Sexual transmission-linked clade Ib MPXV in the DRC: The global spread risk

Introduction The monkeypox (mpox) caused by the MPXV virus is endemic to the dense forest of the east, the west and the central Africa, predominately prevailing in the northern and central Democratic Republic of the Congo (DRC). The DRC has reportedly registered more than 27 000 mpox cases between January 2023 and August 2024, with more than 1,300 deaths [1]. The number of cases could be higher than the reported, assumed to be due to a relatively weak surveillance system prevailing in the country. The total reported cases was 15 664 with 548 deaths in 2024 beginning[2], constantly being reported across 22 out of the 26 provinces (85% of the geographic spread) of the DRC [3]. With increasing number of freshly reported mpox cases, the number of provinces affected has expanded. The two known MPXV clades are Clade I of the Congo basin and Clade II of West Africa, while Clade II has two subclades, Clade IIa and Clade IIb. Clade I exhibits greater disease severity than Clade II. Although mpox case was almost nonexistent outside the African continent before 2018, Clade IIb has become globally infectious since 2022 with increased number of reported cases elsewhere too[4]. Such spread to even outside Africa was primarily attributed to sexual transmission among the gay, multi-sex partners and the transgenders[4,5]. Amusingly, the DRC had not reported Clade IIb MPXV-linked mpox cases in the outbreak as MPXV Clade I was only detected. A new variant of Clade I MPXV (Clade Ib) was reported recently in the DRC[1]. It suggests that the virus adapted with human circulation/transmission. Health authorities reported first Clade Ib outbreak in Kamituga town of DRC in October 2023[6]. As Kamituga is a mining town and has international reach, it bears the risk of catalyzing the spread due to cross-border movement for mining activities. It is a prime reason behind the risk of the epidemic spreading from the DRC to the neighboring countries. Discussion Current Clade Ib mpox DRC outbreak is more widespread compared to earlier outbreaks. It spread to some neighboring countries like the Central African Republic, Burundi, Uganda, Rwanda, Kenya, Zambia and Zimbabwe. Of these, the two most affected countries other than DRC are Burundi and Uganda where transmission was active. Clade Ib cases reported outside Africa were in Sweden, Thailand, India, the USA, Canada, the UK, Pakistan, Germany, Belgium, China and France (Fig. 1). The index cases in these had travelled either to Africa or the United Arab Emirates. Some reported cases were also among family contacts and/or close contacts of the index cases. After spreading from the DRC to neighboring countries, the spread reached Europe. As the novel virulent mpox strain rapidly spread to other African countries, the WHO once again declared it as a public health emergency of international concern (PHEIC). The DRC outbreak was triggered by the cocirculating Clade Ia and Ib strains, as per GISAID’s mpox surveillance data (Fig. 1). The circulating diverse MPXV variants was notably observed at a smaller scale in the affected provinces, while it was not observed in South Kivu province wherein genome analyses showed a single Clade Ib lineage[7]. Sexual contact was observed as the prime reason of community transmission during the 2022 multi-country mpox outbreak by Clade IIb[4]. Subclades Ia and Ib could reportedly spread sexually. As children cases were more than 50%, the novel variant is more worrying and threatening[2], yet its etiology is not fully known. Clade I was more critical compared to Clade II as it caused severe sickness including death. African countries South Africa and Côte d’Ivoire reported multiple Clade II recently.Figure 1.: Phylodynamics of Clade I, showing 391 of 758 genomes collected between Jan 2016 and Jan 2025 updated on 11-02-2025 last; (a) geographical data; (b) phylogeny of collected Clade 1a and 1b (https://gisaid.Org/mpox-phylogeny/mpox-clade-i/). Diagnostic tests are challenging due to altered viral gene. Novel Clade Ib exhibited specific amino acid changes in key viral proteins that interacted with host, impacting its virulence and transmission. The key genetic differences of Clade Ib to other Clades are deletion in OPG032 gene and higher mutation rate of APOBEC3[8-12]. The deleted OPG032 gene which is not seen in other Clades is a unique marker for Clade Ib. It could influence the pathogenicity (virulence profile) of Clade Ib. Higher mutation rate of APOBEC3 in Clade Ib could potentially impact transmissibility (more efficient spreading) and severity (distinct disease presentation). Due to higher genetic diversity compared to other Clades, Clade Ib could potentially evolve and adapt further. Research on Clade Ib remains limited and further studies are recommended. Diagnostic assays to differentiate and identify Clade Ib accurately from others need updates. Understanding gene variation shall help design effective vaccines against emerging novel variants. Coordinated international response efforts on surveillance, diagnosis, treatment and data analyses are needed to identify hotspots and reservoirs for more effective intervention. While no sexually-transmitted Clade I occurred till April 2023[3,13], it was first reported as sexually transmitted when a Belgian tested positive for the same when he visited Kwango province in the DRC, and experienced anal itching and discomfiture the same day