Radboudumc

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Research Medical Parasitology

The malaria vaccine research program covers a broad spectrum of activities from molecule to man with continuous cross talk between basic research, clinical testing and (epidemiological) studies in malaria endemic countries.

Mission:
Clinical development of Plasmodium falciparum vaccines for control and elimination of malaria. We are exploring mechanisms of parasite biology, and pursuing identification of the immune signature of protection against malaria and (clinical) development of  candidate malaria vaccines.


Clinical development of Malaria Vaccines

This represents development and clinical testing of Plasmodium falciparum malaria vaccines and identification of immune correlates of protection. Research activities include studies in the Controlled Human Malaria Infection Model as well as studies in naturally infected populations in malaria endemic countries.

Attenuated Whole Sporozoite Vaccines 
a. Genetically attenuated sporozoites 
b. Wild type sporozoites administered under Chemoprophylaxis (CPS-immunization)

An attenuated sporozoite vaccine should be safe in absolute absence of breakthrough blood infections while inducing complete protection. We generated deletion mutants deficient for essential genes for liverstage development.  Our findings provide the foundation of  the first genetically attenuated parasite  for clinical testing (PfSPZ-GA1). We pioneered a highly efficient immunization protocol for complete and lasting protection in the controlled human  malaria infection model (NEJM 2009, Lancet 2011). This will be translated into a vaccine product (PfSPZ-CVac).

Transmission Blocking Vaccines
Vaccines interrupting malaria transmission aim to reduce the spread of the parasites among humans by preventing infection of Anopheles vectors and represent essential tools for malaria elimination. Such vaccines are an essential tool for eradication. Our vaccine strategy is based on the Pfs48/45 protein only expressed and functionally involved in transmission stages. We have developed a first generation sub-unit of Pfs48/45 as vaccine candidate currently in cGMP production (R0-PF10C) for clinical testing. We are pioneering the next generation functional bioassay for transmission blocking antibodies by using luciferase-tagged cultured parasites for mosquito feeding and study parasite and mosquito factors involved in transmission.  

TropIQ
is our spin-off company aiming for better tools for transmission studies.

Biology of Malaria

Unlike viruses or bacteria, malaria parasites belong to an ancient family of single-cell infectious organisms that have a very complex cellular structure, much like our own cells. These cells consist of many different chambers, so called organelles, each with their own function. The mitochondrion is one such specialized organelle, often referred to as the cell's power plant, while in most cells it is the main site of energy production. Malaria parasites only have a single and abnormal mitochondrion, which is essential for the parasite's survival. Indeed, one of the most effective anti-malarial drugs, atovaquone, kills the parasite by targeting a mitochondrial protein. 

We aim to identify all of the estimated 400-500 mitochondrial proteins. Using this information, we will build a computational model that will allow the prediction of essential proteins. In addition we will start to improve existing methods to modify the parasite DNA in order to remove genes with a role in mitochondria to study their function and verify the computer predictions. Finally, by comparing the experimentally validated malaria mitochondrial model with existing models of human mitochondria, we intend to identify suitable targets for new anti-malarial medicines. These projects are led by Taco Kooij in collaboration with the Centre for Molecular and Biomolecular Informatics (prof.dr. M. Huynen).

Fluorescent tags

Left: a live blood-stage trophozoite with a 'protein export tubule' (Matz et al. 2013).
Centre: live motile mosquito-stage ookinetes showing vesicular localization of copper transporting ATPase (Kenthirapalan et al. 2014).
Right: fully developed liver-stage parasite releasing invasive merozoites (Haussig et al. 2011).

Epidemiology of Malaria

In observational and intervention studies, we aim to understand and interrupt the transmission of P. falciparum. The burden of malaria is unequally distributed in populations with some humans disproportionally receiving infected mosquito bites. We aim to understand what drives this transmission in terms of ecology, mosquito-to-human transmission and the human infectious reservoir for malaria. For this purpose, we use serological and molecular tools to determine spatial patterns in disease transmission and directly assess human infectiousness to mosquitoes by mosquito feeding assays. With this set of tools, we explore the prevalence and epidemiological importance of submicroscopic malaria infections for disease transmission and malaria elimination.

Our work demonstrates that submicroscopic gametocyte densities are highly common, frequently result in mosquito infections and can maintain malaria transmission in areas of low endemicity. We further show that adding transmission-blocking drugs to current malaria therapies can substantially reduce this transmission and aid malaria elimination strategies. The clustering of malaria infections in transmission hotspots may provide an attractive opportunity to target transmission-blocking interventions to these areas that are most important for maintaining transmission.

These projects, led by Teun Bousema, include epidemiological studies on the human infectious reservoir for malaria in Kenya and Burkina Faso and (community) interventions to reduce the transmission of P. falciparum.

Malaria Facility

The Malaria Facility of the Radboudumc represents an unique research/production facility for culturing Plasmodium falciparum malaria parasites and breeding and infection of Anopheles mosquitoes with human and various mice malaria. This unit is world leader in the production of different parasite lifecycle stages, distributing material and participating in many international studies and while pursuing its own mission: to develop a malaria transmission blocking vaccine and to research the transmission of malaria from human to mosquito. Read more



Laboranten

Malaria gevoed

Contact

Tel: +31 24 361 4615
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