“Mpox in MSM: Tackling stigma, minimizing risk factors, exploring pathogenesis, and treatment approaches”

Abstract

Mpox is a zoonotic disease caused by the monkeypox virus (MPV), primarily found in Central and West African countries. The typical presentation of the disease before the 2022 mpox outbreak includes a febrile prodrome 5–13 days post-exposure, accompanied by lymphadenopathy, malaise, headache, and muscle aches. Unexpectedly, during the 2022 outbreak, several cases of atypical presentations of the disease were reported, such as the absence of prodromal symptoms and the presence of genital skin lesions suggestive of sexual transmission. As per the World Health Organization (WHO), as of March 20, 2024, 94,707 cases of mpox were reported worldwide, resulting in 181 deaths (22 in African endemic regions and 159 in non-endemic countries). The United States Centers for Disease Control and Prevention (CDC) reports a total of 32,063 cases (33.85% of total cases globally), with 58 deaths (32.04% of global deaths) due to mpox. Person-to-person transmission of mpox can occur through respiratory droplets and sustained close contact. However, during the 2022 outbreak of mpox, a high incidence of anal and perianal lesions among MSMs indicated sexual transmission of MPV as a major route of transmission. Since MSMs are disproportionately at risk for HIV transmission. In this review, we discusses the risk factors, transmission patterns, pathogenesis, vaccine, and treatment options for mpox among MSM and people living with HIV (PLWH). Furthermore, we provide a brief perspective on the evolution of the MPV in immunocompromised people like PLWH.

1. Introduction

The exact origin of the monkeypox virus (MPV) is yet to be fully understood. However, it is thought to be circulating among wildlife in Central and West Africa [1], and it was proposed that some species of wild squirrels may be the natural host [[2], [3], [4]]. The MPV likely spread to humans through direct contact with infected animals. Hunting, handling, and/or consuming bushmeat may have been associated with humans contracting MPV [5]. MPV can also be transmitted from person-to-person through close contact via respiratory droplets, bodily fluids, or skin lesions of infected individuals [5]. While mpox is primarily endemic to Central and West Africa, sporadic cases and outbreaks have been occurring outside Africa [6]. These cases have been generally associated with travelers returning from endemic regions or importing infected animals. It is important to note that the natural reservoir of the MPV is not defined [7,8]. The exact transmission dynamics and reservoir and/or hosts involved in maintaining and spreading the MPV in nature continue to evolve.

During the 2022 mpox outbreak, most infections were transmitted through close, intimate contact with symptomatic individuals, and male-to-male sexual contact has been a significant transmission mode [[9], [10], [11], [12]]. However, heterosexual transmission, transmission to children through nonsexual skin-to-skin contact with caregivers, needlestick injuries, body piercing, tattooing, and occupational exposures without proper personal protective equipment have also been reported [13,14]. The predominant symptom of MPV infection is skin rashes, often accompanied by anogenital or oropharyngeal/perioral mucosal lesions [15]. Fever, chills, headache, and lymphadenopathy are other commonly reported symptoms among mpox patients. Unlike previous outbreaks, where these symptoms usually preceded skin rashes, up to half of the patients in the current outbreak reported rash as their initial symptom. It has been observed that individuals are infectious from the beginning of the symptoms, and some individuals can transmit the virus before displaying symptoms [16].

Until 1980, vaccination against the variola virus provided approximately 85% protection against mpox [17]. With the discontinuation of vaccination against the variola virus in 1980, a significant portion of the population lacked immunity against variola virus and MPV viruses, rendering them susceptible to MPV infection. Additionally, no specific treatment is available for mpox [18]. During the 2022 outbreak, mucosal transmission through sexual contact emerged as one of the major modes of MPV transmission, other than close contact with pustules or pustular material, which has not been reported in previous outbreaks [10,19]. The mucosal transmission is often linked to recto-genital lesions in men, vaginal lesions in women, and pharyngeal lesions in both genders. Although the mechanism of mucosal transmission of MPV remains poorly understood and requires further investigation, the discovery of these novel transmission routes may have important implications, e.g. the risk of co-infections with HIV and the impact on vaccine responses. In this review, we discuss the role of social stigma associated with men who have sex with men (MSM) in increasing their risk of acquiring infectious diseases, including mpox, the risk factors related to the spread of MPV, the disease pathogenesis of mpox among MSM, as well as currently known prevention and treatment options.

