Re-exposure of Human Volunteers to a Heterologous Strain of P. Falciparum Sporozoites

Study Overview
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Brief Summary
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In a previous study (NL33904.091.10) the investigators challenged 24 volunteers after Chloroquine Prophylaxis Sporozoites (CPS) immunization with 45, 30 or 15 infected mosquito-bites respectively. The availability of this immunized cohort opens the unique opportunity to determine protection to a heterologous challenge for both of the protected and unprotected volunteers as the previous challenge infection might have served as immunological boost to the unprotected volunteers. In the current observational, proof of principle study, the investigators aim to investigate the protection on an individual basis of these previously immunized and challenged volunteers against a heterologous P. falciparum challenge.

Official Title
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Re-exposure of Previously Immunized and Challenged Human Volunteers to a Heterologous Strain of P. Falciparum Sporozoites

Conditions
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Malaria, Falciparum

Intervention / Treatment
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* Biological: Heterologous challenge
* Drug: Malarone treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and ≤ 35 years healthy volunteers (males or females) Good health based on history and clinical examination Negative pregnancy test Use of adequate contraception for females Signing of the informed consent form, thereby demonstrating understanding of the meaning and procedures of the study Agreement to inform the general practitioner and to sign a request to release medical information concerning contra-indications for participation in the study Willingness to undergo a Pf controlled challenge through mosquito bites Agreement to stay in a hotel room close to the trial centre during a part of the study (Day 5 after challenge till treatment is finished) Reachable (24/7) by mobile phone during the whole study period Available to attend all study visit Agreement to refrain from blood donation to Sanquin or for other purposes, during the whole study period Willingness to undergo HIV, hepatitis B and hepatitis C tests Negative urine toxicology screening test at screening visit and the day before challenge Willingness to take a curative regimen of Malarone® Exclusion Criteria: History of malaria (other than participation in ZonMw1 study) or residence in malaria endemic areas within the past six months Plans to travel to malaria endemic areas during the study period Plans to travel outside of the Netherlands during the challenge period Previous participation in any malaria vaccine study and/or positive serology for Pf (except ZonMw1 volunteers) Symptoms, physical signs and laboratory values suggestive of systemic disorders including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric, and other conditions which could interfere with the interpretation of the study results or compromise the health of the volunteers History of diabetes mellitus or cancer (except basal cell carcinoma of the skin) History of arrhythmias or prolonged QT-interval Positive family history in 1st and 2nd degree relatives for cardiac events < 50 years old An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system Clinically significant abnormalities in electrocardiogram (ECG) at screening Body Mass Index (BMI) below 18 or above 30 kg/m2 Any clinically significant deviation from the normal range in biochemistry or hematology blood tests or in urine analysis Positive HIV, HBV or HCV tests Participation in any other clinical study within 30 days prior to the onset of the study Enrollment in any other clinical study during the study period For women: being pregnant or lactating Volunteers unable to give written informed consent Volunteers unable to be closely followed for social, geographic or psychological reasons History of drug or alcohol abuse interfering with normal social function A history of treatment for psychiatric disease A history of convulsions Contra-indications to Malarone®, including hypersensitivity or treatment taken by the volunteer that interferes with Malarone® The use of chronic immunosuppressive drugs, antibiotics, or other immune modifying drugs within three months of study onset (inhaled and topical corticosteroids and oral anti-histaminic are allowed) and during the study period Any confirmed or suspected immunosuppressive or immunodeficient condition, including (functional) asplenia Co-workers or trainees of the departments Infectious Diseases, Medical Microbiology or Parasitology of the Leiden University Medical Centre (LUMC) or Medical Microbiology, Parasitology, Radboud University Nijmegen (RUNMC) A history of sickle cell anaemia, sickle cell trait, thalassaemia (or trait), G6PD deficiency

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Heterologous challenge<br>Biological: Heterologous challenge with 5 infected mosquito bites (NF135) after previous CPS immunization and challenge. Drug: Malarone treatment When thick smear positive, of at day 21 after challenge, all volunteers will be treated with malarone. Other Name: atovaquone/proguanil | Biological: Heterologous challenge<br>* challenge by the bites of 5 Plasmodium falciparum infected mosquitoes.<br>Drug: Malarone treatment<br>* Three days: 4 tablets 250/100mg per day<br>* Other names: atovaquon/proguanil;|
| Active Comparator: Challenge control<br>Biological: Plasmodium falciparum mosquito challenge by the bites of 5 Plasmodium falciparum infected mosquitoes (NF135). Drug: Malarone treatment When thick smear positive, of at day 21 after challenge, all volunteers will be treated with malarone. Other Name: atovaquone/proguanil | Biological: Heterologous challenge<br>* challenge by the bites of 5 Plasmodium falciparum infected mosquitoes.<br>Drug: Malarone treatment<br>* Three days: 4 tablets 250/100mg per day<br>* Other names: atovaquon/proguanil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of prepatent period after challenge infection as measured by microscopy |  | 21 days after challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Parasitemia and kinetics of parasitemia as measured by PCR |  | 21 days after challenge | 
| Frequency of signs or symptoms in study groups |  | 21 days after challenge | 
| • Immune responses between study groups |  | 21 days after challenge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plasmodium, falciparum, malaria, heterologous, immunity