Monkeypox: Newly recognized sexual transmission - A comprehensive and detailed review

Mpox transmission before 2022

Before the recent outbreaks, the epidemiology of mpox was relatively stable and well-characterized. Most of the infections occurred in rural or forested regions of Africa, with human cases typically traced back to direct or indirect contact with infected wild animals. Transmission mechanisms included handling or hunting wild rodents and other small mammals, which serve as natural reservoirs; consuming undercooked or raw meat from infected animals, a common practice in some regions; contact with animal blood, body fluids, or open sores during butchering or food preparation; and animal bites or scratches, allowing the virus direct entry through broken skin, which were the primary routes of transmission.^[4] While secondary, human-to-human transmission was possible, although it was relatively rare and inefficient. It most often occurred among household contacts or caregivers and relied on extended contact with contaminated clothing, bedding, or linens from an infected person, inhalation of respiratory droplets during prolonged close interactions, such as living in the same household, direct non-sexual skin-to-skin contact with infectious lesions or scabs, and handling of lesion material during the care of sick individuals [Figure 1].^[5]

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Figure 1: Mpox transmission.

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While secondary, human-to-human transmission was possible, it was relatively rare and inefficient. It most often occurred among household contacts or caregivers, and relied on:^[5]

• Extended contact with contaminated clothing, bedding, or linens from an infected person.

• Inhalation of respiratory droplets during prolonged close interactions, such as living in the same household.

• Direct non-sexual skin-to-skin contact with infectious lesions or scabs.

• Handling of lesion material during the care of sick individuals.

These patterns meant that outbreaks rarely spread widely among humans and were usually self-limited, often dying out before reaching large urban populations or crossing international borders.

The 2022 outbreak: Everything changed

The 2022 outbreak upended this established narrative. Instead of being confined to people with a history of animal exposure or residence in endemic regions, the majority of new cases arose among individuals with no such risk factors. The virus rapidly propagated within interconnected sexual networks, especially among MSM. The clinical features of these cases were also distinct: patients often presented with genital, anal, or oral lesions, mucosal ulcers, and proctitis, as well as lymphadenopathy in the groin. These symptoms pointed to direct inoculation through mucosal surfaces during sexual activity, rather than casual skin contact or respiratory exposure.^[6]

Epidemiological investigations revealed that the outbreak was sustained through high-frequency sexual contacts, often among individuals with multiple partners or connections to large sexual events. Traditional public health tools, such as contact tracing, became more complex, as sexual networks present unique challenges for identifying and notifying exposed individuals. The clustering of cases within these networks, along with the predominance of mucosal and genital disease, left little doubt that mpox was now behaving as a sexually transmitted pathogen.^[6]

Why did mpox start spreading sexually?

The factors driving this shift are multifaceted and involve both viral and human elements. On the viral side, recent genomic analyses have identified an accumulation of single-nucleotide mutations in circulating mpox strains, particularly those involved in the 2022 outbreak. Some scientists hypothesize that these mutations may have enhanced the virus’s capacity for human-to-human transmission or increased its affinity for mucosal tissues, facilitating direct transmission during sex. While the full implications of these mutations remain under investigation, they point to a virus that is actively adapting to new ecological niches.^[7]

On the human side, sexual behavior itself creates ideal conditions for viral spread. Sexual encounters often involve prolonged, close skin-to-skin contact, direct exposure of mucous membranes, and microtraumas that allow viruses to breach natural barriers. In addition, changes in sexual networks, such as increased numbers of partners, use of dating apps, and large gatherings, can accelerate the spread of infections once they enter these communities. Social and behavioral factors, including stigma, access to healthcare, and public health messaging, further influence the trajectory of outbreaks.^[8]