2. Social stigma of MSM: increased risk of infectious diseases including mpox

The term ’stigma’ is used to describe the pervasive presence of negative beliefs, judgments, and biases that individuals or societies hold against specific groups, characteristics, or behaviors [20]. It encompasses the act of labeling and devaluing individuals based on perceived differences or deviations from societal norms. Stigma often leads to discriminatory actions, exclusion, and the marginalization of affected individuals, harming their mental and physical well-being and resulting in social isolation [21]. Stigma can manifest in various contexts, including mental health, race, sexual orientation, gender identity, and other personal attributes [22]. Those who experience stigma commonly perceive themselves as being distinct and undervalued compared to others.

Sexual orientation refers to a lasting pattern of emotional, romantic, and or sexual attraction towards individuals of the same, opposite, or both sexes. Sexual orientation encompasses a spectrum ranging from individuals exclusively attracted to the opposite sex to those attracted solely to the same sex [23]. Sexual orientation is broadly categorized into three main groups: heterosexual, gay/lesbian, and bisexual. These categories of sexual orientation are observed across various cultures globally. It is important to distinguish sexual orientation from other aspects of sex and gender, such as biological sex, gender identity, and social gender roles defined as cultural expectations of feminine and masculine behavior [24]. Thus, sexual orientation is closely connected to intimate relationships that fulfill deep emotional needs for love, affection, and intimacy. In addition to sexual behaviors, these relationships involve nonsexual physical affection, shared values, mutual support, and long-term commitment [25,26]. Various factors have been suggested to contribute to developing an individual's sexual orientation, including genetic, hormonal, developmental, social, and cultural influences [27,28]. It is often believed that nature and nurture play intricate roles in shaping the sexual orientation of an individual [29]. Gender identity and sexual orientation are shaped by a combination of factors at early events of brain development, including hormonal, genetic, and maternal factors [30]. Animal studies have supported the role of hormones and the genetic makeup of a person in shaping sexual orientation [30,31].

Homosexuality has been a subject of societal controversy [32]. It has evoked different attitudes depending on the type of society cultural, moral, and political circumstances from the beginning of the civilization [33]. Even in contemporary society, homosexual behaviors, desires, and identities are often stigmatized and perceived as negative, immature, or inferior compared to heterosexuality, which promotes social exclusion [34]. Social exclusion is a complex set of interconnected processes that emerge from economic, political, and societal factors [34,35]. Over time, these processes create a sense of distance and marginalization, placing individuals, groups, and communities in a position of inferiority compared to a society's dominant values and norms. Homophobia is considered pervasive globally, posing significant threats to the rights of homosexual individuals through discrimination, harassment, and even criminalization of their sexual orientation [36]. This intolerance often extends to interference in their personal lives, perpetuating social exclusion and increasing the risk of discrimination and hate crimes [37]. Insufficient legal safeguards and support from state institutions further compound the issue, impeding the prevention of discrimination and violence based on sexual orientation.

Social and familial expectations often clash with personal preferences among MSM individuals. This conflict can lead to psychological distress, including symptoms of depression and anxiety, and indulge in high-risk sexual behaviors [38]. Due to fear of social exclusion and stigma related to their sexual orientation, MSM individuals exhibit poor health-seeking behaviors, which increases their risk of acquiring sexually transmitted infections (STIs) [39]. The expressions of social exclusion of MSMs were reflected through their ‘conditioned’ support in the family at the cost of giving up their identity or facing expulsion from family ties and property, exclusion from community participation, denial of decent employment opportunities, lack of legal protection and social security system. They are also at an elevated risk of HIV transmission, stemming from the reuse of needles during substance abuse to alleviate mental distress and engaging in unprotected sexual encounters under the influence of substance use within both heterosexual and homosexual relationships [40]. The criminalization of homosexuality, including severe penalties like imprisonment and death, has contributed to the higher rate of high-risk activities and increased prevalence of HIV among MSM individuals [41]. The fear of disclosure and social stigma associated with their sexual behaviors further prevent them from accessing crucial HIV-related testing, treatment, care, and support services, leaving them hidden and marginalized.

