Efficacy, Safety and Immunogenicity Study of GlaxoSmithKline(GSK) Biologicals' Candidate Malaria Vaccine 257049 in the 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 safety, reactogenicity, immunogenicity, and efficacy of GSK Biological's malaria candidate vaccine 257049 administered as standard doses at 0 and 1 months and 1/5th standard dose at 7 months (delayed fractional dose group) and 257049 administered as three standard doses one month apart (0, 1, 2-month group) in healthy malaria-naïve volunteers aged 18-50 years in the sporozoite challenge model. An additional, delayed sporozoite challenge will assess persistence of protection induced by the primary immune schedule and if an additional dose can provide protection in those unprotected by the initial vaccination series.

Detailed Description
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This protocol posting has been amended to reflect changes in Amendment 1 of the Protocol (20 April 2014). Rationale for Protocol Amendment 1: • In order to assess whether protection is maintained over time, and assess boostability, the protocol has been amended to incorporate another sporozoite challenge, after a single boost of 1/5th standard dose of RTS,S/AS01B, or no boost. Study design: Dependent upon enrolment date during the screening period, the study duration will be approximately 19 months for each vaccinated subject in the delayed fractional dose group, 14 months for each vaccinated subject in the 0, 1, 2-month group, 7 months for each infectivity control subject in the challenge phase and 6 months for each infectivity control subject in the rechallenge phase. Vaccination schedules: 0, 1, 7-month followed by sporozoite challenge 21 days (3 weeks) after the third vaccination, with subsequent boosting/no boosting at Booster Phase Study Day 0 followed by sporozoite rechallenge 3 weeks post boost/no boost. 0, 1, 2-month followed by sporozoite challenge 21 days (3 weeks) after the third vaccination, with subsequent boosting/no boosting at Booster Phase Study Day 0 followed by sporozoite rechallenge 3 weeks post boost/no boost. Safety and immunogenicity will be evaluated during the study up to 3 months after rechallenge (Booster Phase Study Day 105). Treatment allocation: Non-randomized for primary phase; subjects will be enrolled to different study groups in a consecutive manner, to ensure the day of sporozoite challenge (conducted over two days) is the same for all. For the booster and rechallenge phase, subjects unprotected during the first challenge will receive a 1/5th RTS,S/AS01B booster dose while subjects from each group who were protected in the first challenge will be randomized to receive a 1/5th RTS,S/AS01B booster dose or no booster dose. This protocol posting has been amended to reflect changes in Amendment 2 of the Protocol (08 January 2015) Rationale for Protocol Amendment 2: In order to have sufficient blood samples for future assay development or testing, evaluation of Hepatitis B (HBs) cellular-mediated immunogenicity (CMI) was de-prioritised from a secondary outcome measure to a tertiary secondary outcome measure and will only be conducted if sufficient cells are available from the thawn cryotube(s) that will be used for circumsporozoite protein (CS) testing.

