Summary report of the International Coalition of Medicines Regulatory Authorities (ICMRA) workshop on mpox, October 2, 2024

Mpox is a viral disease caused by monkeypox virus (MPXV) and is considered the most important orthopoxvirus infection since the eradication of smallpox. There are two distinct clades of MPXV, clades I (one) and II (two), which are endemic to countries in East and Central and West Africa, respectively. Each clade is further divided into subclades: Ia and Ib for clade I, and IIa and IIb for clade II. All viral strains spread through close contact which can include sexual contact. caused by MPXV clade IIb prompted the Director General of WHO to declare a Public Health Emergency of International Concern (PHEIC) from 23 July 2022 to 11 May 2023. In July 2024, the upsurge of Clade I cases in the Democratic Republic of Congo (DRC) and the emergence of the new virus strain clade Ib, with expansion to neighbouring countries, led to the declaration of a second mpox PHEIC on 14 August 2024.

One of the major challenges during these outbreaks has been the unequal availability of medical interventions, such as antivirals and vaccines, with low-income countries in Africa facing the greatest difficulties. While high-income countries were able to access vaccines more readily, African countries, where mpox is endemic, have struggled with delayed regulatory approvals and inaccessible prices. This disparity has driven regulators worldwide, including members of the International Coalition of Medicines Regulatory Authorities (ICMRA), to explore all possible pathways to improve access to medicines and vaccines for those most in need, particularly in resource-limited settings.  

The objectives of this workshop were to bring together the expertise of regulatory bodies to discuss the most significant evidence gaps with respect to countermeasures, promote the conduct of clinical studies considering the different scenarios surrounding mpox, and explore how best to support access to vaccines and therapeutics in the most severely affected countries. The meeting was chaired by Moji Adeyeye from the National Agency for Food and Drug Administration and Control (NAFDAC) Nigeria and Marco Cavaleri from the European Medicines Agency (EMA).  

Emer Cooke, as the chair of ICMRA, opened the workshop by emphasising the need to foster collaboration to rapidly improve access to medicines, and by underscoring regulatory reliance as an effective strategy to facilitate registration of necessary medical countermeasures. Furthermore, important evidence gaps remain for the use of mpox treatments in the most affected populations and across different settings. A coordinated approach would be more effective in tackling current and future emergencies.

During the workshop, speakers offered an overview of the global epidemiological status of mpox and the World Health Organization (WHO) strategic response plan, proposed vaccine deployment strategies and updates on vaccine donations, followed by a summary of the overall features, regulatory status and evidence available for different mpox vaccines and therapeutics presented by WHO, U. S. Food and Drug Administration (FDA), Japan Pharmaceuticals and Medical Devices Agency (PMDA), UK Medicines and Healthcare products Regulatory Agency (MHRA) and EMA respectively.

After the presentations there was an open discussion on the most relevant issues for these medicines, including evidence gaps, availability, contraindications and how best regulators can foster access to medicines in the most affected regions.

Children are the most vulnerable and severely affected population in Democratic Republic of Congo (DRC) with the highest case fatality ratio, therefore the paediatric component of medicines should be prioritized for discussion. Regarding the MVA-BN vaccine, FDA has granted emergency use authorization (EUA) for children and it has been used in the U.S. without safety concerns and with good results in terms of prevention. In Canada, the vaccine is authorized for immunization of individuals 18 years and older.  However, the Public Health Agency of Canada (via the National Advisory Committee for Immunization) has made a discretionary recommendation related to use in children. 

Recently, the EMA approved an expanded indication to include use in adolescents 12 to 17 years of age, which could support the approval in other countries with high burden of disease in children. The WHO has relied on the EMA approval for prequalification (PQ) of MVA-BN vaccine. All Heads of NRAs of mpox-affected African countries have been informed of the PQ of MVA-BN vaccines and technical support has been offered to facilitate rapid issuance of approvals. WHO PQ assessment reports have been shared with requesting countries after receiving signed confidentiality undertakings.

