Efficacy of GSK Biologicals' Candidate Malaria Vaccine 257049 Against Malaria Disease in Infants and Children in Africa

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of PCD, Overall and by Center

PCD = malaria episode with PFAP \> 5000 parasites/µL accompanied by fever and occurring in a child unwell brought for treatment to a healthcare facility or a case of malaria meeting the PCD of severe malaria disease (see below endpoints on severe malaria for details). Time to all CPFMI episodes is expressed as person-year rate in each group (n/T). Results are by center and across centers, and are uncorrected for double enrollment of 1 subject receiving GSK257049 vaccine.

Time frame: From Month 2.5 to Month 20

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of SCD1, SCD2 and SCD3 (Overall)

SCD1 = malaria episode with PFAP \> 0 and fever at time of presentation or history of fever within 24h of presentation in a subject unwell brought for treatment to a healthcare facility. SCD2 = malaria episode with PFAP \> 500 parasites/μL and fever at time of presentation in a subject unwell brought for treatment to a healthcare facility. SCD3 = malaria episode with PFAP \> 20.000 parasites/μL and fever at time of presentation in a subject unwell and brought for treatment to a healthcare facility. Time to all CPFMI episodes is expressed as person-year rate in each group (n/T). Results are across centers, and are uncorrected for double enrollment of 1 subject receiving GSK257049 vaccine.

Time frame: From Month 2.5 to Month 20

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Centers and Across Centers

CPFMI of PCD = episode of malaria for which PFAP \> 5000 parasites/µL accompanied by presence of fever (axillary temperature ≥ 37.5°C at time of presentation) AND occurring in a child unwell brought for treatment to a healthcare facility OR a case of malaria meeting the PCD of severe malaria disease. Time to all CPFMI episodes is expressed as person-year rate in each group (n/T). Results are presented by center and across centers.

Time frame: From Month 2.5 up to study End (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Secondary Case Definition 1 (SCD1), Across Centers

CPFMI of SCD1 = malaria episode with PFAP \>0 and fever at time of presentation or history of fever within 24h of presentation in a subject unwell brought for treatment to a healthcare facility. Time to all CPFMI episodes is expressed as person-year rate in each group (n/T). Results are presented across centers.

Time frame: From Month 2.5 up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD) and Secondary Case Definition 1 (SCD1), Across Centers

CPFMI of PCD = episode of malaria for which PFAP \> 5000 parasites/µL accompanied by the presence of fever (axillary temperature ≥ 37.5°C at time of presentation) AND occurring in a child unwell brought for treatment to a healthcare facility OR a case of malaria meeting the PCD of severe malaria disease. CPFMI of SCD1 = malaria episode with PFAP \>0 and fever at time of presentation or history of fever within 24h of presentation in a subject unwell brought for treatment to a healthcare facility. Time to all CPFMI episodes is expressed as person-year rate in each group (n/T). Results are presented across centers.

Time frame: From Booster at Month 20 up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of PCD and SCD1, Across Centers

CPFMI of PCD = episode of malaria for which PFAP \> 5000 parasites/µL accompanied by the presence of fever (axillary temperature ≥ 37.5°C at time of presentation) AND occurring in a child unwell brought for treatment to a healthcare facility OR a case of malaria meeting the PCD of severe malaria disease. CPFMI of SCD1 = malaria episode with PFAP \> 0 and fever at time of presentation or history of fever within 24h of presentation in a subject unwell brought for treatment to a healthcare facility. Time to all CPFMI episodes is expressed as person-year rate in each group (n/T). Results are presented across centers.

Time frame: From Month 33 up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of PCD, by Center and Across Centers

CPFMI of PCD = episode of malaria for which PFAP \> 5000 parasites/µL accompanied by the presence of fever (axillary temperature ≥ 37.5°C at time of presentation) AND occurring in a child unwell brought for treatment to a healthcare facility OR a case of malaria meeting the PCD of severe malaria disease. Time to all CPFMI episodes is expressed as person-year rate in each group (n/T). Results are presented by center and across centers.

Time frame: From Month 2.5 to Month 32

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Secondary Case Definition 1 (SCD1)

CPFMI of SCD1 = malaria episode with PFAP \> 0 and fever at time of presentation or history of fever within 24h of presentation in a subject unwell brought for treatment to a healthcare facility. Time to all episodes of CPFMI is expressed as a rate of all CPFMI (RaCPFMI), that is, person-year rate in each group (n/T).

