Mpox Virus

Mpox Morphology and Genetics

Mpox, formerly known as monkeypox, is a highly contagious zoonotic disease caused by the mpox virus (commonly abbreviated to MPXV).² The mpox virus is a member of the genus Orthopoxvirus in the family Poxviridae, which also includes smallpox (also known as variola virus, VARV) and cowpox. Like other orthopoxviruses, mpox is an enveloped, brick-shaped virus with a diameter of ~200-250 nm.²

Poxviruses typically have complex genomes relative to other viruses; the mpox virus genome consists of linear, double-stranded DNA of ~197 kb, encoding approximately 180 proteins.^2,3 The mpox genome contains a core region that is highly conserved with other orthopoxviruses, while each end contains inverted terminal repeats and variable regions that reflect species- and strain-specific characteristics such as infectivity, tropism and distinct immune responses.^2,4

Mpox Clades

Mpox can be subdivided into two main types: Clade 1 and Clade 2. Though the genetic homology of the two clades is as high as 95-99%, substantial differences exist between the diseases caused by each.⁵ Clade 1 causes a more severe illness, has a higher fatality rate of up to 10%, and is endemic to central Africa. In contrast, clade 2 is milder, with 99.9% of those infected surviving. The Clade 2 strain was responsible for a global outbreak in 2022, and is endemic to West Africa.

Mutations to the Clade 1 strain have led to a new substrain called Clade 1b, which has spread rapidly and can cause severe illness, resulting in the 2024 outbreak.⁶

History & Epidemiology of Mpox

Mpox was first identified in 1958 in a research institute in Denmark, which received cynomolgus monkeys from Singapore that subsequently showed symptoms of a non-fatal pox-like condition.⁷ This initial observation led to the original name of monkeypox, but it was not until 1970 that the first human patient with monkeypox was confirmed, in the DRC.⁸ Until 2003, cases were restricted in low numbers to central and western Africa. However, cases significantly increased within Africa between 2000 and 2020, including more than 20,000 suspected cases in the DRC alone.⁵ The first cases outside of Africa were reported in this period, with 47 cases reported in the United States.⁹

Outbreak in 2022

Cases of mpox began to rise in May 2022 in countries that had previously never reported mpox, triggering the WHO to declare a global health emergency in July 2022. Cases peaked in August 2022, with relatively few cases emerging in 2023 (Figure 1), resulting in the WHO announcing an end to the emergency in May 2023. By the end of the outbreak, 207 deaths and nearly 100,000 confirmed cases of mpox had been reported across 122 countries, 115 of which had not historically reported mpox within their borders (Figure 2).¹⁰

By the end of the outbreak, 207 deaths and nearly 100,000 confirmed cases of mpox had been reported across 122 countries, 115 of which had not historically reported mpox within their borders (Figure 2).¹⁰

The 2022 outbreak had a case fatality rate in non-endemic regions of ~0.04%,² having been predominantly caused by a variant of the milder Clade 2 mpox virus, termed clade 2b.¹¹ Given that no animal reservoir for the virus has been identified in non-endemic regions, it is likely that the outbreak was caused by human-to-human transmission.¹²

Outbreak in 2024

A public health emergency was declared by the WHO in August 2024 after cases of mpox began to rise in DRC (Figure 3).

Since the 2022 outbreak, countries where mpox is not historically endemic have continued to see scattered cases that are primarily due to the clade 2 strain. In contrast, the rising cases seen in the DRC are due to a variant of the clade 1 strain, called clade 1b, which is more infectious and clinically more severe. The new strain has mostly spread to neighboring countries in Africa, but recent cases in Sweden and Thailand have been confirmed as belonging to the clade 1 variant. Figure 4 shows all confirmed cases of mpox in 2024, regardless of strain.

Symptoms and Diagnosis of Mpox

Clinical signs of mpox are similar to those of smallpox, though mpox is typically much milder.¹ Mpox is also often mistaken for chickenpox. After exposure to the virus, mpox has an incubation period of 4-21 days.¹² The first symptoms of mpox include:

• Fever
• Chills
• Headache
• Fatigue
• Muscle aches
• Joint pain
• Swollen lymph nodes

Shortly after the fever and swollen lymph nodes, a rash appears, first on the face and then across the whole body. The rash is characterized by lesions, which progress from blisters to pustules to scabs before falling off.

The severity of symptoms is influenced by a number of factors, including the viral strain, initial viral load, whether someone is immunocompromised, age, and other complicating conditions such as dermatitis.¹

Patients are contagious at least while they have symptoms (until scabs have cleared up), and may be able to spread the virus 1 to 4 days before symptoms appear.

Mpox Transmission

Mpox is a zoonotic disease, meaning it can be and has been transmitted from animals to humans. Unlike the closely related smallpox, mpox virus is more promiscuous and can infect many different animal species, including small mammals and primates.^1,12 Small mammals, such as squirrels and rats, are likely to be the disease’s natural reservoir.^1,13,14

Historically, human-to-human transmission of mpox was inefficient, with many cases in Africa arising due to contact with infected animals.¹ Since 2022, the emergence of more infectious strains has resulted in more cases caused by human-to-human contact.