Mental health issues are frequently observed among MSM populations at risk for HIV infection [42]. The mental health challenges not only hinder the effectiveness of HIV prevention efforts but also pose challenges to existing conceptual models [43]. Traditional individual-based risk reduction programs, public health campaigns, and community-based interventions may not adequately serve the MSM, who also manage comorbid mental health issues [44]. To escalate the efficacy of the HIV prevention programs, it is crucial to integrate individual-based approaches to address mental health issues that can hinder prevention efforts [45]. Addressing the mental health challenges of at-risk MSM individuals can serve as a foundation for multiple prevention initiatives and empower those most vulnerable to high-risk sexual behaviors and transmitting infectious diseases.

According to the National Survey on Drug Use and Health (NSDUH), an estimated 2.9% of adult men identified as gay or bisexual in the United States in 2019 [46]. The MSM community faces social stigma related to both mpox and HIV infections [[47], [48], [49], [50], [51]]. This stigma can create barriers to accessing healthcare services, proper diagnosis, and availing treatment. Therefore, it is crucial to address and combat this stigma to ensure the well-being of individuals within the MSM community [52]. The risk factors associated with MPV and HIV mono-infection, as well as co-infection among MSM, include engaging in unprotected sexual activities, having multiple sexual partners, and genital or oral mucosal lesions [53]. These factors increase the risk of transmission of both viruses (HIV and MPV) and underscore the importance of comprehensive sexual health education, use of barrier protection during sexual encounters, regular testing for HIV and other STIs, access to pre-exposure prophylaxis (PrEP) for HIV prevention, combinational antiretroviral therapy for PLWH, and access to mpox vaccines. Establishing a nurturing and non-judgmental atmosphere that fosters open dialogue, promotes awareness, and embraces acceptance is crucial for the MSM community to tackle their high-risk behaviors and prevent disease outbreaks within the community [54]. The interconnection between the social exclusion experienced by the MSM community that led to their high-risk sexual encounters, the high prevalence of HIV transmission among the MSM community, and their vulnerability in the 2022 Mpox outbreak is depicted in [Fig. 1].

Fig. 1.

The interlinked between the men who have sex with men (MSM) and the 2022 Mpox outbreak. The sexual orientation of MSM makes them vulnerable to exclusion from contemporary society, which in turn indulges them in frequent participation in saunas, and private or public sex clubs, where intimate and frequently anonymous sexual contact occurs. Along with that in the MSM community, the proportion of people living with HIV is much higher compared to the general population. Therefore, during the 2022 Mpox outbreak, initial introduction of the MPV infection among MSM make the entire community at higher risk of contracting the disease.

3. The consequences of neglecting mpox endemic in sub-Saharan Africa

Following the mass vaccination program against the variola virus, during the 33^rd World Health Assembly in 1980, smallpox was declared eradicated globally [55]. This was followed by WHO's recommendation to end the global vaccination program against the variola virus. As a result, a significant portion of the world's population lacks immune protection against variola virus [56] and closely related poxviruses, including MPV. Without cross-species protection, the lesser-known mpox became endemic in many West and Central African countries, including Cameroon, the Democratic Republic of the Congo, Gabon, Ghana, Ivory Coast, Liberia, Nigeria, Sierra Leone, and South Sudan, among others, with sporadic reports outside of the endemic regions [56,57]. The lack of awareness about mpox due to the geographic confinement of the disease within endemic African countries has resulted in a knowledge gap regarding the transmission mechanism of MPV [58]. Most mpox cases were known to be self-limiting without reports of community transmissions [59]. In the early 1980s, serological investigations were conducted for MPV antibodies on over 10,000 unvaccinated children in Central and West Africa. The surveys revealed that fewer than 1% of the children were positive for the MPV antibody, signifying the rarity of the disease [60]. During subsequent decades, reported mpox cases kept on increasing [61]. Notably, in 1986, for the first time in history, in the Democratic Republic of the Congo, a chain of human-to-human transmission of MPV was reported [62]. Prior to the 2022 outbreak, epidemiological data indicated a higher risk of mpox among unvaccinated individuals, with the cases predominantly among kids and young adults [63]. The severity of mpox cases during the 2022 outbreak has mostly been mild, and the genomic surveillance data indicates the presence of West African clad B1 lineage with mutations in virulence proteins.

