EHMI9: Experimental Human Malaria Infection After Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Prophylaxis

Sponsor

Radboud University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT01236612

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 almost one million 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 experimental human malaria infections (EHMIs). EHMIs 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, Plasmodium falciparum (P.falciparum) malaria can be radically cured at the earliest stages of blood infection where risks of complications are virtually absent.

The investigators have shown previously, that healthy human volunteers can be protected from a malaria mosquito challenge by immunization with mosquito-bites under chloroquine prophylaxis (CPS immunization). However, it is unknown whether this protection is based on immunity directed towards the liver- or the blood stage of the disease. For future development of vaccines and understanding of protective immunity to malaria, it is important to investigate at which level protective immunity is generated by CPS immunization. Therefore, we aim to investigate whether CPS immunization confers protection to a blood-stage challenge.

Condition or Disease	Intervention/Treatment	Phase
Plasmodium Falciparum Malaria	Drug: Chloroquine prophylaxis Biological: Immunization Biological: Plasmodium falciparum Bloodstage challenge Biological: Plasmodium falciparum mosquito challenge Drug: Malarone treatment	N/A

Study Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

Experimental Human Malaria Infection After Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Prophylaxis

Study Start Date :

Apr 1, 2011

Actual Primary Completion Date :

Jun 1, 2012

Actual Study Completion Date :

Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Immunization + bloodstage challenge	Drug: Chloroquine prophylaxis The chloroquine dose used will be 300mg for the first two days, followed by 300mg per week, for 13 weeks. Biological: Immunization Groups 1 and 2 will be immunized with 3 times 15 bites of Pf infected mosquitoes under chloroquine prophylaxis. Biological: Plasmodium falciparum Bloodstage challenge Groups 1 and 3 will be challenged by intravenous administration of Plasmodium falciparum infected erythrocytes. Drug: Malarone treatment When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone. Other Names: atovaquon/proguanil
Active Comparator: Immunization + mosquito challenge	Drug: Chloroquine prophylaxis The chloroquine dose used will be 300mg for the first two days, followed by 300mg per week, for 13 weeks. Biological: Immunization Groups 1 and 2 will be immunized with 3 times 15 bites of Pf infected mosquitoes under chloroquine prophylaxis. Biological: Plasmodium falciparum mosquito challenge Groups 2 and 4 will be challenged by the bites of 5 Plasmodium falciparum infected mosquitoes. Drug: Malarone treatment When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone. Other Names: atovaquon/proguanil
Placebo Comparator: Control - Bloodstage challenge	Biological: Plasmodium falciparum Bloodstage challenge Groups 1 and 3 will be challenged by intravenous administration of Plasmodium falciparum infected erythrocytes. Drug: Malarone treatment When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone. Other Names: atovaquon/proguanil
Placebo Comparator: Control - Mosquito challenge	Biological: Plasmodium falciparum mosquito challenge Groups 2 and 4 will be challenged by the bites of 5 Plasmodium falciparum infected mosquitoes. Drug: Malarone treatment When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone. Other Names: atovaquon/proguanil

Outcome Measures

Primary Outcome Measures

Duration of prepatent period as measured by microscopy [21 days after challenge]
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]

Secondary Outcome Measures

Antibody production in groups 1, 2, 3 and 4 [393 days]
Cellular immune response in groups 1, 2, 3 and 4 [393 days]
Cytokine profile in groups 1, 2, 3 and 4 [393 days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 35 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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
All volunteers must sign the informed consent form demonstrating their understanding of the meaning and procedures of the study
Volunteer agrees to inform the general practitioner and agrees to sign a request to release medical information concerning contra-indications for participation in the study
Willingness to undergo a Pf mosquito or blood stage challenge
For volunteers not living in Nijmegen: agreement to stay in a hotel room close to the trial center during a part of the study (for groups 1 and 3 from challenge day till 3 days after treatment, for groups 2 and 4 from 5 days after challenge till 3 days after treatment)
Reachable (24/7) by mobile phone during the whole study period
Living with a third party that could contact the clinicians in case of alteration of consciousness or agreement to stay in a hotel room close to the trial center during a part of the study (for groups 1 and 3 from challenge day till 3 days after treatment, for groups 2 and 4 from 5 days after challenge till 3 days after treatment)
Available to attend all study visits
Agreement to refrain from blood donation to Sanquin or for other purposes, during the study period until 393
Willingness to undergo HIV, hepatitis B and hepatitis C tests
Negative urine toxicology screening test at screening visit and day before challenge
Willingness to take a prophylactic regime of chloroquine 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 disease < 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
Pregnant or lactating women
Volunteers unable to give written informed consent
Volunteers unable to be closely followed for social, geographic or psychological reasons
Previous history of drug or alcohol abuse interfering with normal social function during a period of one year prior to enrolment in the study
A history of psychiatric disease
Known hypersensitivity to anti-malaria drugs
The use of chronic immunosuppressive drugs, antibiotics, or other immune modifying drugs within three months of study onset (inhaled and topical corticosteroids are allowed) and during the study period
Contra-indications to Malarone® or chloroquine including treatment taken by the volunteer that interferes with Malarone® or chloroquine
Any confirmed or suspected immunosuppressive or immunodeficient condition, including asplenia
Co-workers of the departments of Medical Microbiology or Internal Medicine of the RUNMC
A history of sickle cell anemia, sickle cell trait, thalassemia, thalassemia trait or G6PD deficiency