The Evolving Landscape of Monkeypox: From Endemic Pathogen to Global Threat

The 2022 mpox outbreak

A 2022 WHO report considered mpox endemic to several African countries, including the DRC, Central African Republic, Benin, Cameroon, Gabon, Ghana, Nigeria, Liberia, Sierra Leone, South Sudan, and Côte d’Ivoire (O’Shea et al., 2022). In May 2022, the WHO announced mpox as a global health emergency and declared a multicountry global mpox outbreak in humans (Jamil et al., 2022). Before May 6, 2022, a cumulative total of 27 cases were active in Africa until a case was reported from the United Kingdom in a traveler from Nigeria (Cohen, 2022). Since then, several cases started to appear across several nonendemic countries. Africa did not report the same increase in the number of cases. The number of cases increased exponentially in nonendemic regions with people with no travel history to endemic areas. On July 23, 2022, the WHO declared mpox as a PHEIC. The weekly trends (Fig. 1a) illustrate the temporal distribution of these cases, including the initial 2022 peak and the significant upsurge in 2024. Many early cases occurred in people who attended an international LGBT+ Pride event held on the Spanish island of Gran Canaria and were linked to transmission chains in European countries. Later reports and case studies showed that the infection was predominantly transmitted via sexual activities between males (men who have sex with men [MSM]) (Gong et al., 2022). These demonstrated the human-to-human spread of mpox outside of endemic regions. The 2022 outbreak lasted about 11 months, as the WHO declared an end to the acute global outbreak in May 2023 and the PHEIC concluded, citing steady control and decline in acute mpox global cases. In total, 111 countries reported cases of mpox infections, with cumulative cases over 87,500 and 141 deaths. The worst-affected countries in this outbreak until May 2023 were the United States (n = 30,194), Brazil (n = 10,941), Spain (n = 7,551), France (n = 4,146), Colombia (n = 4,090), Mexico (n = 4,017), Peru (n = 3,800), the United Kingdom (n = 3,742), Germany (n = 3,691), and Canada (n = 1,484), contributing to 84% of all global cases (Sun et al., 2024). mpox infections have shown a changing demographic pattern over time. From 1970 to 2015, mpox primarily affected children under 10 years (71–83%). However, during the 2017–2018 outbreaks in Nigeria, the median age shifted to 29 years, which further changed to 34 years in the 2022 global outbreak. Similarly, the proportion of male cases increased from 51–64% (1970–2015) to 64% in 2017–2018 Nigeria, reaching 96.8% in the 2022 outbreak. The MPXV was detected in human semen as well, suggesting the MSM subpopulation might be at higher risk of infection (Kipkorir et al., 2022). There is also a disparity based on regions. Africa witnessed more child (0–9 years, 23.08%) cases compared with the cases in regions of Europe and the Americas, where children accounted for <1% of cumulative cases (Ogunleye et al., 2023). The pooled case fatality rate (CFR) before the 2022 global outbreak was estimated to be 8.7%, which varied by clade. However, a WHO report estimated a pooled CFR of 0.08 in the 2022 outbreak, which is significantly lower. Very low CFR of the Clade II variant (<1%), active surveillance, and early diagnosis and treatment are plausible reasons (Tuttle et al., 2024).

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FIG. 1.

(a) Weekly trends of laboratory-confirmed mpox cases (2022–2026). This figure illustrates the temporal distribution of confirmed mpox cases reported to the World Health Organization from January 1, 2022, to January 18, 2026. Data highlight the initial peak during the first PHEIC in August 2022, followed by the significant upsurge starting in late 2024 associated with the second PHEIC. (b) Global geographic distribution of mpox cases per year (2022–2025). These choropleth maps represent the annual cumulative laboratory-confirmed cases and deaths reported globally. The maps track the expansion of the virus from 108 reporting countries in 2022 to the emergence of Clade Ib community transmission in Central and East Africa in 2024–2025. Shading intensity correlates with total case counts, distinguishing between endemic regions in Central Africa and travel-linked outbreaks in nonendemic territories. Data are sourced from the WHO Global mpox Surveillance System. mpox, monkeypox; PHEIC, Public Health Emergency of International Concern; WHO, World Health Organization. Image created using BioRender.

