Risk factors associated with human Mpox infection: a systematic review and meta-analysis

Abstract

Background

Mpox emerged as a significant global public health concern during the 2022–2023 outbreak, impacting populations in both endemic and non-endemic countries. This study reviews and synthesises evidence on the risk factors associated with human Mpox transmission across these regions.

Methods

A systematic search of peer-reviewed original studies was conducted across Scopus, Embase, Web of Science and PubMed databases, covering publications up to 31 March 2024. The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Two authors independently screened the articles by title, abstract and full text. The Newcastle–Ottawa Scale used to assess the risk of bias for included articles. Fixed- or random-effects meta-analysis was conducted when at least two studies reported ORs or relative risks, with 95% CIs. Heterogeneity was assessed using the $I^2$ statistic. This study was registered on PROSPERO (ID: CRD42023459895).

Results

The systematic review identified 947 articles through database searches, of which 31 met our inclusion criteria. The meta-analysis revealed significant risk factors associated with Mpox infection. Interaction with infected animals (OR=5.61, 95% CI 2.83, 11.13), HIV infection (OR=4.46, 95% CI 3.27, 6.08), other sexually transmitted infections (OR=1.76, 95% CI 1.42, 2.19), unprotected sexual activities (OR=1.53, 95% CI 1.13, 2.07), contact with an infected person (OR=2.39, 95% CI 1.87, 3.05), identification as men who have sex with men (OR=2.18, 95% CI 1.88, 2.51) and having multiple sexual partners (OR=1.61, 95% CI 1.24, 2.09) were associated with increased Mpox infection risk. Conversely, smallpox vaccination was associated with a significantly reduced risk of Mpox infection (OR=0.24, 95% CI 0.11, 0.55).

Conclusion

Identification of risk factors associated with Mpox provides insights for strategic public health planning, enabling targeted interventions for high-risk groups and optimising resource allocation to strengthen Mpox control efforts.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Mpox is a zoonotic disease of significant global public health concern, especially due to recent outbreaks in non-endemic countries.

• Prior outbreaks of Mpox have been associated with travel to endemic areas in Western and Central Africa, contact with infected animals and close contact with infectious individuals, particularly in household and healthcare settings.

WHAT THIS STUDY ADDS

• This study enhances the existing evidence on Mpox and provides valuable insight to guide regional and global interventions.

• Our meta-analysis identified key risk factors associated with Mpox infection, including HIV, other sexually transmitted infections (STIs), physical and sexual contact and identification as men who have sex with men.

• HIV infection may increase the risk of Mpox, while Mpox lesions could also facilitate the transmission of HIV and other STIs.

• These findings contribute to evidence-based strategies for the control and prevention of Mpox.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• The results offer essential evidence for policymakers to design targeted intervention and prevention strategies in both endemic and non-endemic countries based on the identified risk factors associated with Mpox.

Introduction

The recent resurgence of human Mpox is a significant concern for global health.¹ Mpox is an Orthopoxvirus, endemic in West and Central Africa, with a clinical epidemiological presentation resembling that of smallpox.^{1 2} The virus was initially identified in captive monkeys in Denmark in 1959 and later in human male from the Democratic Republic of the Congo (DRC) in 1970.2,4 Epidemiologically, Mpox virus has two distinct evolutionary clades: clade I (formerly known as Congo Basin or Central African clade) and clade II (formerly known as West African clade), with present clade IIa and clade IIb being its two subclades.⁵ Compared with clade II, clade I is more pathogenic and severe. Over the past 40 years, the DRC has persistently reported clade I Mpox cases, with the number of annual reports surpassing 1000 cases in the past 20 years.³ Since the initial identification of human Mpox in DRC, clade I remained predominantly confined to the DRC,2,4 characterised by frequent zoonotic spillover events from animal reservoirs, a high rate of morbidity and associated mortality.³ Clade II is more prevalent in West Africa, causing milder disease and a lower mortality rate compared with clade I, the predominant strain in the DRC.⁶

Mpox occurrence across some other African countries has been reported intermittently and is associated with relatively lower mortality rates as compared with DRC.⁷ Between 1970 and 2000, sporadic cases of Mpox were reported in Nigeria, Côte d'Ivoire, Liberia and Sierra Leone.^{3 8 9} This underscores the need for improved surveillance and public health interventions to monitor and contain Mpox outbreaks across Africa. From 2003 to 2021, human Mpox cases were reported outside of Africa, primarily due to individuals travelling from endemic regions.¹⁰ While most cases occurred in travellers, limited local transmission was documented in non-African countries.¹¹ For example, in 2018, human Mpox cases were reported in Israel and the UK; in 2019, it was reported in Singapore, and between 2003 and 2021, Mpox cases were reported in the USA.^{3 9 12} These incidents underscored the potential for Mpox to spread globally through travellers from areas where the disease is endemic to non-endemic regions.³ Additionally, these instances highlight the potential for Mpox to spread beyond its traditional endemic regions, underscoring the importance of global surveillance, early detection and coordinated public health responses to contain outbreaks.

