Title Promoter Affiliations Abstract "Statistical methods for estimating age and time-dependent epidemiological malaria parameters and the analysis of social network data as a new approach to the development of malaria elimination strategies" "Niel Hens, Steven Abrams, Koen Peeters" "Socio-ecological Health Research" "Malaria is a potentially life-threatening mosquito-borne disease causing a wide variety of symptoms such as high fever, chills, headache, and vomiting among others [1]. Of the five-known species of Plasmodium parasites [2], P. falciparum is responsible for the majority of malaria deaths globally as the most severe and prevalent species in Sub-Saharan Africa [3]. Despite increased efforts to eradicate malaria worldwide with a reduced incidence and mortality of about 21% and 58%, respectively, between 2010 and 2015, malaria infections remain the leading cause of deaths in African children. In 2015, about 212 million malaria cases were recorded with 429,000 deaths, 92% of which took place in the WHO Africa region [3]. In order to reduce disease transmission and consequently malaria-related morbidity and mortality, infections should be detected and treated in time. Social network analysis (SNA), an application of mathematical graph theory, could radically improve our understanding of malaria transmission dynamics in low transmission settings, and therefore enhance the effectiveness of targeted screening, treatment strategies and overall malaria elimination campaigns. Since social structures and risk behaviors that modify exposure to malaria infection, such as time spent in high-risk areas and the use of prevention measures and treatment seeking behavior, are typically socially shared, network structures are thought to be highly relevant to understand malaria transmission dynamics. Social networks are not confined to pre-determined geospatial units and the analysis thereof goes beyond accounting for individual-level information, as opposed to contact tracing, to reveal underlying measurable network structures. A vast amount of research has been conducted so far with the aim of estimating quintessential epidemiological parameters related to the transmission of malaria such as the force of infection (i.e., the instantaneous rate at which individuals acquire malaria) and the entomological inoculation rate (i.e., the average number of infectious bites per unit of time). Both mathematical and statistical techniques have been employed to serve this purpose. The aim of this research project is to develop new methodology for the estimation of age- and time-varying epidemiological parameters related to vector-borne diseases. In this research project, I will focus on malaria, which remains an important public health concern worldwide. Nevertheless, the aim is to develop a translational framework applicable for the analysis of data on relevant vector-borne infectious diseases, since a lot of recent outbreaks have been vector-borne (e.g., Zika virus). There are four main objectives in this proposal: (1) Develop methodology to integrate both mathematical and statistical models to estimate age- and timevarying epidemiological parameters such as force of infection and point prevalence based on longitudinal malaria parasitaemia cohort data (WP1); (2) Accommodate for the dependence in recurrent infection times within the same individual, and take into account phenomenon such as unobserved heterogeneity, outcome-dependent sampling and double interval censoring characterising longitudinal cohort data using appropriate statistical models (WP2); (3) Relate heterogeneity in household conditions and individual attributes to social network data and study differences in social network structures between malaria-infected and uninfected individuals using SNA techniques (WP3). (4) Combine the age- and time-dependent epidemiological malaria parameters, estimated in the presence of unobserved heterogeneity, outcome-dependent sampling and accounting for the doubly interval censored nature of the parasitaemia data, with the derived social network structures in a simulation model allowing for the study of elimination strategies (WP4). References: 1. Miller, L. H., et al. (2013). Malaria biology and disease pathogenesis: insights for new treatments. Nature Medicine, 19(2): 156-167. 2. Phillips, M. A., et al. (2017). Malaria. Nature Reviews Disease Primers, 3:17050. 