Official Title
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Efficacy, Safety and Immunogenicity Study of GSK Biologicals' Candidate Malaria Vaccine 257049 in the Sporozoite Challenge Model in Healthy Malaria-naïve Adults

Conditions
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Malaria

Intervention / Treatment
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* Biological: GSK257049 Dosage 1
* Biological: GSK257049 Dosage 2
* Procedure: Sporozoite-infected mosquitoes challenge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria for enrolment to the primary phase: Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol. A male or non-pregnant female 18 to 50 years of age at the time of first vaccination. Written informed consent obtained from the subject before screening procedures. Free of obvious health problems as established by medical history and clinical examination before entering into the study. Available to participate for the duration of the study (approximately 15 months per vaccinated subject in the delayed fractional dose group, approximately 10 months per vaccinated subject in the 0, 1, 2-month schedule and approximately 7 months per subject in the infectivity control group). 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 FDA-approved contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate FDA-approved contraception during the entire treatment period and for 2 months after completion of the vaccination series and/or malaria challenge. Inclusion criteria for enrolment to the booster phase: 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 before screening procedures. Subjects vaccinated in the primary phase of the study (not applicable to new infectivity controls), having undergone sporozoite challenge during the primary phase of the study. Available to participate for the duration of the booster phase of the study (approximately 3 months). 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 booster phase of the study, if the subject: has practiced adequate FDA-approved contraception for 30 days prior to day of booster vaccination, and has a negative pregnancy test on the day of booster vaccination, and has agreed to continue adequate FDA-approved contraception during the entire treatment period and for 2 months after completion of the booster vaccination and/or malaria rechallenge. Exclusion Criteria: For enrolment to the primary & booster phase: Any confirmed or suspected immunosuppressive or immunodeficient condition, including immunodeficiency virus (HIV) infection. Acute disease and/or fever at the time of enrolment to booster phase. Acute disease is defined as the presence of a moderate or severe illness with or without fever. Subjects with a minor illness without fever may be enrolled at the discretion of the investigator. Fever is defined as temperature ≥ 38.0°C (100.4°F) on oral, axillary or tympanic setting. The preferred route for recording temperature in this study will be oral. 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. Note: NHANES I criteria will be applied for all subjects including subjects aged 18-35 years old. An abnormal baseline screening electrocardiogram (EKG), defined as one showing pathologic Q waves and significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm excluding isolated premature atrial contractions; right or left bundle branch block; or advanced A-V heart block. Female who intends to become pregnant during the study or planning to discontinue contraceptive measures. For enrolment to the primary phase: Use of any investigational or non-registered product other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period. Planned administration/administration of a vaccine not foreseen by the study protocol within 7 days of the first dose of vaccines. Prior receipt of an investigational malaria vaccine. Chronic use of antibiotics with antimalarial effects. History of malaria chemoprophylaxis within 60 days prior to vaccination. Any history of malaria. Planned travel to malaria endemic areas during the study period. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s) including latex. History of allergic disease or reactions 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. Any history of anaphylaxis in reaction to any previous vaccination. History of severe reactions to mosquito bites. Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period. Chronic administration of immunosuppressants or other immune modifying drugs within six months prior to first vaccine dose. For corticosteroids, this will mean prednisone, or equivalent, greater than or equal to 20 mg/day. Inhaled and topical steroids are allowed. Family history of congenital or hereditary immunodeficiency. History of splenectomy. Major congenital defects or serious chronic illness. History of any neurological disorders or seizures, except for a single episode of simple febrile seizure in childhood. Any abnormal baseline laboratory screening tests: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), creatinine, hemoglobin, platelet count, total white blood cell count, out of normal range as defined in the protocol. Hepatomegaly, right upper quadrant abdominal pain or tenderness. Personal history of autoimmune disease. Seropositive for hepatitis B surface antigen or Hepatitis C virus. Pregnant or lactating female. Suspected or known current alcohol abuse. Chronic or active intravenous drug use. 