Time frame: From Month 2.5 to Month 32

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD) and Secondary Case Definition 1 (SCD1)

CPFMI of PCD = episode of malaria for which PFAP \> 5000 parasites/µL accompanied by the presence of fever (axillary temperature ≥ 37.5°C at time of presentation) AND occurring in a child unwell brought for treatment to a healthcare facility OR a case of malaria meeting the PCD of severe malaria disease. CPFMI of SCD1 = malaria episode with PFAP \> 0 and fever at time of presentation or history of fever within 24h of presentation in a subject unwell brought for treatment to a healthcare facility. Time to all episodes of CPFMI is expressed as a rate of all CPFMI (RaCPFMI), that is, person-year rate in each group (n/T).

Time frame: From Booster at Month 20 up to Month 32

Percentage of Subjects With Severe PFMI (SPFMI) of PCD, SCD1, SCD2 and SCD3, Across Centers

SPFMI of PCD = PFMI \> 5000 parasites/μL, at least one severity marker and no co-morbidity diagnosis. SPFMI of SCD1 = PFMI \>5000 parasites/μL and with one or more severity marker. SPFMI of SCD2 = PFMI \>0 with one or more severity marker and without co-morbidity diagnosis. SPFMI of SCD3 = PFMI \>5000 parasites/μL, with one or more severity marker, and without co-morbidity or HIV. Severity markers = prostration; respiratory distress; Blantyre score ≤ 2; ≥ 2 seizures in 24 h prior to admission, emergency room and hospitalisation; hypoglycaemia \< 2.2 mmol/L; acidosis BE ≤ -10.0 mmol/L,l \< 5.0 mmol/L; anaemia\<5.0 g/dL. Comorbidities = radiographically proven pneumonia; meningitis; positive blood culture on a blood culture taken within 72 h of admission; gastroenteritis with dehydration. Analysis was performed in a pooled manner across age categories. Results presented are uncorrected for double enrollment of one subject in 5-17 months age category receiving GSK257049 vaccine.

Time frame: From Month 2.5 up to the time when 250 subjects were diagnosed with severe malaria of PCD, SCD1, SCD2 and SCD3 (up to the Month 14 time point for each age category or date of booster dose, whichever occurred first)

Percentage of Subjects With Severe PFMI (SPFMI) of PCD and SCD1

SPFMI of PCD = PFMI\>5000 parasites/μL, at least one severity marker and no co-morbidity diagnosis. SPFMI of SCD1 = PFMI\>5000 parasites/μL and with one or more severity marker. Severity markers = prostration; respiratory distress; Blantyre score ≤ 2; ≥ 2 seizures in 24h prior to admission, emergency room and hospitalisation; hypoglycaemia\<2.2 mmol/L; acidosis BE ≤ -10.0 mmol/L,l ≥ 5.0 mmol/L; anaemia\<5.0 g/dL. Comorbidities = radiographically proven pneumonia; meningitis; positive blood culture on a blood culture taken within 72h of admission; gastroenteritis with dehydration. SPFMI of SCD1 = PFMI\>5000 parasites/μL and with one or more severity marker. Severity markers = prostration; respiratory distress; Blantyre score ≤ 2; ≥ 2 seizures in 24h prior to admission, emergency room and hospitalisation; hypoglycaemia\<2.2 mmol/L; acidosis BE ≤ -10.0 mmol/L,l ≥ 5.0 mmol/L; anaemia\<5.0 g/dL. Results presented are uncorrected for double enrollment of one subject in 5-17 months age category.

Time frame: From Month 2.5 to Month 14

Percentage of Subjects With Severe PFMI (SPFMI) of PCD and SCD1

SPFMI of PCD = PFMI\>5000 parasites/μL, at least one severity marker and no co-morbidity diagnosis. SPFMI of SCD1 = PFMI\>5000 parasites/μL and with one or more severity marker. Severity markers = prostration; respiratory distress; Blantyre score ≤ 2; ≥ 2 seizures in 24h prior to admission, emergency room and hospitalisation; hypoglycaemia\<2.2 mmol/L; acidosis BE ≤ -10.0 mmol/L,l ≥ 5.0 mmol/L; anaemia\<5.0 g/dL. Comorbidities = radiographically proven pneumonia; meningitis; positive blood culture on a blood culture taken within 72h of admission; gastroenteritis with dehydration. SPFMI of SCD1 = PFMI\>5000 parasites/μL and with one or more severity marker. Severity markers = prostration; respiratory distress; Blantyre score ≤ 2; ≥ 2 seizures in 24h prior to admission, emergency room and hospitalisation; hypoglycaemia\<2.2 mmol/L; acidosis BE ≤ -10.0 mmol/L,l ≥ 5.0 mmol/L; anaemia\<5.0 g/dL. Results presented are uncorrected for double enrollment of one subject in 5-17 months age category.