Reemergence as 2024 mpox outbreak

A new strain of Clade I, Clade 1b, emerged during September 2023 in the South Kivu province of the DRC. This new strain appeared to be more severe than that of the 2022 Clade 2b, with higher transmissibility and significant clinical differences (Vakaniaki et al., 2024). By late 2023 and into 2024, it spread to several other African countries, including Burundi, Rwanda, Uganda, Kenya, the Republic of the Congo, the Central African Republic, and South Africa (Vakaniaki et al., 2024). On August 14, 2024, WHO declared the new outbreak a PHEIC, just 15 months after lifting the previous mpox PHEIC. Although a lot of cases could not be laboratory-confirmed due to ongoing conflicts in the affected region of the DRC, the infection was deemed more lethal with higher transmissibility (including sexual transmission). In 1 week of early August, the DRC reported about 2400 suspected cases and 56 deaths. African countries reported more confirmed and suspected mpox cases in 2024 than in all of 2023. Children were particularly more affected, with two-thirds of the cases being under 15 years of age (Parums, 2024). This outbreak was linked to Clade 1b, although the 2022 Clade 2b variant was also present; it was not predominant. Case reports show that sex workers constituted a large proportion of the cases from South Kivu, where Clade 1b predominates (Masirika et al., 2025).

According to a report from WHO, as of May 2025, 30 countries have detected Clade 1b MPXV, with 10 African countries still reporting ongoing community transmission, including DRC, Uganda, Sierra Leone, and Burundi. This global expansion and the varying intensity of case counts across different regions are visualized in the choropleth maps (Fig. 1b). From January 2024 to May 2025, Africa reported 36,310 confirmed cases and 123 deaths due to mpox, with the DRC contributing the majority. Sierra Leone experienced a sharp surge in 2025, becoming the top affected country in recent weeks (Mukherjee et al., 2023). From January 2022 to April 2025, globally, 142,151 confirmed cases and 328 deaths were recorded, out of which 68,840 confirmed cases and 152 deaths were reported from the WHO Region of the Americas and 35,833 confirmed cases and 135 deaths in the African Region. It is important to note that this number could be a huge underestimation, as many cases and deaths could not be laboratory verified, especially in African regions due to social instability, ongoing conflicts, and lack of awareness and necessary infrastructure in the areas of outbreak. Over the past year, mpox case counts plateaued in the African Region, whereas the Eastern Mediterranean and Southeast Asia Regions have consistently reported the lowest case numbers, although an increase was noted in the Eastern Mediterranean earlier in 2025, primarily influenced by a rise in cases in Gulf nations. The European Region has shown a stable trend in recent months. Meanwhile, regions such as the Americas and the Western Pacific saw increased case numbers in early 2024, which later declined. The global average of confirmed mpox cases per month stood at approximately 3253. The African Region contributed the majority, with 28,973 cases, followed by 4891 cases in the Americas and 2355 in the Western Pacific. Among countries outside Africa, Spain recorded the highest monthly count in April 2025, with 93 confirmed cases (Hatmal et al., 2022; Mukherjee et al., 2023). There is a decline in mpox infections since the 2022 peak in the United States and Europe due to the development of targeted vaccination strategies and, more importantly, behavioral changes within high-risk communities, such as reduced sexual partners in the case of men who have sex with men and increased immunity following infection, as it reduced the population of susceptible individuals.

Smallpox versus monkeypox: Direct ancestry or independent descent?

VARV is the causative agent of smallpox, and MPV is the causative agent of mpox. Both belong to the genus Orthopoxvirus and the family Poxviridae, which also consists of other viruses: CPV, vaccinia (VAC), and camelpox (CMLV). The MPV and VARV share approximately 90% of their genome. Still, despite their genetic similarity, phylogenetic and comparative studies show that both viruses have independently descended from Orthopoxvirus, and neither one has descended from the other (Shchelkunova and Shchelkunov, 2022).

Smallpox is a human pathogenic virus, whereas the other viruses in the family Poxviridae are zoonotic. Smallpox was the most dangerous infectious disease humankind has ever faced until its eradication. On the contrary, mpox cannot be compared with smallpox in severity, with the latter being more severe than the former (Shchelkunova and Shchelkunov, 2022). The ecological dynamics for both viruses also differ; smallpox has no known reservoir and only affects humans. In contrast, MPV has multiple animal reservoirs, the most common being monkeys, Gambian pouched rats, and squirrels, supporting the theory of independent zoonotic origin. VARV is strictly human-adapted, having lost several genes related to host range and immune evasion that are still present in mpox, which retains the ability to infect multiple mammalian species, as shown in Figure 3 (Tuttle et al., 2024).

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FIG. 3.

