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Advancing the understanding and management of Mpox: insights into epidemiology, disease pathways, prevention, and therapeutic strategies

BMC Infectious Diseases volume 25, Article number: 529 (2025) Cite this article

Abstract

Mpox, previously known as monkeypox, is a zoonotic viral disease caused by the Mpox virus (MPXV), a member of the Orthopoxvirus genus. This disease is of significant concern due to its zoonotic transmission, which can be challenging to control, its ability to spread easily from person to person, the potential for severe symptoms or even fatality, and its history of frequent global outbreaks. Despite the growing threat, there is still limited research on the pathophysiology of the disease and available disease-modifying treatments. To address this gap, the latest developments in Mpox epidemiology, viral variant detection, and advanced diagnostic tools for accurate MPXV detection have been reviewed. Ongoing preventive measures, including vaccination strategies, have also been examined. Additionally, the genomic and proteomic characteristics of MPXV have been explored, and network and pathway enrichment analyses have been performed to identify potential therapeutic targets. The findings presented in this manuscript suggest the potential for novel disease-modifying treatments. Moreover, emerging technologies, such as artificial intelligence and "big data," are playing a crucial role in advancing disease management and enhancing prevention strategies. This review emphasizes the evolving understanding of Mpox and MPXV variants and underscores the importance of continued research and public health initiatives to combat the disease and prevent future global outbreaks.

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Introduction

Mpox, previously known as monkeypox, is a zoonotic disease caused by the Mpox virus (MPXV), a member of the Orthopoxvirus genus related to smallpox. It can be transmitted from animals to humans and between humans through direct contact, respiratory droplets, body fluids, or contaminated materials [1, 2]. The incubation period ranges from 1–21 days, with symptoms emerging within this timeframe and lasting 2–4 weeks. These include fever, headache, muscle aches, swollen lymph nodes, exhaustion, and a rash that evolves into pus-filled lesions, primarily on the face, hands, and feet. In severe cases, Mpox can be fatal [3]. The severity and duration of symptoms depend on various factors, including the patient's immune status and the viral strain [4,5,6]. One distinctive sign of MPXV infection is lymphadenectasis, which can help differentiate it from other Orthopoxvirus infections [7]. Mpox is endemic to West and Central Africa, though recent outbreaks have occurred in non-endemic regions such as Europe and North America.

Mpox is distinct from Monkey Fever, or Kyasanur Forest Disease (KFD), another zoonotic viral illness. KFD is caused by the Kyasanur Forest Disease virus (KFDV), a Flavivirus related to dengue, Zika, and yellow fever. It is transmitted to humans primarily through tick bites or direct contact with infected animals such as monkeys and rodents [8]. The incubation time ranges from 3–8 days and symptoms include fever, headache, and hemorrhagic manifestations (e.g., bleeding from gums, nose, and gastrointestinal tract in severe cases). In severe cases, Monkey Fever can be fatal. Unlike Mpox, which is more widespread, KFD is endemic to India. While both diseases are zoonotic, they differ in their causative agents, transmission, incubation time, symptoms, and geographic distribution [8].

Recent outbreaks of Mpox have garnered significant attention, driving increased interest in understanding the disease and developing effective treatments [6, 9,10,11,12,13,14,15]. Health agencies are particularly concerned for several reasons: the zoonotic nature of MPXV complicates control efforts, human-to-human transmission raises the risk of widespread outbreaks, and recent outbreaks from 2022 to 2024 have demonstrated the virus's ability to spread rapidly beyond endemic regions. Additionally, while symptoms are generally mild, they can become severe in immunocompromised individuals [16]. The absence of specific treatments for Mpox and the limited integration of vaccines into routine immunization programs further exacerbate the situation. Public awareness remains low, which can delay detection and increase risks for rapid global spread [16].