Time frame: From Month 2.5 to Month 20 at Booster

Percentage of Subjects With Severe PFMI (SPFMI) of PCD and SCD1

SPFMI of PCD = PFMI \>5000 parasites/μL, at least one severity marker and no co-morbidity diagnosis. SPFMI of SCD1 = PFMI \>5000 parasites/μL and with one or more severity marker. Severity markers = prostration; respiratory distress; Blantyre score ≤ 2; ≥ 2 seizures in 24 h prior to admission, emergency room and hospitalisation; hypoglycaemia\<2.2 mmol/L; acidosis BE ≤ -10.0 mmol/L,l ≥ 5.0 mmol/L; anaemia\<5.0 g/dL. Comorbidities = radiographically proven pneumonia; meningitis; positive blood culture on a blood culture taken within 72 h of admission; gastroenteritis with dehydration. SPFMI of SCD1 = PFMI \>5000 parasites/μL and with one or more severity marker. Severity markers = prostration; respiratory distress; Blantyre score ≤ 2; ≥ 2 seizures in 24 h prior to admission, emergency room and hospitalisation; hypoglycaemia\<2.2 mmol/L; acidosis BE ≤ -10.0 mmol/L,l ≥ 5.0 mmol/L; anaemia\<5.0 g/dL.

Time frame: From Month 2.5, from Month 20(booster), from Month 33 up to study end (median follow-up time of 48 months post-Dose 1 for 5-17M age category and of 38 months post-Dose 1 for 6-12W age category) and from Month 2.5 to Month 32 and from Month 20 to Month 32

Percentage of Subjects With Incident Severe Anaemia (ISA) and Malaria Hospitalization (MH) for Case Definitions (CD) Considered

CD considered were CD1 for ISA and CD1 and CD2 for MH. ISA of CD1 was defined as a documented hemoglobin \< 5.0 g/dL identified at clinical presentation to morbidity surveillance system in association with a P. falciparum parasitemia \> 5000 parasites/μL. MH of CD1 was defined as a medical hospitalization with confirmed P. falciparum \> 5000 parasites/μL. MH of CD2 was defined as a hospitalization which, in the judgment of the principal investigator, P. falciparum infection was the sole or a major contributing factor to the presentation. Results presented are uncorrected for double enrollment of one subject in 5-17 months age category receiving GSK257049 vaccine.

Time frame: From Month 2.5 to Month 20

Percentage of Subjects With Incident Severe Anaemia (ISA), Malaria Hospitalization (MH) and Fatal Malaria (FM) for Case Definitions (CD) Considered

ISA CD considered were CD1, CD2 and CD3 (definitions mentioned in the previous outcome measure). MH CD considered were CD1 and CD2 (definitions mentioned in the previous outcome measure).FM CD considered were primary CD (PCD) and sedondary CDs 1 and 4 (SCD1 and SCD4). FM of PCD was defined as a case of severe malaria meeting the primary case definition of severe malaria disease with a fatal outcome. FM of SCD1 was defined as a case of severe malaria meeting the secondary case definition 1 severe malaria disease with a fatal outcome. FM of SCD4 was defined as a fatal case associated with International Classification Disease (ICD10) codes B50, B53 and/or B54. Code B50 corresponds to P. falciparum malaria including mixed infections of P. falciparum with any other Plasmodium species; Code B53 corresponds to other parasitologically confirmed malaria; Code B54 corresponds to unspecified malaria including clinically diagnosed malaria without parasitological confirmation.

