Leiden malaria research activities between 1982-2021 (Leiden University Medical Center, LUMC, The Netherlands)
– Former colleagues Leiden malaria research group (1990-2020)
(current colleagues 2020/2021 – Dr. Blandine Franke-Fayard, Dr. Shahid M. Khan†, Dr. Catherin Marin-Mogollon, Dr. Surendra K. Kolli, Ing. Jai Ramesar, Ing. Hans Kroeze, Ing. Severine Chevalley-Maurel , Ing. Fiona J.A. Geurten).
1976-1982: Leiden University, The Netherlands
The undergraduate/graduate studies were performed at the Faculty of Science (Biology) of the Leiden University, The Netherlands. Graduate research involved studies on the ecology and host-seeking behavior of parasitic wasps, ecology of bird populations (relationships between bird species diversity and forest management) and cell-biology of malaria parasites (genetic and environmental factors underlying sexual differentiation).
1983-1986: Leiden University / Utrecht University, The Netherlands
The PhD studies (cum Laude), funded by the Netherlands Organization for Scientific Research (NWO), were carried out jointly between the Utrecht University and the Leiden University (thesis title: ‘DNA synthesis in malaria parasites’). These PhD studies involved the development of technologies for use of the rodent model of malaria Plasmodium berghei to investigate sexual differentiation and DNA replication in malaria parasites. For example, technologies for in vitro cultivation of blood stages and sexual stages of the parasite (in collaboration with Dr. B. Mons). These technologies have significantly increased the relevance of P. berghei as a model for human malaria and improved the understanding of the biology of malaria parasites at the cellular and molecular level; for example, novel insights into DNA-replication processes during parasite sexual development. Technologies were developed that allowed the first identification, separation and characterization of chromosomes of rodent malaria parasites.
1986-2005: Leiden University / Leiden University Medical Center, The Netherlands
After the PhD studies, research in the Department of Parasitology (Leiden, LUMC) focused on the further development of rodent malaria models to investigate the biology of malaria parasites. This research lead to the introduction and application of advanced molecular techniques in malaria research, such as genomic- (genome sequencing) and post-genomic (transcriptome, proteome) technologies and contributed to the genome sequencing of different malaria parasites and genome-wide studies of gene expression (microarrays, RNAseq analyses, proteome analyses).
A major breakthrough was the implementation of technologies for genetic modification of rodent malaria parasites; technologies that allowed, for the first time, the generation of malaria parasites that retain stable genetic modifications. These and other technologies have opened up new avenues in malarial research and have greatly aided studies on the basic biology of the parasite and studies on host-parasite interactions involved in pathology. For example, these technologies contributed to the functional analysis of many malaria genes (including potential novel vaccine and drug targets), provided insights into molecular processes such as translational regulation of gene expression and permitted real-time in vivo imaging of parasite-host interactions (in collaboration with Dr. A.P. Waters, Dr. B. Franke-Fayard and Dr. S.M. Khan). In 2005 these studies led to the development of the concept of vaccination with genetically attenuated parasites (GAP) and it was shown in rodent malaria models that GAP immunization can effectively protect against malaria infection.
2005-2021: Leiden University / Leiden University Medical Center, The Netherlands
Head of the Leiden Malaria Research Group (Department of Parasitology, LUMC): The current emphasis of the research is on the development of a human malaria vaccine based on genetically attenuated parasites (GAP) and on the identification and analysis of parasite proteins that are (putative) targets for improving current subunit vaccines that are in development. For preclinical evaluation of novel vaccine candidates, the optimized rodent malaria models are used, followed by the translation into human malaria vaccines and clinical evaluation (for example, viral-vectored and mRNA vaccines targeting pre-erythrocytic stages of the human parasite; in collaboration with different international research groups, for example at the Jenner Institute, Oxford). This research is based on the generation of a variety of gene-deletion and transgenic parasites, expressing reporter proteins (such as fluorescent, bioluminescent and OVA proteins), which have proven to be valuable tools in dissecting parasite biology and screening for vaccine candidate antigens. These genetically modified, transgenic parasites are shared by many different labs worldwide; in 2018 more than 170 transgene expressing parasites have been distributed by the Leiden malaria group to more than 50 scientific groups across the world. In addition, CRISPR-Cas9 genetic modification of the human malaria parasite P. falciparum has been optimized for the creation of mutant (gene-deletion and gene-insertion) parasite lines, free of selectable marker genes encoding drug-resistance proteins.
The studies on a GAP vaccine led to the generation of the first malaria vaccine (GA1-Pfspz) consisting of genetically attenuated P. falciparum parasites and the preclinical and clinical evaluation of this vaccine (2015-2020; in collaboration with the biotech company Sanaria, US and Radboudumc, The Netherlands). This vaccine was safe and induced protective immune responses in human volunteers. Current studies are focused on enhancing the efficacy/immunogenicity of a genetically attenuated malaria vaccine and a clinical study testing a second-generation GAP vaccine (GA2) developed in Leiden is planned for 2021 (in collaboration with Dr. B. Franke-Fayard, Dr. M. Roestenberg and Radboudumc, The Netherlands).