The Monkeypox Virus (MPXV), a zoonotic pathogen from the Orthopoxvirus genus within the Poxviridae family, has recently gained attention due to its potential for widespread transmission and severe clinical outcomes. This comprehensive review aims to provide healthcare practitioners with a thorough understanding of the epidemiology, clinical manifestations, and treatment strategies related to MPXV. By exploring the virus’s clinical history, epidemiological trends, and therapeutic options, this article seeks to equip clinicians, particularly those unfamiliar with this emerging zoonosis, with the knowledge necessary to manage Monkeypox effectively. The review also discusses the challenges and gaps in current understanding, emphasizing the importance of ongoing research and vigilance in the face of this evolving public health threat.

1. Introduction

The purpose of this review is to present a comprehensive discussion on the background and fundamental knowledge regarding the Monkeypox Virus (MPXV), a zoonotic disease caused by a member of the genus Orthopoxvirus within the family Poxviridae. This essay aims to serve as an informative tool for practitioners who may not be familiar with the epidemiological factors, clinical signs, and treatment of this viral zoonosis. Therefore, this review provides insight into key aspects of MPXV, including its clinical history, primary clinical manifestations, epidemiology, and treatment strategies, offering readers an updated understanding of the disease.

The Monkeypox Virus (MPXV) is an Orthopoxvirus identified in the genus Orthopoxvirus. Monkeypox is primarily found in the Democratic Republic of Congo, Nigeria, and the Central African Republic, where it is more prevalent. The infection is spread to humans through contact with various primate species and consumption of raw or undercooked meat. Despite increasing recognition, the full extent of the zoonotic and sylvatic transmission cycles of MPXV remains unclear.

This review offers an extensive analysis of the Monkeypox pathogen (MPXV), covering epidemiology, scientific studies, treatment strategies, and related associations. It aims to familiarize readers, particularly those who are less acquainted with this zoonotic disease, with the natural and geographical characteristics of the virus, highlighting the ongoing challenges and the potential risks posed by this pathogen.

1.1. Background and History of Monkeypox Virus

Monkeypox is an Orthopoxvirus zoonosis discovered in Denmark in 1958. The origin of monkeypox virus outbreaks has been linked to the importation of infected African rodents, primarily affecting domestic rodents in Africa. Controlling the transmission of the monkeypox virus and its primary animal reservoirs is crucial for managing outbreaks and preventing the introduction of the virus into non-endemic countries. This comprehensive review will shed light on the epidemiological aspects of the disease, its clinical and laboratory findings, treatment strategies, and the prevention and control of MPXV in humans.

The family Poxviridae consists of several poxvirus genera, including Avipoxvirus, Capripoxvirus, Leporipoxvirus, Orthopoxvirus, Parapoxvirus, and a few unclassified genera. Members of this family have the largest double-stranded DNA with a closed genome and can affect a wide range of hosts, from insects to humans and animals. Individual poxviruses and genera may form distinct membranes on the surface of host cells, evolving into enveloped viruses outside the host envelope, which helps block the formation of host-neutralizing antibodies and confers resistance to disinfection and damage. In nature, some poxviruses replicate in the cytoplasm of respiratory or vascular epithelial cells, causing vasculitis and widespread tissue damage that leads to pustules, widespread hemorrhage, and various other outcomes. Vaccines developed through cross-species immunization with related diseases (e.g., cowpox as a vaccine for smallpox) or species-specific vaccines can prevent particular poxvirus illnesses. A notable historical example is the eradication of smallpox in humans for over 40 years. However, some poxvirus diseases, such as myxomatosis in rabbits, can only be controlled when their host reservoirs are effectively managed.

2. Epidemiology

The study of the incidence, distribution, and determinants of the Monkeypox Virus within human populations involves understanding various characteristics such as culture growth, isolation, genetic assays, polymerase chain reaction, serological tests, and rapid diagnostic methods. Globally, cases of Monkeypox Virus have been reported in countries across different regions, with the highest number of infections occurring in Central and Western Africa, particularly in the Democratic Republic of Congo, South Sudan, and Nigeria. Monkeypox has become a notifiable disease, especially during periods of acute flares or large outbreaks of vesicular disease, often coinciding with the main rainy season. Epidemiological surveys of related orthopoxvirus infections have often focused on wartime and post-conflict environments. The intensity of Monkeypox outbreaks in certain areas has been influenced by factors such as the local poultry population. For instance, in 2015, thirty-one new human Monkeypox cases were identified.

