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

Phase 3

Completed

Conditions: Malaria

Interventions: Biological: Malaria Vaccine 257049
Biological: Cell-culture rabies vaccine
Biological: Meningococcal C Conjugate Vaccine
Biological: TritanrixHepB/Hib
Biological: Polio Sabin Oral Polio Vaccine (GSK)

Registration Number: NCT00866619

Lead Sponsor: GlaxoSmithKline

Brief Summary: The purpose of this observer-blind study is to gather key efficacy, safety, and immunogenicity information on GSK's candidate malaria vaccine in infants and children.

Detailed Description: The protocol posting document has been updated due to a protocol amendment dated 23 January 2012. An analysis time point has been added at Month 20. No changes have been made to the protocol endpoints or statistical methods but protocol endpoints will be analysed on data collected up to Month 20 once these data are available. The rationale is to have the full scope of protocol defined efficacy and safety endpoints related to a primary schedule without booster in both age categories followed up for 20 months earlier than at the initially planned study end time point (Visit 34 or Month 32 time point).

The protocol posting document was updated due to a protocol amendment dated 10 December 2010 to extend the study until December 2013 for all enrolled subjects (interval: Nov 2013-Jan 2014). Including the extension, the mean follow-up time for subjects from 5-17 months will be during 49 months post dose 1 (range: 41-55), while for subjects from 6-12 weeks, it will be during 41 months post dose 1 (range: 32-48). This study is double-blind during the first part and single-blind during the extension part. An analysis will be conducted at the end of the extension including an evaluation of safety and efficacy against clinical malaria, severe malaria and prevalent parasitemia.

The protocol posting document has been updated following the posting of results of the study (January 2015): The study remained double-blind until the end of the extension phase, and the analyses of Month 32 (initial end of study now becoming end of the first part of the study or primary study phase) and of the extension phase were conducted together.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15459

Inclusion Criteria

All subjects must satisfy the following criteria at study entry:

A male or female child of:5-17 months (inclusive) of age at time of first vaccination,or between 6-12 weeks of age at time of first vaccination and NOT have already received a dose of vaccine against diphtheria, tetanus or pertussis or Hemophilus influenzae type B and must be > 28 days of age at screening.
Signed informed consent or thumb-printed and witnessed informed consent obtained from the parent(s)/guardian(s) of the child.
Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol.

All subjects must satisfy the following criteria at the start of the extension phase:

Subjects who were enrolled and who received at least one vaccine dose in the primary trial phase.
Subjects who were present for Visit 35 on or before 30 September 2013.
Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol (e.g. return for follow-up visits) should be enrolled in the study.

Exclusion Criteria

The following criteria should be checked at the time of study entry. If any apply, the subject must not be included in the study:

Acute disease at the time of enrollment.
Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality.
Anemia associated with clinical signs or symptoms of decompensation or hemoglobin ≥ 5.0 g/dL.
Major congenital defects.
History of allergic reactions, significant IgE-mediated events or anaphylaxis to previous immunizations.
Children with a past history of a neurological disorder or atypical febrile seizure.
Children with malnutrition requiring hospital admission.
Children currently meeting the criteria for HIV disease of Stage III or Stage IV severity as defined by the World Health Organization.
History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.
Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to a drug or vaccine that is not licensed for that indication with the exception of studies with the objective of improving the drug treatment or clinical management of severe malaria disease.
Use of a drug or vaccine that is not approved for that indication other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period.
Previous participation in any other malaria vaccine trial.
Receipt of a vaccine within the preceding 7 days.
Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trial.
Any other findings that the investigator feels would result in data collected being incomplete or of poor quality

