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Malaria Vaccine Research

The most severe form of Malaria is caused by the parasite Plasmodium falciparum, which is transmitted by infected mosquitoes. Malaria affects 40% of the world's population. This represents a tremendous human suffering and a burden that impedes the socio-economic development of the affected resource constrained endemic communities. Even though malaria transmission, and therefore the number of clinical cases, has decreased over the past few years, malaria is still causing the annual death of an estimated 1 million children under five years of age.

The overall goal of our research is to develop a vaccine that will prevent or reduce clinical malaria. The strategy is to reproduce and possibly improve naturally acquired clinical protective immunity and to induce this immunity by vaccination in young children. Most morbidity and mortality is seen in children below the age of five. As morbidity and mortality are both associated with the blood stage of malaria, we concentrate on blood stage antigens with the goal of preventing clinical disease rather than the infection per se. In parallel with the vaccine research, we are also engaged in basic research in Malaria immunology and human genetics to understand the basis of susceptibility to Malaria in African populations.

Vaccine development

For more than 10 years we have been developing and testing vaccines designed to induce high levels of specific antibodies against GLURP. GLURP was first tested as a Long Synthetic Peptide in a Phase 1 clinical trial in European adults. This trial demonstrated that it is possible to elicit high titres of GLURP-specific IgG antibodies which are able to kill the parasite in in vitro growth inhibition experiments (ADCI). GLURP was then fused genetically to the C-terminal part of Merozoite Surface Protein 3 (MSP3) and the resulting hybrid protein (GMZ2) was produced on recombinant form in Lactococcus Lactis. GMZ2 adjuvanted by Aluminium Hydroxide has successfully passed phase 1 clinical testing in adult German and Gabonese volunteers and Gabonese children under the age of five.

GMZ2 works by targeting the malaria parasite in the blood stage (merozoite) of the infection. The vaccine stimulates the body’s immune system to produce antibodies and cytokines that target GLURP and MSP3 on the malaria parasite. These killer agents have been demonstrated to completely inhibit malaria parasite growth in animal experiments. Early studies of the GMZ2 candidate malaria vaccine were done by the University of Tübingen among malaria naïve German adults with support from the European Malaria Vaccine Initiative (EMVI). Recent studies done in Africa were conducted by the Medical Research Unit of the Albert Schweitzer Hospital in Gabon with funding from the European Commission – AIDCO and EDCTP. These studies have so far confirmed that GMZ2 is safe for human use. They have further confirmed that GMZ2 is able to induce the production of specific antibodies and memory B-cells targeting the plasmodial proteins GLURP and MSP3 at high levels.

As a result of these early safety studies, GMZ2 has been selected for a multi-centre phase IIb clinical trial to assess its efficacy and safety among young children with a high risk of getting malaria in Burkina Faso, Gabon, Ghana and Uganda. A total of 1870 children aged between 1 and 5 years from the four participating centres; Banfora - Burkina Faso, Iganga – Uganda, Lambaréné - Gabon, and Navrongo - Ghana are taking part in what will be the largest trial to date for GMZ2.

In this multi-centre trial, half the number of the participating children will receive 3 doses each of 100 micrograms of GMZ2, the test vaccine while the other half (control group) will receive rabies vaccine. Over three months, each child will have received three doses of either the test vaccine or comparator. All children will be observed for a period of 2 years. During this time, safety, immune response and clinical information will be collected and assessed to answer the question whether or not the GMZ2 vaccine protects against clinical malaria.

Recently we have also become part of the REDMAL project which aims to test a transmission blocking vaccine in European volunteers. This project is based on the Pf48/45 protein developed by R. Sauerwein and co-workers.

Vaccine research

The major research projects currently are:

Establishment of in vitro growth inhibition models for blood stage malaria

• IgG antibodies against GLURP and MSP3 collaborate with human monocytes to kill Plasmodium falciparum in the in vitro growth inhibition assay - ADCI. This assay has been developed and studied in detail by Pierre Druilhe and co-workers at Institut Pasteur. In order to assess the biological anti-parasite effect of GMZ2 vaccine induced antibody response, we are conducting experiments to establish a reproducible and harmonized ADCI assay in our group. This assay will allow determining whether the ADCI activity can be correlated to protection against clinical malaria

Studies on the genetic susceptibility to malaria

• There is considerable evidence that host genetic factors play a major role in determining the outcome of infection with many pathogens, and studies of malaria in different human populations have identified several genes that affect susceptibility. With a focus on the genes for FcγRs and the complement activation system we try to further understand how IgG antibodies control parasite multiplication in vivo.

An antigen discovery program with a focus on antigens that can target the blood-stage

• The subclass profile of naturally occurring IgG responses has been extensively studied for several major blood-stage malaria vaccine candidate antigens. These analyses have mainly been carried out by ELISA using recombinant proteins or synthetic peptides usually representing subdomains of malaria proteins as test antigens. Such antigen preparations do not always accurately mimic native parasite protein conformations, including post-translational modifications. We have therefore adopted a more global approach to study the targets of the naturally occurring anti-parasite IgG subclass responses through IgG subclass specific Western blot analysis of total parasite proteins expressed in mature blood stage schizonts. Purified Parasitophorous Vacuole Membrane-Enclosed Merozoite Structures (PEMS) are used as a source for parasite antigens, because PEMS preparations i) contain a highly homogeneous synchronous parasite population at the mature schizont stage and ii) they are essentially free of contaminating host cell proteins.

Analysis of immune responses in cohorts of malaria exposed individuals

• The Luminex technology allows measuring the concentration of specific antibodies in small amounts of blood. This is particularly important when assessing antibody responses in paediatric trials since the amount of blood which can be taken from infants and small children is very restricted. We are therefore developing a bead-based assay for the simultaneous detection of antibodies against multiple P. falciparum antigens. Using this system, specific antibody responses are assessed in immunized volunteers and naturally exposed individuals.