Known transmission routes for the virus primarily include the transfer from wild game to humans, particularly in environments where there is free cohabitation and easy access to freshwater and game. Among 369 collected serum samples, 17 tested positive for Monkeypox Virus IgG antibodies, corresponding to a seroprevalence of 4.6%. Interestingly, variant-specific antibodies were more prevalent in females (5.3%) than in males (3.1%). Seroprevalence was also higher in individuals over 60 years of age and those who had lived in the same area for more than 40 years, with rates of 6.2% and 5.5%, respectively. The earliest evidence of IgM antibodies in individuals exposed to Monkeypox came from preliminary serological studies conducted on soldiers who developed a rash following potential exposure during the summer of 1959.

Erridge suggests that the primacy of orthopoxvirus and capripoxvirus in understanding the origins and evolution of hominids is based on bioinformatics and suspected catarrhine-origin viruses. The “ethnophoxer” issue, often overlooked, plays a crucial role in the patterns of Animal-TB-Zoonosis transmission in remote areas. Unusual political, commercial, or recreational behaviors were rare causes of transmission before the eradication of smallpox, especially before the widespread vaccination of humans against varioloviruses.

2.1. Global Distribution and Incidence

The disease was first recognized in laboratory monkeys during smallpox research. The illness was first identified in humans in 1958, in a three-year-old boy in what is now the Democratic Republic of Congo (DRC). In the 1990s, humans who had visited the DRC were also found to be positive for monkeypox IgG antibodies. Human surveillance studies conducted in 2010 revealed that out of 14,788 participants, four individuals tested positive (IgM or a fourfold rise in IgG) for MPXV, resulting in a seroprevalence of 0.0291%. Additionally, a 2012 study of 2,687 non-human primate (NHP) samples found a 0.4% incidence rate, with the lowest yearly incidence observed in NHPs between 2008 and 2011, and the highest in 2012 at 2.6%. In Nigeria, the first monkeypox outbreak occurred in 1971, and at least 27 additional outbreaks have been identified since then.

As of January 2019, 13,115 suspected cases of monkeypox had been identified in West and Central Africa. Children are at a higher risk of human monkeypox (HMPX) infection. Between 2005 and 2013, the mean age of onset for imported cases was 4.5 years. During monkeypox outbreaks in the United States (2003) and Israel (2018), the average age of human patients was 8 to 9 years old. The disease is not equally distributed across all age groups: while all age groups reported between 1 and 13 cases during the 2003 U.S. outbreak, children aged 1 to 9 years accounted for over 90% of the cases. Human monkeypox cases reported to the Integrated Disease Surveillance and Response (IDSR) from September 2020 to September 2021 were predominantly in individuals aged 5 to 39 years, with a higher proportion of suspected and confirmed cases among children aged 5 to 14 years.

2.2. Host Range and Reservoirs

Different host species, including various rodent species and humans, can develop monocytosis secondary to the viremia caused by the Monkeypox virus. Transmission of the virus often occurs through human-to-human contact, with children being particularly susceptible, especially in low-coverage living regions (LCLR). The available data suggest not only that the virus can move and emerge in new areas, but also that there are many interconnected hosts and environments that may facilitate its spread. This raises important questions, such as whether there is a specific host that could act as a key transmitter of the virus in certain regions. If all rodent species, for example, were considered as potential reservoirs, the study of their movement patterns and interactions with humans could help identify critical hosts. This would be vital for controlling the spread of the virus, particularly in previously unaffected areas, and for preventing new outbreaks as populations and environments change.

3. Virology

Monkeypox virus (MPXV) is a double-stranded, enveloped DNA virus with an approximate genome length of 215 kbp. Genomic analyses have identified two distinct genetic clades of MPXV strains, each corresponding to the geographic location of viral isolation. The virus most closely related to MPXV is the variola virus (VARV), which causes smallpox. Although MPXV and VARV share genetic similarities and a compact orthopoxvirus genome, they are distinct species within the same genus, Orthopoxvirus. The Poxviridae family is divided into two subfamilies: Chordopoxvirinae and Entomopoxvirinae. MPXV is classified under Chordopoxvirinae due to its isolation from mammalian reservoirs and its capability for human-to-human transmission. The ITR1980 virus, taxonomically classified as a Zaire-like MPXV, has been identified as the principal source of imported human cases. Human-to-human transmission is a significant concern in the epidemiology and epizootiology of monkeypox. The virus primarily spreads through hematophagy, direct contact, consumption of contaminated foods, and inhalation of aerosolized lesions or secretions. Although many animals could potentially be infected under laboratory and natural conditions, natural monkeypox virus infections have been predominantly reported in humans. Bushmeat has been identified as the principal source of zoonotic virus infection. Epidemiological studies using haemagglutination-inhibition tests have shown that MPXV complicates the control and eradication of other diseases. Regulatory and reference diagnostic tests have been established for the prevention of MPXV infections in animals, particularly poultry.