3. WHO (2016). World Malaria Report 2016. Geneva. Licence: CC BY-NC-SA 3.0 IGO." "The impact of artesunateamodiaquine retreatment and specific malaria humoral immunity on recrudescent malaria infections." "Jean-Pierre Van geertruyden" "Epidemiology and social medicine (ESOC)" "We will compare, in a non-inferiority, randomised, controlled trial, in Congolese children under 5 years of age, the efficacy of ASAQ to quinine as a rescue treatment for uncomplicated P. falciparum malaria. Additionally, given the key role of humoral immunity in protecting against malaria, we will assess antibody levels to merozoite antigens and VSAs in Congolese children under 5 with uncomplicated malaria and their association with anti-malarial treatment outcome." "Eco epidemiology of asymptomatic malaria hotspots, a prerequisite for malaria elimination?" "Wim Van Bortel" "Institut Pasteur du Cambodge, National Center for Malaria Control, Parasitology & Entomology, Socio-ecological Health Research, Entomology" "Investment in malaria elimination is believed to provide one of the highest returns in global health. Elimination however requires a different approach as compared to what is done in present control programs. New insights in the eco-epidemiology of the malaria parasites will be essential in defining this approach, especially for Plasmodium vivax of which current knowledge is relatively poor. In the proposed research program we seek to identify and characterize malaria hotspots that are stable in time at different geographical resolutions for each of the four human malaria parasites (P. falciparum, P. vivax, P. malariae, and P. ovale), with the aim of enabling hotspot targeting for malaria elimination. It is based on the hypothesis that stable hotspots, in which the human reservoir of the parasite consists of mainly asymptomatic cases, 1) feed the temporary (unstable) hotspots in which otherwise the parasite will not persist, and 2) possess a unique combination of host, vector and environmental conditions which determine its stability over time. In a first phase, a unique dataset, previously collected in a project carried out in the most endemic province of Cambodia, will be used to determine stable and unstable hotspots or cold spots at a village resolution. This dataset consists of malaria prevalence (113 villages, 4 surveys, 2 years, >20,000 individuals sampled) and incidence data of symptomatic and asymptomatic cases (PCR, serology & passive case detection) at the village level. In addition, the hotspot information obtained will be linked using spatio-temporal models with human-, parasite-, vector- andenvironment- related factors, all collected in the same time period. In a second phase we will zoom in to a subvillage resolution to refine the analysis by collecting additional data in identified hotspots at individual and household level, as such defining the scale at which risk factors for asymptomatic malaria hotspots occur (individual – household – village – cluster of villages). The relation between the type of hotspot (stable, unstable or cold) defined geographically, and occurrence of symptomatic cases will further be explored. As such, focussing classical epidemiology on asymptomatic instead of symptomatic malaria cases and combining it with environmental, entomological and social science data will provide a novel and useful approach to predict the locality and dynamics of malaria hotspots for each of the four parasite species.We thus expect that this study, unparalleled in available data and combined disciplines, will provide fundamental insights for hotspot targeting, a prerequisite for efficient malaria elimination in many countries." "Reducing severe malaria related child mortality in the Democratic Republic of Congo (DRC) by improving the management and control of malaria associated kidney injury (MAKI)" "Philippe Van den Steen" "Immunoparasitology (Rega Institute)" "Malaria and its complications, including kidney injury, remain a leading cause of child mortality in the DRC.Acute kidney injury (AKI) is emerging as a complication of increasing clinical importance associated withsubstantial morbidity and mortality in children with severe malaria. AKI was identified as the strongest predictorof mortality alongside coma in African children with severe malaria. Data from our previous VLIR-UOS projectsnoted a remarkably ever-increasing incidence of AKI among Congolese children admitted in Emergency unit,and severe malaria was found as the first cause of AKI. The goal of this project is to contribute to the reductionof malaria-related child mortality in DRC by improving management and control of an emerging life threateningmalaria complication which is AKI.To achieve this, the project aims to improve access to an affordable earlydiagnosis of malaria associated acute kidney injury (MAKI) on the one hand, and on the other hand provideclinicians with a way to identify patients at risk for MAKI among children admitted with severe malaria, forefficient patient referral and treatment. Furthermore, through this project, University of Kinshasa researchcapacities will be strengthened with a new expertise on MAKI, which will be used in clinics, in research and inteaching." "Statistical methods for the estimation of age- and time-dependent epidemiological malaria parameters and the analysis of social network data as a novel approach to design malaria elimination strategies." "Steven Abrams" "Global Health Institute (GHI)" "The aim of this research project is the development