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GSK257049 [6-12W] Group	Polio Sabin Oral Polio Vaccine (GSK)	Male or female children between and including 6 to 12 weeks of age \[6-12W\], who received a 3-dose primary vaccination course of the GSK257049 malaria vaccine co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, according to a 0-1-2 Month schedule, followed by either a booster dose of the GSK257049 and Polio Sabin vaccines or a booster dose of Menjugate and Polio Sabin vaccines, at Month 20. All vaccines have been administered intramuscularly in the interolateral left thigh (GSK257049 vaccine); left deltoid (GSK257049 booster dose); left thigh for children under 1 year and left deltoid for children above 1 year of age (Menjugate vaccine); anterolateral right thigh (Tritanrix HepB/Hib vaccine), except for the Polio Sabin vaccine, which has been given orally.
VeroRab Comparator [5-17M] Group	Cell-culture rabies vaccine	Male or female children between and including 5 to 17 months of age \[5-17M\], who received a 3-dose primary vaccination course of the VeroRab vaccine, according to a 0-1-2 Month schedule, followed by a booster dose of Menjugate vaccine, at Month 20. Both vaccines have been administered intramuscularly into the left deltoid.
GSK257049 [6-12W] Group	Meningococcal C Conjugate Vaccine	Male or female children between and including 6 to 12 weeks of age \[6-12W\], who received a 3-dose primary vaccination course of the GSK257049 malaria vaccine co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, according to a 0-1-2 Month schedule, followed by either a booster dose of the GSK257049 and Polio Sabin vaccines or a booster dose of Menjugate and Polio Sabin vaccines, at Month 20. All vaccines have been administered intramuscularly in the interolateral left thigh (GSK257049 vaccine); left deltoid (GSK257049 booster dose); left thigh for children under 1 year and left deltoid for children above 1 year of age (Menjugate vaccine); anterolateral right thigh (Tritanrix HepB/Hib vaccine), except for the Polio Sabin vaccine, which has been given orally.
GSK257049 [5-17M] Group	Malaria Vaccine 257049	Male or female children between and including 5 to 17 months of age \[5-17M\], who received a 3-dose primary vaccination course of the GSK257049 malaria vaccine, according to a 0-1-2 Month schedule, followed by either a booster dose of the same GSK257049 vaccine or a dose of Menjugate vaccine, at Month 20. Both vaccines have been administered intramuscularly into the left deltoid.
GSK257049 [6-12W] Group	Malaria Vaccine 257049	Male or female children between and including 6 to 12 weeks of age \[6-12W\], who received a 3-dose primary vaccination course of the GSK257049 malaria vaccine co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, according to a 0-1-2 Month schedule, followed by either a booster dose of the GSK257049 and Polio Sabin vaccines or a booster dose of Menjugate and Polio Sabin vaccines, at Month 20. All vaccines have been administered intramuscularly in the interolateral left thigh (GSK257049 vaccine); left deltoid (GSK257049 booster dose); left thigh for children under 1 year and left deltoid for children above 1 year of age (Menjugate vaccine); anterolateral right thigh (Tritanrix HepB/Hib vaccine), except for the Polio Sabin vaccine, which has been given orally.
GSK257049 [6-12W] Group	TritanrixHepB/Hib	Male or female children between and including 6 to 12 weeks of age \[6-12W\], who received a 3-dose primary vaccination course of the GSK257049 malaria vaccine co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, according to a 0-1-2 Month schedule, followed by either a booster dose of the GSK257049 and Polio Sabin vaccines or a booster dose of Menjugate and Polio Sabin vaccines, at Month 20. All vaccines have been administered intramuscularly in the interolateral left thigh (GSK257049 vaccine); left deltoid (GSK257049 booster dose); left thigh for children under 1 year and left deltoid for children above 1 year of age (Menjugate vaccine); anterolateral right thigh (Tritanrix HepB/Hib vaccine), except for the Polio Sabin vaccine, which has been given orally.
VeroRab Comparator [5-17M] Group	Meningococcal C Conjugate Vaccine	Male or female children between and including 5 to 17 months of age \[5-17M\], who received a 3-dose primary vaccination course of the VeroRab vaccine, according to a 0-1-2 Month schedule, followed by a booster dose of Menjugate vaccine, at Month 20. Both vaccines have been administered intramuscularly into the left deltoid.
Menjugate Comparator [6-12W] Group	Meningococcal C Conjugate Vaccine	Male or female children between and including 6 to 12 weeks of age \[6-12W\], who received a 3-dose primary vaccination course of Menjugate vaccine co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, according to a 0-1-2 Month schedule, followed by a booster dose of Menjugate and Polio Sabin vaccines, at Month 12. All vaccines have been administered intramuscularly in the left thigh for children under 1 year and left deltoid for children above 1 year of age (Menjugate vaccine); anterolateral right thigh (Tritanrix HepB/Hib vaccine), except for the Polio Sabin vaccine, which has been given orally.
GSK257049 [5-17M] Group	Meningococcal C Conjugate Vaccine	Male or female children between and including 5 to 17 months of age \[5-17M\], who received a 3-dose primary vaccination course of the GSK257049 malaria vaccine, according to a 0-1-2 Month schedule, followed by either a booster dose of the same GSK257049 vaccine or a dose of Menjugate vaccine, at Month 20. Both vaccines have been administered intramuscularly into the left deltoid.
Menjugate Comparator [6-12W] Group	TritanrixHepB/Hib	Male or female children between and including 6 to 12 weeks of age \[6-12W\], who received a 3-dose primary vaccination course of Menjugate vaccine co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, according to a 0-1-2 Month schedule, followed by a booster dose of Menjugate and Polio Sabin vaccines, at Month 12. All vaccines have been administered intramuscularly in the left thigh for children under 1 year and left deltoid for children above 1 year of age (Menjugate vaccine); anterolateral right thigh (Tritanrix HepB/Hib vaccine), except for the Polio Sabin vaccine, which has been given orally.
Menjugate Comparator [6-12W] Group	Polio Sabin Oral Polio Vaccine (GSK)	Male or female children between and including 6 to 12 weeks of age \[6-12W\], who received a 3-dose primary vaccination course of Menjugate vaccine co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, according to a 0-1-2 Month schedule, followed by a booster dose of Menjugate and Polio Sabin vaccines, at Month 12. All vaccines have been administered intramuscularly in the left thigh for children under 1 year and left deltoid for children above 1 year of age (Menjugate vaccine); anterolateral right thigh (Tritanrix HepB/Hib vaccine), except for the Polio Sabin vaccine, which has been given orally.