Time frame: From Month 2.5 to up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)

Percentage of Subjects With Incident Severe Anaemia (ISA), Malaria Hospitalization (MH) and Fatal Malaria (FM) for Case Definitions (CD) Considered

ISA CD considered were CD1, CD2 and CD3 (definitions mentioned in the previous outcome measure). MH CD considered were CD1 and CD2 (definitions mentioned in the previous outcome measure).FM CD considered were primary CD (PCD) and sedondary CDs 1 and 4 (SCD1 and SCD4). FM of PCD was defined as a case of severe malaria meeting the primary case definition of severe malaria disease with a fatal outcome. FM of SCD1 was defined as a case of severe malaria meeting the secondary case definition 1 severe malaria disease with a fatal outcome. FM of SCD4 was defined as a fatal case associated with International Classification Disease (ICD10) codes B50, B53 and/or B54. Code B50 corresponds to P. falciparum malaria including mixed infections of P. falciparum with any other Plasmodium species; Code B53 corresponds to other parasitologically confirmed malaria; Code B54 corresponds to unspecified malaria including clinically diagnosed malaria without parasitological confirmation.

Time frame: From Month 2.5 to Month 32

Percentage of Subjects With Prevalent Parasitemia, Prevalent Gametocytemia and Prevalent Severe and Moderate Anemia

Prevalent parasitemia (PP) was defined as a documented P. falciparum asexual parasite density \> 0 identified at timing of assessment. Prevalent gametocytemia (PG) was defined as a documented P. falciparum gametocyte density \> 0 identified at a cross sectional survey. Prevalent severe anemia (PSA) was defined as a documented hemoglobin \< 5.0 g/dL identified at timing of assessment. Prevalent moderate anemia (PMA) was defined as a documented hemoglobin \< 8.0 g/dL identified at at timing of assessment. Results presented are uncorrected for the double enrollment of one subject receiving RTS,S/AS01.

Time frame: At Month 20 (Booster)

Percentage of Subjects With Prevalent Parasitemia and Prevalent Severe and Moderate Anemia

Prevalent parasitemia (PP) was defined as a documented P. falciparum asexual parasite density \> 0 identified at timing of assessment. Prevalent severe anemia (PSA) was defined as a documented hemoglobin \< 5.0 g/dL identified at timing of assessment. Prevalent moderate anemia (PMA) was defined as a documented hemoglobin \< 8.0 g/dL identified at timing of assessment. Analysis was performed on subjects aged 5-17 months at enrollment. Study End (Early) corresponds to children whose Month 32 visit took place after 30 June 2012 and who had one cross-sectional visit at study end. These children's last study visit was relatively earlier, with a median follow-up time of 14 months post Month 32. Study End (Late) corresponds to children whose Month 32 visit took place before (and including) 30 June 2012, and who had 2 cross-sectional visits after Month 32. These children's last study visit was relatively later, with a median follow-up time of 17 months post Month 32).

Time frame: At Months 32, 44, at study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category) (early and late)

Percentage of Subjects With Pneumonia, All-cause Hospitalization and Sepsis, as Per Case Definitions Assessed

Pneumonia case definitions assessed are PCD and SCD 1, 2 and 3. Pneumonia of PCD was defined as cough or difficulty breathing AND tachypnea (≥ 50 breaths per minute \< 1 year, ≥ 40 breaths per minute ≥ 1year) AND lower chest wall indrawing. Pneumonia of SCD1 was defined as pneumonia of PCD accompanied by chest X-ray (CXR) consolidation or pleural effusion on x-ray taken within 72 h of admission. Pneumonia of SCD2 was defined as pneumonia of PCD accompanied by consolidation or pleural effusion or other infiltrates on a chest x-ray taken within 72 h of admission. Pneumonia of SCD3 was defined as pneumonia of PCD accompanied by an oxygen saturation \< 90%. All-cause hospitalization of PCD was defined as a medical hospitalization of any cause (excludes planned admissions for medical investigation/care or elective surgery and trauma). Sepsis cases were defined as a child with positive blood culture (CD1) or salmonella blood culture (CD2).

Time frame: From Month 2.5 to Month 20

Percentage of Subjects With Fatal Malaria (FM) and All-cause Mortality (ACM) as Per Case Definitions Assessed

Fatal malaria case definitions assessed were PCD and SCD1. Fatal malaria of PCD was defined as a case of severe malaria meeting the primary case definition of severe malaria disease (defined in a previous outcome measure) with a fatal outcome. Fatal malaria of SCD1 was defined as a case of severe malaria meeting the secondary case definition 1 severe malaria disease (defined previously) with a fatal outcome. All-cause mortality case definitions assessed were the case definitions (CD) 1 and 2. All-cause mortality of CD1 was defined as a fatality (of any cause) (including mortality in the community and in hospital). All-cause mortality of CD2 was defined as a fatality (medical cause) (including mortality in the community and in hospital), at the exclusion of trauma which may be diagnosed by verbal autopsy. Results presented are uncorrected for double enrollment of one subject in 5-17 months age category receiving GSK257049 vaccine.

