Unusual global outbreak of monkeypox: what should we do?

Abstract

Recently, monkeypox has become a global concern amid the ongoing COVID-19 pandemic. Monkeypox is an acute rash zoonosis caused by the monkeypox virus, which was previously concentrated in Africa. The re-emergence of this pathogen seems unusual on account of outbreaks in multiple nonendemic countries and the incline to spread from person to person. We need to revisit this virus to prevent the epidemic from getting worse. In this review, we comprehensively summarize studies on monkeypox, including its epidemiology, biological characteristics, pathogenesis, and clinical characteristics, as well as therapeutics and vaccines, highlighting its unusual outbreak attributed to the transformation of transmission. We also analyze the present situation and put forward countermeasures from both clinical and scientific research to address it.

Keywords

monkeypox / poxviruses / vaccine / infectious diseases

1 Introduction

Recently, cases of human-to-human transmission of monkeypox virus (MPXV), which was previously thought to be extremely rare, have been reported in several countries. According to the US Centers for Disease Control and Prevention (CDC), on July 8, 2022, over 50 countries/territories reported more than 8000 confirmed cases in total [1]. Monkeypox spread from Africa to the world in just one month, and most cases have come from Europe. The actual number of cases may be underestimated, in part because of the lack of early clinical recognition of infections previously familiar only in a few countries and limited mechanisms to strengthen surveillance in many countries for diseases previously unfamiliar to most health systems.

Among the family of orthopoxviruses, only four species, smallpox or variola virus (VARV), cowpox virus (CPXV), vaccinia virus (VACV), and MPXV, can cause human infection [2]. MPXV and VARV are close relatives and are the two most important pathogens with potential bioterrorism threats [3]. VARV was once a common severe infectious disease pathogen that has been circulating in humans for at least 3000 years. It is highly pathogenic (mortality rate ~30%) and transmissible [4,5], taking many people’s lives and causing crushing blows to humans. In 1980, the WHO declared that the world had eradicated smallpox owing to the smallpox vaccine [6]. Soon after, the world gradually stopped the smallpox virus vaccination.

Monkeypox is considered to be the most important orthopoxvirus infection in humans since the eradication of smallpox. Monkeypox was first discovered in humans in 1970 [7] and has previously been rare outside of Central and West Africa. Two phylogenetically distinct branches of monkeypox virus have been identified by genome sequencing: the Central African (Congo Basin) branch and the West African branch. Typically, Central African monkeypox viruses are associated with more severe disease, higher mortality, and more frequent human-to-human transmission. Monkeypox virus, in the current outbreak outside of Africa, has been confirmed to belong to a West African strain. Monkeypox viruses have not previously been highly contagious, with a basic reproduction number (R0) lower than 1 in the 1980s [8], higher than 1 in a study previous to this outbreak [9], compared with a high average R0 of 9.5 for the SARS-CoV-2 Omicron strain (from November 1, 2021 to February 9, 2022) [10]. This unusual outbreak requires us to reassess the virus.

Here, we reviewed the warning pathogen, including its epidemiology, biological characteristics, pathogenesis, and clinical characteristics, as well as therapeutics and vaccines, highlighting its unusual outbreak attributed to the transformation of transmission. We also analyzed the present situation and put forward countermeasures from both clinical and scientific research to address it.

2 Epidemiology

MPXV was first detected in 1958 and in an outbreak of vesicular disease in captive monkeys. This is why it is called “monkeypox” [11]. However, the largest animal reservoirs of this virus are not monkeys but rodents, including squirrels and kangaroos. Rodents are the largest group of mammals, with more than 1500 species. To date, MPXV has been detected in a variety of animal species, including squirrels (ropes and trees), rats, striped mice, dormice, and monkeys [12–14]. Like monkeys, humans are considered to be the host of the virus, but the mode of transmission of MPXV from animals to humans is still unclear. Aerosol transmission has been demonstrated in animals [15,16] and may explain a nosocomial outbreak in the Central African Republic [17]. Monkeypox virus is transmitted from one person to another by close contact with lesions, body fluids, respiratory droplets, and contaminated materials, such as bedding. In August 1970, in the equatorial village of Bukenda in Zaire (now the Democratic Republic of the Congo), a 9-year-old child was found to have vesicular skin disease similar to smallpox, which was the first reported human case of monkeypox [18]. The incubation period of monkeypox is usually 6 to 13 days, but it can also be between 5 and 21 days [19,20].