Primary Outcome Measures

Name	Time	Method
Rate of First or Only Clinical Episode of Plasmodium Falciparum (P. Falciparum) Malaria Infection (CPFMI), or Clinical Malaria Episode of Primary Case Definition (CPFMI-PCD)	From Month 2.5 to Month 14	A CPFMI-PCD was defined as an episode of malaria for which P. falciparum asexual parasitemia was greater than (\>) 5000 parasites per microliter (µL) accompanied by the presence of fever \[axillary temperature greater than or equal to (≥) 37.5°C\] at the time of presentation AND occurring in a child who is unwell and brought for treatment to a healthcare facility OR a case of malaria meeting the primary case definition of severe malaria disease. The time to first or only CPFMI-PCD is expressed in terms of rate of first or only CPFMI (RfoCPFMI), that is person-year rate in each group (n/T). Analysis for this outcome was solely performed on subjects in the 5-17 months age category.
Rate of First or Only Clinical Episode of P. Falciparum Malaria Infection (CPFMI), or Clinical Malaria Episode of Primary Case Definition (CPFMI-PCD)	From Month 2.5 to Month 14	A CPFMI-PCD was defined as an episode of malaria for which P. falciparum asexual parasitemia \> 5000 parasites/µL was accompanied by the presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation AND occurring in a child who is unwell and brought for treatment to a healthcare facility OR a case of malaria meeting the primary case definition of severe malaria disease. The time to first or only CPFMI-PCD is expressed in terms of rate of first or only CPFMI (RfoCPFMI), that is, person-year rate in each group (n/T). Analysis for this outcome was solely performed on subjects in the 6-12 weeks (6-12W) age category.