Time frame: From Month 2.5 to Month 20

Percentage of Subjects With Pneumonia, All-cause Hospitalization/Mortality and Sepsis, as Per Case Definitions Assessed

Pneumonia of PCD was defined as cough or difficulty breathing (on history) AND tachypnea (\>= 50 breaths per minute \< 1 year, \>= 40 breaths per minute \>= 1year) AND lower chest wall indrawing,SCD1 was defined as pneumonia of PCD accompanied by chest X-ray (CXR) consolidation or pleural effusion on x-ray taken within 72 h of admission,SCD2 was defined as pneumonia of PCD accompanied by consolidation or pleural effusion or other infiltrates on a chest x-ray taken within 72 h of admission,SCD3 was defined as pneumonia of PCD accompanied by an oxygen saturation less than 90%.All-cause hospitalization of PCD was defined as a medical hospitalization of any cause (excluding planned admissions for medical investigation/care or elective surgery and trauma).All-cause mortality of CD1 was defined as a fatality (of any cause),of CD2 defined as a fatality (medical cause).Sepsis of CD1 was defined as a child with positive blood culture;CD2 defined as a child with positive salmonella blood culture.

Time frame: From Month 2.5 up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)

Percentage of Subjects With Blood Transfusion, as Per Case Definition Assessed

Blood transfusion case definition assessed was the case definition 1 (CD1). Blood transfusion of CD1 was defined as a child with inpatient admission with documented blood transfusion.

Time frame: From Month 2.5 up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Gender and Overall

CPFMI of PCD = episode of malaria for which PFAP \> 5000 parasites/µL accompanied by the presence of fever (axillary temperature ≥ 37.5°C at time of presentation) AND occurring in a child unwell brought for treatment to a healthcare facility OR a case of malaria meeting the PCD of severe malaria disease. Time to all episodes of CPFMI is expressed as a rate of all CPFMI (RaCPFMI), that is, person-year rate in each group (n/T). Analysis was performed on subjects aged 5-17 months and 6-12 weeks at enrollment. Results were presented by gender and overall.

Time frame: From Month 2.5 to Month 32

Height, Weight and Mid Upper Arm Circumference for Age Z-score (HAZ, WAZ and MUACZ)

Anthropometry consisted of length/height for age z-score \[HAZ\] (children \< 2 years length measure and children ≥ 2 years standing height measure), weight for age z-score \[WAZ\] and mid-upper arm circumference for age z-score \[MUACZ\] measurements, where a HAZ \< -1,5 z-score, indicates growth deficit, while a HAZ between -1,0 and ± 1,0 z-score, indicates normal height. A WAZ ≤ -3 z-score indicates a very low weight for age, a WAZ \> -3 and ≤ -2 z-score indicates a low weight for age, a WAZ \> - 2 z-score indicates normal weight. A MUACZ \< -2 z-score indicates children that are wasted, a MUACZ \< - 3 z-score indicates severely wasted children.

Time frame: At Month 20 (Booster)

Height, Weight and Mid Upper Arm Circumference for Age Z-score (HAZ, WAZ and MUACZ)

Anthropometry consisted of length/height for age z-score \[HAZ\] (children \< 2 years length measure and children ≥ 2 years standing height measure), weight for age z-score \[WAZ\] and mid-upper arm circumference for age z-score \[MUACZ\] measurements, where a HAZ \< -1,5 z-score, indicates growth deficit, while a HAZ between -1,0 and ± 1,0 z-score, indicates normal height. A WAZ ≤ -3 z-score indicates a very low weight for age, a WAZ \> -3 and ≤ -2 z-score indicates a low weight for age, a WAZ \> - 2 z-score indicates normal weight. A MUACZ \< -2 z-score indicates children that are wasted, a MUACZ \< - 3 z-score indicates severely wasted children. Note: The early study end refers to children whose last visit in the primary study phase (Month 32) was after 30 June 2012 and who by protocol had one cross-sectional study end and to late study end refers to children whose last visit in the primary study phase (Month 32) was after 30 June 2012 and who by protocol had one cross-sectional study end.