Mpox virus has continued to exhibit human-to-human epidemiological pattern, presenting a significant global health challenge, especially following the 2022–2023 outbreak.¹³ The virus has now spread widely, with transmission occurring via direct contact with lesions, body fluids or respiratory droplets from infected persons.¹⁴ Symptoms of Mpox infection include pustular rash, sore throat, swollen lymph nodes, fever, respiratory problems and in some cases, death.^{1 2} Other severe complications have been reported, including pneumonia, sepsis, corneal infection, pharyngitis, bacterial superinfection and acute respiratory infections also emerging.¹⁵ This outbreak, driven by mutations in clade II, marked the first large-scale spread of Mpox in non-endemic countries, specifically impacting urban and densely populated areas.^{5 10 16} The outbreak demonstrated a deviation from previous transmission patterns,¹⁷ notably among bisexual, gay and other men who have sex with men (MSM).¹⁸ This is often compounded by sexual activities and immunocompromised states, which accelerates the number of Mpox cases.¹⁹ The WHO declared Mpox a Public Health Emergency of International Concern in response.²⁰ New Mpox cases also emerged in countries with no previous history of Mpox, many linked to travel within European Countries and North America.^{1 21 22} The outbreak signalled a departure from the traditional transmission routes.²³ Notably, approximately, 85% of reported cases worldwide were concentrated in the USA, Canada, Spain, France, Colombia, the UK, Mexico, Brazil, Peru and Germany.²⁴ These patterns underscore the need for global surveillance, early detection and targeted public health responses to control the virus spread.

The steep increase and expanded distribution of Mpox in 2024, particularly of the more pathogenic clade 1, in regions beyond the endemic DRC, including Rwanda, Uganda, Kenya, Côte d'Ivoire and Sudan, and non-endemic countries, including Thailand and Sweden, suggests a complex interplay in the transmission dynamic of Mpox.²⁵ The 2022–2024 Mpox epidemic, linked to clade II, primarily spread through sexual transmission among MSM, predominantly affecting young adult males and exhibiting a lower case fatality rate of less than 1%.²⁶ However, the identification of clade Ib in travellers to Sweden and Thailand following the 2024 outbreak highlights the critical role of global travel and trade in facilitating Mpox transmission.²⁵ The ongoing outbreaks highlight the complexities in understanding the factors influencing Mpox transmission, including the roles of head immunity, vaccination and behavioural changes.^{1 27}

The 2024 Mpox outbreak in the DRC presented significantly different epidemiological characteristics compared with the 2022–2023 global epidemic, largely driven by clade II. Notably, the outbreak was linked to two primary outbreaks: clade Ia in endemic provinces, associated with animal-to-human transmission,²⁵ and clade Ib in North and South Kivu, driven mainly by human-to-human transmission.^{28 29} Clade Ib emerged in Kinshasa, Kasai, Tanganyika and Tshopo, with both clades Ia and Ib found in Kinshasa.^{30 31} Most cases reported in the past were notified from the African Region and the Region of the Americas.³¹ The year 2024 alone recorded over 1400 laboratory confirmed cases and, approximately, 51 deaths across 74 countries globally.³² Approximately, 2863 confirmed cases of Mpox were recorded across the African continent, with the majority in the DRC, followed by Uganda and Burundi,²⁸ with these three countries contributing most of the cases. In the DRC, cases have predominantly involved clade I, with an alarming impact younger age group.^{28 33} Over 50% of reported cases and most associated deaths have occurred in this age group, highlighting an elevated paediatric burden for clade I, particularly clade Ia, which is endemic to the African region.²⁸

Following the ongoing Mpox outbreaks, two primary vaccines such as the JYNNEOS vaccine (also known as Imvamune/Imvanex) and Modified Vaccinia Ankara-Bavarian Nordic have been in circulation and have displayed moderate efficacy in reducing symptomatic Mpox infection, although complete immunity was not uniformly achieved.^{32 34 35} The decline in global orthopoxvirus immunity after the cessation of smallpox vaccination decades ago has made Mpox transmission easier.³⁶ An increase in the average age of Mpox cases in Africa supports this hypothesis,³⁷ indicating that, in endemic African and non-endemic regions, the incidence rate of Mpox infection in smallpox vaccinated population was significantly lower as compared with the unvaccinated population.^{21 34} Vaccination remains a cornerstone of global public health strategies to prevent Mpox outbreaks, especially as Mpox continues to pose significant threat.³² The intent to vaccinate among the high-risk groups may be influenced by factors, including accessibility, perceived susceptibility and vaccine awareness, all of which impact vaccination uptake.^{38 39} Importantly, effective outbreak control and protection for healthcare workers, who are among the high-risk groups and in close contacts of infected persons, remain very important.³⁶

The transmission dynamics of Mpox infection on a global scale underscore the urgent need for ongoing investigation into the risk factors associated with the disease to effectively protect high-risk populations.⁴⁰ Despite significant efforts, the lack of standardised epidemiological data across different countries impedes a comprehensive understanding of the factors contributing to Mpox transmission. Existing research on Mpox risk factors reveals notable gaps, particularly in understanding how behavioural, socioenvironmental and ecological factors interact to facilitate the spread of the virus.^{26 32 40} Identifying these risk factors is essential for developing targeted interventions, geographically optimised resource allocation and for providing policymakers and healthcare professionals with evidence-based guidance to raising awareness, combating misinformation and supporting proactive public health measures.

