Commentary

The epidemiology of mpox has undergone profound transition since the global outbreak began in 2022, yet the epidemic is far from over. The largest recorded multi-country outbreaks have demonstrated the extraordinary capacity of mpox for international spread through sexual networks, disproportionately affecting key populations with elevated HIV prevalence and higher risk for severe disease [1-6]. Sustained transmission in Africa and cross-border outbreaks have highlighted the heterogeneity of the epidemic, with some settings experiencing broader community transmission where infants and children are also at risk [2,3,5,6]. Despite important progress in outbreak control, recurrent international spread underscores the need for a coordinated, longer-term approach to prevention and control.

Against this backdrop, the study by Ikoona and colleagues in the Journal of Interventional Epidemiology and Public Health is both timely and important, drawing attention to an overall case fatality of 1.1% in the 2025 Sierra Leone mpox epidemic linked to clade IIb monkeypox virus (MPXV) [7], well above the mortality associated with clade IIb in high income settings [1-6]. Drawing on national surveillance and programme data, the authors demonstrate that higher mpox mortality among people living with HIV was concentrated among those with severe immunosuppression (14-fold higher) and uncontrolled infection (20-fold higher) compared to those with no HIV infection or HIV with viral suppression and preserved immune function. The findings thus further document that HIV infection per se is not the main determinant of poor outcomes, as reported by others for clade IIb [1-3, 5,8] and which remains consistent across contexts and virus clades [2,3,6,8]. Rather, excess mortality in people living with HIV is associated with the consequences of advanced or untreated HIV disease, calling for prompt and effective management of HIV infection in people with mpox. Thus, HIV status remains one important marker of risk for mpox, either due to shared risk factors for exposure or due to higher risk for severe disease or death.

This study also revealed that almost two-thirds of the 60 deaths reported occurred in people without HIV; deaths among the 386 children or 37 pregnant women were not identified. Recent reports have summarized mpox case fatality ratios (CFR) by clade, with global mortality remaining below 1% for clade II, and improving over time for clade Ia (1.7–4%) and clade Ib (0.7%, and 4% in infants) where adequate care is available [2]. Mortality nevertheless remains higher in Africa than elsewhere, regardless of clade [2,3,6,7]. The 1.1% CFR for clade IIb in Sierra Leone was six times higher than the global clade IIb CFR reported over 2022 to 2023 (< 0.2%), although substantially lower than the 7.0% noted in Nigeria (26% in those living with HIV, including children) [5], and the 12 % reported in a smaller outbreak South Africa in 2024 [3], most of whom also had HIV. For comparison, fatality for confirmed clade Ia among hospitalised patients of all ages receiving close clinical monitoring and care in the Democratic Republic of the Congo was 1.7% in historically affected areas, while fatality among suspected cases overall was 2.2%, with higher mortality in young children [2,6]. Conversely, a CFR of up to 0.3% (largely for clade Ib) was seen among mostly adults in newly affected areas [3].

Mortality related to clade Ib has also varied substantially among African countries, ranging in 2024 from no reported deaths in several to 1% in Uganda, 3.2% in Kenya, 3.3% in the Central African Republic (clades Ia and Ib). A CFR of 22% was reported in Cameroon (clades I and II) [3], and a 2026 clade Ib outbreak in Pakistan saw seven infant deaths in a month, linked to transmission in health facilities. Beyond these two settings, no death due to clade Ib has been reported among travel-associated or locally acquired cases [3]. Since January 2025, recorded all-clade CFR has been approximately 0.46% in the WHO African region, compared with 0.17% elsewhere (21 mpox deaths of 12 533 confirmed cases) [3]. Such variation highlights the difficulty of attributing causes of mpox deaths to context- or clade-related factors.

Interpretation of these differences is also constrained by major gaps in surveillance and case-based data in several regions [3]. In Africa, individual case-based data are available for only 1% of cases and, with the exception of the Democratic Republic of the Congo, reported data at global level only capture confirmed cases and deaths [3]. Differences in mortality therefore reflect a combination of case ascertainment, access to diagnosis and care, individual factors including age, comorbidities, modes of transmission and other epidemiological and contextual factors, in addition to any viral strain features. Strengthening surveillance, laboratory capacity, community awareness and tailored clinical care remains critical to improving patient outcomes in all settings. Ikoona and colleagues therefore provide welcome new data on one important determinant of mpox mortality: uncontrolled HIV infection and severe immunosuppression.

The importance of the study extends beyond its epidemiological findings, however. With a multi-pronged strategy, in addition to broader community-based vaccination, Sierra Leone vaccinated over two-thirds (71%) of anti-retroviral therapy clinic enrollees in seven of 16 districts within six weeks of beginning vaccination, reaching almost a fifth of the estimated number of persons living with HIV in the country through this integrated strategy. The study authors achieved linkage of HIV status for nearly 90% of the country’s 5,442 confirmed mpox cases, 73 % with a national unique health identifier and 17% through person-place-and-time matching. This represents a remarkable accomplishment, even belatedly in the course of a large outbreak, and showed that HIV prevalence was 8.7% in people with mpox. Too often, emergency responses generate parallel information systems that fail to communicate with one another. Instead, this report demonstrates how close coordination between emergency management structures, disease programmes and clinical health services, laboratories, and health information systems can produce actionable intelligence during an evolving epidemic.

