Colorized transmission electron micrograph of mpox virus particles (orange) found within an infected cell (brown), cultured in the laboratory. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. © NIAID

Central Africa, especially the Democratic Republic of the Congo (DRC), is highly affected by successive mpox outbreaks. Until now, the extent of genetic diversity of the virus had not been well characterised in this region of the world. For the first time, as part of the AFROSCREEN project[1] and the PANAFPOX project[2], teams from the Institut National de Recherche Biomédicale (INRB) in DRC, IRD and Inserm have provided important new information on the genetic diversity of mpox virus circulating in DRC and on the predominant route of transmission. Results of this work have just been published on the Cell website on 24 October 2024.  

Mpox is a viral zoonosis most likely transmitted from rodents to humans. The first case was reported in the Democratic Republic of the Congo (DRC) in 1970. This disease, which had been endemic mainly in rural and forested areas of West and Central Africa for several decades, spread around the world in 2022, including cases in European countries. For the first time, the disease has spread rapidly between individuals through sexual contact, a mode of transmission rarely observed before. This growing mpox outbreak has led to a declaration of a public health emergency of international concern.

The mpox virus can be divided into two major clades*. Clade I, the ‘historical’ strain of the virus, found in the Congo Basin and Central Africa, and clade II, present in West Africa, with clade IIb, found in Nigeria and responsible for the 2022 mpox outbreak.

The most affected country is DRC, where the number of cases has doubled in recent years, rising from around 3,000 in 2021 to 5,600 in 2022, and from over 14,000 in 2023 to over 20,000 by 1^st September 2024. This increase is accompanied by an alarming expansion of the geographical spread, first in eastern DRC but also in urban areas including the capital city Kinshasa, and in neighbouring countries (Rwanda, Burundi, Kenya and Uganda) previously unaffected by mpox. On 14 August 2024, the substantial rise in mpox cases led the World Health Organisation to declare the mpox outbreak a public health emergency of international concern for the second time. These new infections have been attributed to clade Ib, a new variant of clade I with increased numbers of APOBEC3** mutations, which indicate that the virus has adapted to human hosts.

The study, conducted in DRC between February 2018 and March 2024, aimed to investigate whether the rising numbers of mpox infections in the country were due to zoonotic spillovers or viral evolution linked to human adaptation and sustained human-to-human transmission. A total of of 337 viral genomes from 14 out of 26 provinces were successfully sequenced. All new sequences from the South Kivu province, in eastern RDC, corresponded to the recently described clade Ib. This variant is associated with sexual contact and sustained human-to-human transmission, and the limited genetic diversity is compatible with its emergence in 2023. All other genomes from other provinces (i.e. 95% of cases) belonged to clade Ia, which is characterised by high genetic diversity and a low number of APOBEC3 mutations compared with clade Ib. The study results therefore suggest a predominance of zoonotic transmission of mpox in the human population. The co-circulation of genetically diverse viral lineages in small geographical areas even suggests multiple zoonotic introductions over a short period from one or more reservoir species.

For the first time, a large number of clade I mpox sequences have been analysed. This study has provided important new information about the genetic diversity of mpox viruses circulating in DRC, and shows that there are two modes of transmission: zoonotic transmission (clade Ia), which predominates, and human-to-human transmission, which is emerging (clade Ib) in South Kivu and is spreading rapidly to other regions in DRC and neighbouring countries. The presence of several clade I variants in urban areas, particularly Kinshasa, also highlights the need to continue monitoring the evolution and diversity of the virus in DRC as well as its modes of transmission. It is also urgent to better document the animal reservoirs involved in zoonotic transmission.

* a group of organisms,incliuding a particular organism and all of its descendants.

** APOBEC3 (Apolipoprotein B Editing Complex) are proteins that help protect against viral infections.

[1] Project coordinated by ANRS MIE in partnership with IRD and the Institut Pasteur, and financed by the French Development Agency (AFD).

[2] Multidisciplinary project with a “One Health” approach, funded by ANRS MIE.

