesser degree, for macrophages and fibroblasts. These viruses typically infect the stratum spinosum of the dermis. In cases prior to the present outbreak, the lesion starts with a macule, which is mostly an unraised reddish area of the skin, followed by a papule, in which the skin starts to raise. The following stage is a vesicle, characterized by the presence of clear liquid in its inside. The liquid quickly turns yellowish, characteristic of a pustule. The surface of the lesion progressively thins out and weakens and finally opens to free the content, full of infective viral particles, and forms a crust that eventually falls. However, in the present multi-country outbreak, dermatologists are reporting that the lesions are pseudopustular, with whitish solid content, a necrotic center, and an erythematous hale, which evolve to a more purulent, necrotized, and even ulcerative aspect [56]. As the lesion originated deep in the dermis, usually scars of pockmarks are left as a result of the infection [38,65,66,67][38][65][66][67]. The lesions happen in the outer skin, as well as the accessible mucosae, such as the oral or anal mucosa, but also in the epithelial cells lining the internal organs [68].

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