The implications for research are substantial. First, the findings add to a growing body of evidence from African and other settings that HIV-associated immunosuppression is a major risk factor for severe mpox disease and death [5,8]. They reinforce the need to better understand the interaction between mpox, immune dysfunction, and access to antiretroviral therapy. Reducing mpox mortality among people living with HIV depends not only on the management of mpox itself but also on ensuring timely HIV diagnosis, access to effective antiretroviral treatment, viral suppression, and immune restoration [ 5,6,9]. With respect to the virulence of monkeypox virus clades, while laboratory studies demonstrate higher virulence of clade I over clade II, disentangling this effect from contextual factors and the populations affected in the real world is much more complex. In practice, outbreak setting, underlying conditions in affected individuals, and access to care may have a greater influence on mortality than viral virulence alone, as illustrated by the markedly higher mortality in a small sub-group of people in this and other studies. For greater public health impact, in addition to seeking to understand viral virulence as virus strains evolve, research should also identify and assess interventions to prevent outbreaks, reduce transmission and avert severe outcomes.

Second, the Sierra Leone experience illustrates the value of using routine health service data during outbreaks to identify people at risk and offer preventive interventions. The ability to link surveillance, laboratory, vaccination, and HIV programme data creates opportunities to answer critical operational questions: Which populations are at highest risk? How can services be tailored for them? How were children affected during this outbreak? Which interventions are most effective in preventing severe disease? What is the contribution of vaccination to reducing transmission and mortality? Generating answers to these questions during an outbreak is itself an important research and preparedness function, essential not only for the ongoing global epidemic but also for preparedness against future outbreaks.

The public health implications of this study are thus equally important. The findings underscore the importance of early action to tailor the response to the local context [9] and provide a strong argument for integrating health services for mpox, HIV, and sexually transmitted infections (STIs). Individuals presenting with suspected or confirmed mpox should be offered HIV testing, and when HIV infection is known or confirmed, rapid referral for assessment of immune status and viral suppression and for appropriate care [10]. Conversely, people receiving HIV or STI services should be assessed for their risk of mpox and offered prevention interventions, including vaccination with available third-generation mpox vaccines [11].  Although this study is retrospective, the offer of vaccination directly in antiretroviral therapy clinics and analysis of clinical outcomes in this setting illustrate how a good understanding of risk can support implementation of relevant interventions during an outbreak.

Integration should also extend beyond health care settings. The epidemiology of recent outbreaks indicates that many individuals at risk can be reached through sexual health clinics and antiretroviral treatment centres, but also through community venues and networks, such as bars, nightclubs or saunas, and at events attended by populations at risk. Prevention services can be brought to the places where people are most likely to benefit from them. Some countries have demonstrated innovative delivery models such as ‘pop-up‘ or ‘moonlight’ vaccination, which offer mpox vaccination through community outreach or at night to facilitate access and acceptance among populations at risk.

Vaccination remains a cornerstone of prevention. The Sierra Leone experience reinforces the importance of pre-exposure vaccination of people at risk before exposure occurs. Current data support the effectiveness of available and widely used mpox vaccines, MVA-BN and LC16m8, although important knowledge gaps remain, particularly for immunocompromised populations [11-14]. To facilitate rapid uptake of mpox vaccines for outbreak response, countries should initiate policy and regulatory preparedness based on current guidance [11, 14]. Going forward, individuals who received a single dose of a two-dose vaccine during the outbreak response should be offered the second dose at the earliest opportunity to complete the recommended immunization schedule. Whether additional doses or booster strategies are required for some people living with HIV remains uncertain and merits further investigation.

The study also responds directly to priorities identified in recent calls for a sustained global response to mpox [15]. It demonstrates the feasibility and value of integrated services; highlights the need to identify and protect populations experiencing disproportionate risk; and illustrates how strengthened surveillance and health information systems can support both emergency response and longer-term control efforts. However, these achievements require investment. The linkage of datasets described by the authors depended upon resources, planning, and collaboration that may not be available in every setting. Preparedness plans should therefore include provisions for interoperable information systems, unique patient identifiers where feasible, and mechanisms for rapid analytical capacity during emergencies.

Many questions remain unanswered. The causes of death among individuals without HIV, who represented two-thirds of mpox-linked deaths in this outbreak, require further study, and the experience of children and pregnant women with mpox should be documented. The contribution of vaccination to reduction of disease severity and interruption of transmission during the latter stages of the Sierra Leone outbreak warrants formal analysis. Continued surveillance and data collection are needed to monitor evolving patterns of risk, modes of transmission, and the changing epidemiology of mpox across different settings and virus clades. Further evaluation of vaccine effectiveness and duration of protection of MVA-BN and LC16m8 vaccines, particularly in populations at higher risk, is needed, together with a better understanding of the contribution of indirect (herd) immunity to outbreak dynamics.

Perhaps the most important lesson from Sierra Leone is that mpox can no longer be approached solely as an episodic emergency. With 145 countries having confirmed mpox outbreaks in four years, each month still brings a new national report of a first case of mpox [3]. At the same time, viral genome sequencing continues to reveal circulation of monkeypox virus in animal species in parts of Africa where mpox has been emerging for decades, highlighting the potential for frequent spillover when humans interact with reservoir species [16]. Thus, the persistence of zoonotic and human-to-human transmission of mpox in Africa and continuing international spread demand a longer-term strategy to manage ongoing risk, protect vulnerable populations and eliminate mpox as a public health problem through a One Health approach. Such a strategy should mobilize national and local stakeholders according to the local context; integrate mpox, HIV and STI services and clinical care; strengthen surveillance and data systems; prioritize pre-exposure vaccination of populations at risk; ensure respectful engagement with affected communities and locally relevant risk communication; and embed research in the response to generate actionable new data during an outbreak.