MPXV is categorized into two main clades: the Eurasian/African Orthopoxviruses and the North American Orthopoxviruses [16]. Specifically, clade I (subclades Ia and Ib) is endemic to Central and Eastern Africa, while clade II (subclades IIa and IIb) is primarily found in West Africa, where outbreaks are more common [1, 4, 17]. The 2022 Mpox outbreak, which began in West Africa, was caused by clade II and spread internationally, affecting over 100 countries across multiple continents [18, 19]. Clades I and IIa are zoonotic, whereas clade IIb primarily transmits between humans [20]. Transmission in endemic regions typically occurs through direct contact with infected animals during activities like hunting or processing animal products [21]. Small mammals and non-human primates can carry the virus asymptomatically [22], and various animal species, particularly rodents, serve as reservoirs for MPXV [23].

Human-to-human transmission can occur through sexual intercourse, as well as direct contact with respiratory droplets and bodily fluids [10, 24]. It can also occur through kitchen utensils, clothing, and bedding used by infected individuals [10]. MPXV transmission via direct inoculation has been reported in individuals after being pierced or having a tattoo on their skin, which both methods involve invasive techniques [25, 26]. Vertical transmission of MPXV can also happen from an infected mother to her fetus [10]. Furthermore, human-to-human transmission may occur through close or prolonged contact with infected individuals exhibiting disease symptoms, including face-to-face, skin-to-skin, mouth-to-mouth, or mouth-to-skin interactions [27, 28]. Healthcare workers are reported to have MPXV infection from infected patients in case protective personal equipment (PPE) were not worn [29]. The presence of MPXV in the air, specially from air samples collected around MPXV infected patients, along with patients’ exhaled droplets, may further play a role in MPXV transmission via air [30,31,32,33]. Although studies have not shown any link of human infection via aerosol transmission within the reported outbreaks [30], MPXV has been reported to be stable for up to 90 h in aerosols and might be a possible route for infection [29, 30, 34]. Several studies have demonstrated that aerosolized MPXV can be the source of infections in nonhuman primates [31, 35,36,37].

In contrast, animal-to-human transmission may happen via bites, scratches, direct contact with mucous membranes, body fluids, and tissues, or through the consumption of bush meat [10]. In addition, human-to-animal transmission has been reported in the recent outbreak in France in 2022 [38]. It was a transmission from a male to a dog, in which the dog was sharing a bed with two non-exclusive sexual partners males, and tests have shown that the virus in the dog and the one in one of the males were genetically identical [38, 39]. Additionally, MPXV may be transmitted between animals through direct contact between primates and rodents [18].

This overview will provide an update on the recent Mpox outbreaks comparing them with historical data to highlight trends in disease spread. Key topics to be covered include the latest diagnostic tools for MPXV detection, effective prevention strategies, available prevention methods including vaccines, and newly approved treatment options. A detailed exploration of the protein–protein interactions between MPXV-human hosts will be included, along with suggested potential treatment targets under investigation.

Mpox outbreaks and present situation

The history of MPXV can be tracked back to 1958 when it was first discovered in cynomolgus monkeys used for vaccine research purposes in Denmark [40]. Later, the first human Mpox case was reported in 1970 in Congo in a nine-month-old boy [4, 41]. The first human Mpox case in non-endemic areas was discovered in the US in 2003 [42]. After that, MPXV has been spreading throughout the world in several countries in various numbers until it became a risky outbreak recently. The World Health Organization (WHO) has declared Mpox a public health emergency of international concern (PHEIC) on July 23, 2022, since outbreaks of a high number of Mpox cases were confirmed in a range of countries that have not seen MPXV before [43]. PHEIC status for Mpox was later dropped on May 11, 2023, due to a decline in global cases [44], and later reinstated recently on August 14, 2024, due to an upsurge in Mpox cases in Congo and other neighboring African countries [45]. Figure 1 summarizes the timeline of Mpox outbreaks and major events from the time of MPXV discovery in 1958 until 2024 [6, 45].