(a) This Venn diagram illustrates the distinct evolutionary paths of two major orthopoxviruses. VARV (left) is a human specialist and obligate human pathogen characterized by a reduced genome (∼186 kb), extensive gene loss, and specific terminal inversions. In contrast, mpox (right) is a zoonotic generalist that has retained ancestral accessory and immune evasion genes, enabling it to maintain a broad host range across rodents, primates, and humans. Both viruses share a core set of essential replication enzymes and a deep evolutionary history. (b) The figure depicts the genomic and host-range differences between the variola virus and the monkeypox virus. (Top) While both viruses share essential replication machinery, VARV has undergone significant genome reduction to become a specialized human pathogen. mpox retains the ancestral generalist trait, utilizing accessory genes for immune evasion across multiple species. (Bottom) Both lineages diverged from a common Orthopoxvirus ancestor more than 10,000 years ago, with the diagram highlighting the zoonotic (rodent-borne) origin of the ancestral virus. VARV, variola virus.

Comparative analysis of restriction endonuclease site maps and short DNA sequences depicts the central genomic regions of MPV and VARV as nearly identical (96.3%), which encodes for essential enzymes and structural proteins. At the same time, the terminal genomic factors are distinct, which is attributed to virulence and host-range factors. Comparative analysis of the MPV and VARV genomes indicated that MPV is a distinct species that varies substantially from both major and minor strains of VARV in terms of the genes that cause virulence, suggesting that both MPV and VARV most likely evolved independently from an Orthopox ancestor that resembles CPV (Yong et al., 2020).

Life cycle of MPOX

The mpox life cycle starts with the entry of two different infectious particles into the host cells. First, the most abundant viral particles are known as intracellular mature virions (IMVs). They are single-membrane-bound structures released upon lysis of the cell that elicit a stronger immune response by the production of neutralizing antibodies (NAbs) as well as complement proteins and enter the host by endocytosis or direct contact (Gong et al., 2022). They are highly resistant to external damage and can enhance their survival outside the host. Second, the extracellular enveloped virions (EEVs) consist of a double-membrane structure that helps in facilitating intracellular dissemination and can enter the host cells by direct membrane fusion only. This leads to infection of neighboring cells, leading to the spread of the viral particles, illustrated in Figure 4. Once entered into the host cells, both the viral particles IMVs and EEVs attach to the receptors on the membranes and damage skin cells via glycosaminoglycans. Then upon entry, they transport the viral core to the perinuclear replication compartment with the help of cytoskeleton particles such as microtubules. Thereafter, the viral genome serves as the template for rapid DNA replication. Then IMVs are enveloped to form three-layered intracellular enveloped virions (IEVs) by the Golgi apparatus and move to the surface by actin and microtubules. IEV fuses with the host membrane and by exocytosis forms cell-associated enveloped viruses (Yahya et al., 2026).

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FIG. 4.

Lifecycle of the mpox virus. This diagram illustrates the sequential stages of infection, starting from transmission, cell entry, and uncoating, through cytoplasmic replication and assembly to the final exocytosis of mature viral progeny. Images created using BioRender.

Clinical manifestations

mpox can be transmitted from animals to humans, as well as from humans to humans, whereas the zoonotic reservoirs range from monkeys, squirrels, dormice, rats, nonhuman primates, and other species as well. The transmission occurs through bites and scratches or by consuming improperly cooked meat from infected animals. The direct contact with infected skin surfaces such as lesions or mucosa, and breathing respiratory droplets leads to human-to-human transmission of MPX. Recent reports have indicated instances of sexual transmission of MPX, but they only occurred among MSM (Halder et al., 2025).