Time frame: At Months 32, 44, at study end (early and late) (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)

Antibody Concentrations Against Plasmodium Falciparum Circumsporozoite (Anti-CS)

Anti-CS antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and presented as geometric mean concentrations (GMCs), expressed in ELISA units per milliliter (EL.U/mL). The seropositivity cut-off for the endpoint was a GMC value ≥ 0.5 EL.U/mL. Results were assessed for the first 200 subjects enrolled in each study center.

Time frame: At Day 0 and at Month 3

Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS)

Anti-CS antibody concentrations were determined by ELISA and presented as geometric mean concentrations (GMCs), expressed in EL.U/mL. The seropositivity cut-off for the endpoint was a GMC value ≥ 0.5 EL.U/mL. Results were assessed for the first 200 HIV-infected subjects enrolled in each study center. HIV infection was confirmed if present at screening or identified by morbidity surveillance, not infection confirmed by antibody testing after 18 months of age or by PCR, by the time of the analysis of results up to the Month 14 time point for the respective 5-17 months and 6-12 weeks age categories.

Time frame: At Day 0 and at Month 3

Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS)

Anti-CS antibody concentrations were determined by ELISA and presented as geometric mean concentrations (GMCs), expressed in EL.U/mL. The seropositivity cut-off for the endpoint was a GMC value ≥ 0.5 EL.U/mL.

Time frame: At Months 20, 21 and 32

Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS)

Anti-CS antibody concentrations were determined by ELISA and presented as geometric mean concentrations (GMCs), expressed in EL.U/mL. The seropositivity cut-off for the endpoint was a GMC value ≥ 0.5 EL.U/mL. Results for this endpoint were assessed for Agogo, Lilongwe and Siaya sites.

Time frame: At Month 44 and at study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)

Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS), by Tertile

Anti-CS antibody concentrations were determined by ELISA and presented as geometric mean concentrations (GMCs), expressed in EL.U/mL. The seropositivity cut-off for the endpoint was a GMC value ≥ 0.5 EL.U/mL. Results were presented by tertiles of anti-CS responses in the first 200 participants per site, based on subjects assessed for vaccine efficacy results.

Time frame: At Month 3

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Tertile

CPFMI of PCD = episode of malaria for which PFAP \> 5000 parasites/µL accompanied by presence of fever (axillary temperature ≥ 37.5°C at time of presentation) AND occurring in a child unwell brought for treatment to a healthcare facility OR a case of malaria meeting the PCD of severe malaria disease. Time to all episodes of CPFMI is expressed as a rate of all CPFMI (RaCPFMI), that is, person-year rate in each group (n/T). RaCPFMI was calculated by tertile of anti-CS response post primary vaccination pooled across sites, on subjects in GSK257049-Menjugate Groups (5-17M; 6-12W) and Comparator Groups (5-17M; 6-12W), taking into account the first 200 participants per site.

Time frame: From Month 2.5 to Month 32

Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS), by Tertile

Anti-CS antibody concentrations were determined by ELISA and presented as geometric mean concentrations (GMCs), expressed in EL.U/mL. The seropositivity cut-off for the endpoint was a GMC value ≥ 0.5 EL.U/mL. Results were presented by tertiles of anti-CS responses in the first 200 participants per site, based on subjects assessed for vaccine efficacy results.

Time frame: At Month 21

Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Tertile

CPFMI of PCD = episode of malaria for which PFAP \> 5000 parasites/µL accompanied by presence of fever (axillary temperature ≥ 37.5°C at time of presentation) AND occurring in a child unwell brought for treatment to a healthcare facility OR a case of malaria meeting the PCD of severe malaria disease. Time to all episodes of CPFMI is expressed as a rate of all CPFMI (RaCPFMI), that is, person-year rate in each group (n/T). RaCPFMI was calculated by tertile of anti-CS response post booster vaccination pooled across sites, on subjects in R3R (5-17M; 6-12W) (or R3R below) and C3C (5-17M; 6-12W) (or C3C below) groups taking into account the first 200 participants per site.

Time frame: From Booster at Month 20 to Month 32

Antibody Concentrations Against Hepatitis B Surface Antigen (Anti-HBs)

Antibody concentrations assessed by ELISA, were presented as geometric mean concentrations (GMCs), and expressed in milli-international units per milliliter (mIU/mL). The seropositivity and seroprotection cut-offs were ≥ 10 and 100 mIU/mL, respectively. Results were assessed for the first 200 subjects in each center.

