Efficacy, Safety and Immunogenicity Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Schedules With or Without Fractional Doses, Early Dose 4 and Yearly Doses, in Children 5-17 Months of Age

The primary case definition is: Plasmodium (P.) falciparum asexual parasitemia greater than (>)5000 parasites/microliters (μl) and 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. The incidence is expressed as a person year rate for each group (n/T), representing the number of events (n) reported over the risk period, which was counted in days and expressed as person years at risk (T). The objective of this endpoint was to demonstrate the superiority of a Fx012-14-mFxD Group compared to a standard schedule of RTS,S/AS01E with three full doses (R012-20+R012-14 Group) in terms of vaccine efficacy. This analysis was reported for the R012-20+R012-14 Group (Pooled group) because the interventional strategy (1st dose at Month 0, 2nd dose at Month 1, 3rd dose at Month 2) was the same for both the R012-20 group and the R012-14 group until Month 14.

The primary case definition is P. falciparum asexual parasitemia > 5000 μl and 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.

The secondary case definition is P. falciparum asexual parasitemia > 0 and presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation or history of fever within 24 hours of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. The incidence of clinical malaria for primary and secondary case definition is expressed as n/T, representing the n reported over the risk period, which was counted in days and expressed as T.

The primary case definition is P. falciparum asexual parasitemia > 5000 μl and 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.

The secondary case definition is P. falciparum asexual parasitemia > 0 and presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation or history of fever within 24 hours of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. The incidence of clinical malaria for primary and secondary case definition is expressed as n/T, representing the n reported over the risk period, which was counted in days and expressed as T.

Prevalence of P. falciparum infections of each RTS,S/AS01E schedule at cross-sectional visits. As specified in the statistical analysis plan, a graphical presentation of the prevalence over time was analyzed for this outcome measure and only the percentage values were reported to depict the prevalence of P. falciparum infections.

The incidence of P. falciparum infections is expressed as n/T, representing the n reported over the risk period, which was counted in days and expressed as T.

Assessment of vaccine efficacy (VE) against first or only episodes of incident P. falciparum infections defined by positive blood slide over the entire study period (Month 0 to Month 50) was not done after the Month 21 Interim analysis since it was assumed that almost all children would have already contracted malaria at least once.

A seropositive participant is defined as a participant with antibody concentrations ≥ 0.5 ELISA units per milliliter (EU/mL).

A seropositive participant is defined as a participant with antibody concentrations ≥ 10 milli-international units per milliliter (mIU/mL).

The antibody concentrations were calculated as geometric mean concentrations (GMCs) and expressed as EU/mL.

The antibody concentrations were calculated as GMCs and expressed as mlU/mL.

SAEs assessed included any untoward medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. Related SAEs= Any SAE related to investigational vaccine or related to study participation or to a GSK concomitant medication/vaccine as assessed by the investigator. Fatal SAEs= Any SAEs leading to death.

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product.

SAEs include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Cerebral malaria is defined as Severe P. falciparum malaria with coma (Blantyre coma score less than [<] 3); and if malaria with seizure: coma persisting for > 30 min after the seizure. Other treatable causes of coma should be excluded before diagnosing cerebral malaria (e.g. hypoglycaemia, bacterial meningitis).

Severe malaria is defined as P. falciparum parasitemia > 0 detected by microscopy and/or rapid diagnostic test (RDT) and one or more of the following, occurring in the absence of an identified alternative cause: Impaired consciousness, Prostration, Multiple convulsions, Acidosis, Hypoglycemia, Severe malarial anemia, Renal impairment, Jaundice, Pulmonary edema, Significant bleeding: including recurrent or prolonged bleeding from the nose, gums or venipuncture sites, hematemesis or melaena, Shock, Hyperparasitemia.

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 etiology.

Meningitis is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders.

Seizure is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders.

Generalized convulsive seizure is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders.

An unsolicited AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product.

The assessed parameters (alanine aminotransferase [ALT], creatinine, haemoglobin, white blood cells [WBC], platelets) were summarized according to DAIDS, 2004 (Division of AIDS). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling. Data are presented for those participants who experienced Grade 4 toxicities. Grade 4 hematological toxicities included ALT: > 10.0 x ULN (Upper limit of normal), creatine: > 6.0 x ULN or requires dialysis, WBC: < 1.0 x 103 per microliter, platelets: < 25 x 103/μl and clinical signs of bleeding, and hemoglobin: < 5.0 grams/deciliter and clinical signs of heart failure.

The assessed parameters (ALT, creatinine, haemoglobin, WBC, platelets) were summarized according to DAIDS, 2004 (Division of AIDS). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling. Data are presented for those participants who experienced Grade 4 toxicities. Grade 4 hematological toxicities included ALT: > 10.0 x ULN, creatine: > 6.0 x ULN or requires dialysis, WBC: < 1.0 x 103 per microliter, platelets: < 25 x 103/μl and clinical signs of bleeding, and hemoglobin: < 5.0 grams/deciliter and clinical signs of heart failure.

The assessed parameters (ALT, creatinine, haemoglobin, WBC, platelets) were summarized according to DAIDS, 2004 (Division of AIDS). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling. Data are presented for those participants who experienced Grade 4 toxicities. Grade 4 hematological toxicities included ALT: > 10.0 x ULN, creatine: > 6.0 x ULN or requires dialysis, WBC: < 1.0 x 103 per microliter, platelets: < 25 x 103/μl and clinical signs of bleeding, and hemoglobin: < 5.0 grams/deciliter and clinical signs of heart failure.

Assessed solicited local AEs are: redness, pain and swelling. Any = occurrence of the adverse event regardless of intensity grade. Any redness and swelling = adverse event reported with a surface diameter > 0 millimeters.

Assessed solicited general AEs are: drowsiness, irritability/fussiness and loss of appetite. Any = occurrence of the adverse event regardless of intensity grade or relation to study vaccination.