Mpox Day 45 – The Landscape of Therapeutics and Vaccine Clinical Trials and Recent Developments

September 27, 2024

Day 45 of the 100 Days Mission Mpox clock  

The 100 Days Mission (100DM) clock for mpox started on 14th August 2024, following WHO’s declaration of mpox as a public health emergency of international concern (PHEIC), and Africa CDC’s declaration of mpox as a Public Health Emergency of Continental Security (PHECS) the day before.  

Leading up to Day 100 on 21st November, we will continue to provide updates every 15 days (alternating between minor and major updates) on the status and progress of mpox DTV availability and highlight specific priority actions to ensure products are available to those who need them. Please find the latest updates at https://ippsecretariat.org/news/

On Day 45, we provide our latest major update – a deep dive on the landscape of clinical trials for vaccines and therapeutics, and recent developments across all three tools. There have been some major announcements in the last 15 days such as two million vaccine doses donated between the USA, GAVI and UNICEF (see WHO i-MCM-net for latest figures), and the Pandemic Fund approved US$128.89 million to support 10 countries impacted by the disease. 

These updates are intended to support the work of partners and key initiatives such as WHO’s i-MCM-net, the recently announced mpox Access and Allocation Mechanism (AAM), their 6-month Global Strategic Preparedness and Response Plan and the WHO & Africa CDC joint continental plan. The data used to inform this update has been collected through desk research using public information and direct updates from implementing partners of the 100DM.  

It is important to remember, that while the 100DM goal is to have DTVs approved and ready to scale up within 100 days, the ‘Second 100 Days’ are also critical for enabling scaled manufacturing and rapid roll-out of products to the communities that need them. Groundwork needs to be laid now for this last-mile delivery to happen.  

Epidemiology (as of 27th September)

The number of cases, deaths and countries affected can be tracked on the WHO mpox tracker site. The African region continues to update data on a weekly basis and global data is currently being updated monthly. All totals you see are between January 2022 and August 2024. There is still limited diagnostic capacity to confirm all suspected cases, and this is why IPPS continue to advocate for accelerated development of accurate, rapid point-of-care (POC) testing. 

Priority actions for the next 55 days

In light of the current status of DTVs, we continue to encourage the international community to focus on the following updated priority actions over the next 55 days: 

Overview: the status of DTVs

On Day 45, there are still no approved antigen-based rapid diagnostic tests (RDTs) for all mpox clades. Diagnostics are a critical front-line defence against infectious disease spread. PCR is still the gold standard diagnostic test for mpox.  

FIND has now completed the global landscape analysis for mpox diagnostics with over 200 tests identified (two-fold increase compared to 2022 outbreak). Following the launch of their request for proposals for mpox diagnostics evaluation and accelerated development in low- and middle-income countries, they have received 87 submissions and have now commenced the review of the applications for the selection of the most promising RDTs and POC molecular tests to be included in the evaluation. Initial diagnostic demand modelling has been finalized, and site activation activities have begun for both analytical and clinical evaluations.  

Africa CDC has also published a second edition of a comprehensive and up-to-date list of available molecular diagnostic tests for mpox recommended by its Diagnostic Advisory Committee and shortlisted based on criteria including test performance and ability to detect relevant clades.  

 

On Day 45, there are still no WHO-Listed Authority (WLA) approved therapeutics specifically for mpox. Tecovirimat is approved in the EU (EMA) and USA (USFDA) under animal rule and exceptional circumstances respectively for mpox. 

In 2022, Unitaid conducted a landscape analysis of antivirals against mpox which provides a useful overview of potential therapeutics for the mpox response, including information on potential for access should the different candidates then under evaluation be recommended for use. 

Several trials are planned to further investigate tecovirimat as a mpox treatment, and whether disease severity or participant characteristics will lead to significant differences in clinical outcomes. Other trials are ongoing assessing other potential therapeutic agents against mpox; however, it is important to consider downstream factors such as cost, access and availability when choosing which therapeutics to invest in. For more detail on the status of therapeutic trials see the clinical trials deep dive section below. 

Work is underway to explore whether monoclonal antibodies may play a role in this mpox response, albeit with questions needing answering around speed and accessibility. 

 

On Day 45, MVA-BN, 1 of the 3 WHO-Listed Authority approved vaccines (MVA-BN, ACAM2000 and LC16m8), has been delivered to affected countries but awaiting roll out. MVA-BN has been approved by EMA for use in teenagers. 

Applications submitted to WHO’s call for Emergency Use Listing (EUL) are being reviewed and only MVA-BN has received approval so far. WHO has also developed a mpox Access and Allocation Mechanism (AAM) to get vaccines to all affected countries. So far 265,000 doses of MVA-BN have been delivered to the Democratic Republic of the Congo (DRC) with rollout expected to begin on 2nd October 2024.  