Time frame: At Day 0 and at Month 3

Antibody Concentrations Against Hepatitis B Surface Antigen

Antibody concentrations as assessed by ELISA, were presented as geometric mean concentrations (GMCs), and expressed in mIU/mL. The seropositivity and seroprotection cut-offs were ≥ 10 and 100 mIU/mL, respectively. Results were assessed for the first 200 HIV-infected subjects enrolled in each study center. HIV infection was confirmed if present at screening or identified by morbidity surveillance, not infection confirmed by antibody testing after 18 months of age or by PCR, by the time of the analysis of results up to the Month 14 time point for the respective 5-17 months and 6-12 weeks age categories.

Time frame: At Day 0 and at Month 3

Antibody Concentrations Against Hepatitis B Surface Antigen (Anti-HBs)

Antibody concentrations as assessed by ELISA, were presented as geometric mean concentrations (GMCs), and expressed in mIU/mL. The seropositivity and seroprotection cut-offs were ≥ 6.2 and 100 mIU/mL, respectively. Results were assessed for the first 200 subjects in each center.

Time frame: At Months 20 and 21

Antibody Titers Against Poliomyelitis (Anti-polio) Type 1, 2 and 3

Anti-Polio 1, 2 and 3 antibody titers were presented as geometric mean titers (GMTs). The seroprotection cut-off for the assay was an antibody titer ≥ 1:8.

Time frame: At Day 0 and at Month 3

Number of Subjects With Any and Grade 3 Solicited Local Symptoms

Assessed solicited local symptoms included pain, redness and swelling. Any = the incidence of a particular symptom, regardless of intensity grade. Grade 3 pain = cried when limb was moved, spontaneously painful. Grade 3 redness/swelling = redness/swelling spreading beyond 20 millimeters (mm) of injection site.

Time frame: During the 7-day (Days 0-6) post-primary 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 drowsiness, irritability, loss of appetite, fever \[defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)\]. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination. 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.

Time frame: During the 7-day (Days 0-6) post-primary vaccination period following each dose and across doses

Number of Subjects With Any and Grade 3 Solicited Local Symptoms

Assessed solicited local symptoms included pain, redness and swelling. Any = the incidence of a particular symptom, regardless of intensity grade. Grade 3 pain = cried when limb was moved, spontaneously painful. Grade 3 redness/swelling = redness/swelling spreading beyond 20 millimeters (mm) of injection site.

Time frame: During 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 drowsiness, irritability, loss of appetite, fever \[defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)\]. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination. 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.

Time frame: During the 7-day (Days 0-6) post-booster vaccination period

Number of Doses With Seizures by Diagnostic Certainty Level

Diagnostic certainty levels included: Level 1- Witnessed sudden loss of consciousness and generalized, tonic, clonic, tonic-clonic, or atonic motor manifestations; Level 2- History of unconsciousness and generalized, tonic, clonic, tonic-clonic, or atonic motor manifestations; Level 3- History of unconsciousness and other generalized motor manifestations; Level 4- Reported generalized convulsive seizure with insufficient evidence to meet the case definition; Level 5- Not a case of generalized convulsive seizure.

Time frame: During the 7-day (Days 0-6) post-booster vaccination period, at Month 20 + 7 Day (Days 0-6)

Number of Subjects Reporting Mucocutaneous Changes (All Levels)

Levels of mucocutaneous changes reported were: cutaneous and mucosal change; cutaneous only change; mucosal only change; cutaneous change focused on the nappy/diaper area. Mucocutaneous changes results calculated based on the first 200 subjects in the 6-12 weeks age category in each study center were enrolled, and with available data (i.e. who received a booster dose).

Time frame: During the 30-day (Days 0-29) post-booster vaccination

Number of Subjects Reporting Any Meningitis and Encephalitis Serious Adverse Events (SAEs)

Meningitis and encephalitis SAEs included: meningitis/encephalitis; meningitis/encephalitis viral; meningism; meningitis haemophilus; meningitis meningococcal; meningitis pneumococcal; meningitis tuberculous; encephalomyelitis.

Time frame: At Month 0 until study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)

Number of Subjects Reporting Any Meningitis and Encephalitis SAEs

Meningitis and encephalitis SAEs included: meningitis/encephalitis; meningitis haemophilus; meningitis meningococcal; meningitis tuberculous; encephalomyelitis.

Time frame: From Booster up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)

Number of Subjects Reporting Any Potential Immune-mediated Disorders (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 aetiology.

Time frame: From Month 0 up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)

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. Unsolicited AEs were calculated based on the first 200 subjects enrolled in each study center.

