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

NCT01236612 | Completed DMC

• 1 other identifier: EHMI9
• Study Type: interventional
• Target: 25
• 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 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.

Conditions

Plasmodium Falciparum Malaria

Keywords

Plasmodium; falciparum; malaria; chloroquine; immunity

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• 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

Study Arms (4)

Immunization + bloodstage challenge

EXPERIMENTAL

Drug: Chloroquine prophylaxis; Biological: Immunization; Biological: Plasmodium falciparum Bloodstage challenge; Drug: Malarone treatment

Immunization + mosquito challenge

ACTIVE COMPARATOR

Drug: Chloroquine prophylaxis; Biological: Immunization; Biological: Plasmodium falciparum mosquito challenge; Drug: Malarone treatment

Control - Bloodstage challenge

PLACEBO COMPARATOR

Biological: Plasmodium falciparum Bloodstage challenge; Drug: Malarone treatment

Control - Mosquito challenge

PLACEBO COMPARATOR

Biological: Plasmodium falciparum mosquito challenge; Drug: Malarone treatment

Interventions

Chloroquine prophylaxis DRUG

The chloroquine dose used will be 300mg for the first two days, followed by 300mg per week, for 13 weeks.

Immunization + bloodstage challenge; Immunization + mosquito challenge

Immunization BIOLOGICAL

Groups 1 and 2 will be immunized with 3 times 15 bites of Pf infected mosquitoes under chloroquine prophylaxis.

Immunization + bloodstage challenge; Immunization + mosquito challenge

Plasmodium falciparum Bloodstage challenge BIOLOGICAL

Groups 1 and 3 will be challenged by intravenous administration of Plasmodium falciparum infected erythrocytes.

Control - Bloodstage challenge; Immunization + bloodstage challenge

Plasmodium falciparum mosquito challenge BIOLOGICAL

Groups 2 and 4 will be challenged by the bites of 5 Plasmodium falciparum infected mosquitoes.

Control - Mosquito challenge; Immunization + mosquito challenge

Malarone treatment DRUG

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

Also known as: atovaquon/proguanil

Control - Bloodstage challenge; Control - Mosquito challenge; Immunization + bloodstage challenge; Immunization + mosquito challenge

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
• 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®

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 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

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboud University Nijmegen Medical Centre

Nijmegen, 6500 HB, Netherlands

Location

Related Publications (4)

• Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, van Gemert GJ, van de Vegte-Bolmer M, van Schaijk B, Teelen K, Arens T, Spaarman L, de Mast Q, Roeffen W, Snounou G, Renia L, van der Ven A, Hermsen CC, Sauerwein R. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med. 2009 Jul 30;361(5):468-77. doi: 10.1056/NEJMoa0805832.

  PMID: 19641203 BACKGROUND

• Bijker EM, Bastiaens GJ, Teirlinck AC, van Gemert GJ, Graumans W, van de Vegte-Bolmer M, Siebelink-Stoter R, Arens T, Teelen K, Nahrendorf W, Remarque EJ, Roeffen W, Jansens A, Zimmerman D, Vos M, van Schaijk BC, Wiersma J, van der Ven AJ, de Mast Q, van Lieshout L, Verweij JJ, Hermsen CC, Scholzen A, Sauerwein RW. Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7862-7. doi: 10.1073/pnas.1220360110. Epub 2013 Apr 18.

  PMID: 23599283 RESULT

• Coffeng LE, Hermsen CC, Sauerwein RW, de Vlas SJ. The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection. PLoS Comput Biol. 2017 Jan 12;13(1):e1005255. doi: 10.1371/journal.pcbi.1005255. eCollection 2017 Jan.

  PMID: 28081133 DERIVED

• Nahrendorf W, Scholzen A, Bijker EM, Teirlinck AC, Bastiaens GJ, Schats R, Hermsen CC, Visser LG, Langhorne J, Sauerwein RW. Memory B-cell and antibody responses induced by Plasmodium falciparum sporozoite immunization. J Infect Dis. 2014 Dec 15;210(12):1981-90. doi: 10.1093/infdis/jiu354. Epub 2014 Jun 25.

  PMID: 24970846 DERIVED

MeSH Terms

Conditions

Malaria, Falciparum; Malaria

Interventions

Immunization; 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

• Robert W Sauerwein, MD, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 4, 2010
• First Posted: November 8, 2010
• Study Start: April 1, 2011
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: January 22, 2014

Record last verified: 2014-01

Locations

NL (1)