There is limited evidence for the use of MVA-BN vaccine in paediatric populations under 12 years of age; the safety profile is however not expected to be different in this population. The WHO Strategic Advisory Group of Experts on Immunization (SAGE) has also recommended that the MVA-BN vaccine can be used in children if the benefits outweigh the risks. For these reasons, regulators within ICMRA stand ready to support decisions in countries most affected, including for use in children less than 12 years of age. However, misinformation is of concern and robust communication strategies need to be implemented.

Given the vaccine supply gaps, and the high numbers of doses needed in the most affected countries, a dose-sparing strategy using the intradermal route of administration should be considered. During the 2022 mpox PHEIC, substantial real-world evidence was gathered on this route of administration, showing good effectiveness and safety. Besides MVA-BN, another vaccine, the LC16m8 vaccine, could also be considered for vaccination campaigns and it is approved across all age groups in Japan, with reassuring evidence from its use in a large number of children during the smallpox eradication campaigns. Its preventive effect against mpox is expected, as it induces cross-immunity between smallpox and mpox. LC16m8 induces neutralizing antibodies against MPXV in humans and it showed a preventive effect against mpox in animal studies. The procedure for the WHO emerging use listing of the vaccine is ongoing. However, given that this is a replicative vaccine, its use is not recommended in pregnant women and in immunosuppressed population with a CD4 count below 200 cells/µL, such as people living with HIV (People Living With HIV) that are not under treatment or aware of the infection. Managing this issue in certain regions would be challenging. Data collection on the use of MVA-BN vaccine during pregnancy would be warranted. The donation of vaccines and the immunization campaigns that are about to start, highlight the value of a coordinated approach. Good surveillance systems should be put in place to monitor safety and effectiveness, notwithstanding the challenges in the field. Additionally, immunogenicity studies in the African population, also beyond the planned paediatric studies, should be considered to complement current evidence and promote vaccines confidence.

With respect to new vaccines in development, there is need to discuss the different regulatory pathways for approval and consider alternatives to placebo-controlled studies in case they are not feasible, such as the use of animal models and clinical immune-bridging. Standardization of assays and investigating correlates of protection is of major relevance. Alternative methods of administration, such as needle-free devices, should also be explored.

Detailed results from tecovirimat clinical trials, including PALM-007 together with other ongoing clinical trials in other parts of the world, are eagerly awaited to clarify the role of tecovirimat in the treatment of mpox and define the next research questions. The absence of evidence in assessing the effect of antivirals in blocking transmission, as well as the very few efforts to assess their role for post-exposure prophylaxis were highlighted. An ongoing study is assessing the impact of tecovirimat on immunogenicity of the MVA-BN vaccine. If positive, these results could support the use of these medicines in combination for post-exposure prophylaxis. It has been recognised that early treatment or prophylaxis would give the best chances to antivirals for demonstrating a beneficial effect. Furthermore, gathering information on the role of antivirals in transmission blocking could be highly relevant considering the high viral load found in mpox skin lesions, a key route for transmission. Brincidofovir is the only antiviral besides tecovirimat that can be currently tested in clinical trials, although the safety profile needs to ensure adequate safety monitoring of the patients recruited. Combination therapy clinical trials according to factorial design, e.g. with brincidofovir and tecovirimat, should be considered as early as possible, starting from the populations most at-risk of severe disease.

ICMRA unanimously agreed that fragmentation in clinical research, as has happened so far with mpox, must be avoided, as studies need to be conducted rapidly and efficiently in the best interest of patients. More collaboration towards merging efforts from investigators into larger unified clinical trials is advocated.

Timely regulatory decisions are critical to allow access to vaccines to tackle the spread of monkeypox virus. Regulators stand ready to support each other and to exploit mechanisms of collaboration such as reliance on shared assessments.