This study aimed to quantify risk factors associated with Mpox in both endemic and non-endemic regions, identifying knowledge gaps and vulnerable populations. By analysing data from multiple countries, this research seeks to advance the understanding of Mpox-associated risk factors and contribute meaningfully to global Mpox epidemiology and public health preparedness.

Methods

This systematic review and meta-analysis were conducted and reported following the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.^{41 42} Additionally, the protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO), CRD42023459895.

Search strategy

The search was conducted in four electronic databases, including Scopus, Web of Sciences, Embase and PubMed up to 31 March 2024, with no restriction on the year of publication or geographical region. The search questions were developed based on the medical subject headings and combination of keywords associated with Mpox and risk factors using Boolean functions ‘OR’ or ‘AND’ between different search terms.⁴³ The key search terms were: [‘Mpox’ OR ‘Monkeypox’ OR ‘Orthopoxvirus’ OR ‘Monkeypox virus’ OR ‘MPXV’] AND [‘risk factors’ OR ‘influential factors’ OR ‘impact factors OR ‘exposure’ OR ‘associated factors’ OR ‘determinants’ OR ‘Causes’ OR ‘Relative risk’ OR ‘Reasons’]. The search was supplemented by reviewing non-indexed databases and reference lists of screened studies, focusing on original articles published in English.

Study selection strategies

Following the completion of search, EndNote X9 reference management software⁴⁴ was employed to keep a record of all articles obtained from the electronic databases, duplicates were removed and final studies were screened by title, abstract and full text. Studies were included based on the following criteria: only original articles were considered, specifically international observational studies, including case-control, cross-sectional, prospective and retrospective designs that focused on identifying the risk factors associated with Mpox infection in human subjects. This selection ensures a comprehensive understanding of the various epidemiological perspectives and contexts surrounding Mpox risk factors. Studies were excluded based on the following criteria: those that did not specifically address the risk factors associated with Mpox, studies published in languages other than English, case reports, conference abstracts, review articles, grey literature (including dissertations and theses), editorial letters, studies focusing on animal or non-human populations and studies that lacked complete information.

In the title and abstract review process, two authors (CLJU and WAW) selected articles for full-text review based on predefined inclusion and exclusion criteria. The same authors (CLJU and WAW) conducted the full-text review, screening all articles obtained from the database after removing duplicates. At all stages, disagreements were resolved by discussion and consensus between CLJU and WAW and a third author (NB).

Study outcome and data extraction

This study focused on human Mpox, with the primary objective of assessing the risk factors associated with the disease. The primary outcome was quantified as an OR, accompanied by 95% CIs to provide a statistical context for the findings. Subsequently, data extraction based on the study outcome (human Mpox) was conducted by two independent reviewers (CLJU and WAW) using Microsoft Excel 2016 (Microsoft, Redmond, Washington, USA). The authors extracted the following data from the included studies: the author’s name, country of study, year of publication, study design, study population (sample size, demographic variables like sex, gender, age and sexual orientation), clinical variables (such as disease presentations), characteristics of participants (such as mean/median age), outcome (Mpox) and exposure (risk factors associated with Mpox).

Quality assessment

Two authors (CLJU and WAW) independently conducted a risk of bias assessment for each study using a modified version of the Newcastle–Ottawa scale (NOS) tool intended for observational studies. Any discrepancies were checked by the third author (NB). The NOS assessment scale provides a score ranging from 0 to 9, with scores categorised as low quality (0–4 points), moderate quality (5–7 points) and high quality (8–9 points). Out of the included studies, the majority have 7–8 points regarded as moderate- to high-quality studies. See (online supplemental table S1).

