PfSPZ Vaccine Trial in Malian Children

Study Overview
=================
Brief Summary
-----------------
In this randomized, double-blind, placebo-controlled trial, 268 healthy Malian children aged 6-10 years, residing in Bancoumana and surrounding villages, will be administered three doses of 9.0x10^5 Pf sporozoites (PfSPZ) of PfSPZ Vaccine (or placebo) at 1, 8, and 29-days using direct venous inoculation (DVI). The study is composed of a single cohort with two arms (categorized by placebo control/experimental groups) designed to assess the safety, immunogenicity and protective efficacy of PfSPZ Vaccine. All subjects will receive artemether-lumefantrine (AL) approximately 1- 2 weeks before the first dose of PfSPZ Vaccine or normal saline for clearance of Pf parasitemia. Vaccinated participants and non-immunized controls will be followed for safety and monitored for development of parasitemia through the natural malaria transmission season to estimate vaccine efficacy (VE).

Detailed Description
-----------------
This phase 2 study will enroll healthy Malian children between 6 and 10 years of age residing in Bancoumana and surrounding villages to participate in a randomized, double blind, placebo- controlled study to assess the safety, immunogenicity and protective efficacy of PfSPZ Vaccine. Participants will be immunized with a 3-dose series of 9.0 x10^5 PfSPZ of PfSPZ Vaccine or normal saline (placebo) at 1, 8, and 29 days. Subjects will be screened for eligibility for enrollment. Enrollment will begin with AL dosing approximately 1-2 weeks prior to their first dose of vaccine. Volunteers will be randomized into two arms (1 vaccine arm, 1 control arm) in a 1:1 ratio. Vaccinated subjects and controls will then be followed for safety and assessment for malaria infection during the subsequent malaria transmission season. 268 children between the ages of 6 and 10 years old inclusive will be enrolled as follows: Arm 1(PfSPZ Vaccine): (n = 134) children ages 6 - 10 will receive three doses of PfSPZ Vaccine (9.0x10^5 PfSPZ) via direct venous inoculation (DVI) at 1, 8, and 29 days Arm 2 (normal saline): (n = 134) children ages 6 - 10 will receive normal saline via DVI at 1, 8, and 29 days All subjects will receive artemether-lumefantrine (AL) approximately 1- 2 weeks before the first dose of PfSPZ Vaccine or normal saline for clearance of Pf parasitemia. Vaccinated participants and non-vaccinated controls will be monitored for development of Pf malaria with symptoms and Pf malaria (parasitemia) through the natural malaria transmission season to estimate vaccine efficacy (VE). During the surveillance period, both active and passive surveillance will be used to identify Pf malaria with symptoms. Blood smears will be made at any time a participant presents with a clinical syndrome consistent with malaria and read in real time, with all infections treated. In addition, blood smears will be made every four weeks in all participants as active surveillance for Pf malaria (parasitemia). However, to avoid confounding the primary clinical endpoint, these blood smears will be read retrospectively at the end of the primary surveillance period. Primary Case Definition: Pf malaria with symptoms is defined as a positive thick blood smear at a density of >1000 parasites/uL (P/uL) plus: Measured auxiliary temperature ≥ 37.5 degrees Celsius or history of fever (subjective or objective) in the last 24 hours, or, Symptoms of malaria - Verbal individual (individual able and willing to answer questions): A verbal individual is considered symptomatic if reporting at the time of evaluation at least two of the following symptoms/symptom groups: headache, chills and/or rigors, malaise and/or fatigue, dizziness and/or light-headedness, myalgias and/or arthralgias; or Non-verbal individual (small child or any individual unable or unwilling to answer questions): A non-verbal individual is considered symptomatic if manifesting at the time of evaluation at least two of the following signs/sign groups: drowsiness, irritability and/or fussiness, inability and/or refusal to eat or drink, prostration; or Any individual: Signs of severe malaria (e.g. impairment of consciousness, severe anemia, hemoglobinuria, acute kidney injury, etc.) Secondary Case Definition: Pf malaria with symptoms is defined as a positive thick blood smear at a density of > 0 P/uL plus: Measured axillary temperature ≥ 37.5 degrees Celsius or history of fever (subjective or objective) in the last 24 hours, or, Symptoms of malaria as defined in the primary case definition; or Meeting criteria for severe malaria Pf malaria is defined as: - At least one unambiguous asexual parasite on thick blood smear identified by two independent microscopists after each examining 0.50 μL of blood in a study participant