Fig. 1
figure 1

The timeline of Mpox outbreaks and major events

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As of January 1, 2024, a total of 125 countries have reported more than 9600 Mpox cases and more than 60 deaths [46]. These cases are divided as follows: 7 African countries have reported MPXV-clade I cases, 3 countries (in Africa, Europe, and Asia) have reported MPXV-clades I and II cases, 112 countries (in all continents) have reported MPXV-clade II cases, and 3 African countries have reported MPXV cases of unknown clade [46]. Furthermore, the recent outbreak is due to MPXV-clade IIb with 115 countries reporting MPXV cases for the first time [46]. The cumulative number of cases and deaths since June 2022 stands at more than 100,000 Mpox cases along with more than 200 deaths [47].

MPXV taxonomy, structure, and life cycle

MPXV belongs to the Orthopoxvirus genus within the Poxviridae family based on the most recent update from the International Committee on Taxonomy of Viruses [48]. The most recent Reference Sequence (RefSeq) for MPVX is NC_003310.1 by the National Center for Biotechnology Information (NCBI) [49]. MPXV is one of 13 species in the Orthopoxvirus genus, which are classified as enveloped viruses containing a single linear molecule of double-stranded DNA (dsDNA) [50]. Orthopoxvirus viruses are brick-shaped viruses with dimensions of about 200 × 200 × 250 nm with a characteristic dumbbell-shaped core [10], and a linear dsDNA comprising approximately 186–228 kbp that encodes between 174–233 proteins [50]. The core membrane, enclosing the core/nucleoprotein complex, is surrounded by a palisade layer, together forming what is known as the nucleosome complex [51].

Orthopoxvirus viruses also include the variola virus that causes smallpox disease and the vaccinia virus that causes cowpox disease [7]. As with all other enveloped viruses, MPXV’s infection and replication cycle involves 3 common steps: 1) attachment, entry, and uncoating; 2) DNA and protein synthesis; and 3) viral assembly, maturation, and release [52]. There are a few variations that occur for the MPXV’s replication cycle. Although MPXV is a DNA virus, once it enters the host cell, it will start replicating inside the cytoplasm, instead of inside the nucleus, using various encoded proteins instead of depending on the host cell's proteins [53, 54].

By the end of the replication cycle, two infectious forms of MPXV, i.e., virions, would be released and they include (Fig. 2): the intracellular mature virion (IMV) and the extracellular enveloped virion (EEV) [55]. IMV is an enveloped form of the virus, with its viral core surrounded by a single lipoprotein bilayer membrane [22]. In contrast, EEV is an enveloped form of the virus with an additional outer membrane compared to IMV [22]. IMVs initiate the infection, while EEVs have an extra outer membrane and are essential for evading host immune defenses and promoting viral spread among host species, emphasizing the complex lifecycle of MPXV [56, 57]. IMVs and EEVs can be released during host cell lysis [55], however, EEVs can also be released via exocytosis [21,22,23, 58]. IMVs enter the host cell through micropinocytosis, whereas EEV enters the host cell via fusion [21,22,23, 59]. The fusion process with the host cell membrane relies on several transmembrane proteins, while the stability of the IMVs or EEVs affects transmission between host animals and its spread within the host [60].

Fig. 2
figure 2

A schematic showing the enveloped viral particle of MPXV and key structural proteins. A) EEV virion. B) IMV virion

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Due to its large size, MPXV encounters difficulties in efficiently evading host defenses and replicating speedily with an increased likelihood of triggering an immune response from the host [60]. To evade detection, MPXV has evolved a set of virulence genes that produce proteins capable of manipulating the host's immune response [61]. For example, the virotransducers, are intracellular proteins that reduce the cell response to viral infection. In contrast, the virostealth proteins hinder the visibility of immune system recognition bodies, such as cluster of differentiation 4 (CD4) and major histocompatibility complex 1 (MHC1). In addition, the extracellular viromimic proteins, including viroreceptors that bind to host cytokines and chemokines to disrupt their functions, and virokines, which mimic host cytokines, chemokines, and growth factors to promote viral replication and spread [60,61,62].

