Introduction

The declaration of smallpox eradication in 1980 remains one of the most important public health achievements in history. However, following the cessation of the global smallpox vaccination program there has been a continual increase of an immune-naive population resulting in a steadily increasing mpox risk, particularly in endemic areas1,2,3. Comparisons of mpox incidence in health zones with active mpox surveillance in Democratic Republic of the Congo (DRC) showed an increase from 0.48 cases per 10,000 individuals per year from 1981–1986 up to 11.25 per 10,000 per year in 2006–2007, with the greatest burden of disease among younger age groups born after smallpox vaccine cessation. More recent national level analysis of mpox incidence has shown a continuing of this trend with increasing annual incidence from 2.96 per 100,000 individuals to 11.5 per 100,000 individuals from 2010 to 20234,5. These observations provided a stark warning for the broader global health risk posed by mpox, more than a decade prior to the first public health emergency of international concern (PHEIC) declarations for mpox in 2022.

Monkeypox virus (MPXV), the etiologic agent of mpox, is an emerging zoonotic virus that is divided into two genetically distinct clades: Clade I, endemic in regions of Central Africa, and Clade II, endemic in regions of West Africa. Legacy understandings of mpox epidemiology are that Clade II confers a less severe disease with a case fatality rate (CFR) between <1–6%, compared to Clade I which has been associated with more severe disease progression, higher viremia, and up to a 10% CFR6,7,8,9,10. Since the 2022 global mpox outbreak began, genomic epidemiology of MPXV has improved. Clade II has been divided into two subclades: Clade IIa associated with spread via zoonotic transmission, and Clade IIb, initially described during the 2022 global outbreak with probable emergence in July 2014 in Nigeria accompanied by cryptic transmission in humans until detection in September 2017 with the re-emergence of mpox in the country8,11,12. In September 2023 an outbreak of Clade I mpox associated with human-to-human circulation among sexual networks was reported in South Kivu province, DRC, and genomic analysis of these early cases identified a novel subclade, Clade Ib, associated with more sustained human-to-human transmission13,14. In 2023, there were 14,626 suspected mpox cases in DRC and thus far in 2024 case counts have more than doubles with 30,766 suspected mpox cases reported from January 29–September 202415. This has included rapid geographic expansion of Clade Ia within DRC as well as increasing incidence of Clade Ib16,17 which has also included introduction to neighboring countries including Rwanda, Uganda, Kenya, and most notably Burundi18. Transcontinental spread of Clade Ib has also been reported with travel-associated cases identified in Sweden, Thailand, and India15. As a result, the Africa CDC issued its first public health emergency of continental security declaration, while the World Health Organization (WHO) declared the second PHEIC for mpox19,20,21. This rapid expansion of case counts and geographic distribution has led to the implementation of the first vaccination campaigns on the African continent and regional discussions on disease control and case management in DRC and Nigeria22. Thus, this is an opportune time to reflect on the factors complicating the epidemiology of mpox in Central Africa and discuss the current pressing need for comprehensive and long-lasting mpox control across endemic regions.

Considerations for Clade I mpox virulence and social determinants of health

The DRC, the epicenter of multiple concurrent and numerous historical Clade I mpox outbreaks struggles with high childhood mortality, limited healthcare resources, poor civic infrastructure, and high endemicity of infectious diseases. These factors coalesce into a high health burden for the population. Additionally, the DRC is one of the world’s largest and most biodiverse nations and contains hundreds of different ethnic groups and languages. Many communities across the DRC live at the nexus of human, animal, and environmental health creating complicated and interwoven epidemiologic exposures. Previous research in these rural communities found that exposure to wild animals was nearly ubiquitous across community members23. When discussing the virulence and disease severity of Clade I, these overlapping and confounding factors greatly impact the observed epidemiology of mpox in the DRC. Mpox cases in this region have historically been driven by zoonotic transmission occurring in rural areas with the highest morbidity and mortality being recorded among young children. A longitudinal analysis of mpox epidemiological trends in DRC found that in 2023 suspected cases were highest among children <5 years (35.6% of cases) followed by those 5–15 years (30.4%) with the same trends in CFRs—6.0% for children <5 years and 4.2% for those 5–15 years5. Children are particularly vulnerable to mpox infections due do their high contact rates and younger population dynamics of this region. However, health metrics show that rural children in the DRC have very high childhood mortality and morbidity, and suffer from under-vaccination, comorbidities, and nutritional deficits, all which impact disease immunity and resilience. Estimated Clade I mpox disease dynamics are inherently confounded by the underlying health of the population.