The intersection of these biological and social factors enabled mpox to exploit new transmission pathways, transforming it from a rare zoonosis into a sexually transmissible infection with global reach. This evolution highlights the dynamic nature of infectious diseases and underscores the need for adaptable public health strategies, updated clinical guidelines, and ongoing research to anticipate and respond to emerging threats. The mpox experience also offers important lessons for sexual health: it illustrates how pathogens can leap ecological boundaries and adapt to new transmission routes, demanding vigilance and flexibility from clinicians, public health authorities, and affected communities alike.^[9]

Viral presence in genital tissues

Research has demonstrated that the mpox virus is capable of establishing itself in a wide range of tissues intimately involved in sexual activity. Swabs and samples have repeatedly detected viral DNA and, in some cases, infectious virus in lesions found on the penis, scrotum, vulva, and labia, as well as the anal and rectal mucosa. Additionally, viral genetic material has been identified in bodily fluids such as semen and vaginal secretions, and even in saliva when oral lesions are present. These findings suggest that not only are visible sores a source of the virus, but also that fluid exchanged during sex can serve as reservoirs, allowing transmission even in the absence of obvious lesions. The widespread distribution of the virus in areas directly involved in sexual contact greatly increases the opportunities for exposure and infection.^[10-12]

Mucosal vulnerability during sexual activity

The mucosal linings of the genitals, anus, and mouth are naturally thin, delicate, and richly supplied with blood vessels. Unlike the tougher outer skin, these inner surfaces are specifically designed to facilitate absorption and exchange, making them less resistant to injury. During sex, friction and mechanical action frequently cause microtears or abrasions, tiny injuries that often go unnoticed but are enough to open the door for pathogens. The mpox virus takes advantage of these small breaches to penetrate the body. Moreover, the mucosa is densely populated with immune cells, such as dendritic cells and Langerhans cells, which are intended to protect against infection but can also be hijacked by the virus as entry points. Once inside, the virus can quickly access the bloodstream or local lymphatic system, making the process of infection more efficient. The combination of mucosal fragility, frequent micro-injuries during intercourse, and the strategic presence of susceptible cells dramatically heightens the risk of sexual transmission.^[13]

Genital, anal, and peri-anal lesions as transmission hotspots

Lesions that develop in the genital, anal, and surrounding areas are particularly significant in the spread of mpox. These sores, ranging from flat red spots to raised blisters or pustules, are not only a visible sign of infection but also act as concentrated sources of the virus. Studies show that the fluid within these lesions can contain extraordinarily high concentrations of viral particles, making them especially infectious. When a sexual partner comes into direct contact with these lesions, either through skin-to-skin or mucosa-to-mucosa interaction, the likelihood of transmitting the virus increases dramatically. Even if the lesions are small or partially healed, they may continue to shed virus for some time, posing a risk throughout much of the illness. This makes intimate contact with active lesions one of the most efficient routes for mpox transmission and highlights why outbreaks have been so closely linked to sexual networks.^[14]

Semen: Transmission vehicle or residual biomarker?

Detection of mpox viral DNA in semen has raised important questions about the potential for semen to serve as a vehicle for transmission. In several cases, viral genetic material has been found in semen samples even after the visible symptoms of mpox have resolved, suggesting that the virus or its remnants may persist for weeks. However, it remains under investigation whether the virus found in semen is actually infectious or if its presence merely reflects contamination from adjacent mucosal lesions in the genital tract. Some evidence points to the possibility that live virus can indeed be present in semen, potentially allowing for transmission through ejaculate alone. This uncertainty complicates recommendations for sexual health and disease prevention, as it raises the possibility that individuals may remain capable of spreading the virus even after apparent recovery. The persistence of viral DNA in semen underscores the need for further research to clarify the risks and to guide recommendations regarding condom use, abstinence, and the duration of sexual precautions following mpox infection [Figure 2].^[15]

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Figure 2: Sexual transmission of mpox.