Once the virus enters the host cells, the virus replicates it DNA genome and transcribes mRNA using the host machinery, to produce viral proteins. Key proteins involved in the replication cycle include A29L, H3L, L1R/M1R, E8L, I5L, and A43R which will be discussed in Sect."MPXV Proteins". Protein synthesis is followed by viral assembly into IMVs, and some of these acquire an additional outer membrane to form EEVs. Both IMVs and EVVs can be released from infected cells during host cell lysis. However, EEVs can also be released through exocytosis, avoiding host immune detection.

MPXV genome and genomic viral variants

The genome size of MPXV is 196,858 bp with GC content of 33% according to NCBI’s reference genome sequence (RefSeq NC_003310.1) [49]. There are 10,560 viral sequences available on GISAID’s EpiPox [63], which is thus far the largest genomic database for depositing Mpox data. There are also 8,297 genome assemblies of MPXV genomes deposited at the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) [64] and 8,297 genome assemblies deposited at NCBI [65]. An illustration of EpiPox genomic sequences by isolation geography (continent and country), and collection year is provided in Fig. 3A.

Fig. 3
figure 3

MPXV genomes and viral variants. A Pie charts for the genome frequencies based on isolation continent, isolation country and sample collection year. B Tracking global viral variants of MPXV from September 2023 through August 2024 with restricting the time window between September 2023 and July September 2024. These illustrations are based on Mpox GISAID’s data [66, 67]

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Genomic analysis of MPXV samples by public health laboratories is essential for understanding global outbreaks and pandemic potential. Two distinct MPXV clades have been identified: clade I (with two subclades Ia and Ib) and clade II (with two subclades IIa and IIb), as mentioned above [4]. Clade I, found in the Congo Basin, is associated with up to 10% human mortality and is primarily transmitted by rodents, although human-to-human transmission can also occur, particularly in outbreaks [68]. Clade IIa, present in West Africa, causes a milder disease, has a low mortality rate, and is also a zoonotic infection. Clade IIb is a more recent and distinct genetic variant of the virus which is more commonly found in Central Africa and has been associated with more severe disease and higher mortality rates. The genetic factors underlying the differences in virulence and transmission are not yet fully understood due to the lack of appropriate small animal models that could meet the stringent safety requirements for studies [68].

Since November 2023, Congo has seen a significant increase in Mpox cases and the emergence of the new MPXV clade Ib variant. MPXV clade Ib, which was first identified in Congo has also been detected in Burundi, Kenya, Rwanda, Uganda, and other countries according to GISAID data [69]. Tracking global viral variants of MPXV from September 2023 through August 2024 is shown in Fig. 3B based on GISAID’s data.

MPXV proteins

The MPXV encodes a variety of proteins that play crucial roles in its replication, immune evasion, and pathogenesis. While the exact number of proteins may vary slightly depending on the viral strain, MPXV typically encodes around 200–250 proteins. These include structural proteins, non-structural proteins, and immunoregulatory proteins.

Structural proteins are essential for the formation of the virus particle (virion), its envelopment, assembly, and host-cell entry. These proteins make up the physical components of the virus, allowing it to infect new host cells. Structural proteins include those that form both the EEV and IMV as shown in Figs. 2 and 3. Three key structural proteins in the MPXV envelope are B6R, C19L, and A35R. Envelope protein B6R is crucial for viral particle assembly and may also play a role in immune evasion by interacting with the host's immune system. C19L is involved in immune modulation and may help the virus evade immune detection by interfering with host signaling pathways. A35R contributes to the stability of the virion and is important for ensuring the virus can exit host cells and infect other cells. The IMV is composed of additional key proteins, including A29L, H3L, L1R/M1R, E8L, I5L, and A43R, which play critical roles in the formation and stabilization of the virion.

