A Phase 1 Trial of PfSPZ Vaccine in Healthy Adults to Determine Safety, Tolerability and Efficacy Against Heterologous CHMI

Study Overview
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Brief Summary
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USSPZV7 is a randomized, phase 1, double-blind, placebo-controlled trial of Sanaria® PfSPZ Vaccine administered on Days 1, 8 and 29 by direct venous inoculation (DVI) to assess safety, tolerability, immunogenicity, and vaccine efficacy (VE) against heterologous controlled human malaria infection (CHMI) with the 7G8 clone of Plasmodium falciparum (Pf) conducted at 3 or 12 weeks after the third immunization. The trial is designed to determine if individuals living in a non-malaria endemic area such as the United States (US) are protected against heterologous CHMI conducted at these time points.

Detailed Description
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Randomized, phase 1, double-blind, placebo-controlled clinical trial enrolling healthy adult participants 18-50-years-old living in the US. The trial is designed to measure safety, tolerability, immunogenicity and VE against heterologous controlled human malaria vaccine conducted at 3 or 12 weeks after vaccination. Participants will be randomized to two study groups, vaccine and placebo, in a 3:1 ratio. Treatment assignment will be double blind; however, whether a given participant will be receiving CHMI at 3 or 12 weeks will not be blind. Bias will be minimized by the randomized, double-blind design and by the inability to distinguish vaccine or placebo based on appearance, tolerability or other characteristics discernable by clinical staff or study participants. The study will take approximately 6 to 8 months to complete, not including 2-3 months of recruitment. The period of follow-up for each immunized participant and placebo controls is through 8 weeks post-CHMI. Study participation by individuals will last 4 to 6 months (not including screening) depending upon group assignment.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Clinical Trial of a 3-dose, 28-day Regimen of PfSPZ Vaccine in Healthy, Adult Participants to Determine Safety, Tolerability and Efficacy Against Heterologous Plasmodium Falciparum Controlled Human Malaria Infection Conducted 3 or 12 Weeks After Immunization

Conditions
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Malaria, Malaria,Falciparum