The median age susceptible to mpox has shifted upward over time; nevertheless, all ages are prone to infection. There are three routes to body infection, namely, oropharyngeal, nasopharyngeal, and intradermal routes. Once it enters the body, it undergoes rapid replication and subsequently infection of local lymph nodes. The incubation period lasts from 1 to 3 weeks, and the manifestation of clinical features occurs, such as fever, headache, malaise, chills, shortness of breath, and enlarged lymph nodes. This is often referred to as the prodromal phase, lasting usually from 0 to 5 days and being nonspecific in nature. The onset of fever is often characterized by lymphadenopathy, and it can be either unilateral or bilateral cervical, axillary, and inguinal (Prompetchara et al., 2024). Following the infection stage, the appearance of polymorphic painful skin rashes/lesions occurs on the face and then other parts of the body. Rashes could vary from one to 100 (Islam et al., 2023). The rash development occurs in certain stages, the small rashes (enanthema) starting first from the tongue and mouth, followed by macules on the face and spreading to arms, legs, palms, and soles in a centrifugal distribution fashion. This is distant from smallpox, where the pattern is centripetal. The development of rashes on palms and soles is the hallmark of MPX (Luo and Han, 2022). It undergoes the following phases, such as macular, papular, vesicular, and pustular. These different stages cannot appear at the same time on the body, unlike CPV. The various parts of the body have different lesion distribution frequencies such as 98% for face, 95% for soles, 70% for oral mucous membrane, 28% for genitalia, and 20% for conjunctiva (Islam et al., 2023). The lesions progress on the third day and transform into papules and further into vesicles on the fourth to fifth day. These vesicles are raised and filled with fluid. Following that, the lesions become pustules that are sharply raised and firm structures containing opaque fluid. These pustules begin to dry and form crusts toward the end of the second week. They often persist for 1 week before beginning to detach naturally, leading to skin with increased pigmentation and depressed appearance. Moreover, skin with decreased pigmentation and depressed appearance can occur; partial hair loss in certain areas is also reported, as is excessive scar tissue formation and deformity of facial muscles that can happen subsequent to the healing of facial ulcers. The disease generally lasts from 2 to 4 weeks in most of the cases, with an exception of immunocompromised individuals, chronic diseases, and those without vaccination. It can even lead to secondary infections, bronchopneumonia, loss of vision, sepsis, and encephalitis. The fatality rate ranges from 1% to 0% depending on other factors, such as specific clade, vaccination status, host factors, and availability of medical care. For instance, studies have reported no fatalities among individuals having smallpox vaccination compared with 11% of nonvaccinated individuals (Damon, 2011).

Innate immune responses

Like other disease-causing viruses, the Orthopoxvirus genus has evolved different ways to escape the immune attack imposed by the host and thereby cause infection (Yong et al., 2020). mpox affects the pattern recognition receptors such as TLRs by disturbing the recognition of pathogen-associated molecules (PAMs) and by inhibiting cellular apoptosis through the obstructive functions of various caspases (Prompetchara et al., 2024).

TLR plays an important role in recognizing PAM, followed by elimination of the agent via downstream signaling for an immune response. This is mediated by the binding of TLRs to ligands through the TIR domain, activating a cascade of reactions that activate inflammation-related transcription factors like NF-κB that are critical for nuclear genes involved in immune response (Gong et al., 2022). MyD88, MAL, and SARM are the various intracellular adaptor proteins involved in communication with the TIR domain, which is important for triggering an intracellular immune response (Saghazadeh and Rezaei, 2022). The disruption of these adapter proteins can often lead to the establishment of a viral infection. mpox affects the function of these adaptor proteins by producing a protein, A47R, that interacts with MyD88 and disrupts its physiological function, which inhibits the activity of NF-κB and causes failure of the innate immune system against mpox. Recent computational modeling and molecular dynamics simulations have shed light on a robust ligand for innate immune activation, which is the mpox F14 protein (Chakraborty et al., 2025). It acts as a primary candidate for mediating host–virus interactions through the TLR1/2 heterodimer. Since F14 has a higher binding affinity to the TLR1/2 dimer, this interaction leads to a proinflammatory signaling cascade in mpox patients, driving the production of cytokines through the NF-κB pathway. This makes it a high-priority target for future peptide-based vaccines and immunotherapeutics. Apart from TLRs, the cytosolic DNA-sensing cGAS-STING pathway uses cGAS as the enzymatic sensor that binds to dsDNA in the cytoplasm and triggers the production of interferon-β. Recent research has identified three specific mpox proteins, such as OPG147, OPG188, and OPG200, that inhibit this pathway. Moreover, OPG188 acts as a nuclease that destroys the signaling molecule cGAMP before it can reach the STING receptor. On the other hand, apoptosis is a crucial mechanism to control and prevent the spread of infection to other cells by killing the cells that are infected (Mukherjee et al., 2023). Absent in Melanoma 2 (AIM2) specifically senses viral DNA to trigger the inflammasome and maturation of IL-1β, which is responsible for the intense localized swelling and tissue necrosis seen in mpox lesions, as it triggers a form of programmed cell death called pyroptosis, which ruptures the cell to alert neighboring cells. The inhibition of NF-κB by mpox affects the apoptotic machinery by the production of B12R and C7L that inhibit the activity of caspases; refer to Table 1 (Zarenezhad et al., 2025). Moreover, mpox produces P1L, a protein that mimics the activity of BCL-2 (B cell lymphoma-2) that also inhibits NF-κB function and falls off the cellular apoptosis (Chakraborty et al., 2025). Therefore, mpox produces several proteins that disturb the complement system, chemokines, and cytokines, and targets the ubiquitin-proteasome pathway affecting the host’s inflammatory response.

