Mpox, formerly known as monkeypox, was declared an “international health emergency” by the World Health Organization (WHO) on August 14. This is the highest level of alert the organization can put in place. The aim is to strengthen the fight against this disease by promoting access to care and vaccines in affected countries.
The alert was issued following an outbreak of cases of a new variant of the disease, “clade 1b”. It appeared in the Democratic Republic of Congo (DRC) last September and has since spread to several neighbouring countries, including Rwanda, Burundi, Kenya and Uganda. A case was also detected in Sweden the day after the announcement, proof that the disease could spread beyond Africa, as feared by the WHO.
Mpox was first discovered in humans in 1970, in what is now the DRC. Two variants of the virus exist, the first, called “clade 1”, is present in Central Africa. The second, “clade 2”, is present in West Africa. These are the two “classic” forms of the disease. But in 2017, and then at the end of 2023, two new variants, “clade 2b” and then “clade 1b”, were identified. Mode of transmission, degree of transmissibility, real fatality rate, effectiveness of available treatments… These recently appearing strains still hold many mysteries. Here is what scientists already know, and what they are still trying to understand.
The animal reservoir remains unknown
Mpox is an infectious disease caused by a virus transmitted to humans by infected animals. Researchers suspect rodents to be the source. These could be forest squirrels or the Gambian rat. But the animal reservoir has not yet been formally identified. According to a study published in 2021 by the Pasteur Institute, The genomic history of the virus suggests multiple introductions from animal reservoirs in tropical forests.
Ongoing work could provide more information in the coming months.”The Panafpox 1 projectlaunched in the DRC, which we support, aims to carry out research in wildlife in order to identify the animal reservoir(s) of Mpox. For the moment, the number one suspect is the forest squirrel, but there are probably others,” says Eric D’Ortenzio, Mpox specialist and epidemiologist at ANRS MIE, an autonomous agency of Inserm specializing in emerging infectious diseases.
Not all modes of transmission have been identified
While the classic forms of Mpox – clade 1 and 2 – are transmitted mainly by animals, they can also circulate between humans, through close physical contact. This is why, initially, the disease more often affected people in contact with animals, who sometimes contaminated other members of their family, giving rise to small outbreaks of sporadic infections.
But in 2017, researchers discovered a new form of the disease in Nigeria, where “clade 2” is prevalent. It spread, affecting almost exclusively male homosexual populations. During this spread, the virus mutated and a new variant, called “clade 2b”, appeared. It then spread to many countries in 2022, including France, once again mainly affecting male homosexual populations. The epidemic was contained and the WHO alert was lifted in 2023.
At the end of September 2023, a new variant called “clade 1b” was this time identified in a major outbreak in South Kivu, a mining region in eastern DRC. A scientific study published in June in Nature medicine specifies that this is a virus that is transmitted primarily through sexual contact in at-risk populations, particularly minors and local sex workers – and especially female sex workers. “Clade 1b” therefore seems to have adapted to humans, in the same way as “clade 2b”, explaining why human-to-human transmission is much more sustained than with classic strains.
But researchers do not yet know why “clade 1b” is also affecting women this time. “Is it a new characteristic of the variant, which would be more sexually transmissible, or is it the conditions in South Kivu, where populations of minors and sex workers rub shoulders, that explain this phenomenon?” asks Dr. D’Ortenzio. The expert can simply propose hypotheses. Thus, it could be that it was the initial events of the first outbreaks that shaped the epidemic. Indeed, “clade 2b” arrived in Europe through LGBT gatherings. The virus then spread mainly in this community. For “clade 1b”, it could simply be that it was the female prostitution network and its many clients who favored the spread to women.
What is certain is that “clades 2b and 1b” are transmitted through close contact, such as hugging. But it is not certain that transmission occurs during penetration. This is why researchers speak of “sexual contact” and not “sexual acts.” “The virus has been isolated from semen samples, but it is not yet known whether the infection can be transmitted through semen, vaginal secretions, amniotic fluid, breast milk or blood,” adds Dr. D’Ortenzio.
Is the new strain really more transmissible?
The classic forms of Mpox, “clade 1” and “clade 2”, have R0s between 0.5 and 0.6. This means that each new infected and contagious person will contaminate on average 0.5 to 0.6 people. This is why most sporadic intra-family outbreaks end up disappearing on their own. “Clade 2b”, which caused the 2022 epidemic, is between 1 and 2. Isolation measures and vaccination campaigns were therefore necessary to contain it.