Mpox can be spread by:

• Direct contact with an infected person, including sexual contact
• Talking or breathing in close proximity to another person
• Contact with infected animals, including being bitten or touching their fur or skin
• Contact with contaminated materials

Mpox Life Cycle

Poxviruses are unique in that they produce two different types of infectious particle: extracellular enveloped virions (EEV) and intracellular mature virions (IMV).^15,16 These two different forms of poxviruses have distinct antigens and different methods for entering the cell and being disseminated.16 IMVs consist of the dsDNA genome, lateral bodies that contain proteins for interacting with the host cell and immune system, and a lipid bilayer. EEVs have a similar internal structure, with the addition of a second membrane containing both cellular proteins and unique viral proteins.¹⁵ IMVs are more abundant and may mediate transmission between hosts, while EEVs facilitate local virus dissemination within a host.¹⁵

Mpox infection of cells can be divided into three stages: 1) Viral entry, 2) Replication, synthesis and assembly, and 3) Maturation and release.

Mpox Pathogenesis

Following exposure to an infected person or animal, the mpox virus can enter the body of a new host by mucous membranes, including the eyes, mouth, lungs and genital areas, or at broken skin.²¹ The viral particles infect tissue-resident immune cells such as dendritic cells, allowing the virus to spread systemically via nearby draining lymph nodes. Mpox will then replicate extensively in lymphoid tissues, particularly in the neck and throat.⁵ This initial infection represents the asymptomatic period for mpox. Following this latent period, the first symptoms of mpox start to appear, such as fever, fatigue, and swollen lymph nodes, after which rashes and lesions emerge.

The pathogenesis of mpox occurs by two main mechanisms. Firstly is the inflammatory response by the host immune system to viral invasion and replication. This leads to symptoms such as fever and enlarged lymph nodes. Secondly is that viral infection causes cell death and tissue damage. This is particularly relevant for the skin lesions, which result from skin cells being damaged or destroyed, leading to local inflammation and the formation of pustules filled with fluid and viral particles.

Significant damage to certain tissues, such as the vascular system, respiratory tract and gastrointestinal tract, can result in severe complications including hemorrhagic disease, necrotic disease and obstructive disease. Further, secondary bacterial infections, which may use skin lesions as an entry point, can result in septicemia.

Mpox Vaccines, Prevention & Treatment

Initial mpox infection can be prevented by avoiding contact with infected persons and animals, and avoiding potentially contaminated materials. There is currently no specific vaccine for mpox. The smallpox vaccine provides significant protection against mpox due to similarities between the two orthopoxviruses.²² Older versions of the vaccine consisted of live vaccinia virus (VACV), which is a distinct orthopoxvirus from both mpox and smallpox but which is highly homologous. These live virus vaccines could be dangerous for some people, such as those with compromised immune systems. Third generation smallpox vaccines, such as the recently developed JYNNEOS, constitute non-replicating vaccines that are safe for the immunocompromised population, and have been approved for preventing mpox infection in high-risk groups.²

Many cases of mpox cause only mild symptoms and patients can recover without intervention.²¹ For more severe cases or those at risk for developing severe illness, antiviral drugs originally developed for smallpox can be effective, given the lack of mpox-specific therapies. Tecovirimat, Cidofovir and Brincidofovir have all shown promise in the treatment of mpox. Tecovirimat inhibits formation of EEVs to disrupt viral spread, while Cidofovir and Brincidofovir both inhibit viral DNA polymerase to reduce viral replication. However, there are significant drawbacks of these drugs, including limited treatment windows, toxicity to the liver and kidneys, and a lack of clinical data in human mpox cases.^1,5 New therapies for mpox are therefore urgently needed.

Significant damage to certain tissues, such as the vascular system, respiratory tract and gastrointestinal tract, can result in severe complications including hemorrhagic disease, necrotic disease and obstructive disease. Further, secondary bacterial infections, which may use skin lesions as an entry point, can result in septicemia.

Mpox Proteins

The mpox genome encodes approximately 180 proteins, which have a range of functions including viral entry into the cell, virion replication and assembly, viral egress, and determination of host range. Table 1 below indicates a number of important proteins in viral function and the immune response.

Table 1: Some of the proteins involved in the mpox life cycle. Information sourced from references 3,18.

Mpox Protein Nomenclature

A commonly applied method of naming viral proteins is referred to as Copenhagen nomenclature, in which open reading frames (ORFs) are identified following restriction enzyme digest.^23,24 The biggest genomic fragment resulting from the digest is designated A, and sequentially smaller fragments are given subsequent letter designations. ORFs within each fragment are numbered, while L or R is appended to indicate the directionality of the ORF (left or right). Proteins of other orthopoxviruses, such as vaccinia and variola (smallpox), have been similarly named, which can result in confusion if the genomic fragments do not perfectly line up. For example, A29L in mpox is homologous to A30L in variola and A27L in vaccinia, though they are highly conserved.

Recommended Products

Antibodies for Mpox Proteins

ELISA Kits for Mpox Proteins and Mpox Antibodies

Recombinant Mpox Proteins

References

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