of new advanced, state-of-the-art methodology for epidemiologists, mathematical modellers and biostatisticians interested in modelling vector-borne infectious disease transmission. More specifically, we focus on the estimation of age- and time-dependent epidemiological malaria parameters, correcting for other attribute data, governing the spread and transmission of malaria. In addition, interest is in the identification of key individuals responsible for sustained malaria transmission in low transmission settings. Based on social network analysis techniques, we aim at gaining insights relevant for the development of malaria elimination strategies. In conclusion, the main objectives in this proposal are (1) the development of novel methodology to integrate mathematical and statistical models to estimate time- and age-varying malaria epidemiological parameters in the presence of unobserved heterogeneity; (2) the development of approaches to deal with doubly interval censored observations in combination with outcome-dependent sampling and heterogeneity; and (3) the study of heterogeneity in household conditions and individual attribute data using social network data. Although special attention is directed to malaria, the methodology developed in this project is more widely applicable in the context of vector-borne infections in both human and animal populations." "The impact of artesunateamodiaquine retreatment and specific malaria humoral immunity on recrudescent malaria infections." "J.P. Van geertruyden, Sabine Desager, Robert Colebunders" "Institute of Tropical Medicine, HIV and Tuberculosis" "The Ministry of Health of the Democratic Republic of Congo recommends artesunate-amodiaquine (ASAQ), an artemisinin-based combination therapy, as first line treatment for uncomplicated malaria. Treatment failure for ASAQ is below 10% and the recommend rescue treatment is quinine. However, because of its poor tolerability and prolonged treatment course, the effectiveness of quinine monotherapy is lower than that of any other ACT.In real-life conditions, patients are often retreated with the recommended first line drug, i.e. ASAQ. Luckily, PCR analysis shows that 75 % or more of the ASAQ treatment failures are new infections. Furthermore, recrudescences have low, easy-to-eliminate, parasite densities. Therefore, we will compare, in a non-inferiority, randomised, controlled trial, the efficacy of ASAQ versus Quinine as a rescue treatment for uncomplicated P.falciparum malaria in Congolese children under 5 years of age. Considering the key role of humoral immunity in controlling parasite densities and treatment efficacy, we will determine whether antibody to key merozoite antigens and Variant Surface Antigens (VSA) are associated with parasite densities and treatment outcome. VSA have been recently reported as inversely associated with parasite density and risk of treatment failure. A better understanding of malaria immunity and in particular VSA immunity in children might have implications for the deployment of future malaria vaccines." "Investigation of the structural and functional role of the Plasmodium falciparum circumsporozoite protein in the development of liver stage malaria." "Yann Sterckx" "Medical Biochemistry" "Malaria is one of the 'Big Three' infectious diseases, together with HIV and tuberculosis. According to the World Health Organisation, malaria is endemic in 104 countries thereby endangering the health and lives of 3.4 billion people. Each year around 200 million cases of the disease are documented, including more than half a million deaths. More than 70% of the deceased are children under the age of five. The etiological agents of malaria are parasites from the Plasmodium genus, of which P. falciparum is the most virulent. Malaria parasites are transmitted by mosquitoes, which inject the parasites into the human body during a blood meal. This initiates the infection, which is characterized by two stages. The first stage (known as liver stage malaria) is caused by a form of the parasite called the sporozoite and is typically asymptomatic. The sporozoite infects the liver and develops into the next form of the parasite called the merozoite. This marks the start of the second stage of the malaria known as the blood stage. This phase, during which merozoites infect red blood cells, causes the infamous malaria pathology. Sporozoites are ideal targets for anti-malarial therapies as their elimination from the human host would prevent the onset of disease. Therefore, the sporozoite surface proteins are interesting candidates for the development of novel anti-malarial drugs and vaccine strategies. The presented research project aims at unraveling the mechanistic principles behind several processes that are crucial in the establishment of liver stage malaria. The first is the invasion of hepatocytes by the parasite. While it is known that the parasite's main surface antigen, the circumsporozoite