Statistical analysis (meta-analysis)

At first, this study conducted a narrative synthesis for each identified risk factor. Subsequently, when sufficient data were available, a quantitative meta-analysis was conducted on risk factors that were reported in two or more studies and included the estimated ORs or relative risks.⁴⁵ A forest plot presented the pooled OR for each risk factor associated with Mpox, and the degree of heterogeneity was determined quantitatively using I² index statistic.^{46 47} I² ≥ 75% is a measure of highly significant heterogeneity, I² = 50%–70% is recognised as moderate heterogeneity, 25% <I² <50% denotes a low heterogeneity and I²≤25% presents homogeneity. Thus, heterogeneity is high when Cochran’s Q p value<0.10 and I² ≥ 50%.^{48 49} To ensure a high-quality study, we employed the fixed-effects meta-analysis model when heterogeneity was low or homogeneous, and opted for the random-effects model if it was highly significant, supplemented by sensitivity analyses to identify sources of high heterogeneity.⁴⁵ To explore possible publication bias, funnel plots with Egger’s weighted regression test were used.⁴⁸ All of the analyses were implemented in the R statistical software version 4.3.2 with R-package meta.^{50 51} P value<0.05 was considered statistically significant.

Patient and public involvement

There was no patient involvement due to the study design.

Results

In this systematic review and meta-analysis, 947 studies were identified through database and manual searchers. The articles were exported to the EndNote reference manager, where duplicates were removed. Subsequently, 460 studies were obtained after removing duplicates, and 291 were excluded after screening titles and abstracts. After a full-text review, a total of 138 texts were further excluded for not meeting the inclusion criteria. A total of 31 articles representing 148 499 Mpox cases from 15 countries were included in the narrative synthesis. See figure 1 for the PRISMA flowchart.

Figure 1. Flowchart illustrating the study selection process.

Study characteristics

Table 1 provides full list and characteristics of the included studies. The studies were conducted up to 31 March 2024, in both endemic and non-endemic countries (n=15). Of the 31 included studies, seven were conducted in DR Congo,752,56 one in Nigeria,⁹ two in the USA,^{57 58} two in the UK,^{59 60} four in Spain,61,64 two in Brazil,^{65 66} four in Italy,^{67 68} two in UAE,^{7 69} one in Netherlands,⁷⁰ one in Israel,⁷¹ one in Chile,⁷² one in Portugal,⁷³ one in Belgium,⁷⁴ one in Germany⁷⁵ and four multicountry studies.^{10 24 59} Notably, most original publications Mpox risk factors were recent studies conducted in non-endemic countries.

Table 1. Characteristics of included studies.

No	Author (year)	Country	Study design	Sample size	Mean age	Sex (M/F)	Sexual orientation(MSM/gay/bisexual)
1	Acevedo and Garrido72	Chile	Case-control study	1415	35	Male	–
2	Akilimali et al7	DR Congo	Case-control study	2159	5+	Male/Female	MSM
3	Alegre et al61	Spain	Prospective cohort study	11	35±8	Male	MSM
4	Alhammadi et al77	UAE	Prospective cohort study	176	30.4±7	Male (164)	–
5	Alpalhão et al73	Portugal	Prospective cohort study	42	37	Male	MSM
6	Angelo et al59	15 countries	Prospective cohort study	226	37 (18–68; 32–43)	Male (211)	MSM, gay, bisexual (208 of 211)
7	Berens-Riha et al74	Belgium	Prospective cohort study	169	39	Male/Female	–
8	Candela et al67	Italy	Retrospective cohort	140	37	Male (137)	MSM (134 of 137)
9	Catala et al62	Spain	Prospective cohort study	185	36	Male	MSM: all reported having sex with men.Having multiple sexual partners during the previous weeks.
10	Ciccarese et al68	Italy	Case-control study	16	37	Male	Homosexual and bisexual
11	Cline and Marmon57	USA	Cross-sectional study	250	30–60	Male (242)Female (7)	–
12	Dar et al69	UAE	Case-control study	16	33+	Male	–
13	Doshi et al52	DR Congo	Retrospective cohort	43	11+	MaleFemale (11)	–
14	Estévez et al63	Spain	Retrospective cohort	133	33	Male	–
15	García‐Piqueras et al64	Spain	Retrospective cohort	53	36	Male	MSM (49)
16	Laurenson-Schafer et al76	WHO states	Retrospective cohort	76 293	30–45	Male	MSM (29 854)
17	Lin et al10	39 nations	Prospective cohort study	30 012	30	Male and female	–
18	Martins-Filho et al65	Brazil	Prospective cohort study	9729	20–39	Male	MSM
19	Nolen et al53	DR Congo	Case-control study	13	35	Male and female	–
20	Oeser et al75	Germany	Cross-sectional study	1840	18–59	Trans and non-binary	MSM (trans and non-binary)
21	Ogoina et al9	Nigeria	Prospective cohort study	160	35	Male (114) and Female (46)	–
22	Quiner et al54	DR Congo	Observational study	939	8+	Male (608) and female (331)	–
23	Reynolds et al58	USA	Case-control study	61	18+	Male and female	–
24	Rimoin et al55	DR Congo	Observational study	760	11.9	Male and Female	–
25	Souza et al66	Brazil	Observational study	10 169	15+	Male	MSM
26	Thornhill et al24	16 countries	Case-control study	528	38	Male	MSM
27	Vallejo-Plaza et al86	Spain	Cohort study	158	16–76	Female	–
28	van Ewijk et al70	Netherlands	Observational study	1000	45	Male	MSM
29	Vivancos et al60	UK	Case-control study	86	38 years	Male/female	MSM
30	Whitehouse et al56	DR Congo	Prospective cohort study	3639	14+	Males and Females	–
31	Zucker et al71	Israel	Prospective cohort study	8088	25–46	Male	–