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Predominantly genital manifestations

Unlike the widespread, generalized rash seen in traditional mpox, the sexually transmitted version overwhelmingly targets the genital and nearby regions. Most of the patients present with localized symptoms, often coming to medical attention because of discomfort or visible lesions in their genital area. Common findings include:^[16]

• Blisters or vesicles on the penis or scrotum, sometimes clustered or solitary.

• Ulcers that develop around the foreskin or glans penis may be mistaken for other sexually transmitted ulcers.^[16]

• For women, similar ulcerations can appear on the vulva, labia, or even inside the vagina.

• Painful, pus-filled pustules are scattered in the pubic region or perineum.

• Swollen inguinal (groin) lymph nodes, which can be tender and sometimes mistaken for other conditions such as herpes or syphilis.^[16]

These localized lesions are usually few in number, often just one to three, and are sometimes the first and only sign of infection. In many cases, these sores appear before any systemic symptoms, making them the earliest clue for clinicians.

Perianal and anal symptoms

A particularly distinctive aspect of sexually transmitted mpox is its tendency to cause pronounced symptoms around the anus and rectum. These perianal and anal manifestations can be severe and are a hallmark of sexual transmission, especially among individuals engaging in receptive anal sex. Patients may report:^[17,18]

• Painful, shallow, or deep ulcers around the anal margin

• Bleeding or blood-streaked anal discharge

• Severe rectal pain that can be constant or worsen during bowel movements

• Tenesmus - an urgent, distressing feeling of needing to pass stool, often with little result

• Anal discharge that is mucous-like or purulent, raising concern for bacterial proctitis

• Significant discomfort when sitting, sometimes necessitating medical attention.

Proctoscopy or anoscopy, when performed, may reveal:

• Ulcerations or erosions on the rectal mucosa

• Edema (swelling) and marked redness

• Fragile mucosa that bleeds easily.

The clinical picture can mimic other causes of infectious proctitis, such as those due to gonorrhea, chlamydia (Lymphogranuloma venereum [LGV]), or herpes, posing diagnostic challenges.^[17,18]

Oral and oropharyngeal lesions (following oral sex)

In individuals exposed through oral sexual practices, mpox can manifest in the mouth and throat. These presentations include:

• Painful ulcers or erosions on the lips, tongue, or buccal mucosa

• Lesions or exudate on the tonsils, sometimes accompanied by inflammation

• Sore throat and odynophagia (painful swallowing)

• Swollen cervical lymph nodes, which can be tender and prominent.

These symptoms can easily be mistaken for more common infections such as bacterial tonsillitis, oral herpes, or even infectious mononucleosis, underscoring the importance of considering mpox in the differential diagnosis for at-risk populations.^[19,20]

Systemic symptoms

While classic mpox often caused dramatic, whole-body symptoms, the sexually transmitted form tends to provoke milder, less pronounced general illness. Still, some patients do experience:

• Low-grade fever, sometimes preceding local lesions by a few days.

• Myalgia (muscle aches) and fatigue.

• Chills and malaise.

• Headache or generalized discomfort.

These symptoms may appear before, during, or after the onset of genital or anal lesions. In some cases, individuals may not recall any systemic symptoms at all, contributing to under-recognition of the infection.^[21]

Mild, subclinical, or hidden infections

One of the most concerning aspects of sexually transmitted mpox is the frequency of mild or even asymptomatic infections. Some people may have:

• A single inconspicuous lesion, which may go unnoticed or be dismissed as an ingrown hair or pimple.

• No fever or other general symptoms.

• No rash on the face, trunk, or limbs, making it easy to miss.

• Anal or rectal infection is detectable only by polymerase chain reaction (PCR) testing, with no visible external signs.