Since monkeypox was discovered 60 years ago, it has not received much attention. In recent years, the frequency and geographical distribution of monkeypox in humans have been increasing. In the past 20 years, the number of human cases of monkeypox has increased exponentially, exceeding the number of cases accumulated in the first 45 years after the first detection of monkeypox [19,20]. Poverty and persistent civil strife force people to hunt down small mammals (bush meat) to obtain protein-rich food, thereby increasing the chance of contact with wild rodents that may carry monkeypox [21]. Since its discovery, the disease has been endemic in Central Africa and West Africa, and intermittent and sporadic cases of monkeypox transmission in humans by local wild animals have been reported. In addition, the number of human monkeypox cases in Central Africa and West Africa is increasing, which is considered to be the result of the weakening of cross-protective immunity in the population after the smallpox vaccination was stopped in the early 1980s [20]. In addition, many human cases have been reported in nonendemic areas, including the United States, the UK, Israel, and Singapore [22]. These sporadic outbreaks in nonendemic areas are related to imported rodents or people with a history of travel to endemic areas.

In May 2022, multiple cases of monkeypox were detected in several nonendemic countries. None of the cases reported a travel history to the endemic areas of monkeypox, and there was no epidemiological link between the cases reported in different countries. The early epidemiology of the initial cases reported to the WHO by various countries showed that the cases were mainly reported in men who have sex with men [23]. Currently, research is underway to further understand the epidemiology, source of infection, and mode of transmission. The sudden appearance of monkeypox in several nonendemic countries indicates that there may be a period of undetected transmission, as well as recent expansion events.

3 Biological characteristics

Monkeypox virus belongs to the family Poxviridae, genus Orthopoxvirus. Poxviruses are the largest and most complex group of DNA viruses among all animal viruses [24]. Monkeypox virus is 200–300 nm in size, round brick-shaped or ovoid, and surrounded by a 30-nm outer membrane composed of irregularly shaped tubules. There exist two different forms of infectious virus particles: intracellular mature virions (MVs) and extracellular enveloped virions (EVs). EVs have an extra envelope than MVs. The interior of the viral particle consists of a dumbbell-shaped nucleus and a pair of lateral bodies between the concavities and the outer membrane (Fig.1). Recently, researchers have predicted the structure of the whole proteome of monkeypox variants as well as the small-molecule binding pockets [25]. Monkeypox virus contains soluble antigens, nucleoprotein antigens, and erythrocyte agglutinins and is cross-immunogenic with three other orthopoxviruses that infect humans. Monkeypox virus shares structural and soluble antigens with other orthopoxviruses. It is difficult to distinguish between smallpox virus and poxvirus in complement binding tests and agar diffusion tests.

The genome of monkeypox virus is approximately 197 kb of bipartite covalently closed linear double-stranded DNA and contains an identical but oppositely oriented 6379 bp inverted terminal repeat (ITR) sequence at the end of the genome [26]. The virus contains 190 open reading frames, four of which are located in the ITR sequence [27] (Fig.1). In the central region of the genome are mostly genes encoding important replication enzymes and structural proteins of the virus, which are highly homologous compared to smallpox virus, while genes encoding virulence and host tropism are mostly located at both ends of the genome, which are highly heterogeneous to smallpox virus. At present, the structure and function of many kinds of monkeypox proteins have been predicted and analyzed, and a number of studies on gene variation of monkeypox virus have been released, but the function and expression status of some genes still need further study.

The current outbreak was caused by the West African branch of the virus, which is generally less dangerous than the Congo Basin branch, and genetic differences between the viral genomes of these two branches may explain the differences in viral clearance and pathogenesis [28]. Studies have revealed that the virus strain associated with the monkeypox outbreak identified in May 2022 is a well-characterized divergent clade of monkeypox virus outbreaks in endemic countries in 2018–2019 or represents a recent evolutionary change in the virus [29]. Of course, differences in disease severity may also be influenced by the route of transmission, host susceptibility, and the amount of infected virus, as we will elaborate below.

Monkeypox virus is more stable in dry conditions and can remain viable for a long time in a 4 °C or −70 °C environment, but it does not tolerate high temperatures and can be rendered noninfectious in 20 min at 56 °C. It is resistant to ether but is easily inactivated by organic reagents, such as chloroform, methanol, formaldehyde, ethanol, sodium dodecyl acetate, and formalin.

Monkeypox virus can grow in cells originating from monkeys, rabbits, cattle, guinea-pigs and mice, as well as humans, and produce distinctive cavernous or plaque-like cytopathic effects. Most of the cells infected with monkeypox virus contain many small round or oval eosinophilic inclusion bodies.