The SMART mpox vaccine trial, a clinical trial assessing whether mpox vaccination with MVA-BN works after virus exposure was launched last week in the DRC. Funded by CEPI and the Canadian Institutes of Health Research (CIHR), it will evaluate if the mpox vaccine could reduce the risk of secondary mpox cases, or, if a person contracts mpox, could reduce the severity of illness. Up to 1,500 participants aged over 2 in households with a laboratory-confirmed infection will be invited to take part in the study in Miti Murhesi, South Kivu province, DRC, an area which has recently reported mpox cases. The trial is also planned to start in Uganda and could potentially be extended to Nigeria.

 

Deep Dive: Landscape of mpox Therapeutics Clinical Trials

Since the declaration of mpox as a PHEIC in August 2024, there has been an increased interest in therapeutic trials aimed at identifying effective treatments. As of Day 45, the majority of mpox therapeutic trials focus on tecovirimat, a smallpox antiviral. Whilst it is currently the only approved therapeutic for mpox under animal rule/exceptional circumstances, there are numerous ongoing and planned trials assessing its efficacy and safety across different patient groups and viral clades. 

Scope of Clinical Trials

In collaboration with the Pandemic PACT Research Programme, Grant and Evidence Gap Tracker by the Pandemic PACT Team with GloPID-R and UKCDR, a review of 75 studies from clinical trial registries and 110 studies tracked by the Pandemic PACT grant tracker revealed a comprehensive landscape of ongoing therapeutic research (see table above): 

  • 176 studies were identified of which: 
  • 61 are clinical trials (28 focus on therapeutics, 33 involve vaccines) 
  • 7 focus on diagnostics. 

These studies are distributed across multiple regions, with the majority involving randomized, placebo-controlled, double-blinded trials. Major global efforts are underway in countries such as the USA, Brazil, Argentina, Japan, Thailand, Mexico, South Africa, Canada, and several others. 

However, at present, most clinical trials are taking place outside of Africa which is the region most affected by the current mpox PHEIC.  

Key Active Therapeutic Trials

Tecovirimat remains the primary focus of therapeutic research, with several trials exploring its potential in various settings: 

  1. PLATINUM-CAN (Canada) – A randomized, placebo-controlled trial investigating the safety and efficacy of Tecovirimat in non-hospitalized mpox patients. 
  2. STOMP Trial (USA, Argentina, Brazil, Mexico, Peru, South Africa, Thailand) – This trial aims to assess Tecovirimat’s safety and efficacy across multiple countries, involving a large, diverse patient population. 
  3. UNITY Trial (Brazil, Switzerland, Argentina) – This is aimed at understanding Tecovirimat’s effectiveness in both Clade I and Clade II mpox strains. 
  4. Trials in the DRC are focusing on evaluating Tecovirimat’s safety and efficacy in both adult and paediatric populations. 

Therapeutic Candidates in Development

Beyond tecovirimat, several therapeutics are being explored: 

  • Monoclonal antibodies (mAbs) – Though still in the preclinical stage, mAbs offer potential for rapid post-exposure prophylaxis and targeted treatment, particularly for vulnerable groups like children, immunocompromised populations (like people living with HIV at risk of Advanced HIV disease) or exposed groups (like healthcare workers). 
  • Non-nucleoside small molecules and cyclosporin A are also under preclinical investigation for their potential antiviral effects against mpox. 
  • Additional global efforts include trials assessing alternative therapeutics, such as cidofovir combined with probenecid, and early-stage studies of natural product-based treatments like fungal-based therapies from Iran.

Endpoints and Efficacy Markers

Most of the ongoing therapeutic trials use similar clinical endpoints to assess treatment efficacy. Common endpoints include: 

  • Resolution of lesions: Trials track the time to resolution of lesions, defining this as the first day of scabbing, healing of mucosal lesions, or complete resolution. 
  • Virological markers: These include PCR Ct values from lesion swabs, virus levels in various body fluids, and virus viability at different intervals (e.g., 14 and 30 days). 
  • Biomarkers and safety data: These include liver enzymes, hematologic tests, and serum electrolytes, as well as monitoring for adverse events. 

Challenges and Future Directions

Despite the growing number of trials, several challenges remain: 

  • Clade-specific efficacy: Most trials do not yet target specific mpox clades, leaving gaps in understanding how treatments perform against different strains. 
  • Post-exposure prophylaxis: No current trials focus on assessing therapeutics for post-exposure prophylaxis, a significant gap for frontline workers and vulnerable populations like children, and immunocompromised populations (like people living with HIV at risk of Advanced HIV disease). 
  • Monoclonal antibodies: Preclinical studies of mAbs have shown promise, but there is a need for rapid investment to accelerate into clinical trials and bring these treatments to market. 