Virus transmission is a multistep process, occurring both from one host to another and within the same host. The basic reproductive number, R0, which represents the average number of secondary cases produced by a single infected individual in a fully susceptible population, is typically greater than 5 for MPXV. Virus transmission is closely linked to contagiousness and the environmental conditions that facilitate spread. Viruses with a low R0 tend to be highly fatal, and control efforts often focus on eliminating infected hosts rather than reducing the susceptible host population. The dose-response relationship is dynamic, influenced by factors such as host immunity, duration of infection, tissue tropism, and virus strain. Viruses maintain their presence in infected tissues by exploiting physiological susceptibilities such as pH, enzymes, organ systems, and immune responses. This allows the virus to interrupt the normal function of host cells, leading to clinical symptoms and facilitating further transmission. Maintaining a low level of the virus in the body, such as in respiratory secretions or blood, is crucial for keeping the pathogen functional, alive, and viable. Transmission between hosts primarily occurs through direct contact. The duration during which a pathogen can be shed from an infected host, known as the shedding period, is controlled by the ongoing presence of both quantitative and replicative viral populations within the host.

3.1. Genomic Structure and Classification

The Monkeypox virus (MPXV) belongs to the Poxviridae family, specifically within the icosahedral nucleo-cytoplasmic large double-stranded DNA viruses. These viruses are characterized by a single layer of viral proteins that form highly infectious and pathogenic antigenic envelopes. MPXV is classified as an Orthopoxvirus and is associated with zoonotic viral diseases. Like all poxviruses, MPXV contains a complete set of essential genes necessary for replication in the host and shares a common genetic structure with other members of the Orthopoxvirus genus.

The complete genomic sequence of MPXV was first determined using the Zaire-96 V-002 strain, which was isolated from the earliest known case of Monkeypox virus in 1996. This strain has a linear double-stranded DNA sequence of approximately 168 kbp, with non-repetitive ends and about 11,000 predicted base pairs, including an interactive terminal protein characteristic of the poxvirus family.

As a member of the Orthopoxvirus genus, MPXV differs from the variola virus (VARV), which causes smallpox, in terms of genetic variation and the coding potential of proteins that carry out a wide range of functions. Although MPXV and VARV are related, they are distinct species within the Orthopoxvirus genus. Within this genus, species are further subdivided into strains based on genetic similarities. For example, the MPXV species, as recognized by the International Committee on Taxonomy of Viruses (ICTV), consists of two genetically similar strains: the Western Africa MPXV and the Congo Basin MPXV. These strains were initially distinguished based on their geographic location of isolation and the accumulation of genetic variations over time in the African environment. Another strain, known as the Kupto strain MPXV, was isolated from captive macaques in the Abruzzi area near Rome, Italy. As of now, three MPXV orthopoxviruses associated with monkey species have been identified and classified as separate strains.

Orthopoxvirus species are known for their broad tissue tropism, meaning they can infect a wide range of hosts, including cows, sheep, and other quarantined animals, as well as various wild species such as those affected by monkeypox, MPXV, and the variola virus (VARV), the causative agent of smallpox.

3.2. Transmission Dynamics

The dynamics of monkeypox virus transmission within and between animal and human populations are complex. This complexity arises from the numerous biological, environmental, and social factors that influence how infected animals or people shed the virus and the quantity of virus released into the environment. Each factor that affects virus shedding or virulence can alter the density of susceptible hosts in the environment, thereby influencing the dynamics of transmission. As a result, the routes of infection and the patterns of virus shedding and transmission vary according to the natural host species, their size, reproductive behavior, social organization, human population density, and the relative population size of various infected and at-risk hosts. Additionally, the types, frequency, and intensity of contact between humans and potentially infectious animals are crucial in mediating the risks of human monkeypox infection. This section will now discuss these factors in greater detail.

Transmission Modes and Dynamics of Infection: Monkeypox virus can be transmitted in several ways: from human to human, human to animal, animal to human, and animal to animal, depending on the natural host, intermediate hosts, and the ecological conditions of the enzootic region. Infection can occur directly through contact with fresh lesions or scabs of poxvirus-infected animals, or indirectly through contact with fomites contaminated by viruses from fresh pox scabs.