These subtle presentations can fuel the silent spread of the virus, as individuals may not seek testing or medical care, thereby unknowingly transmitting mpox to sexual partners.^[22]

Confusion with other STIs

The clinical overlap between mpox and other common STIs is considerable. Genital and anal lesions caused by mpox may be clinically indistinguishable from those associated with herpes simplex virus (HSV), primary or secondary syphilis, chancroid, lymphogranuloma venereum (LGV), molluscum contagiosum, and human papillomavirus (HPV). Because these conditions present with similar genital manifestations, mpox may be misdiagnosed, particularly when clinicians empirically treat for more common STIs such as herpes or syphilis without considering mpox or obtaining a comprehensive sexual history. Delayed or missed diagnosis can result in ongoing transmission within sexual networks, complicating outbreak detection and control.^[23]

Laboratory testing

Co-infections

A significant proportion of individuals diagnosed with mpox are also found to have concurrent STIs. Common co-infections include HIV, which may increase the severity and prolong the course of the disease, as well as gonorrhea and chlamydia, particularly affecting the rectum and pharynx. Syphilis is another frequently reported co-infection that can complicate the clinical presentation, while hepatitis B and hepatitis C may also be present, especially in populations with a higher prevalence of these infections. Therefore, all patients with suspected or confirmed mpox should undergo comprehensive screening for STIs. Early identification and treatment of co-existing infections are essential for appropriate patient management, reducing complications, and ensuring complete and effective care.

Mpox as an emerging sexually transmissible infection

The epidemiology of mpox has changed considerably in recent outbreaks, with sexual and intimate contact emerging as an important route of transmission. Although mpox is not exclusively a sexually transmitted infection, it can spread readily through close skin-to-skin and mucosal contact during sexual activity. The frequent occurrence of lesions around the genital, anal, and oral areas has further highlighted the role of sexual contact in transmission. In addition, the clustering of cases within interconnected sexual networks and at venues where people meet for sexual activity has contributed to the rapid spread of the infection. These developments emphasize the need to incorporate mpox awareness, testing, counseling, and preventive measures into existing sexual and reproductive health services.^[26]

Populations at increased risk

Recent outbreaks have affected certain populations more heavily than others. Gay, bisexual, and other men who have sex with men (MSM) have represented a major proportion of cases in several outbreaks, particularly within closely connected sexual networks. People who have multiple sexual partners or frequently establish new sexual contacts may also have a greater chance of exposure. Sex workers and their clients can face additional challenges because of repeated close contact and difficulties associated with partner notification. Individuals living with HIV may be at increased risk of severe or atypical disease, particularly when immune function is compromised. Exposure may also occur among people attending sex-on-premises venues or sex parties and among those using digital platforms to arrange new sexual contacts. International travel and sexual activity while abroad can further facilitate the introduction of mpox into new communities. For these groups, respectful and targeted health education, accessible testing, early diagnosis, and appropriate prevention strategies are essential for reducing transmission.^[27]

Addressing stigma and promoting equitable care

Stigma is an important obstacle to effective mpox prevention and control. Fear of being judged or discriminated against may discourage people from seeking testing or medical care when symptoms develop. Stigma can also make it difficult for individuals to discuss their sexual history openly with healthcare professionals or to inform recent sexual partners about possible exposure. A non-judgmental and confidential approach to care is therefore essential. Public health messages should focus on accurate information and practical prevention rather than associating mpox with a particular sexual identity or community. Ensuring that testing, treatment, vaccination, counseling, and partner-notification services are accessible to everyone can help reduce both transmission and the social barriers surrounding the infection.

Effective public health strategies must focus on behaviors and exposures, not identity or orientation. Messaging should emphasize that anyone can contract mpox through sexual contact, and that seeking help is an important, responsible act. Community engagement and culturally competent care are vital to building trust, encouraging disclosure, and ultimately curbing the spread of mpox.^[28]

Antiviral therapy

Tecovirimat (TPOXX) remains the frontline antiviral for treating mpox, especially in cases where the disease presents with severe symptoms, a widespread rash, or when the patient’s immune system is compromised due to underlying conditions such as HIV, cancer, or immunosuppressive therapies. TPOXX works by blocking the virus’s ability to exit infected cells, thereby halting its spread within the body. This targeted mechanism not only helps alleviate symptoms more rapidly but also reduces the overall duration of illness and lowers the risk of complications such as severe skin damage, bacterial superinfections, or even systemic involvement in vulnerable patients. In clinical experience, patients on TPOXX often report a quicker resolution of lesions and a less intense course of acute symptoms, which can also help limit further transmission, especially in community or household settings.^[29]