Additionally, APOBEC3-mediated GA > AA and TC > TT mutations reported in the genomes of MPV isolates during the 2022 outbreak are hypothesized to be responsible for the attenuated pathogenicity of the virus [[64], [65], [66]]. Future outbreaks might follow different patterns, particularly considering the potential introduction of the more pathogenic Clade I MPV due to ever-increasing intercontinental travel and trade [61]. With the passage of time and lack of attention by global public health watchdogs, mpox, once an endemic in a couple of West and Central African countries, has evolved into a worldwide health emergency [67]. During the 2022 outbreak of mpox, cases of human-to-animal transmission of the MPV were reported [45]; this reverse zoonotic transmission has the potential to expand the natural reservoirs of the virus in the future [68,69]. Unlike the variola virus, it is more challenging to eradicate MPV due to natural zoonotic reservoirs [67]. While cooperation is appreciated, the collaborative clinical research between resource-limited African countries and developed nations was key to the success during the Ebola and Zika epidemics [70,71]. On the contrary, setting up a surveillance program (the “parachute research”) for mpox in DRC in the early 2000s [72], which enabled foreign scientists to gather data and specimens for analysis in their own countries, failed to address the required capacity building for an emergency response to future outbreaks [71,73]. Therefore, efforts should be prioritized to build public health infrastructure in resource-limited African countries and train their front-line responders to address emerging and reemerging viral outbreaks [74].

4. Monkeypox virus (MPV) in human samples and implications for transmission among MSM

The 2022 outbreak of mpox became notable in May 2022, and showed a significant increase in human-to-human transmission, specifically among MSMs [75]. Real-time quantitative polymerase chain reaction (qPCR) is the recommended method of detecting MPV infection [76]. Before the 2022 outbreak, cases reported in Europe and the USA lacked information on the distribution of the MPV in the various organs and tissues in humans as there was no report of fatalities [77,78]. However, during the 2022 outbreak, several studies have detected MPV DNA in anal and oral swabs, semen, and to a lesser extent, urine samples [79]. The concentration of viral DNA has been found to correlate with the amount of replication-competent virus, indicating viral burden, as determined by qPCR being a predictor of infectivity. In a study conducted in France on fifty male (n = 50) patients with confirmed MPV infection, samples were tested from skin, throat, anus, blood, urine, and semen. It was found that a significant proportion of oral and anal swabs were positive for MPV (71–77%), lower proportions of positivity in blood and urine samples (22–31%), and just over half of the semen samples were positive for MPV [79]. The detection of high concentrations of the MPV in the anal region, mouth, and semen aligns with the sexual practices potentially associated with the MPV spread among MSM and skin contact related to sexual or nonsexual proximity.

Following the 2022 outbreak, WHO prioritized research on transmission dynamics, containment strategies, and response measures against mpox [80]. Mathematical modeling studies on MPV transmission were limited and have not adequately considered vaccine efficacy, coverage, and population heterogeneity [81]. A study using mathematical modeling predicted the reproduction number of mpox among MSM at 3.11 globally, 3.57 in Germany, and 3.14 in the UK, respectively [81], which is much higher than the predicted R₀ (less than one) in endemic countries in Africa [17,[82], [83], [84]]. Without public health interventions, the model predicts an exponential increase in the number of new infections in major outbreak pockets in the UK and USA, which is expected to regress with increased public interaction and implementation of a vaccination strategy, especially among high-risk populations. The study also reports that the majority of the current mpox cases among MSM are concentrated in a few pockets of North America and Europe that have lesbian, gay, bisexual, transgender, and queer (LGBTQ+) friendly federal laws and routinely organize pride events, gay sauna, and other gatherings, that have a higher risk of close contacts through anal or genital sexual activity compared to general populations. Another systemic review reports that compartmental, branching process, Monte Carlo (stochastic), agent-based, and network-based modeling techniques were used to study the human-to-human and between-human and animal transmission dynamics of mpox [83]. In the majority of the compartmental models, the following compartments were included: susceptibility (S), exposed (E), infected (I), vaccinated (V), recovered (R), quarantined (Q), and investigate the endemic equilibrium points using a SIR framework [[85], [86], [87]].