Time frame: Within the 30-day (Days 0-29) post-primary vaccination period

Number of Subjects With Unsolicited AEs Related to or Leading to Vaccination Withdrawal

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. Related = AE assessed by the investigator as related to the vaccination. Unsolicited AEs were calculated based on the first 200 subjects enrolled in each study center.

Time frame: Within the 30-day (Days 0-29) post-primary vaccination period

Number of Subjects With Any Unsolicited 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. Unsolicited AEs were calculated based on the first 200 subjects enrolled in each study center.

Time frame: Within the 30-day (days 0-29) post-booster vaccination period

Number of Subjects With Unsolicited AEs Related to or Leading to Vaccination Withdrawal

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. Related = AE assessed by the investigator as related to the vaccination. Unsolicited AEs were calculated based on the subgroup of the first 200 subjects enrolled in each study center, who were reported with HIV infected status ((HIV status either as per general medical history taken at screening or as identified by morbidity surveillance).

Time frame: Within the 30-day (Days 0-29) post-primary and post-booster vaccination period in HIV-infected children

Number of Subjects With Unsolicited AEs Related to or Leading to Vaccination Withdrawal in the Low-weight (LW) and Very Low-weight (VLW) Category

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. Related = AE assessed by the investigator as related to the vaccination. Unsolicited AEs were calculated based on the subgroup of the first 200 subjects enrolled in each study center, who were reported with HIV infected status ((HIV status either as per general medical history taken at screening or as identified by morbidity surveillance). Low-weight subjects were defined as subjects whose weight for age z-score (WAZ) was \> -3 and ≤ -2. Very low-weight subjects were defined as subjects whose weight for age z-score (WAZ) was ≤ -3.

Time frame: Within the 30-day (Days 0-29) post-primary vaccination period in HIV-infected children

Number of Subjects With Unsolicited AEs Related to Vaccination in the Low-weight (LW) and Very Low-weight (VLW) Category

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. Related = AE assessed by the investigator as related to the vaccination. Unsolicited AEs were calculated based on the subgroup of the first 200 subjects enrolled in each study center. Low-weight subjects were defined as subjects whose weight for age z-score (WAZ) was \> -3 and ≤ -2. Very low-weight subjects were defined as subjects whose weight for age z-score (WAZ) was ≤ -3.

Time frame: Within the 30-day (Days 0-29) post-booster vaccination period

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.

Time frame: From Month 0 up to Month 14

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.

Time frame: During the 30-day (Days 0-29) post-primary vaccination period

Number of Subjects With Serious Adversee 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.

Time frame: From Month 0 up to Month 20

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.

Time frame: From Booster (at Month 20) up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)

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.

Time frame: From Month 0 up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)

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.

Time frame: Within the 30-day (Days 0-29) post-booster vaccination period

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.

Time frame: From Month 0 up to Booster (Month 20), from Month 0 up to study end and from Month 20 up to study end

Number of Low-weight (LW) 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. Low-weight subjects were defined as subjects whose weight for age z-score (WAZ) was \> -3 and ≤ -2.

Time frame: From Month 0 up to Month 20

Number of Low-weight (LW) 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. Low-weight subjects were defined as subjects whose weight for age z-score (WAZ) was \> -3 and ≤ -2.

Time frame: From Booster (Month 20) up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)

Number of Very Low-weight (VLW) 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. Very low-weight subjects were defined as subjects whose weight for age z-score (WAZ) was ≤ -3.

Time frame: From Month 0 up to Month 20

Number of Very Low-weight 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. Very low-weight subjects were defined as subjects whose weight for age z-score (WAZ) was ≤ -3.

Time frame: From Booster (Month 20) up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)]

Number of Subjects With Fatal Outcomes, by Gender

Mortality was presented as overall mortality (up to Month 20 and up to study end), mortality due to severe malaria as per secondary case definition(SCD), cerebral malaria as per secondary case definition (SCD), meningitis, fatal all-cause traumas and fatal malaria. SCD= Plasmodium falciparum malaria \> 5000 parasites/mcL and 1 or more markers of severe malaria (prostration, respiratory distress, Blantyre score ≤ 2, seizures 2 or more, hypoglycemia \< 2.2 mmol/L, acidosis BE ≤ -10.0 mmol/L,lactate ≥ 5.0 mmol/L, anemia \< 5.0 g/dL.

Time frame: From Month 0 up to study end (SE - median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)