MSMmen who have sex with men

Regarding clinical characteristics, the studies revealed that the most common symptoms of Mpox include fever, rash, exanthema, lymphadenopathy, myalgia, lesions and headache, with fever being the predominant systemic manifestation.^{9 63 72} Individuals with confirmed Mpox infection were mostly presented with mucocutaneous lesions, most commonly on the genital and anal areas, which support sexual contact as a means of recent Mpox transmission.^{9 24 72} The studies observed that among Mpox-infected individuals, the most reported sexually transmitted infections (STIs) were HIV, which was the most prevalent.^{10 24 59 63 72 76} This may be attributed to the immunodeficiency associated with HIV infection, even in individuals receiving treatment.⁶⁸ While HIV infection significantly increases the risk of contracting Mpox, Mpox lesions could also potentially facilitate the transmission of HIV and other STIs.^{55 72 77}

Risk factors associated with Mpox

The original studies reporting Mpox risk factors identified sociodemographic characteristics, behavioural factors, comorbidities, clinical features and vaccination status as significant contributors. A meta-analysis was conducted on studies reporting ORs and 95% CI to evaluate the association between identified risk factors and Mpox. The results are presented in table 2 and further elaborated in the accompanying narrative explanation below.

Table 2. Risk factors associated with Mpox via meta-analysis.

Factors	Number of articles	Pooled OR (95% CI)	I2(%)	I2 P value
Interaction animals	4	5.61 (2.83, 11.13)	42	0.16
HIV	4	4.46 (3.27, 6.08)	39	0.18
Other STIs	3	1.76 (1.42, 2.19)	40	0.19
MSM	2	2.18 (1.188, 2.51)	0	0.39
Disease comorbidities	3	1.58 (1.31, 1.91)	0	0.78
Sexual activities	2	1.53 (1.13, 2.07)	0	0.74
Multiple sexual partners	2	1.61 (1.24, 2.09)	35	0.22
Close contact with positive person	2	2.39 (1.87, 3.05)	36	0.21
Younger age group (≤ 40 years)	5	2.03 (1.44, 2.85)	0	0.43
Education	2	0.52 (0.26, 1.02)	46	0.17
Smallpox vaccination	2	0.24 (0.11, 0.55)	0	0.47

MSMmen who have sex with menSTIssexually transmitted infections

Interaction with infected animals

Interactions with animal reservoirs play a critical role in Mpox epidemiology, as the virus is primarily zoonotic in origin. Among the included studies, two in endemic regions analytically reported interactions with infected animals as a risk factor for Mpox.^{54 58} The studies reported that close contact with wild animals, daily exposure during an animal’s illness, contact with rashes or eye crusts, scratching, cleaning cages or handling bedding and direct exposure to animals increased the odds of Mpox. Our study detected a moderate heterogeneity (I²=42%, p=0.16), and the fixed-effects model was adopted for meta-analysis. From the result of the forest plot in figure 2A, interaction with animals was found to be a statistically significant risk factor associated with Mpox in endemic areas (OR=5.61, 95% CI 2.83, 11.13, p value<0.0001). These findings reveal that being bitten by rodents at home, handling Mpox-infected animals and daily exposure to their excretions and secretions were statistically and significantly linked to higher odds of human Mpox infection. The results indicated that individuals with direct exposure to infected animals are 5.61 times more likely to contract Mpox compared with those without such exposure.

Figure 2. Forest plot illustrating the associations between Mpox infection and various factors: (A) animal interaction, (B1) HIV status before (B2) and after sensitivity analysis, (C) STIs and (D) comorbidities. STIs, sexually transmitted infections.

HIV

Five studies analytically reported the odds of having HIV as a risk factor for Mpox and a comorbidity-associated Mpox infection.^{9 10 71 72 75} Individuals with advanced HIV (who are immunocompromised) had an increased risk of severe Mpox symptoms and mortality. From our analysis, significant high heterogeneity was detected (I²=87%, p<0.01), and a random-effects model was employed for meta-analysis of the association between HIV and Mpox infection. The estimate obtained showed that HIV is a risk factor for Mpox (OR=4.05, 95% CI 2.02, 8.14, p value<0.0001) (figure 2B). The results indicate that individuals living with HIV are 4 times more likely to contract Mpox compared with those without HIV, underscoring the role of HIV as a significant risk factor for Mpox infection. However, to identify the source of high heterogeneity, we conducted a sensitivity analysis and detected that Acevedo et al’s study⁷² was the source of heterogeneity. Removing the study reduced the heterogeneity to (I²=39%, p=0.18). Subsequently, a fixed-effect model was performed for meta-analysis, and results still indicated that HIV is a statistically significant risk factor associated with Mpox (OR=4.46, 95% CI 3.27, 6.08, p value<0.0001) (figure 2B). The results suggest that individuals with HIV are 4.5 times more likely to contract Mpox infection compared with those without HIV.