Alternative antivirals, such as brincidofovir and cidofovir, serve as secondary options. These are generally considered only when TPOXX cannot be used, due to allergy, unavailability, or if the virus shows signs of resistance, or for patients who develop life-threatening complications, particularly those with severely weakened immune defenses. Both brincidofovir and cidofovir act by interfering with viral DNA synthesis, thus inhibiting viral replication. However, these medications carry a higher risk of adverse effects, most notably kidney toxicity and gastrointestinal issues, which require careful monitoring. The decision to use these drugs involves a nuanced risk–benefit analysis, with close attention to pre-existing health problems and regular follow-up to detect early signs of toxicity.^[29]

Supportive care remains a foundational element in mpox management. This encompasses symptom relief through analgesics for pain, antipyretics for fever, and ensuring adequate hydration to support recovery. In cases where secondary bacterial infections are suspected, particularly if skin lesions become red, swollen, or pus-filled, antibiotics may be prescribed. Specific symptom management, such as topical treatments for proctitis (inflammation of the rectum), can offer significant comfort and prevent further complications. Psychological support and counseling may also be warranted due to the stigma and stress associated with mpox, especially in communities where the disease is less understood.^[29]

Vaccination

Vaccination is a critical tool in both the prevention of mpox and in limiting outbreaks. Two main vaccines are currently available:

1. Modified Vaccinia Ankara (MVA) - Bavarian Nordic (marketed as JYNNEOS, Imvanex, or Imvamune): This vaccine uses a non-replicating MVN virus. Because it cannot multiply in the human body, it is considered safe even for people with weakened immune systems, pregnant individuals, and those with certain skin conditions such as eczema. It can be administered as pre-exposure prophylaxis for people at increased risk, such as MSM in areas with active transmission, healthcare workers, and laboratory personnel handling orthopoxviruses. Post-exposure vaccination is also effective if given within four days of exposure, substantially reducing the likelihood of developing symptoms or, if symptoms occur, leading to a milder course^[30-32]

2. ACAM2000: This vaccine contains a live, replicating vaccinia virus, which provides robust immunity but carries more risks, including the potential for severe side effects in immunocompromised individuals, pregnant women, and people with chronic skin conditions. For these reasons, ACAM2000 is not the preferred choice for mass immunization and is generally reserved for specific high-risk occupational groups after careful screening.^[30-32]

Targeted vaccination strategies focus on those at greatest risk, maximizing community benefit while minimizing unnecessary exposure to vaccine-related side effects. As we learn more about mpox transmission, expanding vaccination to additional vulnerable populations might become necessary, particularly if new outbreaks occur or if the virus’s behavior changes.^[30-32]

Behavioral prevention strategies

Preventive behaviors remain essential in curbing the spread of mpox, both during outbreaks and in endemic regions. Key strategies include:

Avoiding any form of sexual contact, including oral, vaginal, or anal sex, with individuals who have visible lesions or symptoms suggestive of mpox. Lesions may be subtle or located in less visible areas, such as the genitals or perianal region, so vigilance and open communication with partners are important.^[30-32]

Using condoms can help reduce, but not eliminate, the risk of transmission, as the virus may be present on skin not covered by condoms or on contaminated surfaces.

Reducing the number of sexual partners, especially during periods of increased community transmission, decreases the overall risk of exposure and helps break chains of transmission.

Avoiding the sharing of linens, towels, clothing, and personal items with someone known or suspected to have mpox, as the virus can survive on fabrics and surfaces for extended periods.

