Mpox Clades Show Divergent Spread and Severity

New research highlights critical genetic distinctions driving global public health concerns

The mpox virus (MPXV) continues to be a significant global health challenge, with recent outbreaks highlighting the distinct characteristics of its various clades. The World Health Organization has declared public health emergencies for international concern, reflecting the virus’s persistent and evolving threat.

Clade IIb’s Global Surge vs. Clade I’s Endemic Threat

MPXV, the cause of mpox, has spread globally due to factors including reduced population immunity following the cessation of smallpox vaccinations. The virus circulates in endemic regions primarily through zoonotic spillover, but efficient human-to-human transmission, particularly via sexual contact, fueled a major global outbreak from May 2022 to August 2024, affecting over 100,000 people in 115 countries.

Historically, MPXV has been classified into two main clades: Clade I, predominantly found in Central Africa, and Clade II, prevalent in West Africa. Clade II further divides into subclades IIa and IIb. The 2022 global outbreak was largely driven by Clade IIb, which had been dormant for decades until a significant resurgence in Nigeria in 2017. This lineage has demonstrated a faster mutation rate, possibly influenced by the human immune system’s APOBEC3 proteins, which can introduce genetic changes indicative of sustained human-to-human transmission.

In contrast, Clade I MPXV has remained largely confined to endemic countries such as the Democratic Republic of the Congo (DRC), the Republic of Congo, Gabon, Cameroon, and the Central African Republic. However, the DRC has seen a substantial increase in suspected Clade I mpox cases and deaths since 2022, with a notable surge in 2024. This clade has historically been associated with higher fatality rates, particularly in children under 15.

Emergence of Clade Ib and Shifting Transmission Dynamics

A significant development has been the identification of Clade Ib MPXV in the DRC, first noted in the South Kivu province in late 2023. This subclade is genetically distinct from other Clade I sequences in the DRC and has spread both within the country and internationally, with cases reported in countries that had not previously experienced mpox. Genetic analysis of Clade Ib reveals a large genomic deletion, including the loss of the complement control protein (CCP) gene, which researchers hypothesize may contribute to reduced virulence compared to Clade Ia.

Clade Ib outbreaks appear to be driven by increased sexual transmission, including among female sex trade workers. While Clade Ia MPXV in the DRC shows higher genetic diversity and fewer APOBEC3-induced mutations, suggesting less pervasive human-to-human spread, Clade Ib exhibits low genetic diversity coupled with a high abundance of these mutations, indicating recent and sustained transmission. For instance, in late 2023, South Kivu reported an outbreak primarily linked to sexual contact. Later, Clade Ib MPXV was identified there, distinct from other DRC Clade I sequences.

The impact of the CCP gene deletion on virulence remains a subject of study. Animal models have yielded mixed results, with some suggesting a link to decreased illness and death, while others indicate that this deletion alone may not fully explain the differential pathogenicity between clades. Further research is ongoing to clarify the role of the CCP gene and other mutations in Clade Ib’s characteristics.

Vaccines and Therapeutics Offer Protection

Despite clade differences, current smallpox and mpox vaccines, including the nonreplicating MVA-BN (JYNNEOS), are expected to provide cross-protection against all MPXV clades due to the high genetic similarity among orthopoxviruses. Over 1.2 million doses of MVA-BN have been administered in the US with minimal breakthrough cases reported, and those cases generally showed milder disease. Several African nations have also extended the use of MVA-BN to combat Clade I mpox.

Regarding treatment, the antiviral drug tecovirimat is a primary intervention in the US for mpox. However, research indicates it may not improve mpox resolution for either Clade I or Clade IIb infections, and prolonged use can lead to resistant viruses. More studies are urgently needed to evaluate alternative drugs, earlier treatment initiation, and combination therapies, especially given the ongoing spread and the need for effective treatments against all circulating clades.

Mpox, an ancient disease, is re-emerging globally due to declining population immunity, international travel, increased human-animal contact, and extensive sexual networks. The current surge in Clade I cases in the DRC and the spread of the newly identified Clade Ib underscore the urgent need for sustained international assistance to control both lineages in Africa and prevent future outbreaks. Genomic surveillance remains critical for monitoring ongoing mpox activity worldwide.