Efficacy, Immunogenicity and Safety Study of GSK Biologicals' Candidate Malaria Vaccine Evaluating Different Dose Schedules in a Sporozoite Challenge Model in Healthy Malaria-naïve Adults

Study Overview
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Brief Summary
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This study is designed to evaluate efficacy, immunogenicity and safety of various dose schedules of GSK Biologicals' candidate malaria vaccines RTS,S/AS01B (adult formulation) and RTS,S/AS01E (pediatric formulation) in healthy malaria-naïve subjects aged 18-55 years. The purpose of this study is to investigate whether changes in dosing schedule are associated with increased or equivalent protection, and to evaluate the immune mechanisms associated with vaccine efficacy under varying dosing schedules.

Detailed Description
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Protocol Amendment 1 incorporated: additional blood sampling for assessment of parasitemia (polymerase chain reaction [PCR] testing); clarification that blood samples for both peripheral blood mononuclear cells (PBMC) and plasma will be collected for repository storage; revision of volume of whole blood samples to be taken for parasitemia assessment; clarification that urine pregnancy tests will be conducted for all females and not just those of childbearing potential; deletion of visit at Day 1 post day of challenge; clarification that RNA sequencing and not deep sequencing will be performed in this study. Note that as a result of internal change in data standards terminology, the study data collected was converted to cDISC and the statistical analysis plan was amended accordingly. Day 0 in the study design was replaced by Day 1; consequently, Day n was replaced by Day n+1. Thus, the timeframes (Day 0, Day n) of Outcome Measures described in this study record are different to that denoted in the full protocol document posted.

Official Title
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Efficacy, Immunogenicity and Safety Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Various Dose Schedules 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
* Biological: RTS,S/AS01B
* Procedure: Sporozoite-infected mosquitoes challenge.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 of any study specific procedure. A male or female between, and including, 18 and 55 years of age at the time of enrolment. 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. - Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause. Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test at enrolment, and has agreed to continue adequate contraception during the entire treatment period and for two months after completion of the vaccination series and/or malaria challenge. Exclusion Criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day -29 to Day 0), or planned use during the study period. Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe. Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. 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 antimalarial effects. Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting seven days before the first dose. 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 hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV). Documented HIV-positive subject. Previous vaccination against malaria. History of malaria chemoprophylaxis within 60 days prior to vaccination. Any history of malaria (for the vaccine groups). Planned travel to malaria endemic areas during the study period. History of splenectomy. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. Family history of congenital or hereditary immunodeficiency. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine. History of anaphylaxis post-vaccination. Hypersensitivity to latex. History of any reaction or hypersensitivity likely to be exacerbated by chloroquine. History of psoriasis and porphyria, which may be exacerbated after chloroquine treatment. Current use of medications known to cause drug reactions to chloroquine. History of severe reactions to mosquito bites. Major congenital defects. Serious chronic illness. History of any neurological disorders or seizures. Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 37.5°C/99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C/100.4°F for rectal route. - Subjects with a minor illness without fever may be enrolled at the discretion of the investigator. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests. Any abnormal baseline laboratory screening tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, hemoglobin, platelet count, total white blood cells (WBC), out of normal range as defined in the protocol. Evidence of increased cardiovascular disease risk, moderate or high, according to the National health and nutrition examination survey I criteria. Hepatomegaly, right upper quadrant abdominal pain or tenderness. Personal history of autoimmune disease. Administration of immunoglobulins and/or any blood products during the period starting three months before the first dose of study vaccine or planned administration during the study period. Pregnant or lactating female. History of chronic alcohol consumption and/or drug abuse. Female planning to become pregnant or planning to discontinue contraceptive precautions. History of blood donation within 56 days preceding enrolment. 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.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AduFx Group<br>Healthy subjects, between, and including, 18 and 55 years of age, who received RTS,S/AS01B full dose at Month 0 and Month 1 and 1/5th of RTS,S/AS01B full dose at Month 7, and underwent sporozoite challenge. | Biological: RTS,S/AS01B<br>* Subjects will receive intramuscular injection of RTS,S/AS01B.