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Table 1.

The Functional Roles of Key Monkeypox Viral Proteins in the Viral Life Cycle, Highlighting Their Mechanisms of Immune Evasion and Potential as Targets for Therapeutic Intervention

Protein/Gene	Function in viral life cycle	Mechanism of action
B12R (SPI-2)	Immune modulation	Inhibits host caspase-1 and caspase-8 to disrupt pyroptosis and apoptosis pathways, preventing host cell death
F13L (VP37)	Viral maturation	Catalytic protein essential for wrapping intracellular mature virions (IMV) to form enveloped virions; the specific target of the antiviral drug tecovirimat (ST-246)
A36R	Transmission and release	Critical for actin tail formation and the release of extracellular enveloped virions (EEV); acts as a target for peptide-based inhibitors
A35R	Viral envelope structure	A key surface envelope protein; serves as a primary target for neutralizing monoclonal antibodies and binds marine sulfated polysaccharides to block viral entry
A29L	Viral envelope structure	A surface protein often targeted alongside A35R by monoclonal antibodies to effectively neutralize the virus and reduce lung injury
EGF-like protein	Intercellular spread	Viral-encoded growth factor that activates the host EGFR/MEK/FAK signaling pathway, promoting cell motility and rapid viral transmission between cells
I5L, E8L, A43R	Viral entry	IMV surface membrane proteins that facilitate viral entry into host cells via receptor binding and membrane fusion
A33R, A34R	EEV regulation	Proteins involved in the production of extracellular enveloped virions (EEVs); their absence leads to increased EEV production
B5R	EEV regulation	Works in conjunction with A36R; its absence (unlike A33R/A34R) decreases EEV production, making it a potential target for blocking transmission
L1, A27, H3	Immune targets	Surface antigens identified as targets for monoclonal antibodies with the broadest cross-neutralizing activity against orthopoxviruses
DdRp	Viral replication	DNA-dependent RNA polymerase; catalyzes viral genome replication in the cytoplasm and is a target for novel small-molecule inhibitors
Bcl-2-like	Apoptosis regulation	Mimics host Bcl-2 proteins to inhibit the intrinsic apoptotic pathway, ensuring viral survival within the infected cell

Role of B cells and defenses against antibodies

Adaptive immunity acts as a second line of defense, followed by the innate immune response, to control the spread of viral replication in the host. B cells are the site of antibody generation, representing a promising foundation for vaccines like smallpox. Thereby, the vaccinated individuals can potentially be used for immunoglobulin preparations for the treatment of mpox. Monkey models have shown smallpox-specific B cell responses to protect against lethal mpox infections by increasing the production of memory B cells and NAbs. B cells have the tendency to recognize and bind to many mpox proteins involved in immune function and regulation; for instance, the vaccinia (VACV) vaccine provides protection against 14 mpox due to cross-reactive immunity. Moreover, immunoglobulins such as IgM, IgG, and IgA are crucial for the infection process. IgM plays an important role in the primary immune response, and IgG and IgA are responsible for secondary immunity that is long-lasting. MPX patients demonstrate IgM and IgG levels in vaccinated and unvaccinated individuals, whereas IgM levels were prominent after the second day of infection on the onset of rashes that persist until Day 77 in vaccinated and Day 126 in unvaccinated patients. IgG levels appear on Day 1 in vaccinated and Day 2 in unvaccinated patients, persisting until Days 147 and 139, respectively, as illustrated in Figure 5 (Ganesan et al., 2025).

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FIG. 5.

Sequential immunological response and pathogenesis timeline of mpox infection. This schematic delineates the host’s immune activation stages across the typical 2- to 4-week course of infection. The innate phase (Days 1–3) involves PRR-mediated detection of MPXV, which triggers type 1 IFN production and NK cell activation. The adaptive phase (Days 7–9), coinciding with the typical incubation period, is marked by antigen presentation in lymph nodes, triggering T cell activation (CD4⁺/CD8⁺), cytokine release, and IgG production. By Day 14, the establishment of memory B and T cells provides long-term immunity, facilitated in some cases by cross-reactive protection from prior orthopoxvirus exposure. IFN, interferon; MPXV, mpox virus; NK, natural killer; PRR, pattern recognition receptor. Images created using BioRender.

