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

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.

Time frame: From Month 2.5 to Month 14

Population: The analysis was performed on the ATP population for efficacy, which included all children aged 6-12 Weeks who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 3.

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.

Time frame: From Month 2.5 to Month 14

Population: The analysis was performed on the According-to-Protocol (ATP) population for efficacy, which included all children aged 5-17 Months who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 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.

Time frame: At Day 0 and at Month 3

Population: The analysis was performed on the HIV-ATP population for immunogenicity, which included all children included in the HIV-ITT population who received all vaccinations according to the protocol procedures.

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

Population: The analysis was performed on the ATP population for HBs immunogenicity post booster, which included the first 200 children enrolled in Korogwe, Lamberene and Lilongwe study centers in each age category who received the booster dose of GSK257049 vaccine and all vaccinations according to the protocol procedures.

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

Population: The analysis was performed on the ATP population for immunogenicity, which included all first 200 children enrolled in each study center, for each age category who received all vaccinations according to the protocol procedures.

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)

Population: The analysis was performed on the ATP population for immunogenicity, which included all first 200 children enrolled in each study center in each age category who received all vaccinations according to the protocol procedures. Data was not collected for the participants in the 6-12W groups at M44.

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

Population: The analysis was performed on the HIV-ATP population for immunogenicity, which included all children included in the HIV-ITT population who received all vaccinations according to the protocol procedures.

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

Population: The analysis was performed on the ATP population for immunogenicity, which included all first 200 children enrolled in each study center in each age category who received all vaccinations according to the protocol procedures. Data was not collected for the participants in the 5-17M groups for the Manhica site at any given time frame.

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

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 3.

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

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 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.

Time frame: At Day 0 and at Month 3

Population: The analysis was performed on the ATP population for immunogenicity, which included all first 200 children enrolled in each study center in each age category who received all vaccinations according to the protocol procedures.

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

Population: The ATP population for Polio Sabin™ immunogenicity included all subjects from the ATP population for immunogenicity (minus those who received ≥ 2 doses of Polio Sabin™ vaccine prior to Dose 1 of study vaccine, or who received at least one dose of a polio vaccine in co-administration with the study vaccine before one month post Dose 3 blood sample.

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)

Population: The analysis was performed on the Intent-to-Treat (ITT) population, which included all children who received at least one dose of study vaccine.

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)

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine. Data was not collected for the participants in the 6-12W groups for the HAZ, WAZ, MUACZ categories at Month 44 and at Study end Late time frames.

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)

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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)

Population: The analysis was performed on a subset of subjects from the ITT population, which included low weight (LW) children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included low weight (LW) children who received at least one dose of study vaccine.

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)

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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)

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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)

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine and had their symptom sheets filled in.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine and had their symptom sheets filled in.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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)

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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)

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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)

Population: The analysis was performed, across age categories for which groups were pooled from the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on a subset of subjects from the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the ITT population, which included all children who received at least one dose of study vaccine.

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

Population: The analysis was performed on the HIV-ITT population, which included all children who received at least one dose of GSK257049 vaccine and were identified as HIV-infected, that is, confirmed to be HIV-infected via identification as positive for HIV by Polymerase Chain Reaction (PCR), or by antibody at 18 months or older.

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

Population: The analysis was performed on the HIV-ITT population, which included low-weight and very low-weight children who received at least one dose of GSK257049 vaccine and were identified as HIV-infected, that is, confirmed to be HIV-infected via identification as positive for HIV by Polymerase Chain Reaction (PCR), or by antibody at 18 months or older.

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

Population: The analysis was performed on a subset of subjects from the ITT population, which included low-weight (LW) and very low-weight (VLW) children who received at least one dose of study vaccine.

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)]

Population: The analysis was performed on a subset of subjects from the ITT population, which included very-low weight (VLW) children who received at least one dose of study vaccine.

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

Population: The analysis was performed on a subset of subjects from the ITT population, which included very-low weight (VLW) children who received at least one dose of study vaccine.

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)

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 3.

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

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 3.

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

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 3.

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

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 3.

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)

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 3.

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

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 3.

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)

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period starting 14 days post Dose 3.

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)

Population: The analysis was performed on the ATP population for efficacy, which included all children who received all vaccinations according to protocol procedures and contributed to the time at risk in the follow-up period 14 days post Dose 3. Data was not collected for the participants in the 6-12W groups for the PP, PSA, PMA categories at M44, SE (Late).