Other sexually transmitted diseases and comorbidities

The pooled effect from three studies^{9 71 72} that reported on STIs showed that syphilis, concomitant varicella-zoster virus infection, chlamydia, hepatitis B and C, gonorrhoea and histories of other STIs increased the odds of Mpox infection. From the forest plot in figure 2C, an evidence of moderate heterogeneity was detected (I²=40.3%, p=0.19), and a fixed-effects model was performed for meta-analysis. The results indicated that other STIs are risk factors associated with Mpox (OR=1.76, 95% CI 1.42, 2.91, p value<0.0001) (figure 2C). Additionally, three studies^{9 70 72} reported that the presence of comorbidities also increased the odds of Mpox infection. The forest plot analysis revealed no evidence of heterogeneity (I² = 0%, p=0.78), and a fixed-effects model was used for the meta-analysis. The result indicated that commodities are significant risk factor associated with Mpox (OR=1.58, 95% CI 1.31, 1.91, p value<0.0001) (figure 2D). However, the comorbidity studies did not specify the types of comorbidities involved, leaving it unclear which specific comorbidities have a greater impact on Mpox infection.

MSM and unsafe sexual activities

Recent Mpox outbreak saw a rapid surge among the MSM groups in previously unaffected areas, driven by sexual network heterogeneity. The results from two studies^{66 70} indicated that Mpox cases predominantly affected MSM, with a high incidence of lesions in the anogenital region. As no heterogeneity was detected (I²=0%, p=0.39), a fixed-effects model was selected for meta-analysis. Our results indicate that MSM individuals are at a higher risk of contracting Mpox (OR=2.18, 95% CI 1.88, 2.51, p value<0.0001) (figure 3A), with 2.18 times greater odds compared with those who are not MSM. Additionally, two studies^{70 75} reported that unprotected anal sex or engaging in three or more sexual activities, such as oral, anal and/or oral–anal, compared with just one or two activities in the 21 days before symptom onset, significantly increased the risk of Mpox infection. No heterogeneity was detected (I² = 0%, p=0.74), and a fixed-effects model was selected for meta-analysis. From the forest plot, sexual contact was a significant risk factor associated with Mpox (OR=1.53, 95% CI 1.13, 2.07, p value=0.005) (figure 3A). The result indicates that those who engaged in unprotected anal and oral sex had 1.53 times the risk of Mpox compared with those who did not.

Figure 3. Forest plot illustrating the associations between Mpox infection and various factors: (A1) MSM, (A2) sexual activities, (B1) multiple sexual partners before and (B2) after sensitivity analysis, (C1) close contact with a positive case before and (C2) after sensitivity analysis, (D) age, (E) smallpox vaccination and (F) education. MSM, men who have sex with men.

Multiple sexual partners

Four studies reported increased odds of Mpox infection among individuals with a history of multiple sexual partners.^{66 70 72 75} We analysed the data and found significant heterogeneity (I²=92%, p<0.01), and a random-effects model was performed for the meta-analysis. The results indicated that having multiple sexual partners is a risk factor associated with Mpox (OR=1.79, 95% CI 1.04, 3.11, p value<0.0001) (figure 3B). To find the source of heterogeneity, we performed sensitivity analysis and found that two studies^{72 75} were the source, and the heterogeneity was significantly reduced to (I²=35%, p=0.22), after removing the studies. Finally, a fixed-effects model was employed for the meta-analysis and having multiple sexual partners was concluded as a risk factor for Mpox (OR=1.61, 95% CI 1.24, 2.09, p value<0.0001) (figure 3B). The result indicated that those who engage in multiple sex had about 1.6 times higher risk of contracting Mpox compared with those who do not.

Contact with an infected person

Three studies^{70 72 74} reported that previous close contact with a confirmed case, including sharing personal items like glasses and towels, significantly increased the odds of Mpox infection. From our analysis, a high heterogeneity was detected (I²=79%, p<0.01), and a random-effects model was employed for meta-analysis. The result confirmed that close contact with an infected person is a risk factor for Mpox (OR=2.05, 95% CI 1.10, 3.79, p value<0.0001) (figure 3). Based on the results of the sensitivity analysis, the study by van Ewijk et al⁷⁰ was identified as the source of heterogeneity. On its removal, heterogeneity decreased (I²=36%, p=0.21), allowing for the use of a fixed-effects model in the meta-analysis. The analysis concluded that close contact with infected individuals significantly increases the risk of Mpox, with (OR=2.39, 95% CI 1.87, 3.05, p value<0.0001) (figure 3C).