4. Clinical Manifestations

As a zoonotic disease, monkeypox infection is significant due to its clinical similarities to smallpox, a disease eradicated in 1980. Because of these similarities, monkeypox is considered a public health threat. The clinical manifestations of monkeypox can range from an asymptomatic or mild illness with no fever to a severe or fatal illness accompanied by fever. In humans, monkeypox typically presents after an incubation period of 5 to 16 days as an orthopoxvirus exanthematous disease, generally progressing in a biphasic manner. The disease is characterized by a 5- to 23-day prodromal phase, which includes symptoms such as fever, headache, lymphadenopathy, fatigue, and malaise, and eventually evolves into a rash eruption phase. The clinical presentation of the illness can vary, taking one of three distinct forms: vesiculopustular rash (the most common), hemorrhagic rash, and more severe cases that may lead to death. In severe cases, active virus shedding through saliva can continue for up to two months, making the patient contagious and posing a risk of contamination through bed linens, waste items, and other fomites if not properly decontaminated.

Most patients report the appearance of new rashes, typically starting in the oral mucosa and on the face, then spreading down the body to the extremities, such as the hands, feet, and legs. These patients may also exhibit other systemic clinical signs and symptoms, including conjunctivitis, cough, diarrhea, and various upper and lower respiratory tract infections. In fatal cases, the disease can progress to severe anorexia, vomiting, confusion, and seizures due to the virus spreading to the central nervous system, potentially leading to coma. In the Democratic Republic of Congo, many cases are too severe to track or analyze prior to death, although delayed deaths due to secondary infections have been documented. Infected CD1 mice have been observed to develop rat-bite fever as a sequela to the disease. Epidemiological data from the USA between 2003 and 2005 indicate that clinical manifestations of monkeypox are often less severe, with more than half of the identified patients recovering within three weeks. Acute complications included ocular scarring, blindness, monkeypox-associated encephalitis, and pediatric neonatal infection, although no deaths were reported.

4.1. Symptoms and Presentation

Symptoms and Presentation: Inoculation of orthopoxviruses into human tissues typically leads to a localized infection that remains stable during the initial viral cycles. The immune system then responds, resulting in the inhibition of viral replication, cell death, or the resolution of the infection into a latent state. Monkeypox infection generally presents with a clinical syndrome that is similar to, but less severe than, smallpox. However, the clinical presentations can vary widely, sometimes resembling other diseases due to the variability in symptoms. The prodromal phase lasts 3-7 days and is characterized by symptoms such as fever, sore throat or joint pain, chills, frontal headache, anorexia, and sweating. The most common objective signs during this phase include cervical lymphadenopathy and pharyngitis, though these can vary depending on the patient’s age and other factors.

The rash, which develops a few days later, progresses through several stages: macules, papules, fluid-filled vesicles, and pustules, which then crust over and persist. Multiple types of skin lesions may be present simultaneously. In the Democratic Republic of Congo (DRC), pox lesions typically appear on the trunk and occasionally on the head and extremities. Other symptoms commonly observed during the rash phase include fever, sore throat, pharyngitis, lymphadenopathy, and malaise. Many patients also report coughing and may exhibit moderate to severe symptoms resembling pneumonitis. The rash and associated symptoms usually continue for 2-4 days after the fever subsides, then gradually disappear over a period of 1-6 weeks. Bone and joint pain, often reflecting musculoskeletal involvement, can cause pain and sometimes swelling in one or more major joints. Before the rash appears, these patients might be misdiagnosed with other diseases characterized by high fever and convulsions. Travel physicians should remain vigilant, as other diseases could manifest with fever and skin lesions if monkeypox transmission occurs.

4.2. Differential Diagnosis

Monkeypox can be misdiagnosed both clinically and in the laboratory due to its similarity in symptoms and characteristics with several other illnesses, such as smallpox, chickenpox, measles, rubella, yaws, syphilis, staphylococcal carriage, henpox, scabies, hand, foot, and mouth disease (HFMD), varicella, herpes simplex, herpes zoster, shingles, generalized rashes, bacterial skin infections, reticuloendotheliosis, cryptogenic chytomatosis, dengue, and epithelial conditions. In regions where monkeypox is not endemic, diseases like chickenpox, measles, or coxsackievirus infections might be considered by clinical teams during diagnosis. Although there are distinct differences between the signs and symptoms of monkeypox and chickenpox, the overlap in clinical presentations can lead to diagnostic confusion.