Secondary Outcome Measures

Name	Time	Method
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of SCD1, SCD2 and SCD3 (Overall)	From Month 2.5 to Month 20	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.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Secondary Case Definition 1 (SCD1), Across Centers	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)	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.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD) and Secondary Case Definition 1 (SCD1), Across Centers	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)	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.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of PCD, by Center and Across Centers	From Month 2.5 to Month 32	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.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Centers and Across Centers	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)	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.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD) and Secondary Case Definition 1 (SCD1)	From Booster at Month 20 up to Month 32	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).
Percentage of Subjects With Severe PFMI (SPFMI) of PCD and SCD1	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	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.
Rate of All Episodes of P. Falciparum Clinical Malaria Infection (CPFMI) of PCD and of Secondary Case Definitions (SCD) 1, SCD 2 and SCD 3	From Month 2.5 to Month 14	PCD=malaria episode with P. falciparum asexual parasitemia (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. 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 uncorrected for double enrollment of 1 subject receiving GSK257049 vaccine.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of PCD and SCD1, Across Centers	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)	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.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of PCD, Overall and by Center	From Month 2.5 to Month 20	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.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Secondary Case Definition 1 (SCD1)	From Month 2.5 to Month 32	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).
Percentage of Subjects With Severe PFMI (SPFMI) of PCD, SCD1, SCD2 and SCD3, Across Centers	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)	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.
Percentage of Subjects With Incident Severe Anaemia (ISA) and Malaria Hospitalization (MH) for Case Definitions (CD) Considered	From Month 2.5 to Month 20	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.
Percentage of Subjects With Incident Severe Anaemia (ISA), Malaria Hospitalization (MH) and Fatal Malaria (FM) for Case Definitions (CD) Considered	From Month 2.5 to Month 32	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.
Percentage of Subjects With Prevalent Parasitemia, Prevalent Gametocytemia and Prevalent Severe and Moderate Anemia	At Month 20 (Booster)	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.
Percentage of Subjects With Prevalent Parasitemia and Prevalent Severe and Moderate Anemia	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)	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).
Percentage of Subjects With Pneumonia, All-cause Hospitalization and Sepsis, as Per Case Definitions Assessed	From Month 2.5 to Month 20	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).
Percentage of Subjects With Pneumonia, All-cause Hospitalization/Mortality and Sepsis, as Per Case Definitions Assessed	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)	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.
Antibody Concentrations Against Plasmodium Falciparum Circumsporozoite (Anti-CS)	At Day 0 and at Month 3	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.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Tertile	From Booster at Month 20 to Month 32	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.
Antibody Concentrations Against Hepatitis B Surface Antigen (Anti-HBs)	At Months 20 and 21	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.
Percentage of Subjects With Fatal Malaria (FM) and All-cause Mortality (ACM) as Per Case Definitions Assessed	From Month 2.5 to Month 20	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.
Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS)	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)	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.
Antibody Concentrations Against Hepatitis B Surface Antigen	At Day 0 and at Month 3	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.
Number of Subjects With Any and Grade 3 Solicited Local Symptoms	During the 7-day (Days 0-6) post-booster vaccination period	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.
Number of Subjects Reporting Any Meningitis and Encephalitis SAEs	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)	Meningitis and encephalitis SAEs included: meningitis/encephalitis; meningitis haemophilus; meningitis meningococcal; meningitis tuberculous; encephalomyelitis.
Number of Subjects With Unsolicited AEs Related to or Leading to Vaccination Withdrawal in the Low-weight (LW) and Very Low-weight (VLW) Category	Within the 30-day (Days 0-29) post-primary vaccination period in HIV-infected children	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.
Percentage of Subjects With Blood Transfusion, as Per Case Definition Assessed	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)	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.
Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Gender and Overall	From Month 2.5 to Month 32	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.
Height, Weight and Mid Upper Arm Circumference for Age Z-score (HAZ, WAZ and MUACZ)	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)	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.
Antibody Titers Against Poliomyelitis (Anti-polio) Type 1, 2 and 3	At Day 0 and at Month 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.
Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS), by Tertile	At Month 21	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.
Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms	During the 7-day (Days 0-6) post-booster vaccination period	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.
Number of Doses With Seizures by Diagnostic Certainty Level	During the 7-day (Days 0-6) post-booster vaccination period, at Month 20 + 7 Day (Days 0-6)	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.
Number of Subjects Reporting Any Meningitis and Encephalitis Serious Adverse Events (SAEs)	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)	Meningitis and encephalitis SAEs included: meningitis/encephalitis; meningitis/encephalitis viral; meningism; meningitis haemophilus; meningitis meningococcal; meningitis pneumococcal; meningitis tuberculous; encephalomyelitis.
Number of Subjects With Unsolicited AEs Related to or Leading to Vaccination Withdrawal	Within the 30-day (Days 0-29) post-primary and post-booster vaccination period in HIV-infected children	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).
Number of Subjects Reporting Mucocutaneous Changes (All Levels)	During the 30-day (Days 0-29) post-booster vaccination	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).
Number of Subjects Reporting Any Potential Immune-mediated Disorders (pIMDs)	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)	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.
Number of Subjects With Any Unsolicited Adverse Events (AEs)	Within the 30-day (Days 0-29) post-primary vaccination period	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.
Number of Subjects With Serious Adverse Events (SAEs)	From Month 0 up to Booster (Month 20), from Month 0 up to study end and from Month 20 up to study end	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.
Number of Low-weight (LW) Subjects With Serious Adverse Events (SAEs)	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)	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.
Number of Subjects With Fatal Outcomes, by Gender	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)	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.
Number of Subjects With Any Unsolicited AEs	Within the 30-day (days 0-29) post-booster vaccination period	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.
Number of Subjects With Serious Adversee Events (SAEs)	From Month 0 up to Month 20	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.
Number of Subjects With Unsolicited AEs Related to Vaccination in the Low-weight (LW) and Very Low-weight (VLW) Category	Within the 30-day (Days 0-29) post-booster vaccination period	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.
Number of Very Low-weight (VLW) Subjects With Serious Adverse Events (SAEs)	From Month 0 up to Month 20	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.
Number of Very Low-weight Subjects With Serious Adverse Events (SAEs)	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)]	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.