protein (CSP), plays a pivotal part in successful hepatocyte invasion, the structural and functional aspects of this event remain unchartered territory. A thorough structural and biophysical study of the molecular aspects of CSP-mediated hepatocyte invasion will provide relevant insights into the biology of the malaria parasite. Once the parasite has invaded a hepatocyte, it forms a vacuole from within which it exports CSP to the host cell cytoplasm. There, CSP competes with NFkB for binding with the importin proteins in order to dampen NFkB-driven inflammatory responses. This increases the odds of parasite survival inside the infected hepatocyte and, hence, ensures continuation of the life cycle. Although it is known that CSP and importin proteins interact, the structural and biophysical aspects of this encounter have not yet been investigated. Obtaining a detailed picture of this interaction will allow a better understanding of immune evasion strategies adopted by the malaria parasite during the liver stage of the infection. Finally, the fundamental mechanism of CSP export from the parasite to the host hepatocyte cytoplasm will also be investigated. As investigating sporozoite antigens has produced significant scientific breakthroughs in the battle against malaria, it is anticipated that tackling the above-mentioned issues will not only yield insights into the parasite's immunobiology, but also generate a molecular basis to contribute to the design of novel anti-malarial therapies." "Glucocorticoid regulation of systemic immunometabolism in malaria" "Philippe Van den Steen" "Immunoparasitology (Rega Institute), Universität Ulm" "Malaria is a parasitic disease that poses a major health threat to the world with an estimated 219 million cases and 435000 deaths in 2017. Especially the complications of malaria are life-threatening and have ~15% fatality rates despite antimalarial treatment.  These complications include amongst others cerebral malaria, severe anemia and respiratory problems and are further worsened by metabolic disturbances, such as hypoglycemia and hyperlactatemia. Protection against malaria relies on immune mechanisms to limit the parasite proliferation, and on so-called disease tolerance mechanisms which are essential to maintain systemic homeostasis. In this project, we will investigate how glucocorticoids interact with the immune system and with the central carbon metabolism to maintain and optimize systemic metabolic homeostasis during this life-threatening infection. State-of-the-art technologies will be applied to study these regulatory systems in mouse models of malaria and in patients from endemic regions. Overall, this project will provide a novel integrative concept of the function of glucocorticoids in infection and will reveal new insights that will provide novel clues for improved therapy of malaria." "Hemozoin vaccination as a new concept for the prevention of malaria pathology." "Philippe Van den Steen" "Immunobiology (Rega Institute)" "Malaria is a global health concern with about 40% of the world population at risk of being infected. More than 1.5 million people die from this disease every year and in addition, 300 to 500 million clinical cases are reported. Mild or uncomplicated malaria is usually not lethal, whereas severe or complicated malaria has a mortality rate of 20 to 30%. Cerebral malaria (CM) is a main complication and is associated with sequestration of infected erythrocytes onto endothelial walls of microvessels in the brain. In a mouse model for CM with p. berghei ANKA (PbANKA), chemoattraction of activated perforin+ CD8+ T cells to the brain is also essential for the pathogenesis. In this project, we will use the PbANKA model to investigate the role of hemozoin (malaria pigment) in the pathogenesis of malaria immunopathology." "Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria." "Sabine Desager, D'Alessandro" "Institute of Tropical Medicine" "Overall Goal: To identify artemisinin-based combination treatments (ACT) that can be safely and efficaciously used to treat women with malaria in their second and third trimester of pregnancy. This will be attained through the following strategies: 1. Research: To determine the safety and efficacy of 4 ACTs when administered to pregnant women during the second and the third trimester with P. falciparum infection and collect explanatory variables for treatment failure (PCR-corrected) and for recurrent parasitaemia. 2. Capacity Development: To develop disease endemic country research capacity through training and professional development of scientists, building of infrastructure and transfer of technology. 