The prediction of this model suggests that the conditions for persistence and eradication differ from the deterministic models, which indicates that reproduction number dictates the disease trajectory. In the ‘branching process model’ offspring distributions are utilized to generate a model for the propagation of mpox disease [88,89]. In another study, the Monte Carlo stochastic model was used to simulate the MPV transmission from infected patients to their exposed close contacts by tracking the generation order for successive secondary cases. The study demonstrated that without smallpox vaccination, the frequency of new cases increased but did not reach pandemic levels [84]. These studies highlight the utility of diverse mathematical modeling approaches historically used to study MPV transmission. However, these models' applicability to the 2022 outbreak is limited due to underlying assumptions and data constraints. To address this, new empirical epidemiological studies are needed, accounting for disease complexities and global ramifications.

The 2022 mpox outbreak emphasizes the importance of research focusing on neglected zoonoses and allocating resources to manage and contain emerging diseases worldwide. A recent study on the 2022 outbreak of mpox used a transmission model fitted to actual sexual partnership data using Weibull distributions [90], demonstrating that a heavy-tailed sexual partnership distribution, where a few individuals have significantly more partners, can account for the disproportional higher rate of spread of mpox among MSM. This pattern was not evident in previous outbreaks. These findings indicate that the basic reproduction number (R₀) for mpox within the MSM sexual network might be significantly higher than 1, presenting difficulties in containing outbreaks within these communities compared to the general population. Therefore, targeted support and tailored messaging are essential to enhance prevention and early detection efforts among MSM with multiple partners [89].

5. Risk group for the 2022 mpox outbreak

After the 2022 outbreak, MPV infection in the United States declined significantly. However, the risk of resurgence remains high in most jurisdictions if vaccination efforts are not sustained, as modeling analyses indicate that without continued vaccination of high-risk individuals, the likelihood and size of future mpox outbreaks are expected to increase over time [[91], [92], [93]]. The overall risk of mpox is determined by combining the infection probability with the disease impact on the affected population [94]. During the 2022 outbreak, most diagnosed human mpox cases were observed among MSM within the age group of 21–55 years [95], and the presenting genital lesions indicate a potential transmission during sexual intercourse [96]. While transmission through intact skin contact is less likely, it cannot be completely ruled out. Most cases within interconnected sexual networks among the MSM community might be considered a plausible source for the outbreak's initiation.

5.1. MSM-associated risk

A significant proportion of the MSM population remains at risk of MPV infection. Specific sexual behaviors, such as engaging in multiple casual sexual partners within interconnected sexual networks, attending sexual events during the spring and summer months, and participating in chemsex parties, can further facilitate disease transmission [97]. Mpox transmission thrives in enclosed settings such as back rooms, saunas, and private or public sex clubs, where intimate and frequently anonymous sexual contacts occur. These settings create favorable conditions for the rapid spread of MPV infection [98]. During the 2022 outbreak, most MSM mpox patients did not have a recent travel history to the endemic regions in Central and Western African countries [99], affirming that human-to-human close contact is likely the primary transmission route [96]. While a majority of reported mpox cases among MSMs have been described as mild, the high likelihood of infection results in a moderate overall threat. It is important to emphasize that this moderate risk may be higher for vulnerable groups such as the elderly, PLWH, or those with compromised immune systems [100]. [Fig. 2] describes the percentage of MSM and people living with HIV who reported positive for MPV during the 2022 mpox outbreak.

Fig. 2.

MSM community at higher risk of 2022 Mpox outbreak. (A)The pie chart describes the percentage of MSM reported positive for MPV. Out of the total cases of MPV reported during the 2022 Mpox outbreak, 32.00% were MSM, 6.47% were not MSM, and 61.53% did not disclose their status. (B) The pie chart describes the percentage of people living with HIV (PLWH) who reported positive for MPV. Out of the total cases of MPV reported during the 2022 Mpox outbreak, 20.73% were HIV positive, 18.60% were negative for HIV, and 60.66% did not disclose their status. (Source: https://worldhealthorg.shinyapps.io/mpx_global/accessed on 11-05-2023).

5.2. Risk for the general population

The risk of mpox transmission among the general population has been estimated to be low. Large gatherings increase the risk of MPV infection due to the close and frequent interactions among attendees. The data on the spread and pattern of MPV infection among the general population is limited, which warrants continuous monitoring of new cases globally [101].

