Safety, Immunogenicity, and Protective Efficacy of Radiation Attenuated Plasmodium Falciparum NF54 Sporozoites (PfSPZ Vaccine) During Malaria Transmission Season in Healthy African Adult Women of Childbearing Potential in Mali

Study Overview
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Brief Summary
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Background: Malaria is a disease spread by mosquitos. Pregnant women are highly susceptible to malaria. This can lead to poor health outcomes for pregnant women and their babies. Researchers want to test a malaria vaccine in women of child bearing potential (WOCBP) and pregnant women. This has not been done before. Objective: To assess the safety and tolerability of PfSPZ vaccine in healthy Malian WOCBP. Eligibility: Healthy women ages 18 38 who live in Ouelessebougou, Mali, and surrounding villages Design: Participants will be screened with: Physical exam Medical history Blood, urine, and heart tests Multiple-choice test about malaria Participants will get 3 injections by needle into a vein of the study vaccine or a placebo. All 3 will be within 1 month. They will not know whether they receive the vaccine or placebo. Participants will receive treatment to prevent malaria. This will be about 2 weeks before the first and third injections. After the third injection, participants will be followed for about 1 year. They will be tested to see if the vaccine is safe and protects against malaria infection. They will have blood tests. If participants get a rash or injection site reaction, photos of the site may be taken. Any women who become pregnant during the trial will be followed through the end of pregnancy. Babies and their mothers will be followed through the first year of life

Detailed Description
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Pregnant women are highly susceptible to Plasmodium falciparum malaria, leading to substantial maternal, perinatal, and infant mortality. While malaria vaccine development has made significant progress in recent years, no trials of malaria vaccines have ever been conducted in only women of child bearing potential (WOCBP) or in pregnant women. PfSPZ Vaccine (Sanaria, Inc) is an advanced malaria candidate being developed for use in pregnant women, owing in part to its highly favorable safety profile. The vaccine is comprised of aseptic, metabolically active, non-replicating, purified, cryopreserved P. falciparum sporozoites. In multiple double-blind, placebo-controlled trials, there have been no differences in adverse events between vaccinees versus controls. PfSPZ Vaccine induces immune responses to the sporozoite and liver stages of parasite development in the human host and prevents progression to blood stage parasitemia as well as averting disease sequelae; a compelling rationale to test PfSPZ Vaccine for its benefits in this proposed population. Sanaria has already achieved vaccine efficacy against homologous and heterogenous parasite populations in endemic areas following three doses of PfSPZ Vaccine in several studies with 9.0x10^5 and 1.8x10^6 PfSPZ Vaccine and has explored accelerated regimens, such as 1, 8, 29 days. Accelerated PfSPZ Vaccine regimens such as this could induce protection earlier in pregnancy, minimizing the period at risk and improving pregnancy outcomes over the control group. Given this, the Malaria Research and Training Center, the Laboratory of Malaria Immunology and Vaccinology National Institute of Allergy and Infectious Diseases, and Sanaria, Inc. propose to initiate testing of the day 1, 8, and 29 dosing regimen of PfSPZ Vaccine in WOCBP, and in subsequent studies, in pregnant women, using doses of 9.0x10^5 and 1.8x10^6 PfSPZ Vaccine. This will be the first step in a clinical development plan for PfSPZ Vaccine in WOCBP and pregnant women: 1) safety and efficacy studies in non-pregnant WOCBP (this trial), 2) studies of the safety and efficacy of a primary immunization series in all trimesters, and 3) studies to evaluate the safety and efficacy of boosting during pregnancy. A pregnancy registry study (#17-I-N018) has been ongoing in Mali since 2017 to gain background data on maternal/fetal outcomes in the target population in anticipation of this study. Women who become pregnant during the course of this study, and their offspring, will be followed for maternal clinical outcomes and malaria infection.

