Safety, Tolerability, Immunogenicity and Protective Efficacy of PfSPZ Vaccine and PfSPZ-CVac in Indonesian Adults Against Naturally-Transmitted Malaria

Safety, Tolerability, Immunogenicity and Protective Efficacy Against Naturally-Transmitted Malaria in Eastern Indonesia of Two Plasmodium Falciparum Sporozoite Vaccines, Sanaria® PfSPZ Vaccine and Sanaria® PfSPZ-CVac: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial in Healthy Indonesian Adults

The study is a double-blind, randomized, placebo-controlled, Phase 2 clinical trial that will assess the safety, tolerability, immunogenicity and protective efficacy of PfSPZ Vaccine and PfSPZ-CVac against naturally occurring malaria in healthy Indonesian soldiers deployed to eastern Indonesia.

The study is a double-blind, randomized, placebo-controlled, Phase 2 clinical trial that will assess the safety, tolerability, immunogenicity and protective efficacy of PfSPZ Vaccine and PfSPZ-CVac against naturally occurring malaria in 372 healthy Indonesian soldiers aged 18-55 years who will be deployed in malarious eastern Indonesia.

PfSPZ Vaccine and PfSPZ-CVac:

Participants will be randomized to immunization with three doses of PfSPZ Vaccine (Group 1), normal saline (NS) placebo (Group 2) and PfSPZ-CVac (PfSPZ Challenge + CQ) (Group 3) or NS placebo + CQ (Group 4); randomization to four groups will be 1 : 0.5 : 1 : 0.5.

The study has three phases: immunization and follow-up at the home base; deployment to eastern Indonesia for 6 to 9 months (surveillance period #1); redeployment to the home base for 6 months (surveillance period #2); study participation will be up to 20 months per participant, and the entire clinical trial will last approximately 28 months if deployment lasts 9 months. A research monitor (RM) (= medical monitor = safety monitor) and a safety monitoring committee (SMC) will provide safety oversight. External study monitoring will be the responsibility of Sanaria or Sanaria's designated and authorized representative in Indonesia. Screening will be done within 56 days of enrollment and immunizations will be completed prior to deployment. Screening evaluation includes an electrocardiogram (ECG) performed at screening. Subjects with clinically significant abnormal cardiovascular symptoms or findings will be excluded and referred to a cardiologist for further evaluation; individuals with a history of non-febrile seizures will also be excluded. Solicited adverse events will be monitored for 7 days after each PfSPZ Vaccine/placebo administration and for 14 days after each PfSPZ-CVac/placebo administration; unsolicited adverse events will be followed during the immunization period and up to 2 weeks after the last immunization if the deployment schedule allows; serious adverse events (SAEs) will be monitored throughout the study. Follow-up of AEs occurs until resolution or stability. Case report forms (CRFs) will serve as the repository of source documents and other relevant data for each study subject. Only information that cannot be collected initially into the CRF (namely, laboratory test results, ECGs and adverse event (AE) medical records, etc.) will first be collected onto separate source documents before transcription into the CRF. The information in the CRF will then be manually entered directly into the internet data system by independent data entry technicians.

Study Arms:

Group 1 (n=124): Three doses of 9x10^5 PfSPZ of PfSPZ Vaccine. Group 2 (n=62): Three doses of NS. Group 3 (n=124): Three doses of 2x10^5 PfSPZ of PfSPZ Challenge and weekly CQ. Group 4 (n=62): Three doses of NS and weekly CQ.

Inclusion Criteria:

• A male aged 18-55 years at the time of screening.
• Assigned to the battalion of study and programmed to accompany it to eastern Indonesia for the duration of the deployment.
• Freely provides written informed consent to participate in the study.
• Agrees to adhere to Indonesian military medical guidance regarding screening and treatment of malaria.
• Physical examination and laboratory results without clinically significant findings that would jeopardize the safety of the participant or the integrity of the study, and a body mass index (BMI) ≤35 kg/m^2.

Exclusion Criteria:

• Previous vaccination with an investigational malaria vaccine.
• Use of an investigational or non-registered drug or vaccine other than the study vaccine(s) within 30 days before the first study vaccination, or planned use up to 30 days after last vaccination.
• Chronic administration (defined as more than 14 days) of immunosuppressant or other immune-modifying drugs within six months before the first vaccination. This includes any dose level of oral steroids, but not inhaled steroids or topical steroids.
• Administration or planned administration of 1 live or 3 or more other type vaccines in the period beginning 28 days before the first study vaccination and ending 28 days after the last vaccination.
• Confirmed or suspected immunosuppressive or immunodeficient condition.
• Confirmed or suspected autoimmune disease.
• History of allergic reactions or anaphylaxis to CQ or other 4-aminoquinolone derivatives.
• History of serious allergic reactions to a drug (anaphylaxis, or requiring hospitalization).
• History of allergy to phosphate buffered saline or human serum albumin.
• Use or planned use of any drug with anti-malarial activity during the course of the study except for antimalarial medication administered by study clinicians.
• History of splenectomy.
• Laboratory evidence of liver disease (the final decision will be made by the PI and clinical officers, but in general a volunteer will be excluded if any of the screening liver function tests (ALT, bilirubin, gamma GTP) are > double the upper limit of normal measured twice without an explanation for the abnormal values).
• Laboratory evidence of renal disease (serum creatinine > 1.5 mg/dL. measured twice).
• Laboratory evidence of hematologic disease (platelet count or hemoglobin <80% of the lower limit of normal for Indonesia measured twice).
• Abnormal screening ECG showing prolonged QTc interval (>450 msec) or any signs of arrythmia/irregularity, ischemia, cardiac enlargement considered considered indicative of acute or chronic cardiovascular disease.
• Acute or chronic pulmonary, cardiovascular, hepatic, renal or neurological condition, severe malnutrition, or any other clinical findings that may increase the risk of participating in the study as determined by the principal investigator or her designee.
• Administration of immunoglobulin and/or any blood products within the three months preceding the first study vaccination or planned administration during the study period.
• Simultaneous participation in any other interventional clinical trial.
• Other conditions that in the opinion of the principal investigator or her designee would jeopardize the safety or rights of a participant in the trial or would render the participant unable to comply with the protocol or might compromise the integrity of the data.
• Any evidence of active malaria, whether symptomatic or asymptomatic, confirmed by RDT, microscopy or PCR before first injection of PfSPZ Vaccine or PfSPZ-CVac, unless treated by the clinical team.
• History of non-febrile seizures or atypical febrile seizures.
• Under treatment for tuberculosis.
• Laboratory evidence of active infection with hepatitis B, or hepatitis C.
• Subjects with > 10% 5-year cardiovascular risk (fatal and non-fatal) based on the Gaziano scoring system; subjects in the 18-34 year old age group will be assessed as though they are in the 35-44 age group.
• History of psychiatric disorders (such as personality disorders, anxiety disorders, or schizophrenia) or behavioral tendencies (including active alcohol or drug abuse) discovered during the screening process that in the opinion of the investigator would make compliance with the protocol difficult.