5.3. Risk for health care workers (HCWs) and laboratory personnel

Occupational exposure to the MPV is a significant concern as it can persist on surfaces for extended periods [102]. HCWs equipped with proper personal protective equipment (PPE) face a low risk of MPV transmission due to the disease's estimated low impact [103]. Medium risk arises during activities involving contact with a mpox patient's skin lesions or bodily fluids without appropriate PPE [104]. Conversely, unprotected HCWs face high risk if exposed to mpox patients' bodily fluids, inhalation of droplets, or experiencing penetrating sharps injuries. To mitigate mpox risk among HCWs, it is crucial to conduct thorough risk assessments and provide counseling on self-monitoring, timely reporting, and isolation protocols without neglecting the ongoing outbreak response.

Risk among laboratory individuals: The MPV has been classified as an ACDP Category 3 pathogen by the Advisory Committee on Dangerous Pathogens (ACDP) [105]. If the recommended biosafety procedure are followed, the laboratory personnel have a low chance of occupational vulnerability. To ensure safety, each laboratory should conduct site- and activity-specific risk assessments for MPV infections, ensure enhanced safety precautions, and follow the WHO/US-CDC guidelines for specimen collection, handling, shipment, and testing [[106], [107], [108]]. This will require the collaboration of laboratory managers, testing personnel, and occupational health officers at each facility.

5.4. Risk of human-to-animal spillover events

The probability of cross-species spillover of the MPV is influenced by various barriers and bottlenecks, including differences in cellular receptors, immune responses, and other host restriction factors. The risk of MPV transmission from humans to pets is low as the reported cases of reverse zoonosis are limited. While in the USA, the Animal Health Authorities have assessed the risk of human-to-animal spillover of mpox to be very low [109], evidence of human-to-animal transmission of MPV has been reported in France and Brazil during the 2022 outbreak [69,110]. Therefore, monitoring and managing the potential risks associated with human-animal transmission is essential to prevent further transmission and possible disease establishment in wildlife.

6. Pathogenesis of mpox among MSMs

The common and nonspecific symptoms of mpox include fever, swollen lymph nodes, and muscle pain, which start appearing about one to two weeks after getting infected and can be mistaken for seasonal flu or a cold [111]. The immune system is triggered during this stage, leading to the enlargement of inguinal, maxillary, and cervical lymph nodes and the onset of fever [1]. Rashes typically appear in one to three days after the fever and lymph node swelling and follow a centrifugal distribution across the body, suggesting that the rashes appear more prominently on the extremities and face than on the abdomen and trunk [112]. The rash is a crucial feature of mpox and goes through different stages, starting with minor bumps and progressing to vesicles and pustules before finally crusting over [77].

The rashes may sometimes damage the skin, making patients susceptible to secondary opportunistic infections. In rare cases, MPV can cause lung tissue damage and bronchopneumonia, especially in individuals co-infected with the influenza virus [113]. Severe inflammation and bronchopneumonia can make it difficult for patients to breathe and eat. In severe cases, mpox can lead to complications like corneal infection, resulting in scarring and permanent vision loss [114]. During the second week of illness, some patients develop gastrointestinal symptoms like vomiting and diarrhea that can lead to significant dehydration [77]. The accumulation of mutations within the MPV replication complex is predicted to play an important role in the 2022 mpox outbreak [115]. A recent report from the USA showed that during the 2022 outbreak of mpox, patients living with HIV were more prone to experience symptoms like rectal pain and bleeding, tenesmus, pus and blood in stool, and proctitis [15]. This indicates the requirements of close monitoring of PLWH for MPV infection and the development of severe diseases. In addition, the disease pathogenesis of the MPV/HIV co-infected persons needs special attention because the contraction of the body fluids from mpox lesions among MSM makes them more vulnerable to HIV infection. The pathogenesis of MPV/HIV co-infection among MSM is complex and needs to be studied in greater detail using animal models [116]. Additionally, MPV infection can compromise the immune system, making MSM individuals more susceptible to HIV acquisition and worsening the progression of the HIV disease. Furthermore, the presence of HIV can potentially increase the severity of mpox due to the presence of a compromised immune system.

