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Palmarès Prix et Bourse - Palmares Prijs en Beurs - Previous Awards

2018-2020 : Guy Caljon (Prijs) et Nolbert Gumisiriza (Beurs)

The Dubois-Brigué 2020 prize for tropical pathology

Guy Caljon, as only candidate, received the price for his work on “Control of sleeping sickness and Leishmaniasis: from insect bite to effective treatment” for submission.  His work concentrates on the treatment against sleeping sickness and Leishmaniosis, and the role of innate immune responses on the pathological outcome of the diseases. Novel insights have been gained in the early immunological processes that underlie successful systemic colonization of the mammalian host following intradermal inoculation of trypanosomes by the infective bite of a tsetse fly. These recent findings revealed that parasites can co-opt host innate immune responses, i.e. neutrophil functions, for enhanced infection establishment. Conversely in Leishmaniosis, research on the only oral antileishmanial drug miltefosine resulted in unraveling the mechanisms of resistance that is linked to defective drug uptake. Very surprisingly, resistant parasites were found to significantly benefit from exposure to the drug, which strongly advocates for discontinued use of miltefosine in areas where treatment failure is on the rise. Continued research is aimed at obtaining (more) detailed information about the mechanism of action and drug targets. The antileishmanial leads are now further tested in combination treatments to move towards clinical evaluation in the very near future. For the antitrypanosomal leads there appears no immediate commitment to a new human African trypanosomosis drug development programme, but the discovered lead series will further be explored for African animal trypanosomoses.

 

 

Control of sleeping sickness and leishmaniasis: from an insect bite to effective treatment
Guy Caljon
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Guy.Caljon@uantwerpen.be


More than 1 billion people worldwide are affected by neglected tropical diseases, including various parasitic infections that start with the bite of a blood feeding insect. Two major tropical infectious diseases are sleeping sickness or African trypanosomiasis and leishmaniasis, which are transmitted by tsetse flies and sand flies, respectively. Current treatments have multiple limitations such as drug toxicity and an increasing risk of treatment failure. This highlights the need for new medicines or vaccines to tackle these diseases.


The team of Prof. Caljon at the Laboratory of Microbiology, Parasitology and Hygiene (LMPH) of the University of Antwerp aims to identify improved treatments by searching in a systematic manner for new active substances and by acquiring fundamental insights into the biology of the parasite and its interaction with the host. As a unique asset for the parasitology research at LMPH, a new insectarium was established harboring a sand fly colony and tsetse flies, enabling natural infections. Using the established tools, new insights were obtained in (i) the immunological responses in the skin following parasite transmission by an insect bite, (ii) the spread of resistance, (iii) progress in the challenging search for new drugs and (iv) the development of a new diagnostic test.


Although the skin is a natural barrier that should protect us, the studies of Caljon and colleagues showed that recruited neutrophils promote the initiation of trypanosome infections. Natural infection studies showed that mice with a low neutrophil count are surprisingly better protected. This work thus identified this innate immune cell as an important regulator of early infection. Ongoing studies are aimed at unraveling the underlying mechanisms, which could serve as a basis for new transmission-blocking interventions.


Transmission also appears to be strongly dependent on phenotypic properties of parasites, e.g. drug resistance. Since the spread of resistance is detrimental to effective treatment of patients, LMPH systematically evaluates the effect of resistance on transmissibility by the insect and infection of the mammalian host. These studies showed that the spread of paromomycin-resistant Leishmania poses a high risk. Conversely, resistance acquisition against the oral antileishmanial drug miltefosine, results in a profound loss of parasite fitness in the sand fly and vertebrate host. This may explain why these miltefosine-resistant parasites have only been recovered from HIV patients with a defective immune system.  A very surprising finding is that these resistant parasites become drug dependent, where treatment sustains their survival in the host. Such studies are very informative to formulate recommendations for rational drug use and drug combinations to prevent the spread of resistance.


