Malaria-ResearchAn effective vaccine is imperative in the fight against malaria. The Center for Clinical Malaria Studies has been performing research for more than fifteen years to contribute toward the development of such a vaccine.
Controlled human malaria infections in volunteersDuring controlled human malaria infections (CHMI), we infect healthy volunteers with malaria by having them bitten by malaria-infected mosquitoes. Over the course of the infection, doctors and researchers are able to acquire information about the illness, which they can use to develop better treatment methods. In this way, the effectiveness of a new malaria vaccine can also be tested.
Human testing is necessary because the current animal testing models are not precise enough for human malaria. At the Center for Clinical Malaria Studies at Radboud university medical center, we have more than fifteen years of experience with experimental human malaria studies.
What takes place during a controlled human malaria infection?Step 1: Medical examination
Volunteers will receive a comprehensive medical examination. A volunteer can only participate in the study if he or she is completely healthy.
Step 2: The malaria infection
A cage containing mosquitoes infected with Plasmodium falciparum parasites is placed onto the forearms of the volunteers. These mosquitoes are bred in the malaria unit of Radboud university medical center and have never been in the outside world. The malaria parasites are bred according to the highest quality standards and are susceptible to standard antimalarials.
Step 3: Close medical monitoring
Our clinical-researchers monitor the volunteers daily to see if they develop malaria. If the malaria infection was successful, this is always the case. A volunteer will develop malaria within a maximum of 21 days, but usually between the 7th and 11th day after exposure to the infected mosquitoes. For this reason, beginning on the 6th day after exposure, volunteers will be tested daily during which blood samples will be taken until the infection is detected.
Step 4: Malaria treatment
As soon as the malaria parasites appear in the blood, we will treat the volunteer with highly effective antimalarials. It is expected that the malaria infection will cause most volunteers to develop flu-like symptoms such as headaches, muscle pain, fatigue, and sometimes fever. These symptoms usually disappear within a few days. After this malaria treatment, the malaria parasites will disappear from the body entirely and there is no chance that the infection will return.
Malaria vaccine developmentThrough controlled human malaria infections in healthy volunteers, researchers can study the immune response to malaria. We use this knowledge to develop new, better malaria vaccines.
We research how the malaria parasite itself can be used as a vaccine by repeatedly infecting healthy volunteers with malaria while they take antimalarials. The antimalarials prevent the volunteers from becoming ill, but the immune system comes into contact with the parasite and learns how to destroy it. If these volunteers are bitten by mosquitoes with malaria again, they will no longer become sick even without the antimalarials.
Together with the Leiden University Medical Center and the American company Sanaria Inc., a weakened malaria parasite has been developed at Radboud university medical center, in which two genes have been removed. This “genetically modified” parasite stops developing early on, which, as expected, results in no symptoms occurring in the human subject, but it is still recognized by the immune system. In 2017, we will test if this parasite can be used as a vaccine.
Testing malaria vaccinesTesting of a potential vaccine must first be done extensively on laboratory animals. At a later stage, the vaccines will be tested on healthy volunteers. After a malaria vaccine is found to be safe in healthy volunteers, it will be tested whether the vaccine is effective in preventing malaria. Sometimes, this research is conducted among a group of volunteers in countries where malaria is very common, like in Africa. However, these types of studies are often difficult to set up and conduct in Africa. In order to advance the development of malaria vaccines, these types of studies can also be performed in countries where malaria does not occur naturally. This involves healthy volunteers receiving the new vaccine and being exposed to malaria under strictly controlled conditions in order to see whether the vaccine can effectively prevent malaria.
The Center for Clinical Malaria Studies (CCMS) of Radboud university medical center in Nijmegen is one of the few places in the world where the malaria vaccine can be tested on healthy volunteers. In the meantime, the CCMS has accumulated over fifteen years of experience in this area.
In the years to come, multiple studies with promising malaria vaccines will be performed at the CCMS.
At this moment we are conducting two malaria research studies.
with controlled human malaria infections
CHMI-Trans1 & CHMI-Trans2 study (2018)The primary aim of these projects was to develop a controlled human malaria infection transmission model (“CHMI-trans”) or ‘challenge model’ to evaluate the capacity of vaccines, biologics (monoclonal antibodies, or mAbs), and drugs to block malaria parasite transmission. CHMI-trans2 was a sequel on CHMI-trans1 for the optimization of the transmission model.
Outcome: A clinical protocol to measure transition of the malaria parasite from men to mosquito. The novel clinical model will allow testing of transmission-blocking interventions.
PbVac study (2017/2018)This study was focused on the safety and protective efficacy of genetically modified Plasmodium berghei (Pb(PfCS@UIS4)) malaria parasites in healthy volunteers. This multi-center study was performed in close collaboration with Erasmus MC.
Outcome: Immunization with PbVac is safe and well tolerated with induction of functional immune responses in in vitro assays. No complete protection was not observed, but there was significant delay in parasite patency after the controlled human malaria infection challenge.
GA1 study (2017/2018)The primary aim of this project was to determine the safety and tolerability of direct venous inoculation (DVI) of PfSPZ-GA1 in healthy volunteers. Secondary we aimed to investigate the short-term protective efficacy of PfSPZ-GA1 against Controlled Human Malaria Infection (CHMI) by mosquito bite. The GA1 study was a multi-center study with Leiden University Medical Center
Outcome: Immunisations with PfSPZ-GA1 are well tolerated and safe with modest induction of immune responses and modest protection after challenge. However, no definite conclusion can be drawn from this trial on the potential protective efficacy PfSPZ-GA1.