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).

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.

The recent outbreak of Ebola virus (EBOV), in particular the EBOV Sudan strain, is a major cause for concern as there are currently no available vaccines and treatments for this fatal disease. Moreover, surveillance measures are suboptimal and the social response to viral outbreaks hindered by limited acceptance of countermeasures. The Ebola PREP-TBOX consortium aims to make significant strides in developing essential tools and strategies for effective surveillance response, and control of Ebola outbreaks, fostering a safer and resilient future. Our objective is to build a toolbox permitting earliest Ebola outbreak containment. A spatiotemporal model utilizing environmental, animal reservoir, socioeconomic and human movement data will be developed enabling prediction of future outbreaks. The sensitivity of current diagnostics will be improved through innovative viral capture techniques. EBOV exposure and immune response will be tested from human-animal interface samples from the Republic of Congo (RoC), Democratic Republic of Congo (DRC) and Uganda. New treatments for the EBOV Sudan strain will be developed by testing for broad-spectrum activity of the EBOV anti-Zaire Equine polyclonal antibody. Further, development of mosaic antigens, composed of several filovirus strains (incl. EBOV), will create new tools for broad-spectrum vaccine and therapeutic development. Conductance of knowledge, attitude and practice (KAP) studies, gap analysis and targeted trainings in RoC, DRC and Uganda will improve population acceptance for future EBOV outbreak interventions. The training of African researchers by the consortium will increase local skills and competences. Ebola PREP-TBOX is an interdisciplinary and complementary consortium including partners from the Congo Basin (FCRM-RoC, INRB-RDC, UVRI-IAVI-Uganda), Prof. JJ Muyembé (Ebola discoverer 1976) and partners from Europe (Fabentech and Bacfly/CNRS-France, IMAS12-Spain) and the support of G Kobinger (GNL,US).

We will establish for the first time in NTDs an adaptive clinical trial platform and improve clinical research infrastructure in four SSA countries. A drug acting safely on multiple helminths species would be a major leap to tackle NTDs and enable the WHO RoadMap (eWHORM). The cheap and freely-accessible pan-nematode drug oxfendazole (OXF) has such potential. Given the limited portfolio of anthelmintic drug candidates, eWHORM will assess its efficacy in an adaptive clinical trial for simultaneous evaluation against onchocerciasis, loiasis, mansonellosis and trichuriasis. Thus not only the largest group of NTDs, but also diseases that are not (yet) listed will be adressed. This design significantly reduces patient numbers, development time-frames and enables treatment of co-infections. Combined with our highly sensitive molecular tests, we provide a patient-centric approach providing tools for targeted treatment (test and treat) and precision mapping for elimination programs. Strengthening of early career scientists in SSA in all aspects of clinical trial conduct and research including data management, simulation and statistical analysis, will be fostered by introducing a master and PhD program, a mentorship program as well as several webinars. An open-source virtual training and assessment tool for diagnosis of NTDs will complement the knowledge transfer to remote areas in SSA. The consortium encompasses an interdisciplinary partnership from eight different countries (Germany, the Netherlands, Austria, Switzerland, Cameroon, Gabon, Tanzania, and DRC). Each group brings unique knowhow and recognized complementary experience to the project to ensure sustainable capacity building within SSA countries. Through joint development of – and training in – modern, regulatory clinical trial conduct, adaptive clinical trial design and state-of-the-art diagnostics, we will strengthen SSA researchers and clinicians to respond to persisting and future health challenges.

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.