In this work, scientists analyzed cellular immunity in 230 participants in Guinea © Aurélie Wiedemann

Epidemics of Ebola virus disease occur periodically in several sub-Saharan African countries. Two vaccines have already received WHO prequalification[1] against the Ebolavirus Zaire species. However, information on the long-term immune response to these vaccines is still insufficient. We need to consolidate our knowledge on this subject to continue developing the safest and most effective vaccination strategies possible, for both adults and children. In a new study conducted in Guinea, scientists from VRI, Inserm and Université Paris-Est Créteil (U955 Institut Mondor de recherche biomédicale)[2] have taken a further step in this direction. They have shown that the cellular immune response induced by three different vaccine strategies is maintained for up to five years after vaccination. These results, which support current vaccine strategies against Ebola, are published in Nature Communications.

The Ebola virus causes high fevers and hemorrhages, often resulting in death. Many countries in sub-Saharan Africa regularly face epidemic outbreaks.  the Ebola virus caused the largest epidemic known to date in West Africa in 2014. It has since re-emerged several times in the DRC, but also in Guinea. Vaccination is today one of the most effective tools for combating the disease, and one of the major challenges for research and public health strategy is to continue improving knowledge of the immune response induced in the long term by currently available vaccines.

Since 2019, two vaccines have obtained WHO prequalification against the Ebolavirus Zaire strain: the rVSVΔG-ZEBOV-GP vaccine (Ervebo®), developed by Merck, Sharpe & Dohme, Corp. and the vaccine regimen comprising Johnson & Johnson’s Ad26.ZEBOV (Zabdeno®) vaccine and Bavarian Nordic’s MVA-BN-Filo (Mvabea®) vaccine.

In 2022, the international PREVAC consortium (see box at the end), comprising Inserm, NIH and the London School of Hygiene and Tropical Medicine (LSHTM), published a study in the New England Journal of Medicine examining the safety and efficacy of three vaccine regimens:

• The first vaccine regimen tested consisted of one dose of Ad26.ZEBOV vaccine, followed 56 days later by one dose of MVA-BN-Filo;
• The second regimen involved a dose of rVSVΔG-ZEBOV-GP;
• Finally, the third schedule began with a dose of rVSVΔG-ZEBOV-GP, followed 56 days later by a booster dose of the same vaccine.

Published results showed a high serum antibody response  12 months after vaccination. However, it was essential to obtain information on the long-term maintenance of the response, and in particular regarding the cellular response (see box below).

In December 2023, the 5-year follow-up of participants in the PREVAC clinical trial was completed. The results are being analyzed and will enable assessment of long-term immunity. sIn an ancillary study, scientists analyzed cellular immunity in 230 participants in Guinea, just after vaccination, at one year and five years post-vaccination.

“This is the first study from the PREVAC consortium to look specifically at participants’ cellular immune response. It completes the knowledge already acquired on the humoral response at one year and offers the first follow-up results at 5 years”, emphasizes Aurélie Wiedemann, immunologist at VRI and the Institut Mondor de recherche biomédicale (Inserm/Université Paris Est Créteil) and first author of the study.

Using blood samples taken in Conakry, the scientists were able to analyze the response of CD4+ and CD8+ T lymphocytes to vaccination. They showed the presence of anti-Ebola CD4+ T cells five years after vaccination, regardless of the vaccination regimen. The persistence of these responses is important for the maintenance of humoral immune memory in the event of exposure to the Ebola virus. In a subgroup of volunteers, the authors show a correlation between CD4+ T cell response and the quantity of specific antibodies in the long term.

While CD4+ T response is important for maintaining an antibody response, the presence of cytotoxic CD8+ T cells is also crucial for effective antiviral protection. A specific CD8+ T cell response was demonstrated in individuals vaccinated with two of the three vaccine regimens.

“These results will shortly be supplemented by humoral response data – on antibody production – from all PREVAC consortium countries, on a larger number of participants. Nevertheless, these results are promising and suggest that vaccination against the Ebola virus can induce long lasting immunity. They also pave the way for adjusting current vaccination strategies, by making it possible to assess, for example, the need for a long-term booster vaccination”, explains Prof. Yves Lévy, Director of the VRI and final author of the study.

In 2020, the team also published a study in Nature Communications on the immunity of Ebola survivors two years after discharge from hospital. One of the next avenues of research could be to compare the long-term immune response of these survivors with that induced by vaccination, in order to identify possible correlates of protection [1] against infection, as these are currently undetermined.

Thus, this new study could help identify vaccine responses that would be effective against the infection, improve current vaccine strategies, and define long-term booster vaccine strategies to maintain protection for particularly at-risk individuals such as healthcare workers in Africa.