On the other hand, non-structural proteins like A42R, A22R, E4L, E5R, F9R, H5R, and I3L are not part of the virion itself, but are vital for the virus’s replication cycle. Protein A42R plays a role in viral genome replication; A22R is part of the viral core and it is involved in the formation of viral replication machinery; E4L inhibits host responses by interfering with the interferon signaling pathway to promote viral replication; E5R enhances viral genome replication by interacting with host proteins; F9R facilitates the formation of the viral replication complex; H5R is involved in the regulation of the viral life cycle, likely interacting with cellular machinery to promote viral replication; and I3L plays a role in viral assembly and the in the overall viral replication cycle. These proteins play essential roles in immune evasion, host-cell manipulation, and viral replication and assembly. They are involved in processes such as viral transcription, translation, immune modulation, and cellular manipulation. Some key MPXV structural and non-structural proteins are depicted in Fig. 4 to indicate their corresponding gene locations on the viral genome.

Fig. 4
figure 4

A schematic representing the full length of the MPXV genome based on Reference Sequence (Ref. Seq) NC_003310.1. This schematic highlights important structural and non-structural proteins which play key roles in the viral life cycle and its infectivity

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MPXV-host interactions

Mpox develops in two main disease stages after MPXV transmission to humans: an incubation stage lasting typically from 7 to 14 days, but can range from 5 to 21 days, where the infected individual is asymptomatic and non-contagious, followed by a prodromal stage, which is infectious [5, 70]. The incubation stage refers to the period between MPXV entry (through mucous membranes or damaged skin of the host) and the appearance of symptoms. During this time the virus is replicating at the infection site before spreading to regional lymph nodes and the bloodstream and causing primary viremia [21, 70, 71]. In animal-to-human transmission, lymph nodes are in fact the initial infection sites [5].

The prodromal stage occurs after the incubation stage, during which the patient experiences flu-like symptoms that signals the onset of infection. This phase lasts from 1 to 3 days and overlaps with the appearance of rash towards the end of this stage. During this stage the virus continues to spread through the blood stream and lymph nodes leading to secondary viremia and reaching distant organs including the skin. Symptoms like fever, chills, headache, muscle pain, fatigue, sore throat, and lymphadenopathy are prominent in this stage [4, 6, 72,73,74,75]. After the prodromal stage, the characteristic rash (often starting on the face and spreading to the body) appears as a hallmark rash of Mpox and it evolves into vesicles and pustules over 2–4 weeks [4, 6, 72,73,74,75] transitioning into pustules and scabs, which marks the start of the clinical stage. In this stage, MPXV deploys immune evasion strategies by binding to type I interferons, delaying immune activation, and suppressing inflammation, which aids in the spread of symptoms and disease [22, 71, 76].

There have been various atypical presentations of monkeypox virus (MPXV) infection reported in patients, with lesions appearing on different areas of the skin and mucous membranes [77]. For example, erythematous vesicles have been observed on hands, trunk, and legs [77]. Also, vesicles and ulcers have also been reported to appear on male genitals and perianal area [77]. Facial lesions, such as ulcers on the nose, cheeks, and upper lips, as well as bacterial infections in the pharynx and chin, have also been reported [77,78,79]. In some cases, atypical lesions at the same site may progress through different stages (such as vesicles, pustules, and crusts) rather than showing lesions at different stages across various body parts, which is the more typical pattern [80]. Other atypical presentations of MPXV infection include ulcers, papule on hand palm, and finger with acute paronychia and subungual ulcers [81].

MPXV immune evasion pathway

Orthopoxviruses are notable for their ability to evade the host immune system due to a set of genes that bypass pattern recognition receptors and disrupt the cellular apoptosis process [82,83,84]. In the human host, MPXV binds to type I interferons (IFN-alpha, IFN-beta, IFN-omega), delaying STAT1 activation and triggering apoptosis. It also prevents NF-κB nuclear translocation, suppressing inflammation-related genes, and binds to C3b and C4b to block complement activation. The MPXV-human host interactions leading to immune evasion and Mpox summarized in Fig. 5.

