Safety and Protective Efficacy of Intravenous Immunization With Cryopreserved Plasmodium Falciparum Sporozoites Under Chemoprophylaxis

TÜCHMI-002 is a single center, randomized, placebo-controlled, double-blinded, PfSPZ Challenge dose finding trial with two chemoprophylactic regimens and subsequent controlled human malaria infection (CHMI), designed to establish a regimen of PfSPZ Challenge under chemoprophylaxis, with PfSPZ Challenge administered IV, that:

• Is safe and well tolerated.
• Provides consistent sterile protection against CHMI with homologous sporozoites in healthy adult subjects.
• Is a practical regimen for PfSPZ Challenge chemoprophylaxis.

Volunteers will receive three immunizing PfSPZ Challenge IV injections 4 weeks apart under oral chemoprophylaxis. The trial is sequential and has two stages:

A) In the first stage, the PfSPZ Challenge dose is increased sequentially from 3,200 to 51,200 PfSPZ among the three groups. Controls for the three groups will receive 0.9% Sodium Chloride (NaCl) as placebo. All volunteers will receive a standard chemoprophylactic regimen of chloroquine (CQ) for 10 weeks. Briefly, 10 mg/kg CQ base will be given as loading dose followed by weekly doses of 5 mg/kg CQ base. Homologous CHMI is done with 3,200 PfSPZ Challenge IV eight weeks after the last immunizing PfSPZ Challenge injection.

B) In Stage B, accelerated regimens with CQ and CQ plus ER-AZ will be assessed. Initiation of Stage B of the trial is dependent upon demonstration of at least 75% (6 out of 8) protective efficacy against homologous CHMI in Stage A, no PfSPZ Challenge related SAEs and approval by the Safety Monitoring Committee (SMC). CHMI is done with 3,200 PfSPZ Challenge (NF54) IV ten weeks after the last immunization with PfSPZ Challenge under chemoprophylaxis. Injections are either done over 28 or 10 days, chemoprophylaxis is given for 5 weeks and 15 days, respectively. Control groups will receive 0.9% NaCl IV as placebo under the respective chemoprophylactic regimen.

Transition from Stage A to Stage B depends on a positive safety and efficacy review and approval by an independent SMC. Safety and efficacy data will also be submitted to the regulatory authorities (FDA in the U.S. and Paul-Ehrlich-Institute in Germany) as well as to the Ethics Committee. Sponsor, SMC and principal investigator will select PfSPZ dose after review of safety and efficacy data. In case of 100% efficacy of more than one dose regimen and comparable tolerability and safety, the higher PfSPZ dose will be used. Information about the selected dose together with the updated volunteer information document stating the dose will be submitted to the ethics committee for approval before initiation of Stage B. In case that PfSPZ Challenge related SAEs occur or efficacy of the best regimen is below 75% the study will not proceed to Stage B.

Inclusion criteria

The volunteer must satisfy all the following criteria to be eligible for the study:

• Healthy adults aged 18 to 45 years.
• Able and willing (in the Investigator's opinion) to comply with all study requirements.
• Willing to allow the investigators to discuss the volunteer's medical history with their general practitioner ('Hausarzt') if required.
• Residence in Tübingen or surroundings for the period of the trial.
• Women only: Must agree to practice continuous effective contraception for the duration of the study (a method which results in a low failure rate; i.e. less than 1% per year).
• Agreement to refrain from blood donation during the course of the study and after the end of their involvement in the study according to the local and national blood banking eligibility criteria (currently four years in Germany).
• Written informed consent to receive PfSPZ Challenge for immunization and subsequently for CHMI.
• Reachable (24/7) by mobile phone during the immunization and CHMI period.
• Willingness to take CQ and ER-AZ during immunization and a curative antimalarial regimen following CHMI.
• Agreement to stay overnight for observation during the period of intensive follow-up post-challenge if required.
• Answer all questions on the informed consent quiz correctly.
• A body mass index <35.
• A hemoglobin concentration ≥12 g/dl for women and ≥13.5 g/dl for men.

Exclusion criteria

The volunteer may not enter the study if any of the following apply:

• History of Pf malaria.
• Planned travel to malaria endemic areas.
• Use of systemic antibiotics with known antimalarial activity within 30 days of study enrollment (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones, or azithromycin).
• Receipt of an investigational product in the 30 days preceding enrollment, or planned receipt during the study period.
• Prior receipt of an investigational malaria vaccine.
• Immunization with more than 3 other vaccines within the past month.
• HIV infection.
• Any confirmed or suspected immunosuppressive or immunodeficient state, asplenia, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed).
• Use of immunoglobulins or blood products within 3 months prior to enrolment.
• Presence of sickle cell anemia, sickle cell trait, thalassemia or thalassemia trait, glucose-6-phosphate dehydrogenase deficiency.
• Pregnancy, lactation or intention to become pregnant during the study.
• A history of allergic disease or reactions likely to be exacerbated by malaria.
• Contraindications to the use of the following antimalarial medications: atovaquone/proguanil, artemether-lumefantrine, mefloquine, azithromycin and chloroquine.
• History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ).
• History of serious psychiatric condition that may affect participation in the study (including but not restricted to organic, including symptomatic, mental disorders [ICD-10 code: F00-F09], schizophrenia, schizotypal and delusional disorders [F20-F29], mood (affective) disorders [F30-F39], mental retardation [F70-F79], Disorders of psychological development [F80-F89] or any other psychiatric condition that required hospitalization or psychiatric treatment over an extended period).
• Any other serious chronic illness requiring hospital specialist supervision.
• Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 60 g (men) or 40 g (women) per day or a carbohydrate deficient transferrin (CDT) level ≥2.5%.
• Suspected or known injecting drug abuse in the 5 years preceding enrollment.
• Positive for hepatitis B surface antigen (HBs-antigen).
• Seropositive for hepatitis C virus (antibodies to HCV).
• Falling in moderate risk or higher categories for fatal or non-fatal cardiovascular event within 5 years (>10%) determined by non-invasive criteria for cardiac risk.
• Abnormal electrocardiogram on screening: pathologic Q wave and significant ST-T wave changes, left ventricular hypertrophy, non-sinus rhythm except isolated premature atrial contractions, right of left bundle branch block, advanced A-V heart block (secondary or tertiary).
• A QT/QTc interval >450 ms.
• Volunteers unable to be closely followed for social, geographic or psychological reasons.
• Any clinically significant abnormal finding on biochemistry or hematology blood tests, urine analysis or clinical examination.
• Retinal abnormalities.
• History of seizure.
• Any other significant disease, disorder or finding which, in the opinion of the investigator, may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data.

In case of inconclusive results of laboratory tests or other diagnostic procedures, test will be repeated. If doubts about the results persist, volunteers will be considered ineligible.