4 Mechanisms of monkeypox virus transmission and pathogenesis

Monkeypox is a zoonotic disease that spreads relatively inefficiently from person to person [30,31], and the incidence of the disease is increasing year by year [22,30,32]. Transmission is believed to occur via saliva/respiratory excretions or contact with lesion exudate or crust material, which can infect the mucous membranes of the eyes, nose, throat and wounded skin. Studies have shown that it takes prolonged face-to-face contact to spread, such as lasting more than three hours within a 2-m radius without personal protective equipment [33,34]. Monkeypox virus can be transmitted from pregnant women to fetuses through the placenta, or from infected parents to children through skin contact during or after the birth of children [35]. The disease can also be caught by being bitten or scratched by infected animals and eating meat from infected animals that are not properly cooked [36,37], so attention should be given to the quarantine of imported animal monkeypox virus and the investigation of patients’ travel history. In recent years, sexual contact has also been considered a potential route of human spread, especially male-to-male contact [38–40].

Between infection and the occurrence of rashes, a complicated series of events occur: the virus enters the human body through the mucous membrane or damaged skin and is disseminated through the host via the lymph and blood, primarily by infected leukocytes [41]. Then, the virus replicates and multiplies in the regional lymph node and reaches skin epithelial cells and other tissues through the blood circulation [42]. Virus deposit in the skin multiplies for several days before any macroscopic lesions appear. Viral replication and invasion of skin epithelial cells cause superficial inflammation of the dermis, leading to vasodilation, hyperemia, and inflammatory cell infiltration, resulting in a rash (cutaneous vesicles) [43] (Fig.2).

During infection, monkeypox virus replicates and multiplies in cells, and the host immune system recognizes the virus or its surface epitopes, causing an innate or adaptive immune response. Host pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs), which then initiate innate immune responses and activate inflammatory signaling pathways, trigger local inflammation; and strongly secrete proinflammatory cytokines (including IL-6 and TNF-α), chemokines (including CXCL1 and IL-8) and complement proteins [44,45]. The secretion of cytokines and chemokines attracts more immune cells to the infected site and causes clinical symptoms, such as rash and skin lesions.

To counteract the host’s immune defenses, monkeypox viruses have developed an assortment of immunomodulators that work in various ways to undermine or circumvent host antiviral responses triggered by PRRs. Monkeypox in Africa inhibits the activation of T cells through their receptors, preventing the release of inflammatory cytokines in human cells derived from patients who have already been infected with monkeypox [46]. In addition, compared with West African strains, Central African monkeypox strains selectively downregulated host responses, especially host cell apoptosis [47], and secreted immunomodulatory factors to inhibit complement enzymes, thereby increasing the virulence of Central African strains [48]. Clinical recovery and the disappearance of the virus are closely correlated with the appearance of circulating antibodies.

5 Clinical characteristics

Human monkeypox virus is a zoonotic orthopoxvirus with a presentation similar to that of smallpox virus. The incubation period (interval from infection to onset of symptoms) of monkeypox varies from 5 to 21 days [49]. Infected persons usually start with “flu-like” symptoms [50,51], including fever, headaches, fatigue, muscle soreness, and enlarged lymph nodes. Swollen lymph nodes (1–4 cm in diameter) are firm and tender, usually in the submandibular, cervical, or inguinal regions (Fig.2).

A rash usually appears 1 to 3 days after the onset of fever and lymphadenopathy, beginning with macules (lesions with a flat base) and papules (raised firm painful lesions) [52]. Then, the lesions develop quickly into herpes, forming fluid-filled blisters and pus-filled pustules with local lymphadenopathy, followed by scabs or crusts, and each symptom may last 1–2 days [53,54]. Monkeypox lesions are firm, deep-seated, and well circumscribed with a central point of umbilication [55], and the exudate of the lesion is highly infectious. Often, the rash first appears on the face and quickly spreads to the extremities, which mainly affects the face, palms, and soles of the feet. It can also appear on the genitals, mouth, conjunctiva, and cornea [42,56]. In severe cases, the lesions can even cover the whole body. The rash always lasts up to 4 weeks until the lesion desquamates [57].

Monkeypox is often misdiagnosed as chicken pox and smallpox (up to 50% of cases in the Democratic Republic of the Congo were misdiagnosed) [54]. The major difference distinguishing human monkeypox (MPX) from smallpox is the lymph node enlargement caused by MPXV that often occurs at the onset of fever, and varicella zoster virus lesions are usually more superficial in appearance with irregular borders, can be present at multiple stages on any one site on the body, and rapidly evolve from macules to crusts within 24 h [58].