of arrival in Kinshasa[13]. The infection was suggested to have originated outside the DRC (maybe in Belgium), as mpox usually incubated for more than a day to manifest symptoms. Genetic analysis of the samples confirmed Clade I strain similar to the ones circulating in the DRC. The Belgian visited the discretely operating men’s club and indulged in gay sex with multiple partners. Lesions on his anus and genitals grew into painful blisters, and he further developed skin lesions on trunk and buttocks. RT-PCR genome sequencing at the National Institute of Biomedical Research, Kinshasa confirmed Clade I infection. Contact tracing and monitoring was carried out for mpox signs and symptoms in several identified sexual and non-sexual contacts that he had. The contacts among the DRC population that indulged in sex with the subject also tested Clade I positive, with closely related sequences. With six (one female and five males) confirmed cases with no associated death, the infection was the first Clade I-linked MPXV sexual transmission report[13]. Mpox infection cases among the sex workers in the DRC were primarily reported as zoonotically transmitted. The transmission dynamics of Clade I in the DRC is unclear, possibly due to the lack of access to prompt diagnostics, difficulties in linking confirmed case with the source, and hazy epidemiological and contact-tracing over the years. The new findings of sexual and unknown modes of transmission raise concerns even as the outbreak in the DRC continues to rapidly expand. Soon after the first report in April 2023, a male from Kenge town, DRC who had gay sex was confirmed as MPXV infected on 28 July 2023[13]. Notably, he was not among the listed contacts of the infected April 2023 cohort. Unconventional sexual promiscuity is allegedly common in numerous DRC clubs, and the club members also visit other similar clubs far-and-wide in Central Africa and Europe too. With two confirmed 2023 cases, one in April and the other in July, sexual promiscuity hints at a possible risk of global spread of Clade I as was witnessed in the 2022-23 global mpox cases involving Clade II. Although Clade I community outbreak regularly occurs in Cameroon, Central Africa and the DRC (and sporadically in Sudan and South Sudan), human transmission of Clade IIb was observed in most of the WHO-confirmed regions of the outbreak[14]. Non-human primates are also medically considered as mpox susceptible. While squirrel and monkey (small mammals) are rarely linked to outbreak, the natural MPXV reservoir is yet to be ascertained. Animal studies in several DRC provinces are being carried out to characterize the ecology and potential animal reservoir or incidental host, with extension of such studies to other provinces. Eco-epidemiological research collaboration to ascertain the reservoir and host in association with national and international partners may be useful on this. The cases from fresh geographic regions in Kinshasa, Lualaba, and South Kivu suggest its transmission potential. Sporadic cases with suspected infection were identified in travelers to Kinshasa, Lualaba, and South Kivu, thereby triggering the transmission. Suspected human-human transmission in the DRC clearly illustrates an evolving pattern of mpox epidemiology. A hospitalized TB (tuberculosis) patient acquired mpox, as a suspected nosocomial transmission case. Some DRC provinces like South Kivu face food insecurity and challenged with inadequate humanitarian assistance due to civil unrest displacing human settlements. It could increase the vulnerability in local population and may facilitate further spread. Freshly-hit eastern and southern DRC hints at an increasing geographic spread of mpox. It was expected that the pregnant, children and the immunocompromised were susceptible, leading to deaths. As the symptoms overlapped with diseases like scabies, herpes, measles, bacterial dermal infections, chickenpox and medication-associated allergies, mpox diagnosis was challenging. The chances of mpox patients being infected with sexually-transmitted diseases like herpes are relatively high, so also mpox-chickenpox coinfection risk. Regular and rigorous testing to ensure that a patient is treated promptly is essential to prevent disease complication. A standard recommended laboratory mpox testing is detecting the viral DNA through PCR in the skin swab, fluid or the rash crust sample. Earlier used as a safe smallpox preventive, vaccinia vaccine is also effective against mpox. Third-generation smallpox vaccine (like LC16-KMB vaccine) is available as safer alternative now. The LC16-KMB vaccine was licensed in 2022 alongside the earlier approved MVA-BN against MPXV. Due to a similar antigen makeup in both, smallpox vaccine provided 66-90% protection against mpox. Mpox vaccination of susceptible population like children and close contacts with the infected is advised. Smallpox and mpox vaccination drives were stalled (or at least largely compromised with) across many countries during the recent global pandemic. Clinical study to reposition the popular antiviral tecovirimat against mpox is underway in two hospitals in Maniema and Sankuru DRC provinces[3,7]. A request was submitted to national health authority to obtain tecovirimat into the DRC. Other recommended measures to counter MPXV are, increasing the nationwide surveillance, seamless supply of sample collection and transport kits, and logistical support for sample analysis at reference