As for “clade 1b”, researchers suspect that it is more transmissible than classic strains. It has already contaminated at least several hundred people in the east of the DRC and has spread to provinces that were not previously affected, to neighboring countries and a case has even been detected in Sweden, in a traveler. But is it more transmissible than “clade 2b”? “For the moment, researchers remain cautious about transmissibility, because to evaluate it, we must calculate its R0, its incubation period, the intergenerational interval, etc. But we do not yet have all this data”, assures Eric d’Ortenzio. Scientists are working on these questions, in particular those of the Panafpox 2 project, also supported by ANRS MIE.
Lethality depends on the area affected
The same question remains regarding lethality. Currently, it is estimated at 3.6% in the DRC. But a clinical trial conducted by the National Institutes of Health (NIH)the National Institutes of Health in the United States, has shown that mortality drops to 1.7%, a reduction of more than half, when patients are properly managed, that is, with appropriate nutrition, good hydration and antibiotics in case of superinfections. “Mortality is therefore largely linked to a lack of access to care and medicines in remote and poor regions of the DRC,” underlines Dr. D’Ortenzio.
One of the main causes of death from the Mpox virus is linked to severe bacterial skin superinfections, particularly in malnourished children. Mpox can also be fatal in people with HIV who are poorly treated. However, in the DRC, 30% of the population at risk, namely sex workers, are affected by HIV. Almost all of the European deaths during the 2022 Mpox “clade 2b” epidemic episode were, in fact, men with HIV who were poorly treated. “What we do know, however, is that classic clade 1 appears to be more lethal than classic clade 2,” adds Dr. D’Ortenzio.
How many people are infected?
There is currently a great deal of confusion about the number of people affected by “clade 1b”. Some say a few hundred, others several thousand. And for good reason, there are two epidemics underway in the DRC: one linked to the classic “clade 1”, and the other to “clade 1b”. The problem is that less than 40% of suspected cases are tested to confirm the variant, due to a lack of availability of tests in remote areas. The figures can therefore only be approximate.
“Nevertheless, feedback from the field shows that the epidemic is growing in the DRC, whether in the east where the presence of 1b is confirmed, or elsewhere. And we know that neighboring countries, and even Sweden, have been affected by this variant,” says Professor D’Ortenzio. In France, no cases of “clade 1b” have been detected to date. But since the beginning of the year, there have been an average of 10 to 20 cases per month of “clade 2b.”
Vaccine efficacy likely, but to be demonstrated
To date, there are two approved and effective vaccines against Mpox. These are, in fact, smallpox vaccines – which have helped eradicate this disease – which are effective against Mpox thanks to a phenomenon of cross-reactivity. Even though these are two different diseases, several studies have shown that vaccination against “classic” smallpox was between 80 and 85% effective in preventing Mpox “clade 1”, and also “clade 2b”, and that having been previously vaccinated against smallpox reduced the severity of the disease.
A priori, this efficacy should be maintained for Mpox “clade 1b”, but this remains to be demonstrated, because the vaccine has not yet been used in this epidemic context. And for good reason: no vaccine has yet arrived in the DRC, where the majority of “clade 1b” cases are concentrated. “We all tell ourselves that there is no reason why vaccines should not work, but this must be confirmed, and it is not impossible that the percentage of efficacy varies”, notes Eric D’Ortenzio. The alert launched by the WHO should in particular facilitate access to vaccines… and answer this question.
If priority must go to the most affected countries, i.e. the DRC, what will happen to vaccination in France? In 2022, during the Mpox “clade 2b” epidemic, injections were recommended to those most at risk, namely men who have sex with other men. More than 150,000 doses had been administered. People born after the end of compulsory vaccination against smallpox (decided in 1979 because the disease had been eradicated) received two doses. Those born before received a booster dose. All of these people are therefore probably still protected against Mpox today, even if researchers do not know precisely how long the vaccine will be effective. In any case, since vaccine stocks are limited, there is little chance that the authorities will recommend vaccination for the entire population. They could, however, extend it to other at-risk populations, or to caregivers.
The effectiveness of Técovirimat questioned
Tecovirimat was approved in January 2022 by the European Medicines Agency (EMA) for the treatment of monkeypox in exceptional circumstances. But the ongoing clinical trial conducted by the American NIH has just demonstrated that this drug is not effective against “clade 1” to reduce the duration of symptoms. The ANRS MIE is, for its part, conducting the Unity trial, which aims to determine whether Técovirimat is effective on “clade 2” and “2b”. The answer could be known within a few months.
In the meantime, there are no other effective antivirals against Mpox. The only treatments available aim to combat pain, fever, superinfections and to improve rehydration and nutrition. One of the challenges is therefore to find new antivirals.
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