Considerations for the context dependency of Clade I mpox fatality rates

Assessing the case fatality rate for Clade I mpox has been similarly confounded. While disease surveillance and reporting systems have improved greatly in recent years, there has likely been an under-reporting of mpox cases, including mild or subclinical, that have not resulted in hospitalization and/or severe outcomes. This underreporting of true infection rates has likely led to inflated case fatality rates in some areas. For example, Clade I CFR have historically ranged from 1–10% with variations across studies and populations. Recent epidemiological analysis has highlighted the differences found across age groups and estimated an overall CFR of 2.9%. In contrast, mpox case data in Kole, DRC, from 2007–2011 had an associated CFR of 1.4%24. More recently, data from suspected Clade I mpox cases in DRC from 2023 and 2024 result in CFRs of 4.5% and 3.4%, respectively15. Resource limitations have also had critical impacts on mpox surveillance and diagnostic testing which has limited rapid confirmation of suspected mpox cases and contact tracing activities, particularly in rural locations. Taken together, it is important to improve disease reporting structures and consider the impacts of confounding variables such as age, region, and underlying health status when considering mpox CFRs; however, epidemiological data largely suggest that Clade I mpox CFRs typically range from 1–4.5%. The identification of sexual contact-based transmission of Clade I mpox and emergence of Clade Ib further complicates this as atypical disease presentation and could confound the diagnosis of suspected mpox based on clinical presentation alone. Further, historic stigma faced by key populations has likely also impacted health-seeking behaviors, including for mpox. Serologic studies can be a useful tool to retroactively estimate the reporting gap of mpox infections.

Considerations for the role of healthcare access in mpox outcomes

Additionally, limited healthcare resources—poor facilities, staff shortages, supply stockouts, limited electricity—have resulted in suboptimal standards of care for many areas in the DRC, particularly rural areas where mpox cases have been high. Many fatal cases of mpox have been due to subsequent skin infections, pneumonia, immune suppression, malnutrition, or comorbidities and could very well have been preventable in higher resource contexts. Indeed, during the introduction of Clade IIb into high-resource nations, the overall case fatality rate associated with Clade II dropped to below 1% as a significantly greater proportion of cases experienced high standards of care and low comorbidities. This contrasted starkly with data from Nigeria following the re-emergence of Clade II mpox in 2017 where CFRs have ranged from 3–6%6,25. Recent observations from clinical trial data for Tecovirimat (TPOXX) in DRC demonstrated that the provision of supportive care alone resulted in reduced mortality among individuals with severe mpox26.

Considerations for mpox vaccine deployment in DRC

Currently, swift action is needed in response to the growing case counts in Central Africa. The lag in emergency vaccination introduction into African countries represents a significant health justice issue, and mpox vaccines are urgently needed in endemic nations the most. However, vaccination with the modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine as well the future delivery of the LC-16 vaccine27 are not silver-bullet solutions. Coupled with vaccine introduction, more impactful public health communication and education and investments into improving the standard of care in the DRC are needed to effectively address the current outbreak and build resilience against future mpox spread.

Widespread vaccination campaigns in the DRC face many challenges owing to the large and difficult-to-navigate terrain, limited available funding for staff and essential resources, and substandard census records. Indeed, the routine immunization system in DRC faces many challenges in executing population-wide childhood vaccination including ongoing outbreaks of vaccine-preventable diseases (VPDs) such as polio, measles, and yellow fever; emergency COVID-19 vaccination faced similar challenges28. Assessment of supplemental immunization campaigns, deployed in response to cases of VPDs, have found that vaccine distribution repeatedly misses rural and logistically challenging areas. A ring vaccination strategy was deployed in response to multiple Ebola virus disease outbreaks in the DRC between 2019–2024 and while this strategy was able to effectively reduce Ebola virus spread, it’s reliance on resource-intense contact tracing, and logistical issues regarding maintaining cold chain while in remote locations hinders the applicability of ring vaccination to larger outbreaks29,30,31.