Two large studies in collaboration with DNDi (Drugs for Neglected Diseases initiative) and Ghent University have contributed to the discovery of new active substances against leishmaniasis and sleeping sickness. These compounds were found to be highly active and  selective both in vitro and in experimental animals. As a requisite for the treatment of sleeping sickness, the new compounds were found to be active across the blood / brain barrier. Given the major socio-economic impact of trypanosomiasis in animals, the new substances are currently being explored for veterinary use. For the most promising antileishmanial leads, DNDi is coordinating their evaluation in phase I clinical trials. Relevant for the follow-up of patients is the development of a new diagnostic test that can detect all major pathogenic Leishmania species with high sensitivity and specificity. The intention is to include this test as a “test of cure” in future clinical studies in East Africa and India.

 

“From specialized to community-integrated treatment and care for people with nodding syndrome in Uganda”

The Dubois-Brigué scholarship

The jury unanimously considered to give the PhD scholorship to Nolbert Gumisiza for his  PhD thesis on “From Nodding syndrome to Onchocerciasis-Associated Epilepsy in Uganda: epidemiology, clinical characteristics, and management”
Nodding syndrome (NS) is a progressive neurological disorder that is characterized by episodes of periodic vertical head-nodding. The treatment and rehabilitation of persons with NS and other forms of epilepsy require specialised and/or trained human resources. The objective of the PhD is (1) to review the government’s planned strategy of decentralising treatment and care for persons with NS and other forms of epilepsy in northern Uganda, (2) To assess the extent to which these plans were implemented and (3) To generate ideas and strategies to improve the existing models for NS/epilepsy care. The study sites will be health facilities, selected from areas with a high prevalence of NS/epilepsy in northern Uganda;

 

 

2014-2016 : Johan van Griensven (Prijs) et Séverine Thys (Beurs)

"Clinical research in hard to reach contexts: from leishmaniasis in HIV patients to Ebola"

PRÉSENTATION DE M. le Dr   J. van GRIENSVEN

LAURÉAT DU PRIX DUBOIS-BRIGUÉ POUR LA PATHOLOGIE TROPICALE  

par  N. CLUMECK, membre titulaire

L’Académie royale de Médecine de Belgique a reçu cinq candidatures de haut niveau pour le Prix Dubois-Brigué pour la pathologie Tropicale 2014-2016.

A l’unanimité, le Jury a proposé d’attribuer ce prix au Dr Johan Van Griensven de la KUL pour l’ensemble de sa carrière illustré par le travail « Clinical research in hard to reach contexts ; from Leishmaniasis in HIV patients to Ebola ».

Le Dr Van Griensven a obtenu son PhD au Rega Institut à Leuven pour un travail sur l’approche génomique du traitement du SIDA. Il a également obtenu un master en épidémiologie à la London School of Hygiene and Tropical Medicine. Lauréat d’un fellow-ship post-doctoral Baillet-Latour, il a travaillé de nombreuses années en Afrique où il a contribué, par une approche multidisciplinaire, à établir un réseau de recherche clinique avec des plateformes laboratoires, à identifier les besoins en recherche opérationnelles de terrain dans le domaine du HIV, en particulier chez le patients exposés à la Leishmaniose.

Enfin, durant l’épidémie d’Ebola en 2014-2016, par son expérience et leadership il a coordonnés un consortium prestigieux de recherche clinique en Afrique de l’Ouest, évaluant l’utilisation de plasma de convalescents comme traitement d’Ebola en Guinée.

C’est l’Académie Néerlandophone de Médecine qui remettra le Prix Dubois au Dr Van Griensven.

Clinical research in hard to reach contexts: from leishmaniasis in HIV patients to Ebola

par

M. le Dr Johan van GRIENSVEN (Tropical Medicine Antwerp, KUL)  

Visceral leishmaniasis (VL) is a vector-born disease caused by a protozoan infection with the Leishmania donovani species complex. The anthroponotic form is caused by Leishmania donovani and is prevalent in the Indian subcontinent (300,000 cases/year) and East Africa (30,000 cases/year), mainly Sudan and Ethiopia. Untreated, overt disease is universally lethal. HIV has been identified as one of the emerging challenges for VL control. This problem is now especially severe in Ethiopia, where close to 40% of patients with VL are co-infected with HIV. Clinical management of VL-HIV coinfection remains unsatisfactory, especially in East-Africa. Despite increased availability of antiretroviral therapy and VL treatment, the case-fatality rate remains high (reaching 25%). Up to 50% of patients fail to clear parasites from infected tissues and recurrent relapse is frequent (up to 60%).