Performing regular self-examinations for new or unusual genital, anal, or skin symptoms and seeking prompt medical evaluation if suspicious lesions or systemic symptoms develop.

Community education and public health campaigns emphasizing these practices are vital, particularly in populations with higher exposure risk, to foster safer behaviors and reduce stigma associated with the disease.^[30-32]

Understanding asymptomatic viral shedding

A significant area of ongoing research involves clarifying the extent and implications of asymptomatic viral shedding in mpox. While it is established that mpox viral DNA can persist in genital, anal, and sometimes oropharyngeal tissues for weeks after clinical recovery, the infectiousness of this residual viral material remains uncertain. Current evidence suggests that the presence of viral DNA does not always equate to the presence of live, transmissible virus, but the risk of ongoing transmission, particularly through sexual contact, cannot be fully ruled out.^[31,32]

A critical public health question is whether individuals who appear fully recovered and have no visible lesions can still transmit mpox to sexual partners or household contacts. The potential for silent or subclinical transmission is particularly concerning within sexual networks where close and frequent contact occurs. Addressing this knowledge gap will require large, longitudinal studies that track viral shedding dynamics, correlate molecular findings with culture-based assessments of viral viability, and monitor transmission events among contacts.

Improved understanding of asymptomatic shedding will inform guidelines on the optimal duration of isolation and abstinence from intimate contact after recovery. It may also spur the development of more sensitive and specific diagnostic tools capable of distinguishing between infectious and non-infectious viral material. Ultimately, resolving these questions will be pivotal in refining strategies for outbreak containment, contact tracing, and safe reintegration of recovered individuals into their communities.^[31,32]

Viral evolution

The evolution of the current circulating mpox strain, clade IIb, is another area of active investigation. This clade has shown increased adaptability to humans, with evidence of faster mutation rates compared to previously circulating strains. Such changes may enhance the virus’s ability to spread within human populations, potentially leading to larger outbreaks or shifts in clinical presentation. Continuous genomic surveillance is critical, both to detect emergent variants with altered transmissibility or virulence and to anticipate any changes that might affect vaccine effectiveness or antiviral susceptibility.^[31,32]

There is also concern that, as mpox becomes more established in human populations, it could acquire additional adaptations that facilitate more efficient person-to-person transmission, possibly through sexual routes or even through respiratory droplets in certain settings. Ongoing research must remain vigilant for signs of increased severity, changes in age or risk group distribution, and any evidence of vaccine escape.

Clinical protocol integration

As mpox increasingly presents with symptoms resembling other STIs, such as proctitis, genital ulcers, or systemic rash, it is essential to integrate mpox into standard clinical algorithms for STI management. This includes adding mpox testing to diagnostic panels for patients presenting with compatible symptoms, updating guidelines for the evaluation and treatment of genital ulcers and proctitis, and ensuring that high-risk individuals are routinely screened during outbreaks.^[32]

Such integration will facilitate earlier diagnosis, more appropriate treatment, and more effective public health interventions, including contact tracing and targeted vaccination. It will also help destigmatize mpox by framing it within the broader context of infectious disease management, reducing barriers to care, and encouraging affected individuals to seek timely medical attention.^[32]

Monitoring for drug resistance

With increased use of TPOXX as the primary antiviral therapy for mpox, there is a pressing need for robust surveillance systems to detect the emergence of drug-resistant viral strains. Resistance could arise through selective pressure as more patients receive treatment, particularly if the virus is allowed to circulate widely or if therapy is used improperly. Early identification of resistance patterns will be crucial for informing treatment guidelines and for the development of next-generation antivirals with different mechanisms of action.^[32]

Investing in laboratory infrastructure for rapid resistance testing, fostering international data-sharing, and supporting research into novel therapeutics are all key components of a proactive approach to resistance management. By anticipating and preparing for the eventuality of drug-resistant mpox, the medical and public health communities can safeguard the effectiveness of existing treatments and maintain control over future outbreaks.^[32]