This proposal outlines two linked studies aimed at addressing the public health challenge of Mpox in the Democratic Republic of Congo (DRC). The MOVIE study focuses on understanding the kinetics of viral elimination shedding light on how MPXV interacts with host tissues and immune defences, which is crucial for developing containment strategies and potentially influencing endpoint selection in therapeutic trials. The TRACE study aims to determine secondary attack rates in MPXV outbreaks, assessing host susceptibility within specific populations, offering vital data to target interventions towards vulnerable groups and informing vaccine efforts by contributing to the assessment of vaccine efficacy endpoints.

Gambiense human African trypanosomiasis (gHAT) is a neglected tropical disease caused by trypanosome parasites. gHAT is fatal if left untreated. So far, treatment options for gHAT were limited and toxic, forcing control programs to avoid overtreatment through complex diagnostic procedures, including screening with a serological test, laborious microscopic confirmation of seropositives and lumbar puncture for disease stage determination. This resulted in loss of up to 50% of gHAT cases, which remained untreated. Recently a non-toxic single dose oral drug, acoziborole, has shown 98.1% efficacy in a phase III trial, irrespective of gHAT disease stage. Acoziborole removes the need for lumbar puncture and appears safe enough to treat serological suspects without microscopic confirmation (Screen & treat). The STROGHAT project 1° will evaluate effectiveness of a Screen & treat approach to rapidly reduce gHAT prevalence in an entire focus; 2° will extend acoziborole safety documentation; 3° and will analyze costs of this new approach. To achieve these objectives, Screen & treat will be implemented, actively and passively, for 3 consecutive years in the gHAT focus of Nord Equateur in D.R. Congo. Available geographical information will be exploited to specifically target villages where gHAT was recently, or still is present. Detection at a reference laboratory, of the trypanosomes nucleic acids in blood collected before treatment, will retrospectively identify true gHAT cases among the treated serological suspects. After 3 years of intervention, the gHAT prevalence in the focus will be re-estimated. STROGHAT intends to provide the first evidence for recommending Screen & treat to national HAT control programs for elimination of gHAT. Through facilitated diagnosis, increased acceptability and access to treatment, STROGHAT will contribute to achieving the goal of stopping gHAT transmission by 2030, as defined by the World Health Organization.

With the Mpox Biology, Outcome, Transmission, and Epidemiology in South Kivu (MBOTE-SK) project, we seek emergency funding to address one of the most alarming mpox outbreaks currently unfolding: the ongoing emergence of a new lineage of monkeypox virus (MPXV, clade Ib) in South Kivu, Democratic Republic of the Congo (DRC). This outbreak is particularly concerning due to its extensive human-to-human transmission through sexual contact in a densely populated region characterized by a large sex industry and significant cross-border movement. Without swift intervention, there is a high risk of the outbreak spreading internationally, penetrating sexual networks worldwide. In this project, we will leverage our extensive experience with mpox outbreaks in the DRC and our current presence in South Kivu to tackle this outbreak through a combined approach of research and response. To achieve this, we will build on local and national expertise and strengthen the DRC's research institutions, and align with the international response. This project has four foundational pillars, each designed to simultaneously strengthen the response and comprehensively describe clade Ib MPXV, including its clinical presentation, mode of transmission, at-risk populations, and virological evolution. Pillar 1 strengthens active case finding and epidemiological surveillance to map and monitor the spread of clade Ib MPXV. Pillar 2 supports real-time genomic surveillance to track the genetic evolution of the strain. Pillar 3 enhances clinical care through an in-depth clinical characterization study. Pillar 4 engages key populations (including sex workers) to study community spread, vaccine hesitancy and stigma. These four pillars eventually feed into Pillar 5, by informing on how to best target the Ministry of Healths planned vaccination campaign (with the Modified Vaccinia Ankara vaccine) and documenting its impact and real-world effectiveness (using the established platforms of Pillars 1-4).

Background: Monkeypox virus (MPV) is a member of the Poxviridae family that includes smallpox, cowpox and chickenpox viruses. Endemic to equatorial Africa following casual human to animal or human to human transmission , recent events have seen an increased incidence with indications of sexual transmission. The disease is characterized by fever, muscle aches, skin rash, lymphadenopathy, oral sores, sore throat, cough, etc. Within any cluster of high risk contacts of a case mpox; however, not everyone exposed develops clinical disease. Moreover, among those contacts who develop mpox, not everyone gets severe disease or dies. Hypothesis: Host genetic & viral factors explain the differential outcomes following exposure to MPV. Objectives: To determine the host genetic and viral determinants of mpox disease in Kamituga area, South Kivu province, DRC. Specifically, we will (I) establish well phenotyped cohorts of house-hold contacts, (II) determine rare variants via family trios; (III) undertake RNASeq for transcriptomics, and (IV) study differential cellular immunity profiles using digital cell sorting (DCS) , (V) identify viral variants that drive severe disease Methods: Whole exome sequencing (WES), transcriptomics and DCS studies of house-family contacts clinically prequalified by PCR and serological testing. Virus gDNA will be reverse transcribed from sequenced host RNA and characterized by comparative genomics and phylogeny. Potential impact: This project will elucidate host genetic & viral determinants of susceptibility to mpox disease in context of natural exposure and infection; that may serve as correlates of immune protection following vaccination.

Ivermectin is a critical drug for the control and elimination of multiple neglected tropical diseases. Currently, children weighing under 15kg do not receive treatment with ivermectin due to an absence of safety data and the lack of a suitable paediatric formulation. Consequently, these children are left untreated. This results in considerable morbidity at the individual level and a reservoir of infection at the population level. These issues create a critical barrier to achieving the goals of the 2030 NTD roadmap. In 2023, the World Health Organization (WHO) conducted a Paediatric Drug Optimisation (PADO) review to identify critical needs for therapeutics in children affected by NTDs. Recognising the central role of ivermectin in the control of NTDs, along with the opportunity to accelerate progress by expanding treatment to paediatric populations, this report highlighted a paediatric-friendly ivermectin formulation as as a critical priority for NTD programmes worldwide. A novel orodispersible formulation of ivermectin provides the opportunity to address this critical gap. Our consortium brings together leading academic and drug development partners across Europe and sub-Saharan Africa to address this global priority need, with crucial experience in novel therapeutics and navigating the European and African regulatory landscapes. Our consortium will deliver studies to demonstrate the safety, pharmacokinetics and efficacy of the novel, orodispersible formulation of ivermectin suitable for use in young children. This will include conducting a large safety study across West, Central, East and Southern Africa to demonstrate the efficacy of this agent for the treatment of soil transmitted helminthiasis. We will work closely with European and African regulators to ensure that our project delivers both the scientific and regulatory data required to bring this agent to market and transform access to effective NTD treatment for for millions of children worldwide.