Younger age group, education and smallpox vaccination

Five studies that reported risk factors of Mpox showed that younger age (defined as individuals aged $\le$40 years) was positively associated with Mpox.^{9 66 70 74 76} We analysed the data, and no evidence of heterogeneity was detected (I²=0%, p=0.47). Accordingly, a fixed-effects meta-analysis was performed, revealing that individuals under 40 years of age had an increased risk of Mpox infection (OR=2.03, 95% CI 1.44, 2.85, p value<0.0001) (figure 3D). Two studies from Mpox endemic regions^{9 58} reported that the smallpox vaccine was a significant protective factor against Mpox. The forest plot showed no evidence of heterogeneity (I²=0%, p=0.47), and subsequent meta-analysis using a fixed-effects model indicated a statistically significant negative association between Mpox and smallpox vaccination (OR=0.24, 95% CI 0.11, 0.55, p value<0.0001) (figure 3E). The result suggests that the smallpox vaccination was a protective factor against Mpox infection. According to the studies, low levels of education may hinder the development of health literacy, which may contribute to limited understanding of Mpox prevention, treatment and healthcare systems addressing the disease. Two studies^{9 75} have noted that education level was a risk factor for Mpox. We analysed the data, and moderate heterogeneity was detected (I² = 46%, p=0.17), and a fixed-effects meta-analysis was employed, and according to the forest plot, a higher level of education had a negative influence on Mpox infection; however, no statistically significant result was found (OR=0.52, 95% CI 0.26, 1.02, p value=0.06) (figure 3F). Other remaining risk factors associated with Mpox identified in studies were only reported in one independent study, and therefore due to lack of adequate number of studies, a meta-analysis was not conducted. The details of these risk factors can be found in the online supplemental table S2.

Discussion

Human Mpox continues to pose a significant global public health challenge, characterised by sporadic outbreaks that strain healthcare systems and highlight gaps in disease prevention and control strategies. These outbreaks underscore the need for a deeper understanding of the disease’s transmission dynamics, risk factors and the socioenvironmental contexts that drive its spread. This systematic review and meta-analysis aimed to identify risk factors associated with human Mpox in both endemic and non-endemic areas. Our findings based on the comprehensive synthesis of 31 articles from 15 countries identified sociodemographic, clinical and behavioural factors contributing to Mpox infection.

Through meta-analyses, identified risk factors associated with Mpox included contact with infected animals, close contact with infected individuals, having multiple sexual partners, sexual contact, being identified as MSM, belonging to a younger age group ($\le 40$ years), being HIV positive, having other STIs and possessing comorbidities. Conversely, smallpox vaccination emerged as a protective factor, particularly in endemic regions. Although Mpox is endemic in many African countries, epidemiological analytical data from these regions were scarce for conducting a meta-analysis of risk factors.

Contact with infected animals has been identified as a significant risk for Mpox transmission, particularly in endemic regions, such as the DRC and other parts of Central and Western Africa.⁷ The DRC reports most of the cases, where Mpox infections are largely driven by contact with animal reservoirs.⁵⁶ Anthropogenic and demographic changes since the 1980s may have increased local populations exposure to these reservoir species, thereby elevating the risk of animal-to-human transmission.^{52 55} In these endemic regions, Mpox predominantly affects rural villages near tropical rainforests.⁵⁴

As noted by Quiner et al,⁵⁴ humans acquire Mpox primarily through contact with infected animals or through limited human-to-human transmission chains. Activities, such as hunting and preparing bushmeat, have been identified as key drivers of animal-to-human transmission, practices that are prevalent in Central Africa and known to facilitate the emergence of several zoonotic pathogens.^{54 55} Reynolds et al⁵⁸ further confirm that handling infected animals significantly correlates with Mpox infection, particularly via direct exposure to excretions and secretions of infected animals. Adjusted analyses indicate a substantially higher risk of Mpox infection among individuals with frequent or direct exposure to sick animals,^{58 78} underscoring the critical role of animal reservoirs in Mpox transmission dynamics.

The meta-analysis identified HIV, other STIs and the presence of comorbidities are significant risk factors for Mpox. Among these, HIV and STIs, such as syphilis, chlamydia and gonorrhoea, were notably prevalent and strongly associated with increased risk of Mpox in non-endemic countries.910 66 70,72 75 This correlation underscores a critical intersection of public health concerns, suggesting that efforts to control HIV and other STIs could concurrently reduce Mpox susceptibility, especially in high-risk populations, such as the MSM. These findings highlight the potential to develop integrated healthcare strategies that address multiple infectious diseases simultaneously, thereby enhancing the overall epidemic preparedness and control efforts.