Fig. 5
figure 5

Mpox immune evasion pathway map. Nodes on the map correspond to network objects (genes, proteins, or chemicals). The R letter in the blue hexagon above each protein/gene indicates that the protein/gene is a drug target. The type of interaction or relation was reflected by an appropriate symbol placed in the middle of the link. B: binding; c; cleavage IE: influence on expression; TR: transcription regulation; red arrows for inhibition, green arrows for activation, violet arrows for emergent interaction due to disease, intermittent violet arrows for enhanced interaction, gray arrows for unspecified action, violet text boxes for normal process, pink text boxes for pathological processes, blue-lined white text boxes for notes. Map obtained from MetaCore.™ version 21.4 [85]

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Pathways affected by immune evasion

Generating interactions networks using genes/protein that are part of the immune evasion pathway shown is Fig. 5, provides important insight into other potentially perturbed pathways in the human host in response to MPXV infection. Figure 6A shows a small interactions network of all genes/proteins in Mpox immune evasion pathway map from MetaCore™, while Fig. 6B shows an expanded interactions network resulting from adding 20 additional network seed nodes, which are nearest neighbor proteins to any of the proteins in smaller network (i.e., Fig. 6A). Enrichment analysis of the network nodes using Cytoscape [86] version 3.10.1. Network nodes in Fig. 5 are colored based on the top 10 enriched KEGG pathways.

Fig. 6
figure 6

Protein–protein interactions network of human host proteins impacted by MPXV. A Direct interactions network. B Expanded interactions network

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We further conducted an enrichment analysis using MetaCore™ and included the top 10 enriched pathway maps in Table 1, alongside the top 10 KEGG pathways for direct interactions and expanded networks. This highlights pathways potentially affected by Mpox infection. While KEGG results lacked detail for understanding Mpox mechanisms, MetaCore™ provided greater mechanistic insight. Notably, the Mpox immune evasion pathway was the top enrichment result, reflecting our focus on the relevant genes/proteins. The second most significant finding was “glomerular injury in Lupus Nephritis,” suggesting Mpox may cause such injury, as confirmed by a recent report [87]. Additionally, two top results indicated the complement pathway's role in the host response to MPXV, with evidence showing MPXV is neutralized by complement-dependent antibodies in both infected and vaccinated individuals [88]. Two other top 10 pathways involved PKR, which plays a crucial role in the immune response by inhibiting viral replication through translation initiation blockade[89].

Table 1 Top enriched pathway maps using human host that are part of MPXV-host interactions network
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Recent updates on Mpox diagnosis

The WHO currently recommends the use of polymerase chain reaction (PCR) testing for the diagnosis of Mpox, which involves identifying MPVX’s DNA [4]. Recent advancements and studies on the molecular diagnosis of Mpox along with PCR test are summarized in Table 2. It is important to note that there are variations in the expression of IgM and IgG antibodies following Mpox infection, particularly in terms of their timing and duration. IgM antibodies typically appear with the onset of the rash, peak after two weeks, and decline within a year [23, 90]. In contrast, IgG antibodies also rise rapidly at the onset of the rash, peak after six weeks, and can persist in the body for decades [23, 90].

Table 2 Updated list of Mpox diagnostics methods
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Based on the recent outbreaks of Mpox and its presence all around the world, there is an urgent need to advance diagnostic capabilities. Ensuring that all countries have access to affordable and accessible diagnostic tests is crucial, regardless of their economic capacity or healthcare infrastructure. Such advancements would significantly enhance efforts to diagnose patients accurately, identify the circulating viral strains, and contribute to the eventual eradication of the disease [91].

Prevention, vaccination, and other treatment options for Mpox

The integration of public health strategies, vaccination programs, and antiviral research is essential for controlling Mpox outbreaks and protecting public health. These strategies are discussed in the following subsections.