hospitals, increasing the monitoring capacity of facility providers, medical and paramedical professionals, identifying potential transmission routes including sexual, and contact tracing[15]. Suspected samples could also be genetically sequenced to confirm and identify the circulating strain(s). The DRC appears to have little awareness of mpox-associated risks according to WHO. One with especially mpox-related disfigured skin may face social stigma issues. Mechanisms to transmit healthcare messages targeted especially at the gay in the country are nonexistent because of which vulnerability could be high. It is possible that the transmission chain of recently confirmed sexual-transmitted mpox by Clade I MPXV might have been overlooked (or possibly downplayed) earlier. Other concerns that hinder national response capacities worth mentioning include the lack of epidemiological data on the risk factors and infection exposure, prioritisation conflict, low mpox awareness and related hazards among the general and critical population[3]. Identifying the extended risk groups of human population is recommended. Raising awareness about mpox alongside other STDs among especially sexually-active population (with a focus on sex club patrons) in the DRC is suggested. Assisting with reporting and promoting seamless communication among health officials and target community through call centers is also suggested. Pre-empting the verified sexually-transmitted Clade I MPXV and the global mpox outbreak that may be underway is vital for the health agencies and health professionals. MPXV Clade I may raise the possibility of serious illness. Handling stigmatized cases sensitively and data comprehension on human-human transmission within communities is a critical step forward toward the “One Health” strategy especially among the potential mammalian host or reservoir population of the virus. Expanding awareness on the contextual links in MPXV and HIV and their independent and shared risk factors is essential to extend case-specific health solutions. Integrating surveillance and case management in a more robust and flexible healthcare set-up is crucial to tailor-make the solutions as per patient needs. Communicating the associated risks of sexually-transmitted mpox especially among the high-risk population and the affected households need to be strengthened. Supporting, informing and engaging community leaders to implement necessary measures to inform and engage the community on mpox and preventing its spread must be advocated at all levels. It is recommended that nations follow the August 2023 standing recommendations of the Director General of the WHO which explicitly recommended mpox epidemiology surveillance, augmenting laboratory diagnostic capability including genome sequencing, community engagement and risk communication, ensuring vaccine availability, Pre-emptive case management, perpetual support to develop rapid diagnostic techniques and patient-centric interventions. Educating the population with high risk and advocating adoption of appropriate protection practices, risk communication and community engagement initiatives especially targeting health professional, gay, sex workers, people working at or attending the places and events of sexual promiscuity, and other population at high risk (like, ill- or inadequately treated HIV) are essential. Socio-behavioral data may be gathered and situation analysis done to decipher the transmission mechanism and the risk factors. Such data may help in enhancing decision-making and guarantee a need-based response system for the community, priority-based empowerment, providing guidelines to create risk communication strategies and evidence-based community involvement initiatives. Alliances among reliable networks supporting the cause may be forged for community engagement. A two-way feedback system emphasizing on effective measures to comprehend, prevent and resist any discrimination and the attached social stigma may be ensured as these hinder and seriously compromise the response system and adversely affect the outcome. Infection prevention and control measures in public places and healthcare setup are advised. It is crucial to promptly isolate confirmed cases in hospitals, provide protective equipment and hand-washing stations, ensure high-standard hygiene practices especially at the entry or control points in hospitals, and train the staff on the nosocomial infection associated risks and the contamination. Health professionals may use “contact,” “standard,” and “droplet” precautions while handling suspected/confirmed mpox cases to protect themselves taking care that patient is not intimidated, while the patient and the family received the needed emotional support. Conclusion Due to rising Clade 1b cases, its increasing geographic spread and severity on children below five years, urgent public health measures in the DRC and other affected contiguous countries need to be implemented. International collaboration for targeted vaccination programme with equitable access to vaccine especially for the vulnerable groups like children are essential as a committed step towards transmission reduction. Beyond public health measures as discussed, further research to extend our understandings about this novel MPXV strain is also necessary that could ensure the implementation of targeted and effective interventions to reduce the disease burden.

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