Our meta-analyses identified multiple sexual partners, close sexual contact, being identified as MSM, contact with a previously positive case and belonging to a younger age group as significant risk factors for Mpox, particularly in non-endemic countries. Historically, Mpox cases were linked to travel to Western and Central Africa, where the disease is common, with transmission occurring from animals to humans via bodily fluids or between humans through close contact with infectious sores or bodily fluids.^{24 58 59} Such transmission was especially common among household members and healthcare professionals.

Recent evidence, however, indicates a shift towards human-to-human, often via sexual contact. This is supported by the nature and location of lesions, which are predominantly, anal, rectal or genital.79,81 This shift has resulted to an increased risk of Mpox infection among younger individuals, particularly within non-endemic regions and the MSM population.^{82 83} Our findings indicate that the younger demographic faces increased risk due to the discontinuation of Mpox vaccination and increased engagement in sexual activities, highlighting the need for targeted public health intervention to address these evolving transmission patterns.

Our meta-analyses identified smallpox vaccination as a significant protective factor against Mpox, with protection attributed to immunity retained by older individuals vaccinated against it.^{54 58} Studies from endemic countries, such as DRC, demonstrate that individuals vaccinated with first-generation smallpox vaccines were less likely to develop severe Mpox,^{55 70} particularly among those born before the 1980s, when routine smallpox vaccines against emerging variants and willingness of high-risk groups to receive them.^{7 55 56} Given the global Mpox outbreak in 2022–2023, and its ongoing spread in 2024, there is an urgent need to further investigation into vaccine accessibility, equity and uptake. Handling these gaps will be critical for developing efficient public health strategies to manage and prevent Mpox infections in the years ahead.

Several studies have also evaluated the link between Mpox case rates and global health security index (GHSI), which measures a country’s ability to prevent, detect and respond to infectious disease threats.^{84 85} Findings suggest that regions with lower GHSI scores have greater challenges in controlling the spread of zoonotic diseases like Mpox.⁸⁴ These disparities emphasise the need for strengthening the GHS frameworks and ensuring equitable access to healthcare resources, particularly in countries with limited public health infrastructure.

To mitigate the spread of Mpox, it is very important to prioritise key public health measures. Strengthening surveillance systems, improving access to vaccines and treatments and enhancing international collaboration are essential actions. Additionally, targeted risk communication should focus on at-risk populations, such as MSM communities and individuals with underlying immunosuppression, to enhance awareness and reduce transmission rates. Additionally, the role of health system response capacity and country-specific health indicators must be considered, particularly in non-endemic countries. Variations in healthcare infrastructure, public health policies and preparedness likely contribute the Mpox occurrences in these countries. Addressing these factors alongside the identified risk factors of Mpox and transmission patterns is vital to enhancing global prevention and control efforts.

Strengths and limitations

This study provides evidence on the risk factors associated with Mpox through systematic review and meta-analysis across both endemic and non-endemic countries. The findings offer valuable insights to clinicians, public health agencies and policymakers, aiding in treatment decisions, supporting future research and in developing targeted interventions and prevention strategies. Despite these strengths, several limitations warrant considered. First, the review included only English-language studies, which may have excluded relevant research published in other languages, potentially limiting the comprehensiveness of the analysis. Second, insufficient data precluded the meta-analysis of certain risk factors due to the limited data possibly associated with under-reporting driven by fear of stigmatisation, particularly endemic countries in Africa. Third, the findings should be interpreted with caution as the included sample may not fully capture the diversity of the global population, highlighting the need for studies with more representative sample sizes. Additionally, significant knowledge gaps persist due to the limited number of available original studies, many of which are cross sectional or retrospective in design, potentially affecting the overall quality of evidence. The dynamic nature of Mpox research and inconsistencies in outcome ascertainment may have introduced misclassification bias, further emphasising the need for caution interpretation. Addressing these limitations in future research will be essential for advancing our understanding of Mpox risk factors and informing robust public health responses.

Conclusion

This study provides a comprehensive analysis of risk factors associated with Mpox, leveraging meta-analysis to synthesise evidence. Key findings emphasise the intersection of Mpox with HIV and other STIs, particularly among the MSM, underscoring the importance of integrating sexual health intervention into Mpox prevention strategies. Strengthening laboratory testing for HIV and other STIs should be a priority in outbreak control, especially in non-endemic areas where sexual transmission has played a significant role in recent Mpox outbreaks. Additionally, the expansion of Mpox vaccination and outreach programmes to include high-risk groups, such as those engaged in unprotected close intimate contact and sexual activities, as well as those who often attend mass gatherings, aligns with WHO guidelines and represents a critical step in global transmission reduction. Furthermore, the findings highlight the need for robust health system and equitable access to healthcare resources to enhance resilience against re-emerging zoonotic infectious diseases like Mpox.

The funding source had no role in the conception, study design, data collection, analysis, interpretation of the data, writing of manuscript, manuscript review, approval of the manuscript, and decision to submit the manuscript for publication.

Data availability statement

Data are available on reasonable request.