Mpox: a dangerous game of clades and vaccine inequity

The monkeypox virus (MPXV) was discovered in 1958, following two outbreaks of a pox-like disease in colonies of monkeys kept for research purposes. Despite the name “monkeypox,” the true source of the disease remains unknown. Many scientists suspect that African rodents and non-human primates may carry the virus and transmit it to humans. The first human case of mpox was reported in 1970 in what is now known as the Democratic Republic of the Congo (DRC). In 2022, mpox spread globally, whereas previous cases outside endemic regions were rare and typically linked to travel or the importation of animals from areas where the virus is endemic. 

Mpox transmission occurs through direct or close contact with an infected human or animal and through contact with contaminated materials.

There are two types of MPXV: Clade I and Clade II.

There are two types of MPXV: Clade I and Clade II, with their respective subclades.

Clade I Is endemic to Central Africa. Causes more severe illness and has a higher mortality rate.

Clade Ia:

• Endemic in DRC / Central and East Africa
• Affects mostly children, various modes of spreading.

Clade IIb (September 2023):

• Current outbreak in /around DRC
• Affects mostly adults
• Spread predominantly by intimal contact (sexual networks), less by other routes.

Clade II Is endemic to West Africa and is responsible for the global outbreak that began in 2022 (subclade 2a).

Clade IIa:

• Endemic in West Africa for decades
• Low incidence
• Various transmission routes like clade 1a.

Clade IIb:

• Originated in 2022/2023 global outbreak
• >96% men, primarily sexual contact

The clades of the monkeypox virus (MPXV) differ in infection fatality rates (IFR). Clade I (Congo Basin and Nigeria) has an IFR of up to 10%, while clade IIa (West Africa) and the more recent clade IIb are estimated to have an IFR between 1.0% and 3.7%. Transmission rates, measured by the basic reproduction number (R0), are important for understanding spread. A recent study estimated the R0 of MPXV to be around 2.44, higher than previous estimations.

The following figure graphically explains the history of Orthopoxviridae pointing out at the end the presence of the two clades of the monkeypox virus (figure taken from: Brown B, et al. Immunopathogenesis of Orthopoxviridae: insights into immunology from smallpox to mpox. Explor Immunol 2023; 3: 525-53).

Clade IIb outbreak:

On May 21, 2022, the WHO announced that 92 confirmed cases of mpox had occurred in 12 countries outside the endemic areas in Central and West Africa. On July 23, 2022, the WHO Director-General declared this mpox outbreak a public health emergency of international concern (PHEIC). As of October 11, 2023, 90,656 confirmed mpox cases had been reported from 115 locations worldwide.

Even though mpox was endemic in the sub-Saharan Africa, epidemiological, clinical, and virological data from the 2022-2023 outbreak, indicate that transmission through sexual contact, both penetrative and non penetrative, is more effective than transmission through casual skin-to-skin contact. Furthermore, there is a study across 16 countries in which 647 mpox cases were compared. It was noted that of these, 524 (80.9%) affected individuals were middle-aged men who have sex with men (MSM), of which 483 (92.2%) reported sexual contact, a unique clinical feature of this mpox outbreak.

These recent findings during the 2022-2023 outbreak corroborate the idea that the historical paradigm of MPXV ecology, evolution and epidemiology has changed, posing new challenges for the prevention and control of mpox.

Clade Ib outbreak:

In August 2024, the WHO Director-General determined that the upsurge of mpox in the DRC and a growing number of countries in Africa constitutes a PHEIC under the International Health Regulations (2005) (IHR).

The clade Ib MPXV outbreak that began in September 2023 in the DRC has been growing, with an increasing number of cases in the country and spreading to neighboring nations. Burundi, Kenya, Rwanda, and Uganda have each reported their first mpox cases, several of which have travel links to the eastern regions of the DRC. However, some European and Asian countries have reported cases where clade Ib MPXV has been identified. According to available epidemiological data, this clade is spreading rapidly among adults through close physical contact, including sexual contact within networks of sex workers and their clients. As the virus continues to spread, the affected groups are expanding to include children, with transmission also occurring within households and other settings.

Why is there a change in the epidemiology of MPXV?

1. Sexual transmission: Though not confirmed, hypotheses such as the size of the inoculum may be higher, the anatomical site of infection, in addition to a prior sexually transmitted disease may increase the likelihood for transmission.
2. Genetic changes (new clades): Genetic changes, such as the emergence of new clades like clade IIb, have influenced the epidemiology of MPXV, especially during the 2022–2023 outbreak (which is still ongoing to some degree). The sequences collected during the 2022 outbreak show about 50 single-nucleotide polymorphisms (SNPs) different from pre-outbreak sequences. This suggests an unexpectedly high mutation rate for the typically slow-evolving double-stranded DNA Orthopoxvirus. However, further genetic studies are needed to better understand the clade Ib driving the current outbreak.

Lessons learned and actions to be taken:

MPXV has likely circulated in Africa for centuries, with transmission occurring either zoonotically or from human to human. Despite its presence on the continent, intensive preventive measures, such as vaccination, have not been widely implemented.

Increased human travel and migration, combined with environmental changes and risky behaviors, contribute to viral mutations and the spread of diseases. Mpox appears to be no exception to this trend.

Mpox vaccination for high-risk populations (e.g., MSM) and all identified contacts, as recommended by the WHO and CDC, should be implemented globally without delay.

However, a global strategy requires both funding and political will.

Bavarian Nordic, the manufacturer of the Jynneos vaccine informed Africa CDC it could supply up to 2 million doses in 2024 and manufacture up to 10 million doses by the end of 2025 . However, these efforts are limited by the vaccine’s prohibitive price: approximately $200 per course. That steep cost is why mpox vaccines never reached Africa after the 2022 outbreak, and it remains unclear how vaccine procurement will be funded now.

The United States has offered 50,000 Jynneos doses from its national stockpile, and the European Union has ordered 175,000, with individual member countries pledging additional doses and Bavarian Nordic adding another 40,000. Japan has offered 3.5 million doses of LC16m8 (another mpox vaccine which requires only one shot instead of two).

Gavi, the Vaccine Alliance, has introduced a new US$2.5 billion Day Zero Financing Facility designed to provide immediate liquidity for vaccine purchases in the event of a global pandemic. This facility is the first proof of concept for a new collaboration among development finance institutions aimed at providing surge financing for medical countermeasures during pandemics. Following WHO’s designation of mpox as a public health emergency of international concern (PHEIC) on August 13, 2024, the Gavi fund is already being tested. On August 26, the WHO published its response plan for mpox, requesting $135 million from donors to finance it.

We must remember that any endemic transmissible disease can potentially spread globally, regardless of the region—a lesson that is finally beginning to resonate.

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