Additionally, current immunogenicity studies have found that while the MVA-BN vaccine confers a strong antibody response immediately after the 2-dose series, IgG antibodies are observed to decline 1-year post-vaccination32. These durability studies highlight the need for further investigations to address correlations between IgG titers and protective immunity. In a context like the DRC, a vaccine-only solution will not be sufficient. Reaching adequate vaccine coverage has been an enduring challenge in this region and the current MVA-BN series recommendations require two doses 28-days apart, requiring vaccination teams to overcome these logistical challenges and financially support vaccine campaigns twice. Using a dynamic transmission model, Savinkina et al. demonstrated that targeted vaccination campaigns among provinces historically endemic for mpox in DRC with 80% coverage of children ≤15 years could reduce cases and deaths by 59% and 57%, respectively33. Importantly, this would require 40.7 million doses of MVA-BN vaccine. This does not factor in additional considerations for the costs associated with procurement of tens of millions of doses of MVA-BN vaccine nor the manufacturing time associated with this magnitude of required doses. Furthermore, while the MVA-BN vaccine was recently approved for children aged 12–1734, recent epidemiological analysis demonstrates that 66% of mpox cases in the DRC in 2023 were found in children ≤15 years with morbidity and mortality highest among those <5 years of age5. For an mpox vaccine to have a high impact in the DRC it must be authorized and accessible for all age groups. While safety and immunogenicity studies are planned for MVA-BN among children from 2 to <12 years, results from these studies will take time to be accrued35.

Conclusions

Previously held understandings of the epidemiology of mpox are being currently upended as this massive, multisource cluster of concurrent mpox outbreaks continues. Both Clade Ia and Ib are circulating, and public health response has found evidence of multiple different transmission modes, multiple high-risk populations, and multiple geographies for both clades16,33,36,37. Health officials need to urgently address at-risk communities about mpox risk, and the protective measures individuals can take to protect themselves from infection. However, as the epidemiologic lines continue to blur, response efforts become necessarily more complex and crafting a clear and actionable public health message becomes more difficult. This must include rapid analysis and reporting from ongoing data collections across the affected communities, provinces, and countries as well as targeted community engagement and education activities that include direct linkages and partnerships with community advocacy groups and leaders.

A high-impact and lasting response strategy is urgently needed to contain this growing regional mpox outbreak and prevent future outbreaks. In Europe and US, much of the success of the emergency mpox response came from two factors: (1) the relatively straight forward epidemiology of the outbreak–cases were sensitive and specific to the men who have sex with men (MSM) community; and (2) the organization and outreach of lesbian, gay, bisexual, transgender and queer (LGBTQ) networks to their own communities which resulted in rapid uptake of the vaccine and behavior modification. In the DRC, current transmission dynamics do not point to one clearly defined at-risk group; cases have been identified among urban and rural communities, young children and adults, MSM populations, sex workers, and other community members.

In many low- and middle-income countries, systemic poverty-related conditions such as limited basic infrastructure like passable roads and reliable electricity, decades of poor healthcare investments, substandard health education, and limited public health capacity play an important role in the emergence of infectious disease epidemics, the success of containment efforts, and the impact they have on the morbidity and mortality of the population. Improvements to these poverty-related factors will lead to increased standards of care and reduce the morbidity and mortality associated with infectious diseases. While vaccination is efficacious, in a complex landscape like the DRC, achieving vaccine coverage rates high enough to interrupt transmission is exceedingly challenging. Support towards crafting a multi-pronged constellation approach which utilizes vaccination, health education, effective risk communication, public health capacity building, and sustainable healthcare investments is essential as we work towards long-term solutions for emerging infectious diseases in this high-consequence region. Further, while there is an inherent need for mpox containment and mitigation given the current PHEIC, it must also be appreciated that enhanced investment in areas including healthcare access, infrastructure, and surveillance would provide increased preparedness and response activities that extend beyond this public health emergency.