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. For enrolment to the booster phase: Planned use of any investigational or non-registered product other than the study vaccine during the study period. Planned administration/administration of a vaccine not foreseen by the study protocol within 7 days of booster dose of study vaccine. Planned administration of immunoglobulins and/or any blood products during the study period. An abnormal baseline laboratory screening test, graded 2 or more as defined in the protocol. Any abnormal baseline laboratory screening tests out of normal range as defined in the protocol and of clinical concern according to the Principal Investigator. Any other significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in the booster phase of 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK257049-0,1,7M Group<br>Subjects receiving 2 doses of GSK257049 vaccine given at 0 and 1 months and followed 6 months later (At Month 7) by another dose of GSK257049 vaccine. | Biological: GSK257049 Dosage 1<br>* RTS,S/AS01B administered as 0.5 mL dose at 0 and 1 months and 0.1 mL dose at 7 months for 0,1,7 M Group (delayed fractional dose group). In subjects unprotected in the first challenge, to receive a booster with a fractional dose of RTS,S/AS01B followed by rechallenge. In subjects protected in the first challenge, randomization to receive or not receive a booster with a fractional dose of RTS,S/AS01B followed by rechallenge.<br>* Other names: RTS;|
| Experimental: GSK257049-0,1,2M Group<br>Subjects receiving 3 doses of GSK257049 vaccine given one month apart (0,1 and 2 months). | Biological: GSK257049 Dosage 2<br>* RTS,S/AS01B administered as three doses of 0.5mL given one month apart (0, 1, 2 M group) in the challenge model. In subjects unprotected in the first challenge, to receive a booster with a fractional dose of RTS,S/AS01B followed by rechallenge. In subjects protected in the first challenge, randomization to receive or not receive a booster with a fractional dose of RTS,S/AS01B followed by rechallenge.<br>* Other names: S/AS01B;|
| Experimental: Infectivity Control Group<br>Volunteers 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 volunteers. For each volunteer, 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. The challenge is scheduled to occur approximately 21 days (3 weeks) after the last vaccination visit (Study Day 196). Volunteers who reconsent for the boost/rechallenge phase will be rechallenged with sporozoite-infected mosquitoes, scheduled to occur approximately 21 days (3 weeks) after the booster dose (Booster Phase Study Day 21).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Plasmodium Falciparum Parasitemia Defined by a Positive Blood Slide, Following Sporozoite Challenge | The definition of malaria for primary and secondary efficacy outcomes is the appearance of asexual blood stage P. falciparum parasites detected by blood slide at any time post challenge/rechallenge up to 28 days. | 28 days post-challenge (Study Day 245) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of P. Falciparum Parasitemia Infection Defined by a Positive Blood Slide, Following Sporozoite Challenge | The time to onset was expressed in days. The definition of malaria infection for primary and secondary efficacy outcomes is the appearance of asexual blood stage P. falciparum parasites detected by blood slide at any time post challenge/rechallenge up to 28 days. | Up to 28 days post-challenge (Study Day 245) | 
| Number of Subjects With Plasmodium Falciparum Parasitemia Defined by a Positive Blood Slide, Following Sporozoite Rechallenge | The definition of malaria infection for primary and secondary efficacy outcomes is the appearance of asexual blood stage P. falciparum parasites detected by blood slide at any time post challenge/rechallenge up to 28 days. | Up to 28 days post rechallenge (Booster Phase Day 49) | 
| Time to Onset of P. Falciparum Parasitemia Infection Defined by a Positive Blood Slide, Following Sporozoite Rechallenge | The time to onset was expressed in days. The definition of malaria infection for primary and secondary efficacy outcomes is the appearance of asexual blood stage P. falciparum parasites detected by blood slide at any time post challenge/rechallenge up to 28 days. | Up to 28 days post rechallenge (Booster Phase Day 49) | 