For most people, monkeypox is a self-limiting disease with mild symptoms that usually lasts two to four weeks and recovers completely. However, the severity of symptoms is also closely related to the transmission route, the degree of virus exposure and the patient’s own basic diseases. Epidemiologic studies of human monkeypox infections have shown that younger children, pregnant women, and persons not vaccinated against smallpox may suffer from severe disease and complications, including secondary bacterial infections, respiratory distress, pneumonitis, sepsis, gastrointestinal involvement, encephalitis, and corneal infection with ensuing loss of vision [19,52,59]. The proportion of patients who die has varied between 0 and 11% in documented cases and has been higher among young children. The outbreak of monkeypox virus originated from the West African branch, and the mortality of this branch was 3.6%, while that of the evolutionary branch in Central Africa (Congo basin) was 10.6% [41].

Laboratory assays are important components for the diagnosis and identification of monkeypox infection. Medical professionals collected clinical specimens (including vesicular fluid, scabs or lesion swabs, throat swabs, whole blood, and serum) from confirmed or suspected monkeypox patients for further etiological detection [50]. Viral isolation and identification, electron microscopy and real-time PCR are the gold standard detection methods for confirming monkeypox infections, but require sophisticated laboratories with high containment facilities. Specimens of rash, blister fluid, crusts, oropharyngeal or nasopharyngeal secretions are collected and infected with Vero cells in virus growth medium for virus amplification until CPE advances throughout for virus isolation and identification. Intracytoplasmic, round-to-oval inclusions may be observed under an electron microscope measuring 200 to 300 μm with sausage-shaped structures centrally. Other molecular and antigen detection tests such as immunohistochemistry and immunofluorescence, can be used to assist the clinical diagnosis of monkeypox, and serological assays are mainly used for epidemiological investigation. Serologic testing requires paired acute and convalescent sera for MPXV-specific IgM detection within 5 days of presentation, or IgG detection after 8 days [52]. It is worth noting that monkeypox needs to be differentiated from other diseases such as smallpox, chicken pox, herpes zoster, and herpes simplex.

6 Therapeutics and vaccines

At present, there are no specific treatments available for monkeypox infection. As a self-limited disease, most people infected with monkeypox do not require special treatment. The main treatment methods are symptomatic support treatment; prevention and treatment of complications; rest; replenishment of water and nutrition; strengthening nursing; keeping eyes, nose, the oral cavity and skin clean; and antibiotics can be used to prevent secondary infection. There are antiviral drugs for smallpox that could also be used to treat monkeypox under certain circumstances. Tecovirimat, smallpox vaccine, cidofovir, brincidofovir, and vaccinia immune globulin (VIG) can be used to control a monkeypox outbreak [60] (Tab.1). However, there are no data on the effectiveness of cidofovir, brincidofovir, and VIG in the treatment of monkeypox complications. It is unknown whether or not a person with severe monkeypox infection will benefit from treatment with either antiviral; however, its use may be considered to deal with emergencies in such instances.

Tecovirimat (TPOXX), an antiviral drug used to treat smallpox, was also approved by the Food and Drug Administration (FDA) for monkeypox in January 2022. Tecovirimat targets and inhibits the activity of the highly conserved orthopoxvirus VP37 protein and blocks the interaction with cellular Rab9 GTPase and TIP47, to prevent the formation of egress competent enveloped virions necessary for cell-to-cell and long-range dissemination of the virus, inhibiting long-range dissemination of the virus [81]. Studies on the therapeutic efficacies of the antiviral drug Tecovirimat in a variety of animal species have shown that Tecovirimat is effective in treating orthopoxvirus-induced disease, and the clinical signs of disease were elevated in Tecovirimat-treated animals, compared to placebo-treated animals [82–84]. Human clinical trials indicated the drug was safe and tolerable with only minor side effects [85,86]. However, the data on the effectiveness of Tecovirimat in treating human cases of monkeypox are not available.

Because monkeypox virus is closely related to the virus that causes smallpox, the smallpox vaccination also has cross-immunity to other orthopoxvirus infections, including monkeypox. Studies suggest that the smallpox vaccine is at least 85% effective in preventing monkeypox. However, since the World Health Organization declared that smallpox was eradicated in 1980 [6], countries gradually stopped the smallpox vaccination, so that people under the age of 40 or 50 years around the world no longer benefit from the protection provided by the previous smallpox vaccination program and are not immune to monkeypox. Even people who have been vaccinated against smallpox have limited protection against the monkeypox virus due to the decline in their immunity over time.