<br>Procedure: Sporozoite-infected mosquitoes challenge.<br>* Mosquitoes infected approximately 2-3 weeks earlier that are likely to contain sporozoites in their salivary glands will be allowed to feed on the subjects. For each subject, five mosquitoes will be allowed to feed over five minutes, after which they will be dissected to confirm how many were infected, and the salivary glands scored. If required additional mosquitoes will be allowed to feed until a total of five infected mosquitoes with a minimum of 2+ salivary gland scores have fed. The challenge occurs approximately 90 days (three months) after the last vaccination. Subjects will be monitored during 28 days after having bitten by mosquitoes and when parasites are found in their blood, they will be treated with appropriate anti-malarial drugs.<br>|
| Experimental: 2PedFx Group<br>Healthy subjects, between, and including, 18 and 55 years of age, who received RTS,S/AS01E double dose at Month 0 and Month 1, and 1/5th of double dose RTS,S/AS01E at Month 7, and underwent sporozoite challenge. | Biological: RTS,S/AS01E<br>* Subjects will receive intramuscular injection of RTS,S/AS01E.<br>Procedure: Sporozoite-infected mosquitoes challenge.<br>* Mosquitoes infected approximately 2-3 weeks earlier that are likely to contain sporozoites in their salivary glands will be allowed to feed on the subjects. For each subject, five mosquitoes will be allowed to feed over five minutes, after which they will be dissected to confirm how many were infected, and the salivary glands scored. If required additional mosquitoes will be allowed to feed until a total of five infected mosquitoes with a minimum of 2+ salivary gland scores have fed. The challenge occurs approximately 90 days (three months) after the last vaccination. Subjects will be monitored during 28 days after having bitten by mosquitoes and when parasites are found in their blood, they will be treated with appropriate anti-malarial drugs.<br>|
| Experimental: PedFx Group<br>Healthy subjects, between, and including, 18 and 55 years of age, who received RTS,S/AS01E full dose at Month 0 and Month 1, and 1/5th of RTS,S/AS01E full dose at Month 7, and underwent sporozoite challenge. | Biological: RTS,S/AS01E<br>* Subjects will receive intramuscular injection of RTS,S/AS01E.<br>Procedure: Sporozoite-infected mosquitoes challenge.<br>* Mosquitoes infected approximately 2-3 weeks earlier that are likely to contain sporozoites in their salivary glands will be allowed to feed on the subjects. For each subject, five mosquitoes will be allowed to feed over five minutes, after which they will be dissected to confirm how many were infected, and the salivary glands scored. If required additional mosquitoes will be allowed to feed until a total of five infected mosquitoes with a minimum of 2+ salivary gland scores have fed. The challenge occurs approximately 90 days (three months) after the last vaccination. Subjects will be monitored during 28 days after having bitten by mosquitoes and when parasites are found in their blood, they will be treated with appropriate anti-malarial drugs.<br>|
| Experimental: Adu2Fx Group<br>Healthy subjects, between, and including, 18 and 55 years of age, who received RTS,S/AS01B full dose at Month 0 and 1/5th of RTS,S/AS01B full dose at Month 1 and Month 7, and underwent sporozoite challenge. | Biological: RTS,S/AS01B<br>* Subjects will receive intramuscular injection of RTS,S/AS01B.<br>Procedure: Sporozoite-infected mosquitoes challenge.<br>* Mosquitoes infected approximately 2-3 weeks earlier that are likely to contain sporozoites in their salivary glands will be allowed to feed on the subjects. For each subject, five mosquitoes will be allowed to feed over five minutes, after which they will be dissected to confirm how many were infected, and the salivary glands scored. If required additional mosquitoes will be allowed to feed until a total of five infected mosquitoes with a minimum of 2+ salivary gland scores have fed. The challenge occurs approximately 90 days (three months) after the last vaccination. Subjects will be monitored during 28 days after having bitten by mosquitoes and when parasites are found in their blood, they will be treated with appropriate anti-malarial drugs.<br>|
| Active Comparator: Adu1Fx Group<br>Healthy subjects, between, and including, 18 and 55 years of age, who received RTS,S/AS01B full dose at Month 0 and 1/5th of RTS,S/AS01B full dose administered at Month 7, and underwent sporozoite challenge. | Biological: RTS,S/AS01B<br>* Subjects will receive intramuscular injection of RTS,S/AS01B.<br>Procedure: Sporozoite-infected mosquitoes challenge.<br>* Mosquitoes infected approximately 2-3 weeks earlier that are likely to contain sporozoites in their salivary glands will be allowed to feed on the subjects. For each subject, five mosquitoes will be allowed to feed over five minutes, after which they will be dissected to confirm how many were infected, and the salivary glands scored. If required additional mosquitoes will be allowed to feed until a total of five infected mosquitoes with a minimum of 2+ salivary gland scores have fed. The challenge occurs approximately 90 days (three months) after the last vaccination. Subjects will be monitored during 28 days after having bitten by mosquitoes and when parasites are found in their blood, they will be treated with appropriate anti-malarial drugs.<br>|