 

Deep Dive: Landscape of mpox Vaccine Clinical Trials

Overview

As of September 2024, there are 44 active vaccine candidates for mpox and smallpox. This development landscape shows a diversified approach beyond traditional live-attenuated vaccines, with many new platforms, particularly mRNA-based candidates, entering preclinical stages. Of the 44 candidates, 23 candidates in exploratory and preclinical stages, and 10 candidates are in late-stage trials. 4 mRNA-based candidates are now in development, with several in preclinical phases, signalling a shift toward newer vaccine platforms alongside traditional methods. 

Clinical Trials 

A detailed search through various clinical trial registries (PACTR, SANCTR, WHO ICTRP) identified 30 studies actively recruiting participants. This includes 17 vaccine trials, highlighting the following key interventions: 

1. Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) Vaccine: 

  • Represents 52.9% of the vaccine trials (9 trials). 
  • Trial phases range from Phase I to IV across different global sites. 
  • Trials are focusing on vaccine safety, immune response, and long-term protection against mpox.

2. LC16m8 Mpox Vaccine: 

  • Accounts for 17.6% of trials (3 trials). 
  • Conducted across Phase I, III, and IV, focusing on both safety and immunogenicity. 

3. VAC∆6 Vaccine: 

  • 11.8% of the trials (2 trials), exploring both early and later phases (Phase I and II/III). 

4. RNA-based multivalent vaccine candidates: 

  • Candidates like BNT166a and mRNA-1769 are new entrants, with trials in Phase I/II. 
  • These vaccines target both mpox and smallpox, with an emphasis on rapid scalability and flexibility in response to new viral strains. 

Geographic distribution

The research for mpox vaccines is being conducted in a variety of locations worldwide. The United States is leading the effort with nine studies, followed closely by Brazil with seven trials and India with six. Although there are fewer trials taking place in Africa, several countries, including the DRC, South Africa, Nigeria, Cameroon, and the Central African Republic, are actively involved in vaccine research. 

Challenges and Opportunities 

  • Regulatory Pathways: While several vaccines are in advanced stages (Phase III and IV), it’s crucial to expedite regulatory approvals, especially for regions with limited access to vaccines. 
  • Manufacturing and Scale-Up: Efforts must be intensified to scale up manufacturing capabilities, supported by procurement agreements to secure demand, for the most promising candidates, particularly in Africa, where vaccines are critically needed. 
  • Post-trial Planning: Beyond trial success, ensuring equitable distribution of vaccines in regions with high vulnerability is essential. 

 

Summary of Deep Dive 

The therapeutic landscape for mpox has seen substantial growth, with phase III Tecovirimat trials dominating the research space. While Tecovirimat has not yet proven highly effective in certain populations, trials continue to explore its utility across different patient groups. Meanwhile, monoclonal antibodies and other antivirals offer potential as future solutions, but these treatments remain in early stages of research. Continued global collaboration and investment are needed to expand therapeutic options, particularly for vulnerable populations and healthcare workers. 

As of September 2024, there are 44 active mpox and smallpox vaccine candidates, with a diverse range of platforms including mRNA, live attenuated virus, and recombinant protein approaches. Most candidates are in exploratory or preclinical phases, with some reaching registration and stockpile stages. Notable candidates include MVA-BN, LC16m8, ACAM2000 and emerging mRNA vaccines like BNT166a. Research is globally distributed, with the U.S., Brazil, and India leading trials, while African nations participate in fewer studies. 

Proposed Actions: 

  • Accelerate Trial Completion and Approvals: Ensure rapid data sharing and collaboration across global sites to expedite the completion of late-phase trials. 
  • Expand Access to Approved Vaccines: Push for equitable vaccine access in Africa and other affected regions, potentially through regional manufacturing initiatives. 
  • Monitor Emerging Platform technologies: Continue tracking diversified approaches, including the new multivalent and whole virion vaccines, ensuring preparedness for both mpox and other poxvirus outbreaks. 
  • Expand Research to Specific Clades and Vulnerable Populations: Conduct trials or trial extensions focusing on Clade I and Clade II efficacy, especially in high-risk populations. 
  • Fast-track Monoclonal Antibody Development:  Provide funding and investment to fast-track preclinical mAb candidates and initiate phase I/II trials as soon as possible. 
  • Support Development of Novel Antivirals: Increase financial support and technical guidance for preclinical candidates, with an emphasis on early translation into clinical trials.