Increasingly, basic and laboratory research is conducted on neglected tropical diseases, including VL. However, what is currently lacking is patient-centered clinical research that can directly benefit patients affected by VL, and particularly VL-HIV co-infection. This gap exists due to a combination of scientific and operational challenges that few have managed to surmount.

Over the last eight years, a number of achievements have been made. First, we established a clinical research network in Ethiopia, with laboratory platforms and associated funding. This network brings together the required complementary expertise to conduct clinical trials in complex, remote settings and targeting hard to reach populations, including DNDi (a non-profit R&D organization), Médecins Sans Frontières (field operational partner) and two Ethiopian universities. Second, we identified key research gaps and documented the operational reality of VL management in the field. This includes three publications in the Lancet Infectious Diseases journal (van Griensven et al. 2010, van Griensven et al. 2013, Diro et al. 2015). Importantly, we have led a pivotal trial on secondary prophylaxis to prevent VL relapse in HIV infected patients (Diro et al. 2015). We identified monthly administration of pentamidine infusions as a safe, feasible and effective intervention to reduce the relapse rate within a setting with weak public health structures. Additionally, we contributed to a randomized clinical trial comparing high dose AmBisome treatment with AmBisome combination therapy, with the latter achieving very good cure rates (>90%) in preliminary analysis. These interventions are major improvements for VL-HIV patient management. Both interventions are expected to be integrated in the revised World Health Organization (WHO) guidelines to be issued in 2017.

Preventive strategies constitute a complementary approach to reduce morbidity and mortality of VL-HIV co-infection. As the first ever, we have started an innovative research line aiming to tackle VL at the early stages by preventing the onset of the disease in Leishmania exposed/infected HIV patients. Within our study area, we have identified two HIV clinical cohorts, with a total of over 3000 HIV-infected patients in follow-up in VL endemic areas. A multi-site longitudinal follow-up study is ongoing to evaluate the evolution of Leishmania markers over time and the associated risk of developing disease (VL). This study could lay the foundation of a screen & treat strategy, by providing risk estimates and a clinical prediction tool to identify those at highest risk. This subgroup will then qualify for an interventional study.

We have leveraged our experience with clinical research in challenging conditions to take up the role as leader and coordinating investigator of a prestigious clinical research consortium during the 2014-2016 Ebola outbreak in West-Africa, evaluating the use of convalescent plasma as a treatment against Ebola in Guinea. The intervention was found safe and feasible to organize in the middle of an overwhelming outbreak. Although the use of plasma as per WHO guidelines did not lead to a clear survival benefit, this remains a pivotal finding, as it will completely alter WHO guidance. In addition, via dose-response studies integrating the level of anti-Ebola antibodies present in the plasma, we identified ways to enhance the efficacy of this intervention, to be explored further in animal studies. The findings have been published in the New England Journal of Medicine in two linked manuscripts (van Griensven et al. 2016, van Griensven et al. 2016).

In conclusion, responding to the observation that too little field clinical research is done for neglected tropical diseases that occur in complex and resource constrained settings such as VL-HIV co-infection, the work performed over an eight year period demonstrates that it is feasible to conduct high quality clinical research on neglected tropical diseases in very complex setting, if bringing together all the required complementary expertise. We now aim to leverage the acquired experience to tackle the clinical research gap for cutaneous leishmaniasis and other neglected diseases, and to rapidly respond to clinical research needs for emerging infectious disease outbreaks.

"Perception of neglected zoonotic diseases among livestock owners in the tropics: The added value of Anthropology to the One Health approach for integrated control".

PRÉSENTATION DE Mme le Dr S. THYS
LAURÉATE DE LA BOURSE DUBOIS-BRIGUÉ 2016
par
N. CLUMECK, membre titulaire  

La Fondation Dr Albert Dubois pour la pathologie Tropicale distribue cette année une bourse pour une dernière année de doctorat (PhD) et un prix pour un travail de haut niveau dans le domaine des pathologies tropicales.

Le jury, que j’ai eu l’honneur de présider, était constitué pour la partie néerlandophone des Professeurs Stany Geerts, Greet Ieven et Jozef Vercruysse, et pour la partie francophone des Professeurs Yves Carlier et Françoise Portaels.

