Community Circulation of Clade Ib Mpox Outside of Africa—Are We Prepared?

Mpox is a spectrum of disease caused by monkeypox virus (MPXV), which is divided into clades I and II (with subclades Ia/Ib and IIa/IIb).¹ In 2022, simultaneous detection of non-travel-associated mpox cases in multiple countries was the initial sign that clade IIb was circulating in non-endemic areas, primarily via sexual networks among gay, bisexual, and other men who have sex with men (MSM). Subsequently the World Health Organization (WHO) declared a Public Health Emergency of International Concern (PHEIC). The following year, a new MPXV lineage—clade Ib—emerged in the Democratic Republic of the Congo (DRC) and spread into neighboring countries, leading to a second PHEIC being declared.² A recent decline in cases led the WHO to end the clade Ib mpox PHEIC on September 5^th, 2025. Regardless, clade Ib mpox has remained a global threat, continuing to spread with more than 40,000 cases reported in Africa and multiple travel-associated cases, including seven in the United States (U.S).³

On October 10^th 2025, the first case of clade Ib mpox occurring outside of Africa with no linkage to travel was reported in Spain.⁴ This was followed by three non-travel-associated clade Ib mpox cases reported in Los Angeles, California.⁵ Additional locally acquired cases have been reported in the Netherlands, Portugal, Italy, and Malaysia.⁶ This signals a shift in the epidemiology of clade Ib mpox, which is reminiscent of how the 2022–2023 clade IIb mpox epidemic began, raising questions about the risk of clade Ib mpox and our preparedness (Table). To assess the risk of clade Ib, we can compare its characteristics with clade IIb, which spread rapidly across the globe but was controlled by behavioral and medical interventions.

Table.

Urgent Questions for Clade Ib Mpox

Theme	Question	Actionable Steps
Epidemiology	What is the current community-level spread of clade Ib?	Upscaling of clade-specific wastewater surveillance
	Will clade Ib spread in heterosexual networks and household settings, as it has in Africa?	Epidemiological studies & contact tracing
Transmission	Does clade Ib spread more efficiently than clade IIb, or by additional modes of spread?	Epidemiological studies & contact tracing
	How much shedding of clade Ib occurs pre-symptomatically, or before appearance of distinctive mpox symptoms?	Prospective cohort studies with serial sampling
Pathogenesis	What is the pathogenicity of clade Ib, and how does it depend on route of exposure?	Clinical studies, in vitro and animal models
	What is the spectrum of clinical phenotypes for clade Ib vs clade IIb?	Detailed clinical case series
Immunity	How does prior infection with clade IIb affect probability and severity of clade Ib infection?	Observational studies of cohorts with prior infection
	How effective is MVA-BN vaccination against clade Ib, and how durable is this protection?	Observational studies of vaccine effectiveness
Diagnostics & Therapeutics	Can clade-specific diagnostic testing be made available and accessible?	Diagnostic availability assessment; improved sub-lineage diagnostics
	Are available antivirals and other therapeutics effective against clade Ib? Would post-exposure use increase their effectiveness?	Clinical studies, in vitro and animal models

The efficiency and route of human-to-human transmission of clade Ib will influence its spread and our ability to contain potential community transmission. While clade IIb was mostly confined to MSM sexual networks, clade Ib in Africa spread largely via heterosexual contact, among people with multiple sexual partners, including sex workers. Additionally, a higher proportion of clade Ib MPXV infections were among children, indicating likely secondary household transmission.⁷ A crucial question is how clade Ib’s higher incidence in children in Africa will translate to other settings, i.e. how much is secondary community transmission driven by virus phenotype vs anthropogenic factors, such as transmission via heterosexual vs MSM contact. Another question is how transmission will be affected by differences in African vs Western household structure, comorbidities, and healthcare.

During the clade IIb mpox epidemic, the modified vaccinia virus Ankara-Bavarian Nordic (MVA-BN) vaccine was found to be effective, with two-doses providing superior effectiveness.¹ Post-exposure prophylaxis (PEP) using these vaccines was also found to be effective, although to a lesser degree and data are limited.¹ There have been no published clinical studies of vaccine effectiveness for clade Ib. Additionally, it is unknown how durable immunity is from previous vaccination or natural infection and whether waning or partial immunity increases the risk of asymptomatic shedding. A case series found cases of clade IIb occurring less than one year after prior infection or two-dose MVA-BN vaccination, and vaccine booster doses may be required.⁸ It is estimated that only 23% of the population at risk for clade IIb mpox in the U.S were fully vaccinated (primarily MSM).⁹ Thus, it is uncertain how existing vaccination status and prior infection will influence the community spread of clade Ib.

Rapid diagnosis of mpox is important for patient isolation and preventing chains of transmission. Patients may present with a variety of symptoms and interact with many different parts of the healthcare system. Clinicians must recognize the spectrum of disease manifestations and think about clade-specific testing. Clade IIb-specific polymerase chain reaction (PCR) testing, which became available during the 2022–2023 PHEIC, will not detect clade Ib and mutations can affect clade-specific tests. Thus, laboratories need to first conduct generic orthopox/MPXV testing, and a positive orthopox/MPXV test but negative clade IIb result should directly prompt testing for clade Ib. At present, clade Ib-specific testing may need to be done at regional public health laboratories, which could delay time to diagnosis. Increasing laboratory capacity for clade Ib (as well as developing diagnostics that work across clades and at point-of-care) will be important for timely diagnosis and supportive care.

Wastewater surveillance is a critical tool to track cryptic MPXV circulation in a community. Sequencing-based MPXV wastewater monitoring should be considered an essential sentinel surveillance tool that allows us to track and trace all current clades of MPXV and potential evolutionary adaptations of concern. The co-circulation of clade Ib and clade IIb in a specific subset of the global population could increase the risk of recombination between viruses of different clades, potentially resulting in new phenotypes. A potential recombination event between clade Ib and IIb was recently detected in traveler returning to England, furthering this concern.¹⁰

Overall, the emergence and current co-circulation of clade Ia, Ib, and clade IIb in Africa, and recent spread of clade Ib mpox in the U.S, Europe, and Asia is a reminder that emerging infectious diseases are global issues that require timely coordinated response. The disproportionate burden of mpox in African countries despite effective vaccines highlights how equitable access and international investment are critical to stopping outbreaks at their origins—not only from an equity perspective, but also from economic and health security standpoints. The global spread of clade IIb and Ib should also be recognized as sentinel events, highlighting essential gaps in pandemic preparedness.