Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis
NCT ID: NCT01422954
Last Updated: 2013-04-29
Study Results
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Basic Information
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COMPLETED
NA
20 participants
INTERVENTIONAL
2012-01-31
2013-04-30
Brief Summary
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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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
BASIC_SCIENCE
QUADRUPLE
Study Groups
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Chloroquine immunisation
This group will receive chloroquine prophylaxis, and three times infected mosquito-bites.
Chloroquine prophylaxis
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.
Immunization
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.
Controlled Human Malaria Infection
Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.
Malarone
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Mefloquine immunisation
This group will receive mefloquine prophylaxis and infected mosquito-bites.
Mefloquine prophylaxis
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.
Immunization
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.
Controlled Human Malaria Infection
Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.
Malarone
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Mefloquine control
This group will receive mefloquine prophylaxis, and uninfected mosquito-bites.
Mefloquine prophylaxis
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.
Immunization
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.
Controlled Human Malaria Infection
Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.
Malarone
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Interventions
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Chloroquine prophylaxis
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.
Mefloquine prophylaxis
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.
Immunization
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.
Controlled Human Malaria Infection
Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.
Malarone
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Good health based on history and clinical examination
3. Negative pregnancy test
4. Use of adequate contraception for females
5. Signing of the informed consent form, thereby demonstrating understanding of the meaning and procedures of the study
6. Agreement to inform the general practitioner and to sign a request to release medical information concerning contra-indications for participation in the study
7. Willingness to undergo a Pf controlled infection through mosquito bites
8. 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)
9. Reachable (24/7) by mobile phone during the whole study period
10. Available to attend all study visits
11. Agreement to refrain from blood donation to Sanquin or for other purposes, during the whole study period
12. Willingness to undergo HIV, hepatitis B and hepatitis C tests
13. Negative urine toxicology screening test at screening visit and the day before challenge
14. Willingness to take a prophylactic regime of chloroquine or mefloquine and curative regimen of Malarone®
Exclusion Criteria
2. Plans to travel to malaria endemic areas during the study period
3. Plans to travel outside of the Netherlands during the challenge period
4. Previous participation in any malaria vaccine study and/or positive serology for Pf
5. 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
6. History of diabetes mellitus or cancer (except basal cell carcinoma of the skin)
7. History of arrhythmias or prolonged QT-interval
8. Positive family history in 1st and 2nd degree relatives for cardiac events \< 50 years old
9. An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system
10. Clinically significant abnormalities in electrocardiogram (ECG) at screening
11. Body Mass Index (BMI) below 20 or above 30 kg/m2
12. Any clinically significant deviation from the normal range in biochemistry or hematology blood tests or in urine analysis
13. Positive HIV, HBV or HCV tests
14. Participation in any other clinical study within 30 days prior to the onset of the study
15. Enrollment in any other clinical study during the study period
16. For women: pregnancy or lactation
17. Volunteers unable to give written informed consent
18. Volunteers unable to be closely followed for social, geographic or psychological reasons
19. History of drug or alcohol abuse interfering with normal social function
20. A history of treatment for psychiatric disease or moderate or severe psychological episode in volunteer
21. A history of convulsions in volunteer
22. Severe depression, anxiety disorder of psychosis in first or second degree family
23. Contra-indications to Malarone®, chloroquine or mefloquine including hypersensitivity or treatment taken by the volunteer that interferes with Malarone®, chloroquine or mefloquine
24. 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
25. Any confirmed or suspected immunosuppressive or immunodeficient condition, including asplenia
26. Co-workers or trainees of the departments of Medical Microbiology, Parasitology, or Internal Medicine of the Leiden University medical Centre
27. A history of sickle cell anemia, sickle cell trait, thalassemia, thalassemia trait or G6PD deficiency
18 Years
35 Years
ALL
Yes
Sponsors
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ZonMw: The Netherlands Organisation for Health Research and Development
OTHER
Radboud University Medical Center
OTHER
Responsible Party
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Principal Investigators
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Leo G Visser, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Leiden University Medical Centre
Locations
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Leiden University Medical Centre
Leiden, , Netherlands
Countries
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References
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Bijker EM, Schats R, Obiero JM, Behet MC, van Gemert GJ, van de Vegte-Bolmer M, Graumans W, van Lieshout L, Bastiaens GJ, Teelen K, Hermsen CC, Scholzen A, Visser LG, Sauerwein RW. Sporozoite immunization of human volunteers under mefloquine prophylaxis is safe, immunogenic and protective: a double-blind randomized controlled clinical trial. PLoS One. 2014 Nov 14;9(11):e112910. doi: 10.1371/journal.pone.0112910. eCollection 2014.
Related Links
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Roestenberg et al. Protection against a Malaria Challenge by Sporozoite Inoculation, NEJM 2009.
Other Identifiers
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ZonMw2
Identifier Type: -
Identifier Source: org_study_id
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