Official Title
-----------------
Phase 2 Trial of Safety, Immunogenicity, and Efficacy Against Plasmodium Falciparum Malaria of PfSPZ Vaccine in Children in Mali

Conditions
-----------------
Malaria, Malaria,Falciparum

Intervention / Treatment
-----------------
* Biological: Sanaria® PfSPZ Vaccine
* Other: Normal Saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Parent(s) or guardian(s) willing and able to provide consent prior to initiation of any study procedures Stated willingness of parent(s) or guardian(s) to comply with all study procedures and availability for the duration of the study Malaria comprehension exam completed by parent(s) or guardian(s) and passed with a score of ≥80% or per investigator's discretion Healthy children 6-10 years of age at enrollment (inclusive) Parent(s) or guardian(s) are able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process Willing to have blood samples stored for future research Exclusion Criteria: Medical, behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the participant's parent and/or legal guardian to understand and comply with the study protocol Menstruating females (in order to avoid cultural implications of further assessing pregnancy potential i.e. sexual activity in this age group) Hemoglobin (Hgb), WBC, absolute neutrophils, and platelets outside the local laboratory-defined limits of normal and ≥ 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 ≥ Grade 2 (subjects may be included at the investigator's discretion for 'not clinically significant' abnormal values) Infected with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C Sickle cell disease by history Taking or planning to take seasonal malaria chemoprophylaxis Clinically significant abnormal electrocardiogram (ECG) such as abnormal QTc History of receipt of the following: Investigational malaria vaccine in the last 2 years Immunoglobulins and/or blood products within 6 months of enrollment Investigational product within 3 months of enrollment Chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone ≥20 mg/day or equivalent) or immunosuppressive drugs within 30 days of enrollment Live vaccine within 30 days of enrollment Killed vaccine within 14 days of enrollment or planned receipt of a killed vaccine within 14 days of scheduled vaccination Known medical problems: Pre-existing autoimmune or antibody-mediated diseases (e.g. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren's syndrome, or autoimmune thrombocytopenia) 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) Immunodeficiency disorder Asplenia or functional asplenia Diabetes Deep venous thrombosis or thromboembolic event Seizures (exception is simple febrile seizures during childhood) Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 10 Years

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

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

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

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, placebo controlled, with concurrent arms
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (PfSPZ Vaccine)<br>134 children ages 6 - 10 will receive three doses of PfSPZ Vaccine (9.0x10^5 PfSPZ) via DVI at 1, 8, and 29 days | Biological: Sanaria® PfSPZ Vaccine<br>* non-adjuvanted, live (metabolically active), radiation-attenuated, non-replicating, whole sporozoite (SPZ) vaccine designed to prevent malaria infection caused by Plasmodium falciparum (Pf).<br>|
| Placebo Comparator: Arm 2 (normal saline)<br>134 children ages 6 - 10 will receive normal saline via DVI at 1, 8, and 29 days | Other: Normal Saline<br>* placebo control- saline<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of PfSPZ Vaccine in children with respect to the occurrence of possibly, probably, or definitely related serious adverse events (SAEs) | Proportion of vaccinees compared to controls experiencing related SAEs from V1 to 26 weeks after V3 | vaccination 1 to 26 weeks after vaccination 3 | 
| Vaccine efficacy against first episode of Pf malaria with symptoms by time-to-event analysis | VE computed as one minus the estimated hazard ratio (HR) for first episode of Pf malaria with symptoms from 2 weeks after V3 to 26 weeks after V3 in the modified ITT (mITT) population. | 2 weeks after vaccination 3 to 26 weeks after vaccination 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability in children | The differences in proportions of vaccinees compared to controls experiencing unsolicited AEs from the time of V1 to 14 days after V3 (or last immunization). The differences in proportions of vaccinees compared to controls experiencing laboratory abnormalities from time of V1 to 14 days after V3. The differences in proportions of vaccinees compared to controls experiencing solicited AEs during the 7 days following each immunization. | Vaccination 1 to 14 days after Vaccination 3 | 
| Vaccine Efficacy (VE) by Hazard Ratio (HR) | VE computed as one minus the estimated HR for first episode of Pf malaria detected by thick blood smear (TBS), from 2 weeks after V3 to 26 weeks after V3 in the mITT population. | 2 to 26 weeks after Vaccination 3 | 
| Antibody responses to Pf circumsporozoite protein (CSP) | Antibody levels to PfCSP by standardized ELISA comparing protected and unprotected vaccinees and controls. | 2 to 26 weeks after Vaccination 3 | 

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