| Anti-circumsporozoite (Anti-CS) Repeat Region Antibody Concentrations | Anti-CS antibody concentrations were determined by Enzyme Linked Immunosorbent Assay (ELISA) and expressed as EU/mL. | 7 days before vaccination (D-7), post-dose 1 at Day 28, post-dose 2 at Days 42, 56, 98, 196, at DoC Primary Phase (PP) (Day of CHMI = Day 217), at DoC PP (Day 217) + 7, 14, 28, 42, 56, 70, 84, 159 days (Days 224, 231, 245, 259, 273, 287, 301, 376). | 
| Anti-CS Repeat Region Antibody Concentrations for the Rechallenge Phase | Anti-CS antibody concentrations were determined by Enzyme Linked Immunosorbent Assay (ELISA) and expressed as EU/mL. | At Day 0 of rechallenge (pre-booster dose) and at DoC PP (Day 217 = Day of rechallenge) | 
| Frequency of CS Repeat and T-cell Epitope (RT)-Specific Cluster of Differentiation 4 (CD4) T-cells | Frequency of Cluster of Differentiation 4 (CD4) polypositives T-cells with at least 2 cytokines/activation markers between CD40-Ligand (CD40-L), interferon gamma (INF-g), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-a) was assessed for peripheral blood mononuclear cells (PBMC) with intracellular cytokine staining (ICS). | 7 days before vaccination (D-7), post-dose 1 at Day 14, post-dose 2 at Day 42, at DoC PP (Day of CHMI = Day 217), at DoC PP (Day 217) + 7, 28, 84, 159 days (Days 224, 245, 301, 376). | 
| Frequency of CS Repeat and T-cell Epitope (RT)-Specific CD8 T-cells | Frequency of CD8 polypositives T-cells with at least 2 cytokines/activation markers between CD40-L, INF-g, IL-2 and TNF-a was assessed for PBMC with ICS. | 7 days before vaccination (D-7), post-dose 1 at Day 14, post-dose 2 at Day 42, at DoC PP (Day of CHMI = Day 217), at DoC PP (Day 217) + 7, 28, 84, 159 days (Days 224, 245, 301, 376). | 
| Antibody Concentrations Against Hepatitis B Surface Antigen (Anti-HBs) | Anti-HBs antibody concentrations were determined by Chemiluminometric Immunoassay (CLIA) and expressed as miliinternation units per mililier (mIU/mL). | 7 days before vaccination (D-7), post-dose 1 at Day 28, post-dose 2 at Days 42, 56, 98, 196 after first dose, at DoC PP (Day of CHMI = Day 217), at DoC PP (Day 217)+ 7, 14, 28, 42, 56, 70, 84, 159 days (Days 224, 231, 245, 259, 273, 287, 301, 376). | 
| Anti-HBs Antibody Concentrations for Rechallenge Phase | Anti-HBs antibody concentrations were determined by Chemiluminometric Immunoassay (CLIA). | At Day 0 of rechallenge (pre-booster dose) and at DoC PP (Day 217 = Day of rechallenge) | 
| Anti-CS Repeat Region Immunoglobulin G (IgG) Avidity Index for the Challenge Phase | The avidity index percentage was calculated by anti-CS repeat region concentration under chaotropic reagent/anti-CS repeat region concentration without chaotropic reagent. The median and inter-quartile (Q1 and Q3) range was reported at the prespecified time-points. | Post-dose 1 at Day 28, post-dose 2 at Days 56, and 196, DoC PP (DoC = the day of CHMI, Day 217), DoC PP (Day 217) + 84 days (Day 301) and DoC PP (Day 217) +159 days (Day 376) | 
| Anti-CS Repeat Region IgG Avidity Index for the Rechallenge Phase | The avidity index percentage was calculated by anti-CS repeat region titer under chaotropic reagent/anti-CS repeat region titer without chaotropic reagent. The median and inter-quartile (Q1 and Q3) range was reported at the prespecified time-points. | Pre-booster dose (Booster phase Day 0) and at DoC Booster/rechallenge phase (Day of Controlled Human Malaria Infection - Day 21) | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = significant pain at rest, that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. | Within the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were fatigue, gastrointestinal symptoms (nausea, vomiting and/or abdominal pain), headache and fever [defined as axillary temperature equal to or above (≥) 38.0 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever ≥ 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. | Within the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. | Within the 7-day (Days 0-6) post- booster vaccination period | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were fatigue, gastrointestinal symptoms, headache and fever [defined as axillary temperature equal to or above (≥) 38.0 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever ≥ 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. | Within the 7-day (Days 0-6) post- booster vaccination period | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | Within 30-days (Days 0-29) post-primary vaccination | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | Within 30-days (Days 0-29) post- booster vaccination | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | Within 30-days (Days 0-29) post-first CHMI | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | Within 30-days (Days 0-29) post- second CHMI | 
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From study start to end of Primary Phase (Study Day 245) | 
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | During the entire study period (Up to Day 105 of Booster Phase) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Efficacy, Sporozoite challenge model, Malaria, Immunogenicity, Malaria- naïve adults, Safety