7. Vaccine recommendation for mpox and its efficacy among MSM

JYNNEOS (developed by Bavarian Nordic) is a Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) based vaccine initially developed as a 3^rd generation smallpox vaccine [117] is approved by the FDA against MPV in people aged 18 years and above [91]. To ensure optimal protection against mpox, individuals must receive two doses of the vaccine within four weeks intervel. In animal studies, JYNNEOS demonstrated robust protection against MPV, with most of the animals receiving the vaccines developing sterilizing immunity, effectively preventing the disease without showing any symptoms [118]. As of August 2, 2023, the current guidelines from the CDC recommend vaccination against mpox for individuals who meet the following criteria: (1) if someone has known or suspected exposure to a person with mpox, (2) If someone has had a sex partner diagnosed with mpox within the past two weeks, (3) For gay, bisexual, or men who have sex with men (MSM), as well as transgender, nonbinary, or gender-diverse individuals who, in the past 6 months, have been diagnosed with sexually transmitted diseases (e.g., chlamydia, gonorrhea, or syphilis), or have had more than one sexual partner. (4) If someone has engaged in any of the following within the past 6 months: had sex at a commercial sex venue, such as a sex club or bathhouse, or engaged in sexual activities related to a large commercial event or in an area (city or county) where monkeypox virus (MPV) transmission is occurring, or engaged in sex in exchange for money or other items, or has a sexual partner who belongs to any of the high-risk groups mentioned above, or has HIV or other causes of immune suppression and has had recent or anticipated future risk of monkeypox exposure from any of the scenarios mentioned above, or works in settings where there is a chance of monkeypox exposure, and persons who work with orthopoxviruses in a laboratory [119].

A recent study from Israel included 2054 males who met the eligibility criteria for vaccination. Of these, 1037 individuals (50%) received a single dose of the JYNNEOS (MVA-BN) vaccine during the study recruitment period and completed at least 90-day follow-up, the other 50% served as placebo control. Over the study duration, five infections occurred in vaccinated individuals, whereas 16 infections were confirmed in the unvaccinated group. Utilizing a Cox proportional hazards regression model with time-dependent covariates and accounting for sociodemographic and clinical risk factors, the study reports that the estimated vaccine effectiveness was 86% (95% confidence interval, 59–95%). These findings indicate that a single dose of MVA-BN in a high-risk cohort is significantly associated with a reduced risk of MPV infection [91]. Another case-control study using a nationwide Epic electronic health record (EHR) database (Cosmos) in the USA estimated the efficacy of JYNNEOS during the period from August 15 to November 19, 2022 [120]. Case patients were identified based on having either a diagnosis code for MPV or a positive laboratory result for orthopoxvirus or MPV.

On the other hand, control patients were selected if they had a new diagnosis of HIV infection or a prescription for preexposure prophylaxis against HIV. Out of 2193 case-patients, 25 individuals, and 8319 control patients, 335 received two vaccine doses. The estimated adjusted vaccine effectiveness for complete vaccination in these groups was 66.0%. Additionally, 146 case patients and 1000 control patients received only one dose of the vaccine, with the estimated adjusted vaccine effectiveness calculated at 35.8%. In another case-control study among MSM and transgender adults aged 18–49 years between August 19, 2022–March 31, 2023, the vaccine efficacy (VE) was estimated among a total of 309 case-patients (diagnosis of confirmed or probable MPV or Orthopoxvirus infection, made on or after August 19, 2022) with a matched 608 control patients (patients attended a clinic for sexually transmitted infections (STI), HIV care, or HIV preexposure prophylaxis (PrEP) on or after August 19, 2022) [121]. The adjusted VE was 75.2% for partial vaccination (1 dose) and 85.9% for complete vaccination (2 doses). Among the full vaccination group, the adjusted VE was 70.2% among immunocompromised participants and 87.8% among immunocompetent participants, respectively. Overall, these studies indicate that although the smallpox vaccine comes out to help trim the rapid spread of the current outbreak of Mpox among MSM, this vaccine cannot provide sterilizing protection against the MPV and has blunted efficacy for immune-compromised patients [122]. Additionally, the current vaccines are not available in mpox-endemic countries in Africa, which keeps the possibility of spreading the infection in non-endemic locations.