[1] Prequalification means that a vaccine meets WHO standards of quality, safety and efficacy. On the basis of this recommendation, UN agencies and the Gavi Alliance can purchase the vaccine for at-risk countries.

[2] This analysis was carried out in collaboration with the SISTM team at the Bordeaux Population Health Research Center (UMR 1219 Université de Bordeaux/Inserm).

[3]  These are immunological markers associated with protection against infection: for example, post-vaccination antibody levels against hepatitis B are a good correlate of protection. In other words, in the context of vaccination, they designate the parameters that scientists monitor to find out whether the vaccine works and protects effectively against infection.

Presence of hepcidin (in brown) in the epidermis of a patient with pustular psoriasis. © Élise Abboud

Psoriasis is a chronic inflammatory disease characterised by the rapid and excessive multiplication of skin cells. Although research is progressing and certain treatments are already able to improve the daily lives of patients, this disease remains incurable. The team led by Carole Peyssonnaux, Inserm Research Director at Institut Cochin (Inserm/CNRS/Université Paris Cité) has shown that a hormone that regulates iron in the body, called hepcidin, is produced by the patients’ skin and is essential for triggering psoriasis. This discovery opens up new avenues for treatment. Drugs that block the action of hepcidin could be a therapeutic alternative in psoriasis. These findings have been published in Nature Communications.

Psoriasis is a chronic inflammatory disease that primarily affects the skin. It is common and affects 2 to 3% of the world’s population. Despite many treatment options available to improve patient care, psoriasis remains a chronic condition with no definitive cure.

Characterised by red patches covered with scales, the disease manifests as an excessive proliferation of epidermal cells and an excess of immune cells in the skin, accompanied by a local inflammatory reaction.

Over the last few decades, much progress has been made in understanding the disease, such as the identification of certain genetic factors. Several studies, whose findings are still little known by the scientific community, have also shown that there is an accumulation of iron in the skin of psoriasis patients. We know that the regulation of iron levels in the body is controlled by a hormone called hepcidin. While hepcidin is primarily synthesised by the liver, it can be produced by other organs or tissues under disease conditions.

For years, the Iron and Immunity team at Institut Cochin, led by Inserm Research Director Carole Peyssonnaux, has studied hepcidin closely. Despite the proven presence of iron in the epidermis of psoriasis patients, the production by the skin and the potential role of this ‘iron hormone’ in psoriasis had never been investigated. The researchers therefore decided to study this avenue more closely.

The team[1] started by showing that hepcidin was expressed in the skin of patients with psoriasis, particularly in severe forms such as pustular psoriasis, which is characterised by the accumulation of a type of white blood cell – neutrophils – within the epidermis.

To further study the role of hepcidin in psoriasis, the team then developed new mouse models in which the hepcidin gene was specifically inactivated or overexpressed in the epidermis. The scientists then showed that when this gene was activated, certain characteristics of psoriasis were induced, including skin lesions and the recruitment of neutrophils in the epidermis. Conversely, when the gene was inactivated, the psoriasis markers disappeared.

‘Hepcidin plays a key role in the development of psoriasis. Based on our findings, we show that when psoriasis is triggered, the hepcidin produced by the epidermis plays a crucial role in retaining iron in the skin cells. With iron being an essential metal for cell proliferation, this retention promotes cell division in the epidermis of “psoriatic” skin. What is more, hepcidin-mediated iron retention also contributes to the recruitment of neutrophils, another characteristic of psoriatic skin lesions, particularly pustular’, explains Peyssonnaux.

The next step would be to explore these findings in greater depth, with the goal of developing drugs to block the action of hepcidin and therefore potentially benefit patients with psoriasis, particularly those suffering from an acute and resistant form. With this in mind, the team is developing, with the support of Inserm Transfert[2], new drugs capable of neutralising hepcidin, in order to test them in animal models of psoriasis.

‘In the future, if our findings prove conclusive, such drugs could be used as maintenance therapy following a flare-up, during phases of remission, to prevent recurrence of the disease. Additional studies will determine whether hepcidin also plays a role in other inflammatory skin diseases’, concludes Peyssonnaux.