Modified Vaccinia Ankara (MVA) is an attenuated vaccinia virus that cannot achieve complete replication in mammalian cells. MVA-BN (also known as Imvamune, Imvanex, or Jynneos) is an alternative smallpox vaccine, which the FDA licensed to prevent monkeypox in 2019. At present, it is mainly used for work that has exposure risk and as a vaccination for an exposed population, and it is not currently available to the general public. The effectiveness of MVA against monkeypox was concluded from a clinical study on the immunogenicity of MVA and efficacy data from animal studies [87–89]. The immunogenicity of MVA-BN showed noninferiority compared with another FDA-licensed live smallpox vaccine, ACAM2000 [90,91]. However, the traditional replicative smallpox vaccine has safety problems in the general population, and the safety of MVA has been fully proven in a number of clinical trials. MVA-BN has excellent safety, tolerability, and immunogenicity. There were no major safety problems, especially regarding cardiac safety, in both healthy and immunocompromised people in trials [72,92]. In addition, in people who have been vaccinated, MVA-BN can quickly boost the long-term B cell memory response induced by the previous traditional smallpox vaccine [93]. As reserve resources, smallpox vaccines such as Tiantan strian developed and produced by China and Aventis Pasteur Smallpox Vaccine (APSV) of the United States have the potential to prevent monkeypox in case of emergency.

7 Future countermeasures

Today, the monkeypox virus has spread outside of Africa, and this outbreak is unusual in that there are so many confirmed cases of monkeypox of unknown origin in a short period of time in a nonendemic area that it is impossible not to be concerned. There are many possible reasons for this unusual outbreak of monkeypox, including a decrease in the proportion of people immunized against smallpox, increasingly frequent international travel, and mutations in the adaptation of monkeypox viruses to human hosts [23,29,94]. However, with years of human experience in fighting infectious diseases, we do not need to panic.

In essence, zoonotic diseases are infectious diseases. Therefore, the same principles of prevention and control of infectious diseases apply to zoonotic diseases, such as monkeypox. These principles can include the following: controlling the source of infection, cutting off the transmission route, and protecting vulnerable and susceptible populations.

To prevent underdiagnosis and misdiagnosis, clinicians, especially dermatologists and epidemiologists, should treat monkeypox infection as a clinical syndrome of varicella for differential diagnosis and should contact disease prevention and control or relevant agencies for sequencing identification [40]. Positive and suspected patients and animals should be isolated promptly, and reverse and positive contact tracing should be initiated.

Severe restrictions on the importation of wildlife, especially any African rodents, should also be imposed. Residents and travelers to endemic countries should avoid contact with sick animals (rodents, marsupials, primates), dead or alive, that may carry monkeypox virus and should avoid eating or handling wild animals. Any illness during travel or after return from an endemic area should be reported to a health professional. Health workers and other caregivers who care for patients with suspected or confirmed monkeypox should implement standard control precautions for contact and droplet infection. Samples collected from suspected monkeypox patients or animals suspected of being infected with monkeypox virus should be handled safely by trained personnel in an appropriately equipped laboratory.

Emphasis should always be placed on maintaining good hygiene habits. Other prevention measures include applying suds or alcohol-based disinfectants to maintain hand hygiene before eating and after using the toilet and after contact with suspected infected people or animals. Medical masks should also be worn in crowded places.

Since the global declaration of smallpox eradication in the 1980s, populations around the world no longer benefit from the protection provided by previous smallpox vaccination programs, and thus, populations born after this time generally lack the appropriate immunity and are in a susceptible group. In addition, even those who have been vaccinated against cowpox are at risk, as antibody immunity greatly reduces with time. If a vaccine is available, the vaccination of high-risk close contacts should be considered after a risk-benefit assessment.

We should not relax our vigilance; instead, we should strengthen awareness of the prevention of the monkeypox virus, and scientists should strengthen the research of the virus itself to fully understand the virus and explore the cause of this unusual outbreak. In addition, we should develop better and more accurate diagnostic reagents for the timely detection of imported cases. At the same time, one should start stockpiling potent vaccines and antiviral drugs to avoid being in a passive situation when cases arise.

For thousands of years, the development of human society has always been intertwined with the emergence, prevalence, and control of different infectious diseases. Only by continuously gaining a deeper understanding of the epidemiological patterns of infectious diseases can we do our best to keep human beings free from infectious diseases and guard their health and dignity.

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