B cells also play an important role as specialized antigen-presenting cells by the upregulation of CD28 and inducible costimulatory molecules that activate and proliferate poxvirus-specific CD4⁺ and CD8⁺ T cells. This represents the interplay between T and B cell responses. B cells use their membrane-bound B cell receptor, which is a form of antibody, to bind specifically to mpox viral antigens (such as A35R or H3L). The B cell internalizes the virus, breaks it down, and presents these processed peptide fragments on its surface using major histocompatibility complex (MHC) class II molecules. B cells then present the antigen to CD4⁺ helper T cells. Then, the activated T cells provide signals (cytokines and CD40L binding) that cause the B cells to proliferate, undergo affinity maturation, and differentiate into plasma cells, which then secrete high amounts of soluble, NAbs (IgG, IgM, IgA). These findings represent strong evidence of the role of immunoglobulins in broad protection against mpox infections (Saghazadeh and Rezaei, 2022).

B cells contribute significantly to humoral immunity against mpox by generating NAbs that target two unique viral forms: IMVs and EEVs. The most prevalent viral type, IMVs, is the main target of NAbs, although EEVs, which are covered in an extra lipid membrane formed by the host, provide a bigger immunological obstacle. EEVs show strong resistance to complement-mediated neutralization, which lowers the overall effectiveness of NAb responses and makes it easier for the virus to avoid host defenses. Therefore, it is essential to comprehend the structural and antigenic distinctions between these two viral types, especially the surface-exposed membrane proteins of EEVs, to rationally design vaccines that are broadly protective. Immunoinformatic techniques provide a promising way to discover and predict important components of the EEV membrane that may be useful targets for vaccines. The creation of multi-epitope vaccines that can concurrently target both IMV and EEV forms can be directly influenced by these discoveries, potentially increasing the vaccine’s efficacy and breadth against mpox (Ganesan et al., 2025).

Transmission

mpox is a zoonotic viral disease caused by the mpox virus that belongs to the same family as the smallpox virus, poxviridae. It can be transmitted from animals to animals, animals to humans, and humans to humans. African rodents such as rope squirrels, tree squirrels, Gambian rats, and primates present as natural hosts for the mpox virus. A recent wildlife surveillance study strongly suggests fire-footed rope squirrels to be an animal reservoir of the MPXV that caused an outbreak in sooty mangabeys in Côte d’Ivoire (Kupferschmidt, 2025). This is the first direct evidence of cross-species viral mpox transmission. The zoonotic transmission can take place via invasive routes (bites, scratches by infected animals) or noninvasive routes (touching or hunting the infected animal, cleaning its living space, processing, and consumption of its meat). Human-to-human transmission was rare before the 2022 outbreak (O’Shea et al., 2022). Historically, human cases were mainly related to direct contact with infected animals or a visit to epidemic regions. In 2018, a case of a traveler from Nigeria demonstrated a secondary transmission as health care staff got infected with the virus. Humans can contract the virus from other humans via blood transfusion and close contact that involves respiratory droplet infection through food exchange and sexual activity, as well as via fomites in the surroundings of the infected person (Ogunleye et al., 2023). Vertical transmission has also been recorded (Jamil et al., 2022). During 2007 and 2011, four pregnant women had mpox infections; one had a healthy infant, two had miscarriages, and the other died in infancy with manifestations of diffuse maculopapular lesions. However, in the 2022 outbreak, no pregnant women were shown to transmit the disease to their infants (Hatmal et al., 2022). The pattern of transmission shifted in the 2022 outbreak, as sexual transmission appeared to be the predominant mode of transmission. Despite the detection of the virus in the seminal fluid of the infected person, it is not certain if the transmission happens sexually. Instead, it is thought to be spread by direct contact with the skin lesions and infections via microabrasion on skin caused by sexual activities. Reports from the 2022 outbreak showed a differential abundance and lifetime of the virus in different parts of the human body. It is mostly always found in the skin samples of the infected individual. The virus is detected in 60–70% of samples collected from the anus and throat, 50% in semen, and only 20% of blood samples. The viral load was also found to be much higher in the skin samples of the patients. Replication-competent viruses, which can cause secondary infections, are also more abundant in the skin compared with that of other body parts. In immunocompetent patients, the virus is detected by quantitative PCR for a median time of 25 days in skin samples, 13 days in semen, and 1 day in the blood. The virus goes undetectable in the skin post 41 days of infection (Ganesan et al., 2025). The tropism of the virus may account for undetectable cases as well as asymptomatic infections; however, the evidence of the latter is still debated. The virus enters the human body via two entry gates, the respiratory epithelium and skin epidermis, and by infecting first dendritic cells and fibroblasts, respectively, it eventually infects the lymphatic system, where it replicates and causes secondary viremia and spreads to the whole body (Prompetchara et al., 2024). Reported cases from the 2022 outbreak are majorly associated with community spread. There are also reports of environmental contamination and accidental transmission with used needle injuries; therefore, a systemic approach to assess the risk of transmission and proper safety measurements for health care workers is required. However, indirect cases via fomites have still been lower than in previous outbreaks. Asymptomatic cases have been rare in the outbreak but were reported among sexual health care workers in France and Belgium. Modeling has implied that presymptomatic transmission may have occurred (De Baetselier et al., 2022).