Intervention / Treatment
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* Biological: PfSPZ Vaccine
* Biological: PfSPZ Challenge (7G8)
* Other: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adults (male or non-pregnant female) 18 to 50 years of age. Able and willing to participate for the duration of the study. Able and willing to provide written informed consent and satisfactorily complete a test of understanding with a passing score >80%. Physical examination and laboratory results without clinically significant findings. Women of childbearing potential must agree to use effective means of birth control (e.g. oral or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, abstinence, use of a condom by the sexual partner or sterile sexual partner) during the entire study. Women with a history of surgical or chemical sterilization (e.g. tubal ligation, hysterectomy, other). Willing to refrain from blood donation for 3 years following CHMI. Agree not to travel to a malaria endemic region during the trial. Exclusion Criteria: Unable to provide informed consent including inability to pass the test of understanding, which is written in English for the US-based study sites. Receipt of a malaria vaccine in a prior clinical trial. History of a splenectomy or sickle cell disease. History of a neurologic disorder (including non-febrile seizures or complex febrile seizures) or formal history of migraine headache. Current use of systemic immunosuppressant pharmacotherapy. Receipt of a live vaccine within 4 weeks of first immunization or of 3 or more non-live vaccines within 2 weeks of first immunization. Women who are breast-feeding, pregnant or planning to become pregnant during the study period. Known allergy to atovaquone-proguanil (Malarone®), artemether-lumefantrine (Coartem®), or any component of the investigational products. A history of malaria in the 2 years prior to screening. Participation in any study involving investigational vaccine or drug within 4 weeks prior to enrollment that in the estimation of the site PI might adversely affect the individual's safety or the quality of data to be collected. Evidence of increased cardiovascular disease risk; defined as >10% five-year risk by nonlaboratory method. Plan to participate in another investigational vaccine/drug research during the study. Plan for major surgery between enrollment until 28 days post-CHMI. Use or planned use of any drug with anti-malarial activity that would precede or coincide with malaria challenge or vaccination. Anticipated use of medications known to cause drug reactions with atovaquone-proguanil or artemether-lumefantrine such as cimetidine, metoclopramide, antacids, and kaolin. Positive HBsAg or positive HIV or HCV testing consistent with active infection. An abnormal electrocardiogram, defined as one showing pathologic Q waves and significant STT wave changes; left ventricular hypertrophy; any non-sinus rhythm including isolated premature ventricular contractions, but excluding isolated premature atrial contractions; right or left bundle branch block; or advanced (secondary or tertiary) A-V heart block; or other clinically significant abnormalities on the electrocardiogram as determined by the consulting cardiologist. Any clinically significant deviation from the normal range in biochemistry or hematology tests measured at screening and not resolving. Any medical, psychiatric, social, behavioral or occupational condition or situation (including active alcohol or drug abuse) that, in the judgment of the site PI, impairs the volunteer's ability to give informed consent, increases the risk to the participant of participation in the study, affects the ability of the participant to participate fully in the study, or might negatively impact the quality, consistency, integrity or interpretation of data derived from their participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1a: PfSPZ Vaccine<br>45 participants will receive 3 doses of 9.0x10^5 PfSPZ Vaccine on Days 1, 8, and 29 with a total dose of 2.7x10^6 PfSPZ Vaccine. Group 1a: Approximately half (22/23) of the volunteers will undergo CHMI 3 weeks after last immunization by exposure to 3.2x10^3 PfSPZ Challenge (7G8). | Biological: PfSPZ Vaccine<br>* PfSPZ vaccine consists of radiation-attenuated, aseptic, purified Plasmodium falciparum (NF54) sporozoites (SPZ) cryopreserved in liquid nitrogen vapor phase (LNVP) at -150C to - 196C. PfSPZ Vaccine is composed of PfSPZ derived from the NF54 strain of Pf, which is thought to be from West Africa. PfSPZ Vaccine is diluted in phosphate buffered saline (PBS) with human serum albumin (HSA) to achieve the correct dosage and is administered by DVI.<br>Biological: PfSPZ Challenge (7G8)<br>* PfSPZ Challenge (7G8) is similar to PfSPZ Vaccine but has not been attenuated by radiation and is therefore infectious.PfSPZ Challenge (7G8) is composed of PfSPZ derived from the 7G8 clone of Pf, which is from Brazil.<br>|
| Active Comparator: Group 1b: PfSPZ Vaccine<br>45 participants will receive 3 doses of 9.0x10^5 PfSPZ Vaccine on Days 1, 8, and 29 with a total dose of 2.7x10^6 PfSPZ Vaccine. Group 1b: Approximately half (22/23) of the volunteers will undergo CHMI 12 weeks after last immunization by exposure to 3.2x10^3 PfSPZ Challenge (7G8). | Biological: PfSPZ Vaccine<br>* PfSPZ vaccine consists of radiation-attenuated, aseptic, purified Plasmodium falciparum (NF54) sporozoites (SPZ) cryopreserved in liquid nitrogen vapor phase (LNVP) at -150C to - 196C. PfSPZ Vaccine is composed of PfSPZ derived from the NF54 strain of Pf, which is thought to be from West Africa. PfSPZ Vaccine is diluted in phosphate buffered saline (PBS) with human serum albumin (HSA) to achieve the correct dosage and is administered by DVI.<br>Biological: PfSPZ Challenge (7G8)<br>* PfSPZ Challenge (7G8) is similar to PfSPZ Vaccine but has not been attenuated by radiation and is therefore infectious.PfSPZ Challenge (7G8) is composed of PfSPZ derived from the 7G8 clone of Pf, which is from Brazil.<br>|
| Placebo Comparator: Group 2a: Normal Saline Controls<br>15 participants will receive 3 doses of normal saline on Days 1, 8, and 29. Group 2a: Approximately half (7/8) of the volunteers will undergo CHMI 3 weeks after last immunization by exposure to 3.2x10^3 PfSPZ Challenge (7G8). | Biological: PfSPZ Challenge (7G8)<br>* PfSPZ Challenge (7G8) is similar to PfSPZ Vaccine but has not been attenuated by radiation and is therefore infectious.PfSPZ Challenge (7G8) is composed of PfSPZ derived from the 7G8 clone of Pf, which is from Brazil.<br>Other: Normal Saline<br>* 0.9% sodium chloride<br>* Other names: Placebo;|
| Placebo Comparator: Group 2b: Normal Saline Controls<br>15 participants will receive 3 doses of normal saline on Days 1, 8, and 29. Group 2b: Approximately half (7/8) of the volunteers will undergo CHMI 12 weeks after last immunization by exposure to 3.2x10^3 PfSPZ Challenge (7G8). | Biological: PfSPZ Challenge (7G8)<br>* PfSPZ Challenge (7G8) is similar to PfSPZ Vaccine but has not been attenuated by radiation and is therefore infectious.PfSPZ Challenge (7G8) is composed of PfSPZ derived from the 7G8 clone of Pf, which is from Brazil.<br>Other: Normal Saline<br>* 0.9% sodium chloride<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine efficacy (VE) | VE computed as one minus the estimated risk ratio for Pf malaria (parasitemia) detected by PCR beginning 7 days after CHMI up to 28 days in the modified intention to treat population (proportional efficacy analysis) combining data across the two CHMI timepoints. | 7 days after CHMI up to 28 days | 
| Adverse events | The differences in proportions of vaccinees compared to controls experiencing related moderate, severe, or serious solicited and unsolicited adverse events and laboratory abnormalities after vaccination. | Day of immunization to 28 days post immunization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VE for CHMI at 3 weeks | VE computed as one minus the estimated risk ratio for Pf malaria (parasitemia) detected by PCR beginning 7 days after CHMI up to 28 days in the modified intention to treat population (proportional efficacy analysis) for CHMI at 3 weeks. | 7 Days after first CHMI up to 28 days | 
| VE for CHMI at 12 weeks | VE computed as one minus the estimated risk ratio for Pf malaria (parasitemia) detected by PCR beginning 7 days after CHMI up to 28 days in the modified intention to treat population (proportional efficacy analysis) for CHMI at 12 weeks. | 7 Days after second CHMI up to 28 days | 
| Antibody levels to PfCSP measured by ELISA | Antibody levels to PfCSP measured by ELISA comparing vaccinees to controls, and protected (no parasitemia occurring post CHMI) to non-protected (parasitemia occurring post CHMI) vaccinees. | Pre vaccination 1 to Day 141 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Plasmodium falciparum, Sporozoites, PfSPZ Vaccine