Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis

Condition(s) targeted: Malaria; Plasmodium Falciparum

Intervention: Chloroquine prophylaxis (Drug); Mefloquine prophylaxis (Drug); Immunization (Biological); Controlled Human Malaria Infection (Biological); Malarone (Drug)

Phase: N/A

Status: Completed

Sponsored by: Radboud University

Official(s) and/or principal investigator(s):
Leo G Visser, MD, PhD, Principal Investigator, Affiliation: Leiden University Medical Centre

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: Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Primary outcome: Duration of prepatent period after challenge infection as measured by microscopy

Secondary outcome:

Development of parasitemia as measured by PCR

Frequency of signs or symptoms in study groups

Cellular immune responses between study groups

Humoral immune responses between study groups

Minimum age: 18 Years. Maximum age: 35 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Age > 18 and < 35 years healthy volunteers (males or females) 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: 1. History of malaria 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

Leiden University Medical Centre, Leiden 2333 ZA, Netherlands

Roestenberg et al. Protection against a Malaria Challenge by Sporozoite Inoculation, NEJM 2009.

Roestenberg et al. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 2010.

Starting date: January 2012
Last updated: April 26, 2013