Safety and Preliminary Protective Efficacy of Genetically Attenuated GA2 Parasites.

Inclusion Criteria: * Subject is aged ≥ 18 and ≤ 35 years and in good health. * Subject has adequate understanding of the procedures of the study and agrees to abide strictly thereby. * Subject is able to communicate well with the investigator, is available to attend all study visits. * Furthermore, the subject will remain within the Netherlands from day -1 till day +28 after each parasite exposure. After CHMI, subjects have to be reachable by phone (24/7) from day -1 until day 35. * Subject agrees to inform his/her general practitioner (GP) about participation in the study. * Subject agrees to refrain from blood donation to Sanquin or for other purposes throughout the study period and for a defined period thereafter according to Sanquin guidelines. * Non-pregnant, non-lactating females of reproductive potential (i.e., have a uterus and are neither surgically sterilized nor post-menopausal) agree to use adequate contraception and to not breastfeed for the duration of study. * Subject agrees to refrain from intensive physical exercise (disproportionate to the subjects' usual daily activity or exercise routine) for twenty-one days following each immunization and during the malaria challenge period. Exclusion Criteria: * Any history, or evidence at screening, of clinically significant symptoms, physical signs or abnormal laboratory values suggestive of systemic conditions, such as cardiovascular, pulmonary, renal, hepatic, neurological, dermatological, endocrine, malignant, hematological, infectious, immune-deficient, psychiatric or other disorders, which could compromise the health of the volunteer during the study or interfere with the interpretation of the study results. These include, but are not limited to, any of the following: a. Body weight \<50 kg or Body Mass Index (BMI) \<18.0 or \>30.0 kg/m2 at screening. b. A heightened risk of cardiovascular disease, defined as: An estimated ten-year risk of fatal cardiovascular disease of ≥5% at screening, as determined by the Systematic Coronary Risk Evaluation (SCORE); i. An estimated ten-year risk of fatal cardiovascular disease of ≥5% at screening, as determined by the Systematic Coronary Risk Evaluation (SCORE); ii. History, or evidence at screening, of clinically significant arrhythmia's, prolonged QT-interval or other clinically relevant ECG abnormalities; or iii. A positive family history of cardiac events in first or second degree relatives (according to the system used in medical genetics) \<50 years old. c. Functional asplenia, sickle cell trait/disease, thalassemia trait/disease or G6PD deficiency. d. History of epilepsy in the period of five years prior to study onset, even if no longer on medication. e. Positive HIV, HBV or HCV screening tests. f. Chronic use of i) immunosuppressive drugs, ii) antibiotics, iii) or other drugs that might have an influence on the immune system (excluding inhaled and topical corticosteroids and incidental use of oral anti-histamines), within three months prior to study onset or expected use of such during the study period. g. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past five years. h. Any history of treatment for severe psychiatric disease by a psychiatrist in the past year. i. History of drug or alcohol abuse interfering with normal social function in the period of one year prior to study onset, positive urine toxicology test for cocaine, amphetamines or cannabis at screening. * For female subjects: breastfeeding, or positive urine pregnancy test at screening or prior to immunization or prior to CHMI. * Any history of malaria, positive serology for Pf, or previous participation in any malaria (vaccine) study or CHMI. * Known hypersensitivity to or contra-indications (including co-medication) for use of atovaquone/proguanil or artemether/lumefantrine, or history of severe (allergic) reactions to MB. * Receipt of any vaccinations in the three months prior to the start of the study or plans to receive any other vaccinations during the study period or up to eight weeks thereafter. Exceptions are made for influenza vaccination and for vaccination against the coronavirus SARS-COV2 or any other vaccination which cannot be reasonably withheld or postponed. * Participation in any other clinical study in the 30 days prior to the start of the study or during the study period. * Being an employee or student of the department of Parasitology, Medical Microbiology or Infectious Diseases of the RadboudUMC or the LUMC. * Any other condition or situation that would, in the opinion of the investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol or would compromise the integrity of the data.