Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis

NCT01422954 | Completed DMC

• 1 other identifier: ZonMw2
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Malaria; Plasmodium Falciparum

Outcome Measures

Primary Outcomes (1)

• Duration of prepatent period after challenge infection as measured by microscopy

  21 days after challenge (day 239 of the study)

Secondary Outcomes (4)

• 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

Study Arms (3)

Chloroquine immunisation

ACTIVE COMPARATOR

This group will receive chloroquine prophylaxis, and three times infected mosquito-bites.

Drug: Chloroquine prophylaxis; Biological: Immunization; Biological: Controlled Human Malaria Infection; Drug: Malarone

Mefloquine immunisation

EXPERIMENTAL

This group will receive mefloquine prophylaxis and infected mosquito-bites.

Drug: Mefloquine prophylaxis; Biological: Immunization; Biological: Controlled Human Malaria Infection; Drug: Malarone

Mefloquine control

PLACEBO COMPARATOR

This group will receive mefloquine prophylaxis, and uninfected mosquito-bites.

Drug: Mefloquine prophylaxis; Biological: Immunization; Biological: Controlled Human Malaria Infection; Drug: Malarone

Interventions

Chloroquine prophylaxis DRUG

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.

Chloroquine immunisation

Mefloquine prophylaxis DRUG

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.

Mefloquine control; Mefloquine immunisation

Immunization BIOLOGICAL

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.

Chloroquine immunisation; Mefloquine control; Mefloquine immunisation

Controlled Human Malaria Infection BIOLOGICAL

Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.

Chloroquine immunisation; Mefloquine control; Mefloquine immunisation

Malarone DRUG

When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.

Also known as: atovaquon/proguanil

Chloroquine immunisation; Mefloquine control; Mefloquine immunisation

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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®

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (1)

Leiden University Medical Centre

Leiden, 2333 ZA, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 25396417 DERIVED

Related Links

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

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Interventions

Immunization; atovaquone, proguanil drug combination; Proguanil

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques; Primary Prevention; Preventive Health Services; Health Services; Health Care Facilities Workforce and Services; Communicable Disease Control; Public Health Practice; Public Health; Environment and Public Health; Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Leo G Visser, MD, PhD

  Leiden University Medical Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2011
• First Posted: August 25, 2011
• Study Start: January 1, 2012
• Primary Completion: December 1, 2012
• Study Completion: April 1, 2013
• Last Updated: April 29, 2013

Record last verified: 2013-04

Locations

NL (1)