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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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

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

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.