Prevention

To prevent the transmission of Mpox between animals and humans and among humans, several measures can be implemented [117]. These measures aim to control both primary transmission (animal-to-human) and secondary transmission (human-to-human). Exposed pet animals should be isolated from other animals and humans in designated areas, while Mpox patients must also be isolated until fully recovered. Specific precautions should be taken in various settings, including healthcare facilities and airports, such as wearing PPE, maintaining physical distance, and using disinfectants [29]. The WHO recommends that infected patients remain at home in a well-ventilated room and avoid contact with others [4]. Other self-care and prevention methods as outlined by the WHO include [4]: if patients must be around others, they should cover any skin lesions and wear masks; patients should wash their hands thoroughly after touching sores, disinfect shared items, and can use saltwater rinses for mouth sores and warm baths with baking soda or Epsom salts for body sores; over-the-counter pain relief can be administered; and avoid actions that could spread the rash, such as popping blisters or shaving affected areas.

Vaccines

Mpox is a vaccine-preventable disease, similar to influenza, polio, cholera, and COVID- 19 [118,119,120,121,122], but vaccination is not part of mandatory national programs. It is recommended for high-risk individuals (pre-exposure) and those exposed to the virus (post-exposure), ideally within 4 days of contact or 14 days if the individual is asymptomatic [4]. Mpox vaccines (Table 3) can prevent the disease and generate sufficient antibodies, although efficacy may decline over time and vary by dose [123].

Table 3 FDA approved vaccines that can be used to protect from Mpox
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Vaccination against Mpox reduces transmission, controls outbreaks, and lessens disease severity. While mass vaccination is not currently recommended due to the assessed risks and benefits, targeted vaccination campaigns combined with behavioral changes in high-risk groups have been effective in reducing the spread of Mpox [100, 123]. A study of the 2022–2023 US outbreak showed high transmission rates among high-risk populations, especially men with male-to-male sexual contact. The vaccination campaign, covering 37% of the high-risk population, prevented 21.2% of cases, while combining vaccines with behavior changes prevented up to 64% of cases, leading to a significant flattening of the epidemic curve [131]. These findings highlight the effectiveness of integrated prevention strategies in reducing the disease burden during outbreaks.

Furthermore, a closer look at adverse events following immunization (AEFI) data from the Netherlands and the World Health Organization highlighted a range of reactions, primarily focused on injection site issues and typical systemic responses. These reactions, while generally mild, offer valuable insights into the safety profile of the Mpox vaccines and help to inform both public health strategies and individual decisions regarding vaccination [129].

Small-molecule antiviral drugs

Several antiviral drugs have been investigated for the treatment of Mpox, as outlined in Table 4. Numerous studies have evaluated their effectiveness in managing the disease.

Table 4 Approved small-molecule chemical antiviral drugs for Mpox and examples of ongoing clinical trials
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Drugs and vaccines under active development for Mpox

There are several drugs that are currently being under active development for the treatment and/or prevention of Mpox, according to the Cortellis Drug Discovery Intelligence (CDDI) database [151], These drugs are listed in Table 5.

Table 5 Drugs under active development for Mpox and/or other Orthopoxviruses
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Suggested targets for therapeutic intervention and drug repurposing based on network pharmacology

In the quest for effective treatments for Mpox, identifying viral and host proteins that facilitate virus-host interactions is crucial. These proteins play essential roles in the virus's life cycle, making them promising targets for drug discovery. By focusing on these putative targets, researchers can develop novel therapeutic strategies aimed at disrupting the mechanisms through which the virus replicates and spreads. To aid in this effort, we have summarized relevant genes and proteins in Table 6 which provides a comprehensive overview of the key viral and host factors involved in Mpox pathogenesis. This table highlights the potential significance of identified drug targets in therapeutic interventions to guide future research directions. We also hypothesize that drugs targeting protein targets listed in Table 6 can be repurposed for combating Mpox and should be studied thoroughly by the scientific community.