L’Académie royale de Médecine de Belgique a reçu cinq candidatures pour la bourse Dubois-Brigué 2016.

A l’unanimité, le jury a considéré que la bourse devait être attribuée au Dr Séverine Thys de l’Université de Gand pour la poursuite de son travail doctoral sur la « perception de zoonoses négligées chez les éleveurs dans les tropiques et de l’apport de l’anthropologie pour une approche intégrée du contrôle de ces zoonoses ».

Séverine Thys a été diplômée en 2004 à l’ULB en anthropologie et a obtenu un master complémentaire en Public Health à l’ULB en 2009. Depuis 2012, elle est assistante académique à l’Institut de Médecine Tropical où elle coordonnée le réseau stratégique sur les zoonoses négligées, projet financé par la coopération belge. Depuis 2014, elle a entamé un travail de thèse doctoral à l’UZ Gent pour laquelle elle reçoit aujourd’hui la bourse de la Fondation Dubois.

 

Perception of neglected zoonotic diseases among livestock owners in the tropics: The added value of Anthropology to the One Health approach for integrated control

 par Mme le Dr Séverine THYS (Tropical Medicine Antwerp, ULB, UGent)

Livestock owners in developing countries are most vulnerable to Neglected Zoonotic Diseases (NZD) and their risk behavior leads to more intense and complex transmission patterns. We hypothesize that innovative NZD control strategies can be developed via a bottom-up culture-sensitive approach, leading to interventions that are better adapted to the local reality and more sustainable than current ones. This doctoral project assesses cultural, cognitive and social drivers explaining people’s behavior with regard to animal husbandry, zoonoses and their control in their specific ecosystem. Through a ‘One Health’ inter-sectoral approach the project documents the extent of human-animal-ecosystem interface of four NZDs (echinococcosis, taeniasis-cysticercosis, rabies and Ebola) and examines the “when”, “how”, “where” and “why” of exposure from a socio-anthropological perspective. The underlying hypothesis of this work is that an integrated control “toolbox” for NZDs should include an inter-sectoral and transdisciplinary approach including the socio-anthropological perspective. Therefore, this doctoral project sets out to explore in particular the possible contribution of the social sciences to better control NZDs with the aim to break the vicious cycle of poverty and poor health among livestock owners in endemic and epidemic areas in developing countries.

So far the candidate’s studies focused mostly on the role of anthropology within the framework of inter-sectoral collaborations between animal and human health (Thys et al., 2016). The Dubois-Brigué scholarship will allow her to study more in-depth the environmental dimension, which is the third main pillar of the One Health concept (Zinsstag, 2012). This additional PhD year granted by the Dubois-Brigué Foundation will offer the doctoral candidate the opportunity to learn and adopt a socio-ecosystem approach for zoonotic health problems which is an approach well developed and supported by the South-East Asian One Health movement in general (Roger et al., 2016). Hosted during her scholarship in Indonesia at the One Health/EcoHealth Resource Center of the Universitas Gadjah Mada in Yogyakarta, the grantee will also strengthen her career development towards an overseas post-doc position. Based on the findings generated for Indonesia from her previous multi-country One Health research activity on zoonoses research prioritization and One Health curriculum (see www.snndz.net/research-collaborations/snndz-research-activities/one-health-methods-research/), she will start elaborating a research proposal in the framework of a socio-ecological approach together with Indonesian One Health experts and identified stakeholders. A long term collaborative project in the field of One Health and Anthropology is very relevant and in very high demand among disease control managers and researchers in this particular region of the world where increased zoonotic disease transmission is strongly associated with agricultural expansion, cultural practices and a rapidly increasing livestock trade due to a fast economic growth (Vandersmissen and Welburn, 2014). Moreover, far-reaching environmental challenges (endangered species conservation, air pollution, destruction of coral reefs, deforestation, water security, increased urbanization,…) are emerging in Indonesia which should be addressed from a multisectoral and multi-disciplinary approach at various levels (Bordier and Roger, 2013). A socio-ecological analysis framework such as the one proposed by the PhD candidate seems a useful contribution, both scientifically and operationally.

BORDIER M., ROGER F., Zoonoses in South-East Asia: a regional burden, a global threat, Anim. Health. Res.Rev., 1–28 (2013).

