Malaria, a disease caused by the parasite Plasmodium, is one of the world's major infectious diseases. With approximately 627.000 deaths a year, there is desperate need for an effective vaccine. Though a number of vaccine-candidates have been developed, they have yet to achieve the level of efficacy necessary to eliminate malaria. It has been shown previously that healthy human volunteers bitten by malaria-infected mosquitoes while taking chloroquine, medicine that prevents malaria, are fully protected against a subsequent malaria challenge. This is called CPS-immunization. The unprecedented effectiveness of CPS-immunization makes it a good model to identify what immune responses protect against malaria, to further guide vaccine development. In this study we will use CPS-immunization to induce protection against malaria in healthy subjects and then analyse their immune response to a malaria challenge infection.
Rationale: Malaria, a disease caused by the parasite Plasmodium, is one of the world's major infectious diseases. With approximately 627.000 deaths a year, it is both a chief cause of morbidity and mortality as well as a significant contribution to ongoing poverty in endemic countries. Ultimately, the key to malaria control and hopefully eradication, would be an effective vaccine. Though a number of vaccine-candidates have entered the pipeline of pre-clinical and clinical development, they have yet to achieve the level of efficacy necessary for effective malaria prevention. It has been shown previously that healthy human volunteers can be fully protected against malaria infection with a homologous parasite by immunization with Plasmodium parasites while taking chloroquine chemoprophylaxis (ChemoProphylaxis and Sporozoites, CPS-immunization). The unprecedented efficacy of CPS-immunization makes it a unique model to identify pre-erythrocytic target antigens for the development of a subunit vaccine. Identification of antigens that play a significant role in the development of sterile protection against malaria will provide a basis for the development and evaluation of more effective sub-unit candidate vaccines. Primary objective: • To delineate the antibody repertoire directed against the pre-erythrocytic stages of Plasmodium falciparum induced by CPS-immunization. Secondary objectives: * To assess the functionality of CPS-immunization induced antibodies. * To determine T-cell antigen specificities in CPS-immunized, protected volunteers. Exploratory objectives: * To assess the functionality of CPS-immunization induced T-cells. * To explore the adaptive and innate immune responses during CPS-immunization and early malaria infection. Study design: This is a single-centre, randomized open-label study. A total of 15 volunteers will be divided into two groups, one scheduled to receive CPS immunization (Group 1, n=10) and one to receive only chloroquine prior to malaria challenge (Group 2, n=5). Study population: The study population will be comprised of male and female healthy subjects. A total of 15 subjects will be enrolled to participate in the study and randomized. Intervention: In the immunization group a total of four CPS immunizations will be performed, with 15 bites from Plasmodium infected mosquitoes per immunization, over a period of four months, during which volunteers will take chloroquine prophylaxis. The control group will take only chloroquine prophylaxis during this period. All volunteers will undergo Controlled Human Malaria Infection (CHMI) by exposure to 5 bites from Plasmodium falciparum sporozoite infected mosquitoes.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
15
Subjects will receive four 'immunizations' with bites from 15 Plasmodium infected mosquitoes during each immunization, while taking chloroquine prophylaxis.
Subjects will receive bites from 5 Anopheles mosquitoes infected with Plasmodium falciparum, NF54 strain.
Registered for prophylaxis against infection with Plasmodium falciparum and the treatment of acute infections.
Registered for use as an antimalarial agent for the treatment of acute infections with Plasmodium falciparum. One tablet contains: atovaquone 250 mg, proguanil(hydrochloride) 100 mg
Radboud university medical center
Nijmegen, Gelderland, Netherlands
Generation of B-cells for delineation of antibody responses against Plasmodium falciparum pre-erythrocytic stages in CPS-immunized, protected volunteers.
After immunization and Controlled Human Malaria Infection (CHMI) blood will be drawn to isolate plasmablast for further delineation of the antibody responses following CPS-immunization.
Time frame: On day 232-238 of the study (6-11 days after challenge malaria infection)
Functionality of CPS-immunization induced antibodies for protection against pre-erythrocytic stages of Plasmodium falciparum.
On day 107 and day 142 of the study (14 days after the 3rd CPS-immunization and 14 days after the 4th immunization) blood will be drawn for IgG isolation, which will be used to determine the functionality of these antibodies against the pre-erythrocytic stages of Plasmodium falciparum.
Time frame: On day 107 and day 142 of the study (14 days after the 3rd CPS-immunization and 14 days after the 4th immunization)
The specificity of CPS-immunization induced T-cell responses against pre-erythrocytic stages of Plasmodium falciparum.
Before the first immunization and six weeks after the malaria challenge infection leukapheresis will be performed to isolate T-cells, which will be used to determine the activity of T-cells against specific target antigens of the pre-erythrocytic stages of Plasmodium falciparum.
Time frame: On day 1-14 and on day 267-280 of the study (before the first immunization and after Controlled Human Malaria Infection (CHMI))
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