Official Title
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Randomized, Placebo-Controlled, Double-Blind Study to Assess Safety, Immunogenicity, and Protective Efficacy of Radiation Attenuated Plasmodium Falciparum NF54 Sporozoites (PfSPZ Vaccine) During Malaria Transmission Season in Healthy African Adult Women of Childbearing Potential in Mali

Conditions
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Malaria

Intervention / Treatment
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* Biological: PfSPZ Vaccine
* Other: Normal Saline


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Females of child bearing potential aged greater than or equal to 18 and less than or equal to 38 years Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process In good general health and without clinically significant medical history Willing to have blood samples stored for future research Available for the duration of the study Must be willing to use reliable contraception (defined as: pharmacologic contraceptives [parental delivery] or pre-existing intrauterine or implantable device) from 21 days prior to study day 1 to 28 days after last vaccination Report being interested in becoming pregnant within the next 1-2 years EXCLUSION CRITERIA: Pregnancy at the time of enrollment/vaccination, as determined by a positive urine or serum human chorionic gonadotropin (beta-hCG) test Biologically unable to become pregnant secondary to: surgical sterilization, premature ovarian insufficiency (defined as no menses for greater than or equal to 12 months without an alternative medical cause) Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the participant to understand and comply with the study protocol Hemoglobin (Hgb), WBC, absolute neutrophils, and platelets outside the local laboratory-defined limits of normal and greater than or equal to Grade 2 (subjects may be included at the investigator s discretion for not clinically significant abnormal values) Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal and greater than or equal to Grade 2 (subjects may be included at the investigator s discretion for not clinically significant abnormal values) Infected with human immunodeficiency virus (HIV) Known or documented sickle cell disease by history (Note: known sickle cell trait is NOT exclusionary) Clinically significant abnormal electrocardiogram (ECG) such as abnormal QTc. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies including urinalysis History of receiving any investigational product within the past 30 days Participation or planned participation in a clinical trial with an investigational product prior to completion of the follow-up visit 28 days following last vaccination OR planned participation in an investigational vaccine study until the last required protocol visit Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months History of a severe allergic reaction (Grade 2 or higher or per PI discretion) or anaphylaxis Severe asthma (defined as asthma that is unstable or required emergent care, urgent care, hospitalization, or intubation during the past two years, or that has required the use of oral or parenteral corticosteroids at any time during the past two years) Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren s syndrome, or autoimmune thrombocytopenia Known immunodeficiency syndrome Known asplenia or functional asplenia Use of chronic (greater than or equal to 14 days) oral or IV corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone greater than or equal to 20 mg/day) or immunosuppressive drugs within 30 days of vaccination Receipt of a live vaccine within the past four weeks or a killed vaccine within the past two weeks prior to Vaccination #1 and every subsequent vaccination day Receipt of immunoglobulins and/or blood products within the past six months Previous receipt of an investigational malaria vaccine in the last five years Known allergies or other contraindications against use of artemeter/lumefantrine Other condition(s) that, in the opinion of the investigator, would jeopardize the safety or rights of a participant participating in the trial, interfere with the evaluation of the study objectives, or would render the subject unable to comply with the protocol

Ages Eligible for Study
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Maximum Age: 38 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Arm 1: (n= 100) will receive 3 doses of PfSPZ Vaccine (9 x10(5)) via direct venous inoculation (DVI) at 1, 8, 29 days. | Biological: PfSPZ Vaccine<br>* PfSPZ vaccine is comprised of aseptic, metabolically active, non-replicating, purified, cryopreserved P. falciparum sporozoites.<br>|
| Experimental: Arm 2<br>Arm 2: (n= 100) will receive 3 doses of PfSPZ Vaccine (1.8 x10(6)) via DVI at 1, 8, 29 days. | Biological: PfSPZ Vaccine<br>* PfSPZ vaccine is comprised of aseptic, metabolically active, non-replicating, purified, cryopreserved P. falciparum sporozoites.<br>|
| Placebo Comparator: Arm 3<br>Arm 3: (n=100): will receive 3 doses of normal saline (placebo) injection via DVI at 1, 8, 29 days. | Other: Normal Saline<br>* Sterile isotonic (0.9%) normal saline is a clear liquid, making it indistinguishable from the study product when drawn up into a syringe; and will be used as a placebo, rather than a comparator vaccine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of local and systemic adverse events (AEs) graded by severity occurring within 7 days after each vaccine administration. | Assess safety and tolerability of PfSPZ Vaccine primary series in healthy Malian WOCBP when given at 1, 8, 29 days at two doses (9 x10(5); 1.8 x10(6)). | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P. falciparum blood stage infection defined as time to first positive blood smear (detection of at least 2 P. falciparum parasites by microscopic examination of 0.5 microliter) starting immediately following 3rd injection over 24 weeks. | Assess the efficacy of PfSPZ Vaccine primary series in healthy Malian WOCBP when given at 1, 8, 29 days at two doses (9 x10(5); 1.8 x10(6)). | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy, Tolerability, Immune, Response, Vaccination