Table 6 MPXV and human host genes/proteins suggested as therapeutic targets for Mpox based on network analyses described in work
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Updates on Mpox Resources and Innovative Solutions

The integration of innovative resources such as genomic databases, artificial intelligence applications, data-sharing initiatives, and various open-source educational tools plays a crucial role in enhancing our understanding and management of Mpox. Table 7 provides and up-to-date list of resources available for researchers and healthcare professionals.

Table 7 List of popular innovative Mpox resources and databases
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Conclusions

In conclusion, the evolving landscape of Mpox presents significant challenges and opportunities for public health and drug discovery research. As this zoonotic disease continues to spread internationally, understanding its epidemiological trends, transmission dynamics, viral variants, and disease pathways becomes increasingly critical to develop preventive measures and specific disease-modifying therapeutics. This updated review has highlighted the importance of early detection and innovative diagnostic tools, alongside effective preventive measures, such as available vaccines and small-molecule therapeutic agents. In addition, ongoing research into disease pathways, including viral-host interactions and immune response mechanisms, is essential for the development of targeted therapies. The genomic analyses, network pharmacology, and enriched pathway studies highlighted critical interactions between MPXV and host immune responses, informing future drug discovery research and public health strategies. Furthermore, the integration of advanced technologies, including AI and big data analytics, is hoped to revolutionize viral variant tracking, disease management, and response efforts. As we move forward, it is imperative that we remain vigilant and proactive in addressing this emerging public health threat, continually adapting our strategies to new developments in the prevention and treatment of Mpox.

Data availability

All data are presented within the manuscript. Supporting data files for the network and enrichment results can be accessed on GitHub at https://github.com/rhajjo/Mpox.

Abbreviations

bp:

Base pairs

CDC:

Centers for Disease Control and Prevention

CD4:

Cluster of differentiation 4

CDDI:

Cortellis Drug Discovery Intelligence

CP:

Core protein

CRISPR:

Clustered regularly interspaced short palindromic repeats

DRC:

Democratic Republic of the Congo

EEV:

Extracellular enveloped virion

ELISA:

Enzyme‐linked immunosorbent assay

FDA:

US Food and Drug Administration

GISAID:

Global Initiative on Sharing All Influenza Data

IMV:

Intracellular mature virion

IV:

Intravenous

MC:

Molluscum contagiosum

MCV:

Molluscum contagiosum virus

MHC1:

Major histocompatibility complex 1

MPXV:

Monkeypox virus

MC:

Molluscum contagiosum

NCBI:

National Center for Biotechnology Information

ORF:

Open reading frame

PHEIC:

Public health emergency of international concern

PCR:

Polymerase chain reaction

RT-PCR:

Real-time polymerase chain reaction

RPA:

Recombinase polymerase amplification

TEM:

Transmission electron microscopy

WHO:

World Health Organization

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Acknowledgements

R.H. and D.A.S. acknowledge funding from the Deanship of Scientific Research at Al-Zaytoonah University of Jordan (Grant Number 2023 - 2022/17/50).

Funding

Funding provided by the Deanship of Scientific Research at Al-Zaytoonah University of Jordan (Grant Number 2023 - 2022/17/50).

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman, 11733, Jordan

    Rima Hajjo, Osama H. Abusara & Dima A. Sabbah

  2. Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Rima Hajjo

  3. Board Member, Jordan CDC, Amman, Jordan

    Rima Hajjo

  4. Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman, 11942, Jordan

    Sanaa K. Bardaweel

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Contributions

Idea and conceptualization, network and pathway analysis, genetic epidemiology analysis, writing first draft, editing manuscript and reviewing literature (R.H.). Writing first draft, editing, collecting data and reviewing previous literature (O.A.S). Writing first draft, editing, collecting data and reviewing literature (D.A.S.). Idea, writing first draft, editing, collecting data and reviewing previous literature (S.K.B).

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Hajjo, R., Abusara, O.H., Sabbah, D.A. et al. Advancing the understanding and management of Mpox: insights into epidemiology, disease pathways, prevention, and therapeutic strategies. BMC Infect Dis 25, 529 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12879-025-10899-2

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BMC Infectious Diseases

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