Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis

Study Overview
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Brief Summary
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Malaria is one of the major infectious diseases in the world with a tremendous impact on the quality of life, significantly contributing to the ongoing poverty in endemic countries. It causes 800.000 deaths per year, the majority of which are children under the age of five. The malaria parasite enters the human body through the skin, by the bite of an infected mosquito. Subsequently, it invades the liver and develops and multiplies inside the hepatocytes. After a week, the hepatocytes burst open and the parasites are released in the blood stream, causing the clinical phase of the disease. As a unique opportunity to study malaria immunology and efficacy of immunisation strategies, a protocol has been developed in the past to conduct controlled human malaria infections (CHMIs). CHMIs generally involve small groups of malaria-naïve volunteers infected via the bites of P. falciparum infected laboratory-reared Anopheline mosquitoes. Although potentially serious or even lethal, P. falciparum malaria can be radically cured at the earliest stages of blood infection when risks of complications are virtually absent. The investigators have shown previously that healthy human volunteers can be protected from a malaria mosquito (sporozoite) challenge by immunization with sporozoites (by mosquito bites) under chloroquine prophylaxis (CPS immunization). Interestingly, sterile protection in 100% of the human CPS immunized volunteers was achieved by a relatively miniscule dose, i.e. a total of 45 infectious mosquito bites, strikingly 20-fold more potent than the 1000 bites needed in a model using irradiated mosquitoes. One possible explanation for this efficient induction of protective immunity, is the immune modulating effect of chloroquine. The investigators aim to assess this possible immune modulating effect in CPS immunization by comparing immunization with P. falciparum sporozoites under chloroquine with immunization under mefloquine prophylaxis, which has the same antimalarial effect, but not the immune modulating effects known from chloroquine.

Official Title
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Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis

Conditions
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Malaria, Plasmodium Falciparum

Intervention / Treatment
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* Drug: Chloroquine prophylaxis
* Drug: Mefloquine prophylaxis
* Biological: Immunization
* Biological: Controlled Human Malaria Infection
* Drug: Malarone


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 infection through mosquito bites Agreement to stay in a hotel room close to the trial center 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 visits 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 prophylactic regime of chloroquine or mefloquine and curative regimen of Malarone® Exclusion Criteria: History of malaria 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 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 20 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: pregnancy or lactation 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 or moderate or severe psychological episode in volunteer A history of convulsions in volunteer Severe depression, anxiety disorder of psychosis in first or second degree family Contra-indications to Malarone®, chloroquine or mefloquine including hypersensitivity or treatment taken by the volunteer that interferes with Malarone®, chloroquine or mefloquine 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 asplenia Co-workers or trainees of the departments of Medical Microbiology, Parasitology, or Internal Medicine of the Leiden University medical Centre A history of sickle cell anemia, sickle cell trait, thalassemia, thalassemia trait or 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Chloroquine immunisation<br>This group will receive chloroquine prophylaxis, and three times infected mosquito-bites. | Drug: Chloroquine prophylaxis<br>* Standard prophylactic regime: a loading dose of 300 mg on day 14 and day 17 and then 300 mg once a week, starting on day 21, for a total duration of 13 weeks. On day 0, day 3, day 7 and day 10, this group will receive a placebo.<br>Biological: Immunization<br>* Group 1 and 2 will receive three immunizations with Plasmodium falciparum infected mosquito-bites. Group 3 will receive an equal number of uninfected mosquito-bites.<br>Biological: Controlled Human Malaria Infection<br>* Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.<br>Drug: Malarone<br>* When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.<br>* Other names: atovaquon/proguanil;|
| Experimental: Mefloquine immunisation<br>This group will receive mefloquine prophylaxis and infected mosquito-bites. | Drug: Mefloquine prophylaxis<br>* Mefloquine prophylaxis, starting with a loading regime of split doses during the first three weeks: 125 mg on day 0, day 3, day 7, day 10, day 14 and day 17 and 250 mg once a week from day 21 onwards for a total duration of 13 weeks.<br>Biological: Immunization<br>* Group 1 and 2 will receive three immunizations with Plasmodium falciparum infected mosquito-bites. Group 3 will receive an equal number of uninfected mosquito-bites.<br>Biological: Controlled Human Malaria Infection<br>* Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.<br>Drug: Malarone<br>* When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.<br>* Other names: atovaquon/proguanil;|
| Placebo Comparator: Mefloquine control<br>This group will receive mefloquine prophylaxis, and uninfected mosquito-bites. | Drug: Mefloquine prophylaxis<br>* Mefloquine prophylaxis, starting with a loading regime of split doses during the first three weeks: 125 mg on day 0, day 3, day 7, day 10, day 14 and day 17 and 250 mg once a week from day 21 onwards for a total duration of 13 weeks.<br>Biological: Immunization<br>* Group 1 and 2 will receive three immunizations with Plasmodium falciparum infected mosquito-bites. Group 3 will receive an equal number of uninfected mosquito-bites.<br>Biological: Controlled Human Malaria Infection<br>* Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.<br>Drug: Malarone<br>* When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.<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 (day 239 of the study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of parasitemia as measured by PCR |  | 21 days after challenge (day 239 of study) | 
| Frequency of signs or symptoms in study groups |  | Day 0 - day 358 of study | 
| Cellular immune responses between study groups |  | Day 0 -day 358 of study | 
| Humoral immune responses between study groups |  | Day 0 - 358 |