Meanwhile, caution should be exercised while administering the smallpox vaccines to immunocompromised persons as the live attenuated vaccine may cause severe and potentially life-threatening complications in immunocompromised individuals like PLWH, people undergoing chemotherapy for cancer treatment, and organ transplant patients [123]. Furthermore, considering the likely mucosal transmission of the MPV, mucosal immunity could play a crucial role in establishing long-lasting immune responses. It is unclear whether the available vaccines can effectively generate robust mucosal immunity. The mucosal dendritic cells (DCs) and IgA secretion at the mucosal interface need further investigation to better understand their role in protecting mucosal transmissions. Case reports of mpox in individuals with a history of smallpox vaccination suggest that smallpox vaccines may not provide lifelong immunity against MPV [124]. As a result, booster doses might be necessary, especially for individuals with ongoing exposure risk factors. The optimal timing for booster vaccinations must be determined using pre-clinical animal models.

Additionally, a uniform vaccination approach is required to address the global problem effectively, and it is logical to provide vaccinations on a priority bases to the high-risk groups like MSMs with interconnected social and sexual networks in newly impacted countries. However, the vaccination strategies in endemic regions, like parts of the Africa, may need to focus on populations at the most significant risk of animal exposure. Alongside vaccination, there is an urgent requirement for improved treatments for those affected by the disease. These initiatives should be prioritized alongside traditional infection control and prevention methods to foster trust within the affected communities.

8. Treatment options

In the 2022 outbreak of mpox, the MSM community got a disproportionally higher infection rate than the general population. It is also well known that the prevalence of HIV is higher among MSMs due to several comorbid conditions. Whether HIV is an independent risk factor for acquiring MPV infection remains unknown. However, PLWH with unsuppressed viremia remains at higher risk of developing severe mpox disease if they are infected with MPV [[125], [126], [127]]. In the general population, mpox is self-limiting and only requires symptomatic care to prevent dehydration, and in rare cases antibiotics to prevent/treat secondary bacterial infections [128]. There are no approved antivirals to treat mpox. USA-FDA recommends use of tecovirimat in immunocompromised persons along with brincidofovir, and vaccinia immune globulin intravenous (VIGIV) as required [129]. Tecovirimat, referred to as TPOXX or ST-246, has received FDA approval to treat smallpox in both adults and children [130]. Tecovirimat binds with orthopoxviruses VP37 (a phospholipase protein), and blocks its interaction with cellular Rab9 GTPase and TIP47, essential for creating enveloped virions. Thereby halting the cell-to-cell and long-distance spread of the virus.

A retrospective study reviews the efficacy of tecovirimat for severe mpox among HIV-positive and negative people under the CDC EA-IND protocol. Out of 154 people who received the treatment, 82 were HIV-negative, and 72 were positive for HIV. The overall treatment outcome was similar between the groups [125]. It must be noted that tecovirimat may lower the plasma concentration of rilpivirine, an essential component of CAB/RPV long acting treatment as part of the combinational antiretroviral therapy (cART) for PLWH [131]. Brincidofovir (Lipid-conjugated analog of cidofovir) or cidofovir (inhibits OPXV DNA polymerase) should be added to tecovirimat in critically ill patients or to patients in whom tecovirimat is contraindicated. While prescribing Brincidofovir among PLWH, it should be considered that HIV Protease inhibitors and cobicistat can boost its plasma concentration [131]. VIGIV (vaccinia immune globulin intravenous) is recommended for immunocompromised patients unable to mount desirable immune responses due to HIV infection or solid organ transplant. For patients receiving VIGIV infusion, vaccination with live viruses (varicella, measles, mumps, and rubella) should be deferred for three months [132]. In a comprehensive review, we discussed the use of all EUA-granted drugs against mpox, their limitations in inhibiting viral replication in strains having the signature mutations reported in the 2022 MPV, and the importance of the development of MPV-specific therapeutics for the current and future mpox outbreaks [133].

9. Conclusion

This review sheds light on the complex web of challenges of mpox 2022 outbreak within the context of the MSM community. It underscores the pressing need to address the medical aspects of mpox and the socio-cultural stigma that often surround it. By considering the multifaceted nature of the risk factors and pathogenesis, we have discussed the need to develop more inclusive and effective preventive strategies and personalized treatment interventions for the MSM community. As we navigate the intersection of healthcare and social dynamics among the sexual minorities like MSM, by fostering inclusivity, education, and collaboration of them with general population, we can aspire to a future where stigma is replaced by empathy, risk factors are mitigated through knowledge, and treatment approaches are grounded in a deep understanding of the challenges faced by the MSM community in the context of mpox and any future outbreaks of sexually transmitted diseases.