Experimental Human Malaria Infection by PfSPZ

Study Overview
=================
Brief Summary
-----------------
The study is a single center, varied dose, open label study. A maximum of eighteen volunteers will be exposed to live NF54 P. falciparum sporozoites (PfSPZ Challenge) by intradermal injection. Volunteers will be divided into three groups of 6 volunteers, each group spaced 25 days apart (21 days after the last challenge of the last volunteer from the previous dose group).

Detailed Description
-----------------
In every group on day 1, two volunteers will be injected. On day 3 the remaining four volunteers of the group will be injected. Injections in subsequent volunteers are always spaced at least one hour apart in any group. Injection of subsequent (groups of) volunteers will only commence if the previous injection was shown to be safe. Three different doses of PfSPZ will be administered: a dose of 2,500 PfSPZ Challenge (Group 1); a dose of 10,000 PfSPZ Challenge (Group 2) if not all volunteers become thick smear positive (TS+) in Group 1; and a dose of 25,000 PfSPZ Challenge (Group 3) if there is not 100% TS+ in Group 2. If all volunteers in Group 1 (2,500 PfSPZ Challenge) become thick smear positive, then Group 2a will receive 1,000 PfSPZ Challenge. If all volunteers in Group 2a become TS+, the volunteers in Group 3a will receive 500 PfSPZ Challenge. If all volunteers in Group 2 (10,000 PfSPZ Challenge) become TS+, Group 3b will receive 5,000 PfSPZ. If less than 100% of volunteers in Group 2a (1,000 PfSPZ Challenge) become TS+ then Group 3c will receive 1,750 PfSPZ Challenge. The clinical, biological, parasitological and immunological data of these groups' volunteers will be compared. Volunteers and the investigator will not be blinded, but the laboratory personnel will be blinded.

Official Title
-----------------
Experimental Human Malaria Infection by Intradermal Injection of Plasmodium Falciparum Sporozoites (PfSPZ Challenge)

Conditions
-----------------
Malaria

Intervention / Treatment
-----------------
* Biological: PfSPZ Challenge


Participation Criteria
=================
Eligibility Criteria
-----------------
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 sporozoite 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 (Day 5 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 (Day 5 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 day 140. 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 curative regimen of Malarone® Exclusion Criteria: History of malaria Plans to travel to malaria endemic areas during the 140 day study period Plans to travel outside of the Netherlands during day 0-28 of the study 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® including treatment taken by the volunteer that interferes with Malarone® Any confirmed or suspected immunosuppressive or immunodeficient condition, including asplenia Co-workers of the departments of Medical Microbiology or Internal Medicine of the Radboud University Nijmegen Medical Centre or Sanaria Inc. A history of sickle cell anemia, sickle cell trait, thalassemia , thalassemia trait or G6PD deficiency

Ages Eligible for Study
-----------------
Minimum Age: 19 Years
Maximum Age: 34 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>to receive a dose of 2,500 PfSPZ Challenge | Biological: PfSPZ Challenge<br>* each volunteer to receive a single dose<br>* Other names: aseptic, purified, cryopreserved Plasmodium falciparum sporozoites;|
| Experimental: Group 2<br>to receive a dose of 10,000 PfSPZ Challenge | Biological: PfSPZ Challenge<br>* each volunteer to receive a single dose<br>* Other names: aseptic, purified, cryopreserved Plasmodium falciparum sporozoites;|
| Experimental: Group 3<br>to receive a dose of 25,000 PfSPZ Challenge | Biological: PfSPZ Challenge<br>* each volunteer to receive a single dose<br>* Other names: aseptic, purified, cryopreserved Plasmodium falciparum sporozoites;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of volunteers with Plasmodium falciparum Infection | To achieve a 100% infection rate of human volunteers by intradermal injection of aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge)as measured by 100% thick smear positivity (thick blood smears) of all volunteers from one group | Upto 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kinetics of infection | To compare parasite kinetics between different doses of intradermal injection of PfSPZ Challenge as measured by: A significant difference in time of thick smear positivity between the groups of volunteers A significant quantitative difference in parasitemia as measured by retrospective PCR between the groups of volunteers A significant difference in kinetics of parasitemia between the groups of volunteers as measured by retrospective PCR A difference in occurrence or intensity of signs or symptoms between the groups of volunteers | Upto 7 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Malaria Challenge, Plasmodium falciparum, Controlled human malaria infection, PfSPZ Challenge