ROGER F., CARON A., MORAND S., PEDRONO M., de GARINE-WICHATITSKY M., CHEVALIER V., TRAN A., GAIDET N., FIGUIÉ M., de VISSCHER M.-N., BINOT A., One Health and EcoHealth: the same wine in different bottles?, Infect. Ecol. Epidemiol., 6, 30978. doi:10.3402/iee.v6.30978 (2016).

THYS S., MWAPE K.E., LEFÈVRE P., DORNY P., PHIRI A.M., MARCOTTY T., PHIRI I.K., GABRIËL S., Why pigs are free-roaming: Communities’ perceptions, knowledge and practices regarding pig management and taeniosis/cysticercosis in a Taenia solium endemic rural area in Eastern Zambia,  Vet. Parasitol., 225, 33–42 (2016).

VANDERSMISSEN A., WELBURN S.C., Current initiatives in One Health: consolidating the One Health Global Network, Rev. Sci. Tech., 33, 421–32 (2014).

ZINSSTAG J., Convergence of EcoHealth and One Health, Ecohealth, 9, 371–3. doi:10.1007/s10393-013-0812-z (2012).

2010-2014 : Stijn Deborggraeve (Prijs) et (Kimberley Bouckaert (Beurs)

2005-2009 : Benoît Vanhollebeke (Prijs)

pour ses recherches portant sur la trypanosomiase humaine africaine et portant spécifiquement sur les mécanismes qui déterminent l'infectivité ou non de certaines espèces de trypanosomes pour l'homme

PRÉSENTATION DE M. LE Dr. B. VANHOLLEBEKE (U.C.L.) 

par M. WÉRY, membre titulaire

Après avoir très brillamment complété des études de bioingénieur à l’U.C.L., Benoît Vanhollebeke a décidé de consacrer son travail de doctorat à une thématique en rapport avec les pays en voie de développement. C’est ainsi qu’il a rejoint le groupe de Parasitologie Moléculaire à l’U.L.B., dirigé par notre Collègue Etienne Pays, pour étudier les relations complexes entre le parasite Trypanosoma brucei et l’homme, chez qui cet organisme provoque la maladie du sommeil, un fléau du continent africain.On  savait  depuis  Laveran  (1912)  que  l’homme  est  intrinsèquement  résistant  à  Trypanosoma brucei mais pas à certaines espèces voisines comme T. b. rhodesiense qui peuvent néanmoins infecter l’homme et produire la maladie du sommeil en échappant à notre système de défense naturel contre ce parasite.

Le groupe d’Etienne Pays avait montré, en 2003, que la protéine sérique appelée apolipoprotéine 1 était responsable de notre immunité contre T. brucei, grâce à sa capacité à tuer très efficacement ce parasite. Nous savions également que l’infection de l’homme par T. brucei rhodesiense était due à la neutralisation de l’apoL1 par une protéine spécifique de ce parasite.

La première contribution de Benoît Vanhollebeke dans ce contexte fut de participer à l’élucidation du mécanisme par lequel l’apoL1 tue T. brucei. Ce travail, publié dans le prestigieux journal Science en 2005, révéla la faculté inattendue de l’apoL1 de créer des canaux ioniques dans la membrane du lysosome, la vacuole digestive du parasite. Les recherches suivantes du lauréat furent consacrées à l’étude du processus par lequel le parasite absorbe avidement l’apoL1 en dépit de sa toxicité. Cette longue et complexe analyse révéla que l’apoL1 est associée dans certaines particules d’HDL à d’autres protéines dont l’Haptoglobin Related Protein (HPR) ressemblant fort à l’haptoglobine, qui joue un rôle essentiel dans la capture de l’apoL1 par le trypanosome. En effet, en liant l’hémoglobine comme le fait aussi l’haptoglobine, l’HPR est reconnue par un récepteur de surface du parasite, auquel donc les particules d’HDL porteuses de l’HPR et de l’apoL1 se fixent efficacement. Le doctorant démontra que la fonction originale du récepteur est de fixer le complexe haptoglobine-hémoglobine, pour internalisation de l’hémoglobine dans le parasite et utilisation de l’hème comme facteur de croissance. Dans le sang humain, la présence des particules d’HDL porteuses du complexe HPR-hémoglobine est donc mal comprise par le parasite, qui internalise rapidement ces particules aussi porteuses de la toxine apoL1, ce qui entraîne sa destruction. On peut donc parler d’un système d’attaque de type « cheval de Troie », car le sang humain contient des particules trypanolytiques déguisées sous forme de facteur de croissance pour le parasite. Cette découverte importante, totalement originale, donna lieu à plusieurs publications de haut niveau dans « Proceedings of the National Academy of Science, New England Journal of Medicine et Science ».

