A Study to Evaluate the Efficacy, Immunogenicity and Safety in a Sporozoite Challenge Model of a Fractional Booster Dose of GSK Biologicals' Candidate Malaria Vaccine Administered to Previously Vaccinated Healthy Malaria-naïve Adults

Study Overview
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Brief Summary
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MALARIA-092 (NCT03162614) study was designed to evaluate the efficacy, immunogenicity and safety of various dose schedules and formulations of GSK Biologicals' candidate malaria vaccine (RTS,S/AS01E) in healthy malaria-naïve subjects aged 18-55 years. The purpose of this study (follow-up to MALARIA-092 [NCT03162614] study) is to evaluate if protection can be extended with an additional Fx booster dose and if unprotected subjects can be protected following a Fx booster dose. In this booster study, subjects from MALARIA-092 (NCT03162614) study who completed vaccination and challenge will receive a Fx booster dose of RTS,S/AS01E and undergo a second controlled human malaria infection (CHMI) three to four weeks after vaccination. Additionally, subjects will be newly enrolled and will only undergo the sporozoite challenge as infectivity controls.

Official Title
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Efficacy, Immunogenicity and Safety Study Evaluating a Fractional (Fx) Booster Dose of GSK Biologicals' Candidate Malaria Vaccine (SB257049) in a Sporozoite Challenge Model in Healthy Malaria-naïve Adults

Conditions
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Malaria

Intervention / Treatment
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* Biological: RTS,S/AS01E (SB257049)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Only for subjects from MALARIA-092 study (NCT03162614): • Subjects vaccinated and having undergone sporozoite challenge during the primary study (MALARIA-092 [NCT03162614]). For all subjects: Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol. Written informed consent obtained from the subject prior to performing any study-specific procedure. Healthy subjects as established by medical history and clinical examination before entering into the study. Available to participate for the duration of the study. Female subjects of non-childbearing potential may be enrolled in the study. Female subjects of childbearing potential may be enrolled in the study, if the subject: Has practiced adequate contraception for 30 days prior to Day 1, and has agreed to continue adequate contraception during the entire treatment period and for two months after malaria challenge (only for subjects from the MALARIA-092 study [NCT03162614]). Has practiced adequate contraception for 30 days prior to malaria challenge, and has agreed to continue adequate contraception up to two months after malaria challenge (only for the infectivity control subjects). Has a negative pregnancy test at enrollment. For the infectivity control subjects: • Male or female subjects between, and including, 18 and 55 years of age. Exclusion Criteria: For all subjects except the infectivity control subjects: Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine. History of anaphylaxis post-vaccination. For all subjects: Use of any investigational or non-registered product other than the study vaccine during the period starting 30 days before Day 1 (Day -29 to Day 1) (for P-Fx and NP-Fx groups)/before the malaria challenge (for infectivity control subjects), or planned use during the study period. Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to Day 1 (for P-Fx and NP-Fx groups) or malaria challenge (for infectivity control subjects). For corticosteroids, this will mean prednisone ≥20 mg/day, or equivalent. Inhaled and topical steroids are allowed. Administration of long-acting immune-modifying drugs at any time during the study period. Chronic use of antibiotics with anti-malarial effects. Planned administration/administration of a vaccine not foreseen by the study protocol in the period within seven days of Day 1 (for P-Fx and NP-Fx groups) or the malaria challenge (for infectivity control subjects). Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product. Seropositive for Human Immunodeficiency Virus, Hepatitis B surface antigen or Hepatitis C Virus. Planned travel to malaria endemic areas during the study period. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. History of any reaction or hypersensitivity that would prevent the subject from utilizing all of the following: chloroquine, atovaquone/proguanil, artemether/lumefantrine. Current use of medications known to cause drug reactions that would prevent the subject from utilizing any of the following: chloroquine, atovaquone/proguanil, artemether/lumefantrine. History of severe reactions to mosquito bites. Acute disease and/or fever at the time of enrollment. Fever is defined as temperature ≥37.5°C/99.5°F for oral, axillary or tympanic route. Subjects with a minor illness without fever may be enrolled at the discretion of the investigator. Hepatomegaly, right upper quadrant abdominal pain or tenderness. Any abnormal baseline laboratory screening tests: ALT, AST, creatinine, hemoglobin, platelet count, total WBC, out of normal range. Personal history of auto-immune disease. Administration of immunoglobulins and/or any blood products during the period starting three months before Day 1 (for P-Fx and NP-Fx groups)/the malaria challenge (for infectivity control subjects), or planned administration during the study period. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions. History of chronic alcohol consumption and/or drug abuse. History of blood donation within 56 days preceding enrollment. Any other significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in this study. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests. Evidence of increased cardiovascular disease risk, moderate or high, according to the National Health And Nutrition Examination Survey I (NHANES I) criteria. Only for infectivity control subjects: Previous vaccination against malaria. History of splenectomy. Family history of congenital or hereditary immunodeficiency. Major congenital defects. Serious chronic illness. History of any neurological disorders or seizures. Diagnosed with malaria within the last 5 years (inclusive).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: P-Fx group<br>Healthy subjects, between and including 18 and 55 years of age, vaccinated with RTS,S/AS01 vaccine (different doses/formulations) and protected following the first challenge at the time of the MALARIA-092 study (NCT03162614), who received, in the current study, a fractional (Fx) booster dose of RTS,S/AS01E 12 months after completion of the vaccination course in the Malaria-092 study, and underwent sporozoite challenge. | Biological: RTS,S/AS01E (SB257049)<br>* Subjects from the P-Fx and NP-Fx groups will receive one Fx booster dose of RTS,S/AS01E at Day 1.<br>|
| Experimental: NP-Fx group<br>Healthy subjects, between and including 18 and 55 years of age, vaccinated with RTS,S/AS01 vaccine (different doses/formulations) and not protected following the first challenge at the time of the MALARIA-092 study (NCT03162614), who received, in the current study, a fractional (Fx) booster dose of RTS,S/AS01E 12 months after completion of the vaccination course in the Malaria-092 study, and underwent sporozoite challenge. | Biological: RTS,S/AS01E (SB257049)<br>* Subjects from the P-Fx and NP-Fx groups will receive one Fx booster dose of RTS,S/AS01E at Day 1.<br>|
| No Intervention: InfectivityCtrl group<br>Healthy subjects, between and including 18 and 55 years of age, who did not receive, in the current study, any immunization but underwent sporozoite challenge. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting Plasmodium Falciparum (P. Falciparum) Parasitemia (Defined by a Positive Blood Slide) Following Sporozoite Challenge (in All Study Groups Versus Infectivity Controls) | Occurrence of P. falciparum parasitemia (defined by a positive blood slide) following sporozoite challenge. Post-challenge, parasitemia was determined by microscopy of Giemsa-stained thick blood films (smear). Microscopy was performed on thick smears using a validated standard operation procedure. P. falciparum infection was defined as asexual blood stage P. falciparum parasite density greater than (>) 0 detected by blood slide reading. For the analysis of proportion affected (relative risk), all subjects included in the analysis were considered at risk of infection and no censoring or elimination was applied for subjects not completing the entire protocol-defined post-challenge follow-up (Day 50 - 28 days post challenge). | During the sporozoite challenge dose follow-up period (from Day 22 up to Day 50) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of P. Falciparum Parasitemia (Defined by a Positive Blood Slide) Following Sporozoite Challenge | For the analyses of time to onset of parasitemia (Kaplan-Meyer and log-rank), time at risk started on first day of challenge. Time at risk was censored on Day 50 (28 days post challenge), drop-out date, start date of anti-malarial treatment or date meeting an endpoint, whichever occured first. Time-at-risk was calculated as: censor date - date challenge + 1. | During the sporozoite challenge period starting at Day 22 (after the vaccine dose administered at Day 1), up to Day 50 | 