Elaborate prevention and therapeutics

The urgent need for effective prophylactic measures is highlighted by the MPXV’s reappearance in both endemic and nonendemic areas. A multifaceted strategy is required for successful prevention because mpox is spread via zoonotic overflow and human-to-human contact through bodily fluids, skin lesions, respiratory droplets, and contaminated items.

Individuals exposed to the mpox virus should be isolated in separate bathrooms and monitored for 21 days after their last exposure. All movements should be restricted only to medically essential purposes. No exposure to the skin lesions and oral secretions of the infected individuals. PPE used by health care individuals must include eye protection and an N95 or FFP2 respirator because the virus spreads primarily through direct contact with infectious lesions or fluids, respiratory secretions, and contaminated materials. The gear protects against both large respiratory droplets and smaller, potentially airborne particles, which can infect the eyes, nose, or mouth. Proper measures for handling waste management and soiled laundry are to be ensured. Individuals with smallpox vaccines were more protected or developed a less serious infection than those with no history of the vaccine (Christodoulidou and Mabbott, 2023). Hence, smallpox vaccines and their modern modifications are recommended by the Advisory Committee on Immunization Practices for pre- and postexposure prophylaxis. Pre-exposure for within 4 days to a maximum of 4 weeks of exposure and postexposure in severe cases with high risk, including health care professionals (Cohn et al., 2023; Garcia-Atutxa et al., 2024). The various therapeutics and vaccines available for the prevention of mpox are mentioned in Tables 2 and 3, respectively.

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Table 2.

Monkeypox Preventive Therapeutics, Mechanism, Lifecycle Stages, Administrative Strategies, and Key Insights

Vaccine	Type/Mechanism	Target/Lifecycle stage	Administration and safety	Key clinical insights	References
JYNNEOS (MVA-BN)	Third Gen, live-attenuated, nonreplicating	Prevention/Cross-protection	Two doses (28 days apart) via subcutaneous or intradermal routes	FDA approved; safe for immunocompromised and pregnant populations; effectiveness is 66–89% after two doses	(Ahmad et al., 2026; Prajapati et al., 2026)
ACAM2000	Second Gen, live vaccinia, replication-competent	Prevention/Cross-protection	Single dose; percutaneous administration via 15 jabs with a bifurcated needle	Contraindicated for immunocompromised individuals; associated with risks of myopericarditis and encephalitis	(Kandeel et al., 2023)
LC16m8	Third Gen, attenuated (missing B5R protein)	Prevention/Cross-protection	Single dose; five-puncture bifurcated needle inoculation	Licensed in Japan for all ages, including pediatric use; recommended for WHO stockpiles	(Hatmal et al., 2022)

FDA, Food and Drug Administration; WHO, World Health Organization.

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Table 3.

Monkeypox Preventive Vaccines, Mechanism, Lifecycle Stages, Administrative Strategies, and Key Insights

Vaccine	Type/Mechanism	Target/Lifecycle stage	Administration and safety	Key clinical insights	References
Tecovirimat (TPOXX)	Antiviral (small molecule)	Maturation and release: Inhibits the VP37 (F13) wrapping protein	Oral or intravenous administration	Primary therapeutic for severe cases; long-term use in immunocompromised patients may lead to resistance	(Russo et al., n.d.)
Amphotericin B	Antifungal (experimental for mpox)	Viral entry: Destroys lipid rafts and cholesterol in host membranes	Proposed as an entry inhibitor	Antiviral effect exploits the virus’s reliance on host cholesterol for cell invasion	(Peruzzu et al., 2023)
Cidofovir/Brincidofovir	Nucleoside analogs	Replication: Competitive inhibition of DNA polymerase (F8 subunit)	Demonstrated efficacy in animal models	Acts as a broad-spectrum agent against orthopoxviruses	(Prévost et al., 2024)
Host protein targets	PPI network (EGFR, TRAF6, UBC)	Entry/Survival: Modulates host signaling pathways	Repurposed drugs (e.g., Sunitinib, Niclosamide)	High-centrality host proteins are identified as universal therapeutic targets via bioinformatics	(Hatmal et al., 2022)
Imatinib mesylate	Anticancer drug (tyrosine kinase inhibitor)	Release: Inhibits the formation of the actin tail	Preclinical/Experimental	Targets the host cytoskeleton to block the efficient release and spread of virions	(Hatmal et al., 2022)

PPI, protein–protein interaction.