Plus récemment, le Dr Vanhollebeke contribua de façon décisive à la démonstration qu’en Afrique, de nombreux sujets ont acquis des mutations de l’apoL1 qui leur permettent de résister à l’infection par T. brucei rhodesiense, le prix à payer pour cette adaptation étant le développement progressif d’une insuffisance rénale terminale. Ce travail, publié à nouveau dans Science, devrait donner lieu à des développements importants,  aussi  bien  dans  le  contrôle  de  la  maladie  du  sommeil  que  dans  la  compréhension de l’insuffisance rénale chronique, une maladie très fréquente mais largement incomprise.

Benoît Vanhollebeke est un chercheur doué d’une intelligence exceptionnelle et d’une haute compétence technique. Actuellement il effectue un stage post-doctoral aux Etats-Unis, pour lequel son projet de recherche a été classé premier sur 672 par le prestigieux « Human Frontiers Science Programme ». Etant donné sa grande valeur reconnue par tous, le Dr Vanhollebeke a obtenu l’exceptionnelle faveur d’être nommé Professeur assistant à l’issue de son travail de thèse. Il ne fait aucun doute que le Prix Dubois est le premier d’une longue série.

Résumé du travail de M. le Dr B. VANHOLLEBEKE (U.C.L.), Couronné par l’Académie

THE TRYPANOLYTIC FACTOROF HUMAN SERUM : A TROJAN HORSE

African trypanosomes, the prototype of which is Trypanosoma brucei, are protozoan parasites of huge clinical, veterinary and economical importance. They develop in the body fluids of various mammals (including humans) where they face and manipulate many different aspects of the immune system. The extent of this interplay is pivotal to both host and parasite survival, and depending on parasite virulence and host susceptibility, infection duration ranges from some months to several years. At the end, host survival is invariably compromised.

Humans and few other primates provide however a striking exception to this fatal outcome. They are indeed fully protected against most trypanosome infections through the presence in their blood of a so-called trypanosome lytic factor (TLF). The TLF is known to circulate mainly in the form of a high density lipoprotein particle characterized by the simultaneous presence of two primate-specific proteins : haptoglobin-related protein (Hpr) and apolipoprotein L-I (apoL-I).

We have contributed to delineate the respective roles played by Hpr and apoL-I in the lysis process.

ApoL-I was shown to be the exclusive toxin of the TLF. In its absence humans get fully susceptible to any trypanosome infection. The toxin was shown to kill the parasite after endocytosis through the generation of ionic pores in the lysosomal membrane. Those pores dissipate membrane potential and trigger the influx of chloride ions from the cytoplasm into the lysosomal compartment, leading to an eventually fatal uncontrolled osmotic phenomenon.

ApoL-I efficient delivery to the parasite relies on Hpr. African trypanosomes indeed fulfil their heme nutritional requirements by receptor-mediated internalization of the complex formed by haptoglobin, an evolutionary conserved acute-phase protein, and hemoglobin, resulting from physiological intravascular hemolysis. This heme uptake by the auxotrophic parasites contributes to both growth rate and resistance against host oxidative burst. In human serum, the trypanosome receptor is unable to discriminate between Hp and the closely related TLF-bound Hpr, explaining TLF efficient endocytosis.

As such, the TLF acts as a Trojan horse, killing the parasite from inside the cell after having deceived its vigilance through the high similarity between heme-delivering haptoglobin and toxin-associated Hpr.

1985-1989 : Marc Coosemans (Prijs)

"Développement d'une stratégie de lutte contre le paludisme dans une région rizicole au Burundi"

1980-1984 : Maurice Steinert, Etienne Pays, Nestor Van Meirvenne et Dominique Le Ray (Prijs)