| Other: Control Group<br>Healthy subjects, between, and including, 18 and 55 years of age, who did not receive any immunization but underwent sporozoite challenge. | Procedure: Sporozoite-infected mosquitoes challenge.<br>* Mosquitoes infected approximately 2-3 weeks earlier that are likely to contain sporozoites in their salivary glands will be allowed to feed on the subjects. For each subject, five mosquitoes will be allowed to feed over five minutes, after which they will be dissected to confirm how many were infected, and the salivary glands scored. If required additional mosquitoes will be allowed to feed until a total of five infected mosquitoes with a minimum of 2+ salivary gland scores have fed. The challenge occurs approximately 90 days (three months) after the last vaccination. Subjects will be monitored during 28 days after having bitten by mosquitoes and when parasites are found in their blood, they will be treated with appropriate anti-malarial drugs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With at Least One Occurrence of Plasmodium Falciparum (P. Falciparum) Parasitemia for Each Vaccination Schedule 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. 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 315 - 28 days post challenge). | Following sporozoite challenge starting 3 months after the last vaccine dose (Day 287) for up to 28 days post-challenge (Day 315). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of P. Falciparum Parasitemia After Sporozoite Challenge for Each Vaccination Schedule | For the analyses of time to onset of parasitemia, time at risk started on first day of challenge. Time at risk was censored on Day 315 (28 days post challenge), drop-out date, start date of antimalarial treatment or date meeting an endpoint, whichever occurs first. | Following sporozoite challenge starting 3 months after the last vaccine dose (at Day 287) for up to 28 days post-challenge (at Day 315). | 
| Anti-Circumsporozoite (Anti-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 1.9 EU/mL. The GMC calculations were performed by taking the anti-log of the mean of the log transformations (base 10). Antibody concentrations below the cut-off of the assay were given an arbitrary value of half the cut-off (=1.0) for the purpose of GMC calculation. | At Day 1, Day 59, Day 197, Day 227, Day 287, Day 315, and Day 377 for subjects from AduFx, 2PedFx, PedFx, and Adu2Fx Groups. At Day 1, Day 197, Day 227, Day 287, Day 315, and Day 377 for subjects from Adu1Fx Group | 
| Anti-Hepatitis B (Anti-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 6.2 mIU/mL. | At Day 1, Day 59, Day 197, Day 227, Day 287, Day 315, and Day 377 for subjects from AduFx, 2PedFx, PedFx, and Adu2Fx Groups. At Day 1, Day 197, Day 227, Day 287, Day 315, and Day 377 for subjects from Adu1Fx Group | 
| Number of Subjects With Any Solicited Local Symptoms | Solicited local symptoms assessed are pain, redness and swelling. Any occurrence of symptom regardless of intensity grade. Any Redness or any Swelling symptom = any symptom greater than (>) 0 millimeter (mm). | Within the 7-day period (Days 1-7) after dose 1, dose 2 (except for Adu1Fx Group) and dose 3. | 
| Number of Subjects With Any Solicited General Symptoms | Solicited general symptoms assessed are fatigue, gastrointestinal symptoms, headache and fever. Any occurrence of symptom regardless of intensity grade. Fever was defined as temperature equal or greater than (≥) 37.5 degrees Celsius (°C) for oral route, axillary or tympanic route or 38.0°C for rectal route. | Within the 7-day period (Days 1-7) after dose 1, dose 2 (except for Adu1Fx Group) and dose 3. | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) After Any Vaccination | 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. | Within the 30-day period (Days 1-30), after any vaccination (across doses) | 
| Number of Subjects With Any Unsolicited AEs After Challenge | 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 the 30-day (Days 1-30) period post-challenge | 
| Number of Subjects With Any, Fatal or Related Serious Adverse Events (SAEs) After Each Vaccination | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | Within the 30-day period (Days 1-30) after any vaccination (across doses) | 
| Number of Subjects With Any, Fatal or Related SAEs During the Whole Study Period | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Day 1 up to study conclusion (Day 377) | 
| Number of Subjects With Any AE and SAE Leading to Withdrawal From Further Vaccination | 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. SAEs include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Day 1 up to study conclusion (Day 377) | 
| Number of Subjects With Potential Immune Mediated Diseases (pIMDs) | Potential immune-mediated diseases (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 377) | 
| Number of Subjects With Meningitis | Meningitis is to be reported as an adverse event of specific interest and tabulated per study group. | From Day 1 up to study conclusion (Day 377) | 
| Number of Subjects With Abnormal Laboratory Values Gradings | 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 (Grade 0 [GR0], Grade 1 [GR1], Grade 2 [GR2] Grade 3 [GR3]) and tabulated by group. Grading scale is taken from the [FDA guidance for industry: toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials (September 2007)]. | At Visit 1 Screening (Day -89 to Day 1), Day 36, Day 59, Day 204, Day 227, between Day 292 & Day 313, and Day 315 for each vaccinated subject.For Infectivity Control subjects at Visit 1b Screening (Day 231 to Day 287),between Day 292 & Day 313,and Day 315 | 
| Number of Subjects With Any, Fatal or Related SAE, After Challenge | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From day of challenge (Day 287) to the end of the challenge phase (Day 315) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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healthy volunteers, Malaria, malaria vaccine, controlled human challenge, RTS,S/AS01