3. Networking: To coordinate research efforts on treatment and prevention tools of malaria in pregnancy and, by doing so, finalise a common research agenda and promote the rational use of available resources. Rationale:Although malaria is the most important human parasitic disease, few studies on antimalarial drugs have been carried out in pregnant women. Pregnant women are a high-risk group requiring effective antimalarials but they are systematically excluded from clinical trials for fear of teratogenicity and embryotoxicity. This has complicated evidence-based recommendations for the prevention and treatment of malaria during pregnancy. There is insufficient information on the safety and efficacy of most antimalarials in pregnancy, including exposure in the first trimester. The World Health Organization (WHO) recommends effective ACT in the second and the third trimester and several African countries are already implementing it. Though the experience on the use of ACTs and on their safety and efficacy in pregnancy is increasing (over 1,000 documented pregnancies, mainly in South East Asia), this information is still limited, particularly in Africa. Therefore, we propose to test 4 potential candidates, the fixed dose combinations of artemether-lumefantrine (AL), amodiaquine-artesunate (AQ-AS), mefloquine-artesunate (MQ-AS) and dihydroartemisinin-piperaquine (DHA-PQ). This choice of candidate drugs was based on the target drug profile for case-management consisting of a range of criteria including known efficacy in children (cure), safety in pivotal phase-3 trials in children and adults; practicality of the dosing regimen (duration [e.g. 3 vs 7 days]; formulation (co-formulated tablets requires less tablets]), tolerance, current availability in the population, and cost. By contemporaneously testing several drug regimens, we will shorten the time of data collection and determine the relative ‘value’ of each treatment, providing the basis for an informed choice by programs and policy makers. In addition, PK data and in vitro parasite’s drug sensitivity will be related to treatment outcome and will help in understanding the drugs’ pharmacodynamic. The capacity building component has been formulated taking into account the individual needs of the participating African institutions and the complementary expertise between European and African partners. The investigators involved in this proposal recently held a meeting (in Barcelona under the umbrella of the MIPC) where the respective African research institutions where classified according to the criteria at page 7 of the guidelines for the applicants. Most institutions involved in this proposal where at level 3 or 4 for most but not all components. An African sister institution was identified and will benefit for a substantial share of the capacity building component of this proposal. Networking will be carried out under the umbrella of the MIPC, an initiative of 23 African and European institutions interested in contributing to the control of malaria in pregnancy. Considering that the Consortium comprises most groups involved in research on malaria in pregnancy, from the most biological questions (immunology, parasitology) to operational research, e.g. effectiveness of a given intervention, it represents a powerful body within which south-south and north-south interactions and exchanges can and will occur. The Consortium can also facilitate linkages with other MIP stakeholders so that new and efficient ways of preventing and treating MiP in Africa are found and implemented as speedily and effectively as possible. Specific research objectives 1. To compare the efficacy of AL, AQ-AS, MQ-AS and DHA-PQ on outcomes occurring during the 63-day active follow up post-treatment (parasitological failure and haematological recovery) and at delivery (birth weight and placenta malaria); 2. To determine the safety profile of AL, AQ-AS, MQ-AS and DHA-PQ in terms of tolerability and adverse events from treatment until 6 weeks post partum; 3. To determine the relation between drug pharmacokinetics (Day 7 levels of the partner drug) and response to treatment; 4. To asses the in vitro susceptibility of P. falciparum isolates collected before treatment to several drugs, including the partner drug tested, and to correlate their IC50 to treatment response; Specific capacity development objectives 1) To develop the capacity of southern partner institutions for conducting GCP-compliant multicentre trials in Africa 2) To standardise short-term training on key methodologies across all Consortium-led MiP trials through cost effective approaches and centralised training where appropriate 3) To develop sustainable strategies for the long term training of future generations of African scientists. Specific networking objectives 1. To agree upon and produce standard operating procedures for all project-related activities, from data collection, laboratory procedures to data analysis and dissemination strategies; 2. To interact with the larger MIPC, present and discuss the results obtained in the light of other ongoing research activities, e.g. malaria prevention; 3. To coordinate capacity building activities and create a common training program tailored to the participati"