The differential diagnosis of monkeypox includes several conditions that present with similar symptoms, such as chickenpox, smallpox, and measles. Other vesicular diseases that should be considered include herpes simplex, herpes zoster, varicella-zoster, coxsackievirus infections, staphylococcal pyoderma, scabies, syphilis, yaws, eczema, burns, acute contact dermatitis, insect bites (e.g., flea bites), hidradenitis suppurativa, and rashes associated with atopic dermatitis or other skin conditions (e.g., nummular eczema or lichen simplex chronicus). Molluscum contagiosum, allergic dermatitis, fungal rashes, pityriasis rosea, mumps, and Gianotti-Crosti syndrome (also known as symmetric postanogenital acrodermatitis) should also be considered. Potential etiologic agents for such exanthems include adenovirus, coxsackievirus B, echovirus, cytomegalovirus, parvovirus B, and human herpesvirus 6 (HHV6). Additional conditions to consider in the differential diagnosis are Bier spots, juvenile systemic granuloma, secondary syphilis, and hemangioma displacement. A thorough differential diagnosis of monkeypox involves examining all relevant factors, including epidemiological context, clinical presentation, and laboratory findings, to distinguish it from other similar conditions and to ensure accurate diagnosis and appropriate management.

5. Diagnosis

The clinical symptoms of monkeypox virus infection often resemble those of other infectious diseases, making it difficult to identify specific symptoms unique to monkeypox. The clinical diagnosis of human monkeypox cases is challenging because other viral exanthematous fevers, such as those caused by varicella-zoster, enteroviruses, as well as other exanthematous diseases caused by bacteria or rickettsiae, can produce symptoms that are difficult to distinguish from those caused by the monkeypox virus. Confirming a human monkeypox case requires access to an appropriate diagnostic laboratory, which may be limited in regions where the virus is not endemic. Indirect-solid phase enzyme-linked immunosorbent assays (ELISA) have been adapted to detect anti-POXV immunoglobulin antibodies in human and animal sera. Recombinant protein antigens, including the envelope 360 protein, have also been evaluated for their potential to detect anti-POXV antibodies in human and animal sera. Diagnosing monkeypox typically requires performing serological tests on an individual with compatible symptoms, followed by further laboratory testing for confirmation.

Active virus isolation is most effectively accomplished during the viremic period within the first week of infection, when the virus can be readily detected in whole blood or other appropriate body fluids. The diagnosis of monkeypox is relatively straightforward when patients present with vesicular or pustular rashes and when lesion fluid, swabs, scabs, or biopsies are obtained. The virus is usually not excreted in the urine, and if it is, this typically does not occur until the second week of infection. In immunized patients, rashes are common and can present as vesicular or pustular with axillary or inguinal involvement. The second most preferred diagnostic specimen is a swab taken from vesicular or oral or nasal mucosal vesicles. Samples for monkeypox testing can also include saliva, oral swabs, and urine. Typically, swabs should be obtained from the base of the vesicle, and unroofed pustules using a sterile scalpel blade are ideal. Sterile swabs can also be used to wipe the base of open vesicles or unroofed pustules. Routine swabs processed for virus isolation and identification are also suitable. The optimal time for sampling for virus isolation is likely between day 5 of the rash and the appearance of the first facial scabs around day 11. After this period, the patient is unlikely to be contagious, as the virus primarily spreads through droplets or direct contact. If the sample is collected after the virus has dried on the scabs, transmission from the specimen becomes less certain.

5.1. Laboratory Testing Methods

■ Serology: If a macular, papular, vesicular, and/or pustular rash is present, possible differential diagnoses include smallpox.

■ Polymerase Chain Reaction (PCR): This test can be used to differentiate orthopoxviruses.

■ Next Generation Sequencing (NGS): This test can be used to differentiate orthopoxviruses.

Monkeypox is a rare, zoonotic virus with a clinical course similar to variola (smallpox), which was eradicated in 1980. The monkeypox virus belongs to the Orthopoxvirus family, which also includes cowpox, a virus with an uncertain origin that is believed to have existed for hundreds of years. The epidemiological characteristics and clinical manifestations of monkeypox have been well-studied and are summarized below. Monkeypox is transmitted to humans from animals, and outbreaks have been documented in Central and West Africa. In several countries, including the United States, the identification of monkeypox is a reportable condition. Although monkeypox is easily transmissible, its impact outside Africa is generally limited, with cases typically confined to sporadic imports or nosocomial transmission.