| Anti- Circumsporozoite (CS) Repeat Region Antibody Concentrations | Anti-CS antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in Enzyme-linked immunosorbent assay Unit per milliliter (EU/mL). The cut-off for the assay was equal to 1.9 EU/mL. GMC calculations are performed by taking the inverse logarithm of the mean of the log concentration transformations. Antibody concentrations below the cut-off of the assay will be given an arbitrary value of half the cut-off of the assay for the purpose of GMC calculation. | At Day 1, prior to challenge (Day 22), 28 days post-challenge (Day 50) and at study end (Day 190) | 
| Anti-Hepatitis B (HBs) Immunoglobulin G (IgG) Antibody Concentrations | Anti-HBs IgG antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in milli-International Unit per milliliter (mIU/mL). The cut-off for the assay was equal to 6.2 mIU/mL. GMC calculations are performed by taking the inverse logarithm of the mean of the log concentration transformations. Antibody concentrations below the cut-off of the assay will be given an arbitrary value of half the cut-off of the assay for the purpose of GMC calculation. | At Day 1, prior to challenge (Day 22), 28 days post-challenge (Day 50) and at study end (Day 190) | 
| Number of Subjects With Any Solicited Local Adverse Events (AEs) in the Booster Vaccination Groups | Solicited local AEs assessed are erythema, pain and swelling. Any occurrence of AE regardless of intensity grade are reported. Any Erythema or any Swelling symptom = any symptom recorded with a surface diameter greater than 0 millimeter. | Within 7 days after vaccination (day of vaccination and 6 subsequent days) in the booster vaccination groups | 
| Number of Subjects With Any Solicited General AEs in the Booster Vaccination Groups | Solicited general AEs assessed are fatigue, gastrointestinal symptoms (nausea, vomiting, diarrhea and/or abdominal pain), headache and fever. Any occurrence of symptom regardless of intensity grade and relationship to the vaccination. Fever was defined as temperature equal or greater than 37.5 °C (preferably oral route measure). | Within 7 days after vaccination (day of vaccination and 6 subsequent days) in the booster vaccination groups | 
| Number of Subjects With Any Unsolicited AEs After Vaccination, in the Booster Vaccination Groups | An unsolicited adverse event is any untoward medical occurrence in a clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. An unsolicited adverse event is any event reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. | Up to 21 days after booster vaccination period (day of vaccination and 20 subsequent days), after booster vaccination | 
| Number of Subjects With Any Unsolicited AEs After Challenge, in All Study Groups | An adverse event is any untoward medical occurrence in a clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. | Within 29 days after challenge (day of challenge and 28 subsequent days) | 
| Number of Subjects With AEs of Specific Interest (Potential Immune-mediated Diseases [pIMDs] and Meningitis), in All Study Groups | AEs of specific interest are potential immune-mediated diseases (pIMDs) and meningitis. pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. | From Day 1 up to study conclusion (Day 190) | 
| Number of Subjects With Serious Adverse Events (SAEs) (Any, Fatal or Related to Investigational Vaccine) During the Whole Study Period, in All Study Groups | An SAE is any untoward medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect in the offspring of a study subject. | From Day 1 up to study conclusion (Day 190) | 
| Number of Subjects With Abnormal Laboratory Values | Biochemistry (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST] and Creatinine) and hematological (Hemoglobin, Platelets, White Blood Cells [WBC] decrease and WBC increase) laboratory values were presented according to toxicity grading scales and tabulated by group. Grading scale adapted from FDA guidance for industry: toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials (September 2007). | At screening, Day(D)1, D8, D22 (day of first parasitemia) and D50 (28 days post-challenge) for the booster vaccination groups; and at screening, D22 (day of first parasitemia) and D50 (28 days post-challenge) for the infectivity control subjects | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, RTS,S/AS01E vaccine, Fractional dose, Sporozoite challenge