The integrated molecular interactome highlights the sophisticated strategies employed by the MPXV to manipulate host cellular machinery through specific protein–protein interactions, as detailed in Table 4. Most mpox cases resolve completely within 2–4 weeks, but complications can arise in some instances. Severe complications reported include encephalopathy and a retropharyngeal abscess. Additional complications such as secondary skin infections, sepsis, bronchopneumonia, encephalitis, corneal infection, and deep abscesses have also been documented (Manoharan et al., 2022). Pitted scarring is the most frequently observed sequela, with vision loss due to orbital infections reported in some cases. Notably, severe complications and long-term effects were more common in unvaccinated individuals compared with those who had been vaccinated.

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Table 4.

Molecular Landscape of mpox–Host Protein–Protein Interactions and Potential Therapeutic Intervention Points

Viral protein/Subunit	Host target(s)	Host pathway/Function	Cellular localization	Potential inhibitors	Primary references
D11L/D9L	EGFR, TRAF6, UBC	Cell survival; NF-κB signaling	Membrane/Cytoplasm	Sunitinib; Gefitinib	(Yi et al., 2024)
M2	B7.1 (CD80), B7.2 (CD86)	T cell activation; CD28/CTLA4 block	Cell surface	Abatacept (analogue)	(Kleinpeter et al., 2019)
F17	cGAS-STING	Cytosolic DNA sensing; Type I IFN evasion	Golgi/Cytoplasm	Resiquimod	(Ahmad et al., 2026)
OMCP	NKG2D receptor	NK and T cell cytotoxicity	Secreted/Surface	Monoclonal antibodies	(Alakunle et al., 2024)
VH1	STAT1, STAT2	Interferon signaling cascade	Cytoplasm	Fostamatinib; Palbociclib	(Bottini et al., 2023)
CrmA/F1/N1	Caspases 1, 8, 9	Apoptosis inhibition; cell survival	Mitochondria	B13 mimics	(Ekert et al., 1999)
C6	TRIM5α	NF-κB activation and IFN induction	Cytoplasm	Proteasome inhibitors	(Yi et al., 2024)
A35R/I5L/E8L	GAGs/Chondroitin	Viral attachment and host cell entry	Host membrane	Amphotericin B; marine polysaccharides	(Huang et al., 2025)

IFN, interferon; GAGs, glycosaminoglycans; NK, natural killer.

Recent advances, clinical trials, and research gaps

Significant progress has been made in diversifying the medical countermeasures against mpox, particularly with the deployment of third-generation vaccines such as JYNNEOS (MVA-BN) and LC16m8. Recent clinical trials, including large-scale efficacy studies of LC16m8 in Colombia, have been pivotal in assessing cross-clade protection and safety in high-risk populations. On the diagnostic front, the integration of CRISPR-Cas12a with Recombinase Polymerase Amplification (RPA) has emerged as a promising avenue for rapid, point-of-care detection in resource-limited settings, potentially bypassing the need for sophisticated thermal cyclers (Matthews et al., 2025; Yang et al., 2023). Furthermore, genomic surveillance has become more robust, allowing for the real-time tracking of Clade Ib as it expands across Central Africa and beyond.

Despite these advances, critical loopholes remain that jeopardize global containment efforts. A primary concern is the over-reliance on tecovirimat (TPOXX); as the dominant antiviral in clinical trials, its potential for inducing viral resistance and its lack of definitive efficacy data for Clade I present a significant therapeutic risk. Moreover, a profound evidence gap exists for vulnerable groups, including children, pregnant women, and individuals with advanced HIV, who are frequently excluded from clinical trials despite suffering the highest morbidity and mortality. These challenges are compounded by systemic inequities in vaccine and diagnostic access; currently, testing rates in endemic regions like the DRC hover far below the 80% threshold required for outbreak control, highlighting a disconnect between global scientific innovation and local public health implementation.