Monkeypox infection is most often asymptomatic but can cause severe disease, characterized by a febrile prodrome with myalgia, headache, and lymphadenopathy. Among patients who develop the typical macular/papular rash associated with a poxvirus, mortality rates in Central Africa have been reported to reach as high as 11 percent, depending on the virus’s virulence. The most severe form of monkeypox, however, occurs in young children. In this immune-naïve population—born after the cessation of smallpox vaccination—fatal infection can occur with an incidence as high as 20 percent. Additionally, there is a severe cutaneous scarring disease that, unlike the facial scarring caused by smallpox, primarily affects the extremities. Severe monkeypox has not been reported in children who have been vaccinated against smallpox.

6. Prevention and Control

Those who are not already infected can be immunized with the vaccinia virus vaccine to prevent monkeypox infection. A review conducted by CDC experts and published in WHO’s Weekly Epidemiological Report outlined five main considerations for using Orthopoxvirus vaccines for the prevention and outbreak control of MPXV.

1. Purpose of Vaccination: The selection of the vaccine will depend on the purpose of the vaccination program, which may differ based on whether the objective is to protect the public or contain an outbreak.
2. Vaccine Licensing and Stockpiling: The use of the vaccine will be governed by its licensing status, and in some cases, vaccines may need to be stockpiled.
3. Contraindications: Live viral vaccines, specifically Orthopoxvirus vaccines, have several contraindications listed in their instructions.
4. Cross-Protection: Because orthopoxviruses are related, a vaccine for one orthopoxvirus can provide protection against another poxvirus. Therefore, a small vaccine stockpile can be used to produce two vaccines for different orthopoxviruses.
5. Additional Considerations: Other factors, such as vaccine effectiveness, adjuvants, route of administration, timing of administration after exposure, use of simultaneous vaccinations, potential vaccine-virus transmission to contacts, and minimizing contact with pregnant women, were all discussed. It was agreed that there should be no live-virus vaccine policy options for managing individuals in various transmission settings if solvent-based vaccination is feasible, supported by available clinical evidence.

Public health authorities should prioritize people who have come into direct contact with a confirmed monkeypox case or are suspected monkeypox patients, according to WHO. When dealing with confirmed, probable, or suspected cases, or when smallpox or monkeypox vaccination is possible and warranted, recommended measures include contact tracing, listing (including categorized contacts), and clinical appraisal. Animals and products associated with a case should not be moved unless absolutely necessary due to humanitarian or public health urgency, which may indicate they need to be humanely euthanized or treated properly. Infected animals have been slaughtered, and their remains are being buried. The natural reservoir for monkeypox has not been confirmed, making it challenging to implement surveillance measures to control its spread.

Public awareness and training campaigns should include vaccine information at all infection control points, and alternative activities should be considered. It is recommended to conduct monkeypox outbreak monitoring investigations, ensuring that specific measures for affected animals are implemented as needed.

6.1. Vaccination Strategies

The need for a preventive vaccine against MPXV (Monkeypox virus) in both humans and animals is widely recognized. The development of veterinary vaccines has been considered essential to prevent zoonotic transmission to humans. However, the use of such vaccines in warfare or specialized scenarios is not feasible, and there are concerns about the potential risks of using live vaccines in certain settings. Alongside these considerations, new standards for the development of immunity against possible threats, including aeromedical immunizations, have been proposed. Details of experimental human immunizations as part of new medical countermeasures have been published, emphasizing the critical need for a robust defense infrastructure to prepare for potential bioterrorist threats.

Significant progress has been made in the development and production of safer and more acceptable vaccines, including those intended for use in both single and multiple doses. Large quantities of developmental vaccine supplies already exist, and the need for prompt multi-dose administration may no longer be necessary in the event of an outbreak. As the prevalence of diseases like monkeypox and smallpox reaches endemic levels, the strategic distribution of vaccines becomes crucial in controlling their spread.

In past efforts, such as the eradication of smallpox, the implementation of ring vaccination played a significant role. Smallpox was eradicated just two years after the widespread application of ring vaccination began in 1967. Over the following eight months, 62 countries conducted smallpox ring vaccination activities. Understanding the animal reservoir of monkeypox is essential for recognizing the unique clinical manifestations of the disease in humans and for managing the disease in animal populations. Typically, animal host species are identified through thorough examinations, which provide the necessary tools for assessing both domestic and wild animals in endemic regions.

Control efforts should focus on high-risk areas, particularly in markets where animal-to-human transmission is more likely, similar to the approach used in managing avian influenza. Following the confirmation of monkeypox in the Congo, further investigation into the effects of mass human vaccination on the occurrence of the disease, especially among unvaccinated populations, is needed. Local transmission is influenced by suboptimal immune responses in populations, particularly in sub-Saharan Africa, where the resurgence of disease post-eradication could occur as vaccination efforts wane.

