Safety and Protective Efficacy of Pb(PfCS@UIS4)

Study Overview
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Brief Summary
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In the underlying study, a genetically modified P. berghei parasite is used. P. berghei is one of the four Plasmodium species that causes malaria in rodents. The hypothesis is that immunization of humans with P. berghei will induce a cross-species immune response without the risk of a breakthrough infection. To further increase the potential for protective efficacy, the P. falciparum circumsporozoite (CS)- protein gene has been integrated in the P. berghei parasite, generating a genetically modified P. berghei parasite, abbreviated as Pb(PfCS@UIS4).

Official Title
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Safety and Protective Efficacy of Genetically Modified Plasmodium Berghei (Pb(PfCS@UIS4)) Malaria Parasites in Healthy Volunteers

Conditions
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Malaria,Falciparum, Plasmodium Falciparum, Plasmodium Berghei, Controlled Human Malaria Infection (CHMI)

Intervention / Treatment
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* Biological: Pb(PfCS@UIS4)-infected mosquitoes
* Other: Challenge infection P. falciparum


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is aged ≥ 18 and ≤ 35 years and in good health. Subject has adequate understanding of the procedures of the study and is able and willing (in the investigator's opinion) to comply with all study requirements. Subject is willing to complete an informed consent questionnaire and is able to answer all questions correctly. Subject is able to communicate well with the investigator and is available to attend all study visits, lives in Rotterdam or in proximity to the trial centre (can be on site within 1 hour) or is willing to stay in a hotel close to the trial centre during part of the study (phase 1: from day of immunization to day 12 post-immunization; phase 2: from day of immunization to day 8 post-immunization. The subject will remain within the Netherlands from day -1 until day +28 after immunization during phase 1; from day -1 until day 12 after each immunization during phase 2, and during the challenge period, will not travel to a malaria-endemic area during the study period, and is reachable (24/7) by mobile telephone throughout the entire study period. Subject agrees to their general practitioner being informed and contacted about their participation in the study and agrees to sign a form to request the release by their General Practitioner (GP), and medical specialist when necessary, to the investigator(s), of any relevant medical information concerning possible contra-indications for participation in the study. The 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 current Sanquin guidelines (3 years minimum, depending on serology). For female subjects: subject agrees to use continuous adequate contraception** and not to breastfeed for the duration of study. Subject agrees to refrain from intensive physical exercise (disproportionate to the subject's usual daily activity or exercise routine) during the malaria challenge period. Subject agrees to avoid additional triggers that may cause elevations in liver enzymes including alcohol from baseline up to 1 week post treatment. Subject has signed written informed consent to participate in the trial. Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: 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, haematological, infectious, immunodeficient, psychiatric and 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. 1.1. Body weight <50 kg or Body Mass Index (BMI) <18 or >30 kg/m2 at screening. 1.2. A heightened risk of cardiovascular disease, as determined by: an estimated ten year risk of fatal cardiovascular disease of ≥5% at screening, as determined by the Systematic Coronary Risk Evaluation (SCORE); history, or evidence at screening, of clinically significant arrhythmia's, prolonged QT-interval or other clinically relevant ECG abnormalities; or a positive family history of cardiac events in 1st or 2nd degree relatives <50 years old. 1.3. A medical history of functional asplenia, sickle cell trait/disease, thalassaemia trait/disease or G6PD-deficiency. 1.4. History of epilepsy in the period of five years prior to study onset, even if no longer on medication. 1.5. Screening tests positive for Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) 1.6. Chronic use of i) immunosuppressive drugs, ii) antibiotics, iii) or other immune modifying drugs within three months prior to study onset (inhaled and topical corticosteroids and oral anti-histamines exempted) or expected use of such during the study period. 1.7. Any recent or current systemic therapy with an antibiotic or drug with potential anti-malarial activity (chloroquine, atovaquone-proguanil, arthemether-lumefantrine, sulfadoxine-pyrimethamine, doxycycline, tetracycline, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, erythromycin, hydroxychloroquine, etc.) (allowable timeframe for use at the Investigator's discretion). 1.8. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years. 1.9. Any history of treatment for severe psychiatric disease by a psychiatrist in the past year. 1.10. 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 or amphetamines at screening or at inclusion, or positive urine toxicology test for cannabis at inclusion. For female subjects: positive urine pregnancy test at screening and/or at the baseline visits, including baseline of immunizations (I-1) and or baseline before CHMI (C-1). Any history of malaria, positive serology for P. falciparum, or previous participation in any malaria (vaccine) study. Known hypersensitivity to or contra-indications (including co-medication) for use of sulfadoxine-pyrimethamine, piperaquine, chloroquine, Malarone®, artemether-lumefantrine, primaquine or history of severe (allergic) reactions to mosquito bites. Receipt of any vaccinations in the 3 months prior to the start of the study or plans to receive any other vaccinations during the study period or up to 8 weeks thereafter. 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 Medical Microbiology and Infectious Diseases of the Erasmus MC or Radboudumc, or the department of Internal Medicine of the Radboudumc or Havenziekenhuis. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - five Pb(PfCS@UIS4)-infected mosquitoes<br>(Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes | Biological: Pb(PfCS@UIS4)-infected mosquitoes<br>* Pb(PfCS@UIS4)-infected mosquitoes<br>|
| Experimental: Group 2 - 25 Pb(PfCS@UIS4)-infected mosquito bites<br>(group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites | Biological: Pb(PfCS@UIS4)-infected mosquitoes<br>* Pb(PfCS@UIS4)-infected mosquitoes<br>|
| Experimental: Group 3 - 75 Pb(PfCS@UIS4)-infected mosquito bites<br>(group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites | Biological: Pb(PfCS@UIS4)-infected mosquitoes<br>* Pb(PfCS@UIS4)-infected mosquitoes<br>Other: Challenge infection P. falciparum<br>* Challenge infection with bites of five infected Pf mosquitoes<br>|
| Other: Group 4 - Infectivity control group of Phase 1<br>Infectivity control group of Phase 1 | Other: Challenge infection P. falciparum<br>* Challenge infection with bites of five infected Pf mosquitoes<br>|
| Other: Group 5 - Infectivity control group of Phase 2<br>Infectivity control group of Phase 2 | Other: Challenge infection P. falciparum<br>* Challenge infection with bites of five infected Pf mosquitoes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] | Frequency and magnitude of adverse events in study groups following one or more exposures to Pb(PfCS@UIS4)-infected mosquitoes. | Groups 1&2: from exposure to Pb(PfCS@UIS4)-infected mosquitoes until 28 days thereafter. Group 3: from first exposure until 21 days after fourth/final exposure (=until day immediately prior to CHMI, i.e. approximately 15 weeks after first exposure). | 
| Presence of Breakthrough Parasitemia Following Exposure to Pb(PfCS@UIS4)-Infected Mosquito Bites | Presence of breakthrough parasitemia following (first) exposure to Pb(PfCS@UIS4)-infected mosquito bites, as determined by thick blood smear microscopy | Groups 1-3: from (first) exposure until 28 days thereafter. | 
| Time to Parasitemia After CHMI [Efficacy] | Time to parasitemia after CHMI with the wild-type NF54 P. falciparum strain, as detected by qPCR [Efficacy] | Groups 3&4: from day of CHMI until 28 days thereafter | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of Pb(PfCS@UIS4) as Assessed by ELISA | Immunogenicity of repeated Pb(PfCS@UIS4) immunization as assessed by fold change in anti-P. falciparum IgG from baseline to post-immunization (day prior to CHMI), as measured by ELISA. | Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization) |