[1]In collaboration with the team of Selim Aractingi (Cochin Hospital) and Hervé Bachelez (Saint-Louis Hospital)

[2] Patent WO2016/146587 / EP3268027B1 and US11203753B2

Vaccination © Inserm/Depardieu, Michel

The ANRS DOXYVAC trial, promoted and funded by ANRS Emerging Infectious Diseases, and conducted by research teams from Inserm, AP-HP, Université Paris Cité and Sorbonne Université (France), shows that a rapid rollout of smallpox vaccination with MVA-BN (Modified vaccine Ankara) among HIV-positive men who have sex with men significantly reduces the risk of mpox by 99%. The results of this study were published in The Lancet Regional Health-Europe on 31 July 2024.

In May 2022, cases of mpox, formerly known as monkeypox, were reported in more than 100 countries where the disease was not endemic. In France, the first case was reported on 19 May, with a rapid increase in infections among men who have sex with men (MSM).

The ANRS DOXYVAC trial, which began in 2021, was designed to study how to improve protection against sexually transmitted infections (STIs) in HIV-positive men who have sex with men.* So, when it became apparent during the course of the study that mpox cases could occur in the trial population, a smallpox vaccination was conducted, as soon as preventive  vaccination in multi-partner MSM was recommended  by French Health Authorities (HAS) on 11 July 2022.

To date, there is no specific vaccine against mpox. However, the virus is closely related to that of human smallpox, and the smallpox vaccine has been shown to be more than 95% effective in protecting against mpox. The vaccine used in the trial, Imvanex® (MVA-BN: Modified vaccine Ankara) from Bavarian Nordic, is a third-generation vaccine. This type of vaccine is produced from smallpox virus with the same antigens as historical smallpox. More specifically, it contains a highly attenuated form of the vaccinia virus known as “modified vaccinia virus Ankara”, a virus that does not cause disease in humans and cannot reproduce in the cells of people who are vaccinated. This means that the vaccine cannot cause local or systemic infections, particularly in immunocompromised people (such as those infected with HIV).

The aim of the analysis among participants of the ANRS DOXYVAC trial was to assess the incidence of mpox infection in participants before (9 May-10 July 2022) and after the launch of the MVA-BN vaccination campaign (from 11 July 2022), and to study the respective effects of vaccination and sexual behaviour adopted during the epidemic period on changes in incidence.

Of the 472 participants included in the analysis, 20% had been vaccinated against smallpox in childhood. The incidence rate** of mpox among trial participants, all of whom were on HIV pre-exposure prophylaxis (PrEP) and had a history of bacterial STIs, was high (49.3 per 1,000 participant-months between 9 May and 20 September 2022).

Vaccination implementation was rapid: 86% (341/398) of eligible participants had received at least one dose of MVA-BN vaccine by 20 September 2022. People were also particularly receptive to the prevention messages and recommendations, especially those with more than ten sexual partners in the last three months who are most at risk. Their sexual behaviour changed significantly before and after 9 May, leading to a reduction in the proportion of people with more than 10 partners in the last 3 months (45% compared with 38%). A significant reduction in the incidence rate of mpox was observed between the period prior to vaccination (67.4 per 1,000 months between May 9 and July 10, 2022) and the period following the launch of the vaccination campaign (24.4 per 1,000 months between July 11 and September 20, 2022).

This trial demonstrated that the rapid implementation of smallpox vaccination with MVA-BN in MSM undergoing PreP significantly reduced the risk of mpox, with an estimated 99% reduction in incidence between the two periods. The reduction in risky sexual behaviour among those most at risk also probably contributed to the reduction in incidence, but to a lesser extent than the vaccination programme.

This study emphasises that identifying and prioritising at-risk populations, delivering targeted prevention messages and awareness campaigns, ensuring the availability of a smallpox vaccine and, above all, the rapid rollout of vaccination to people at risk should enable health authorities to control a future mpox epidemic like the one that occurred in 2022.

* DOXYVAC has demonstrated the efficacy of post-exposure doxycycline in reducing the occurrence of chlamydial infections, syphilis and, to a lesser extent, gonococcal infections.

** Incidence is the number of new cases of a disease in a year in a given population (not to be confused with prevalence, which refers to the number of sick people at a given time). The incidence rate of a disease corresponds to the number of individuals having contracted a disease per 1,000 people exposed to the risk of this disease (in the DOXYVAC trial, it is calculated for one month) (https://www.ined.fr/en/glossary/incidence-of-a-disease/).