6.2. Public Health Interventions

Monkeypox is a zoonotic disease that is typically transmitted from infected animals to humans and poses a significant concern for public health systems worldwide. Strategies have been developed for surveillance, outbreak investigations, and control, and appropriate therapy has been recommended for patients suffering from monkeypox. The Global Health Security Agenda, an international initiative aimed at strengthening health systems and preventing the global spread of infectious diseases, has identified monkeypox as a priority emerging and dangerous infectious disease in many affected countries. Monkeypox has been circulating in Africa for more than four decades, resulting in hundreds of confirmed and suspected outbreaks.

Patients diagnosed with confirmed or suspected monkeypox should be placed in isolation within healthcare facilities, with appropriate infection control measures implemented wherever possible. These patients should be managed according to universal precautions, and contacts should be monitored for 21 days after potential exposure to the virus. Once a monkeypox outbreak is confirmed, coordinated mass vaccination campaigns should be conducted for high-risk populations, including contacts and contacts of contacts. In 2016, the World Health Organization (WHO) declared that monkeypox was endemic in the Democratic Republic of the Congo, with outbreaks caused by a novel divergent strain of the virus.

Several factors can hinder our ability to control and prevent monkeypox. Public health education for local and international travelers to monkeypox-affected areas is crucial for mitigating the spread of the virus by increasing awareness of the signs and symptoms of monkeypox and potential exposure risks. Additionally, public health education should be provided to local community groups to enhance ongoing community knowledge and awareness of monkeypox and to promote ways to reduce the risk of transmission from animals to humans.

7. Treatment Strategies

There are currently no specific treatment modalities available for MPX (monkeypox), so the management approach by NBCPs (National Biodefense Communications Plans) is primarily symptom-based, without directly targeting the causative agent. However, several therapeutic approaches have been proposed, ranging from supportive care aimed at relieving symptoms and increasing survival chances to antiviral therapies. In this section, we will explore some of the antiviral therapies discussed in the literature.

Despite supportive care, it is evident that several individuals who contracted MPX—likely from contact with infected animals—experienced a mortality rate ranging from 3% to 20%, highlighting the need for further research into antiviral options. Existing data on the treatment of MPX infections and adverse events associated with the MPX vaccine have been indexed and selectively sourced. PubMed was utilized to gather data through free-text searches using the term “monkeypox” in the title/abstract along with related search terms such as “vaccine,” “treatment,” and “antiviral or drug.” Additionally, references from relevant articles were reviewed for further information. We also examined WHO technical notes, CDC diagnostic notes, S-OIV 2020 materials accessed on February 17, 2020, and previously accessed WHO resources. Finally, we used Google to access the official MPX CDC page and other related clinical resources. This process involved data indexing, article identification, selective sourcing of information, and applying the Pandemic-Potential Monkeypox Classification to aid in the categorization below.

7.1. Antiviral Therapies

Antiviral medications are used to combat viral illnesses caused by DNA or RNA viruses. For the treatment of MPXV (Monkeypox virus) infection, several antiviral drugs with various mechanisms of action have been proposed. These drugs have been evaluated for their in vitro and/or in vivo activity against orthopoxvirus diseases. To enhance therapeutic intervention, several factors must be considered, including the potential efficacy of the drug in combating MPXV, its safety profile or any adverse effects, and the protocol for administering the treatment.

In Chapter 5, Dr. J. G. Marsden described seven anti-orthopoxvirus experiments that were conducted to evaluate the effectiveness of these drugs in combating MPXV infection in various animal models. The findings from this research are summarized as follows: L-CDV, TNX-801, cidofovir, and tecovirimat (DINBV) were found to be effective against MPXV in vitro in preclinical studies. Cidofovir has also been associated with temporary resolution of MPXV infections in animal models. CMX001, I3-01, and tecovirimat have all shown positive safety profiles in phase 1 trials. Among these drugs, tecovirimat (CTN) is currently the only antiviral medication approved for the treatment of MPXV disease.

In clinical studies, patients with systemic MPXV disease were administered tecovirimat intravenously three times per month over four weeks, with doses ranging from 2.2 to 15 mg, and intramuscular (IM) doses varying from 0.5 to 5.0 mg per kg of body weight.

7.2. Supportive Care

Current guidelines and best practices for supportive care of patients with Monkeypox virus infection are not well-established in the literature. The available knowledge and guidelines are based on weak and unsystematic evidence. However, supportive care remains a crucial component of the strategy for reducing mortality associated with Monkeypox virus infection.

Supportive measures for Monkeypox virus patients should focus on identifying and managing both infectious and non-infectious conditions that may arise during hospitalization. This includes supervirulent secondary bacterial infections, ICU-level supportive care, CNS-associated secondary bacterial infections, intubation, ventilation, airway management, ECMO, diarrhea, encephalitis, headache, fever, and immunization of healthcare personnel and contacts of infected individuals. Priority should be given to monitoring the patient’s vital signs and managing complications, including the appropriate administration of antibiotics or antiviral drugs, along with other essential therapeutic interventions. Supportive care should also address the psychological impact on patients, incorporating general symptomatic treatments to relieve pain, discomfort, and other complications from the first medical contact throughout the infectious period and until discharge from the hospital. A proposed treatment algorithm for supportive care measures and emergent interventions for patients diagnosed with Monkeypox includes the following steps:

Management steps:
– Provide evidence supporting the recommended epidemiological perspectives.
– Link the findings to the Monkeypox outbreak.
– Document central line, intubation, and ventilation data for patient outcomes.
– Provide evidence of neurological deterioration as a result of Monkeypox.
– Note that Pseudomonas aeruginosa has been linked to Monkeypox-infected patients in two studies.
– Note that Staphylococcus aureus has been linked to Monkeypox-infected patients in one study.
– Provide evidence that acetaminophen is useful in controlling body temperature.
– Provide evidence that ibuprofen/NSAIDs are effective in controlling body temperature.

8. Conclusion and Future Directions

The Orthopoxvirus, Monkeypox virus (MPXV), is responsible for causing monkeypox in humans, a zoonotic disease that has been endemic in Central and Western Africa. Surveillance programs indicate a steady increase in the number of cases. One of the most perplexing aspects of the disease is the duration it takes for progression from the primary to secondary stages. Asymptomatic primates carry a significant reservoir of MPXV, contributing to sporadic transmission to humans. This review provides comprehensive knowledge on the disease’s spread in susceptible populations and details immune responses. However, the study lacks case-control studies, proper data documentation, and long-term tolerability studies of the vaccines.

Our research examines the spread dynamics of the disease, its effects, immunity, prevention, and treatment. Monkeypox is highly contagious among non-immunized individuals and can lead to minor to major complications, particularly due to immunosuppression. The disease is diagnosed using polymerase chain reaction (PCR) tests, as well as Zika and Syphilis tests. Written informed consent is necessary for testing and treatment. Current prevention and control strategies include smallpox and MPXV vaccines. Unfortunately, the smallpox vaccine is currently reserved only for pre-exposure vaccination of healthcare workers. Post-exposure therapies include vaccinia immune globulin and cidofovir. Recently, a combination of ST-246 and CMX001 has shown effectiveness in preventing smallpox.

Monkeypox occurs in both essential and sporadic forms. The essential form of MPXV infects many people during the endemic season in Central and Western Africa, particularly affecting susceptible populations such as sexual partners and young adults. The virus causes zoonotic diseases among people living near rainforests. Seventy-five percent of those affected experience fatigue, and a few vulnerable individuals may succumb to the disease.

8.1. Research Gaps and Emerging Areas of Study

Several areas of research on the Monkeypox virus remain completely unexplored and further insights are expected to enrich and improve existing knowledge. In particular, there is limited evidence to guide the most appropriate pharmacological and/or supportive treatment approach in patients with Monkeypox infection. This is especially important given that four different genotypes of the virus have been identified, and virulence patterns may vary accordingly. A dedicated prospective trial, including randomization to one of the available therapeutic options, is urgently needed to determine the best treatment strategy for Monkeypox in different clinical settings. Notably, most of the current evidence comes from healthcare scenarios in non-endemic countries. Strong evidence of the efficacy and safety of a dedicated treatment strategy is particularly needed in highly endemic countries with significant human-to-human transmission potential.

Further research could also focus on drug repositioning or exploring other antiviral drugs or drug classes that have not yet been investigated. This could open the door to broader and more general interventions. Monkeypox remains an emerging infectious disease with an unknown or not fully understood source. Although the disease’s fatality rate can vary, it certainly has the potential to cause severe illness and even death.

More effective diagnostic tools are crucial for strengthening surveillance and epidemic management frameworks.As new diagnostic technologies emerge, future studies should evaluate the efficacy of detecting Monkeypox virus using advanced methods such as magnetic beads-coupled antigen detection and novel molecular technologies like loop-mediated isothermal amplification (LAMP). Additionally, future research should aim to prospectively assess the effectiveness of convalescent plasma therapy in treating Monkeypox.

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