Long-Term Follow-up of Children for a 2-Year Period to Confirm the Safety and Immunogenicity of GSK 257049 Vaccine

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00323622
• Collaborator: (none)
• Enrollment: 1,737
• Location: 1
• Arms: 8
• Duration (Months): 25
• Patients Per Site Per Month: 69.6

Study Details

Study Description

Brief Summary

The RTS,S/AS02A vaccine (or GSK 257049 vaccine), GSK Biologicals' candidate Plasmodium falciparum (P. falciparum) malaria vaccine is being developed for the routine immunization of infants and children living in malaria endemic areas. The vaccine would offer protection against malaria disease due to the parasite P. falciparum. The vaccine would also provide protection against infection with hepatitis B virus (HBV).

This phase IIb trial is being carried out following the demonstration of efficacy of the candidate malaria vaccine in children in Mozambique: there, the vaccine demonstrated approximately 30% efficacy against clinical episodes of malaria and approximately 58% efficacy against severe malaria disease.

In this study, the children from Mozambique (NCT= NCT00197041) are followed-up to assess the safety, immunogenicity and efficacy of the candidate malaria vaccine for a two year period commencing 21 months after Dose 1.

This protocol posting deals with objectives & outcome measures of the extension phase at year 2. During this extension study, no new subjects will be recruited and no vaccine will be administered.

The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Condition or Disease	Intervention/Treatment	Phase
Malaria	Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049; Biological: Engerix™-B; Biological: Hiberix®; Biological: Prevnar™; Drug: sulfadoxine-pyrimethamine; Drug: amodiaquine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 1737 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: An Open Study for a 2-year Period to Confirm the Safety and Immunogenicity of the Candidate Malaria Vaccine RTS,S/AS02A in Mozambican Children Aged 1 to 4 Years at the Time of First Vaccine Dose.
• Study Start Date: Apr 1, 2005
• Actual Primary Completion Date: May 1, 2007
• Actual Study Completion Date: May 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1-RTS,S/AS02A <24M Group Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049; IM injection in the deltoid muscle; Other Names: RTS S/AS02A vaccine
Experimental: Cohort 1-RTS,S/AS02A ≥24M Group Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049; IM injection in the deltoid muscle; Other Names: RTS S/AS02A vaccine
Experimental: Cohort 2-RTS,S/AS02A <24M Group Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049; IM injection in the deltoid muscle; Other Names: RTS S/AS02A vaccine ; Drug: sulfadoxine-pyrimethamine; 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance; Drug: amodiaquine; 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance
Experimental: Cohort 2-RTS,S/AS02A ≥24M Group Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 of the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049; IM injection in the deltoid muscle; Other Names: RTS S/AS02A vaccine ; Drug: sulfadoxine-pyrimethamine; 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance; Drug: amodiaquine; 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance
Active Comparator: Cohort 1-Prevnar-Hiberix <24M Group Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Biological: Hiberix®; IM injection in the deltoid muscle; Biological: Prevnar™; IM injection in the deltoid muscle
Active Comparator: Cohort 1-Engerix-B ≥24M Group Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Biological: Engerix™-B; IM injection in the deltoid muscle
Active Comparator: Cohort 2-Prevnar- Hiberix <24M Group Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Biological: Hiberix®; IM injection in the deltoid muscle; Biological: Prevnar™; IM injection in the deltoid muscle; Drug: sulfadoxine-pyrimethamine; 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance; Drug: amodiaquine; 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance
Active Comparator: Cohort 2-Engerix-B ≥24M Group Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Biological: Engerix™-B; IM injection in the deltoid muscle; Drug: sulfadoxine-pyrimethamine; 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance; Drug: amodiaquine; 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Serious Adverse Events (SAEs) [Throughout the entire study period: from Month 21 to Month 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).]

   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.

Secondary Outcome Measures

1. Anti-circumsporozoite Protein (CS) Antibody Concentrations. [At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).]

   Concentrations for anti-CS antibodies are presented as Geometric Mean Concentrations (GMCs), expressed in Enzyme-Linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off of 0.5 EL.U/mL. Subjects were pooled across age ranges for this outcome measure.

2. Anti-hepatitis B (HBs) Antibody Concentrations. [At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).]

   Concentrations are presented as geometric mean concentrations (GMCs), expressed in milli-international units per milliliter (mIU/mL). Anti-HBs antibody concentration levels were measured in blood samples from Cohort 2 only.

3. Time to First or Only Clinical Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Primary Case Definition [From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041]

   Malaria infection by Plasmodium falciparum was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges.

4. Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 1 [From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041]

   PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 1 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges.

5. Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 2 [From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041]

   PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 2 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films in an unwell child brought for treatment with a history of fever (axillary temperature equal or above 37.5 degrees Celsius) within 24 hours or documented fever. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was performed on Cohort 1 subjects, with groups pooled across age ranges.

6. Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 3 [From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041]

   PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 3 was defined as the presence of P. falciparum asexual parasitaemia above 15000 per microliter (µL) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.

7. Number of Primary Case Definition Clinical Episodes of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) [From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041]

   PFMI was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The number of PFMI episodes (EPFMI) per person-year (pyr) was tabulated, using as unit EPFMI episode per pyr. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.

8. Number of Subjects With Anemia. [At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).]

   Anemia was indicated by a hematocrit level (HL) below (<) 25%. The numbers of subjects with HL below (<) and above or equal (≥) 25 %, and with missing HL results were tabulated. In the tabulation below, the number of subjects falling into the "HL ≥25%" category corresponds to the number of subjects with anemia as asked per outcome. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.

9. Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) Parasitemia [At Months 33 (M33) and 45 (M45) (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).]

   Subjects prevalent for P. falciparum parasitemia were defined as subjects with the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films.Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 33 Months to 69 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

• Completion of Visit 7, Month 21 of 104297 (NCT= NCT00197041).

• Written informed consent obtained from the parent(s) or guardian(s) of the subject

Exclusion criteria:

• Planned use of any investigational or non-registered drug or vaccine during the study period.

• Simultaneous participation in any other clinical trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Maputo		Mozambique

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

• Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Aide P, Sigauque B, Milman J, Mandomando I, Bassat Q, Guinovart C, Espasa M, Corachan S, Lievens M, Navia MM, Dubois MC, Menendez C, Dubovsky F, Cohen J, Thompson R, Ballou WR. Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet. 2005 Dec 10;366(9502):2012-8.
• Aponte et al. A 4 years follow-up of the safety, immunogenicity and efficacy of the candidate malaria vaccine RTS,S/AS02A in children vaccinated at aged 1 to 4 years in a malaria-endemic region of Mozambique. Abstract presented at the 56th Annual Meeting ASTMH, Philadelphia, PA, USA, 05-07 November 2007.
• Sacarlal J, Aide P, Aponte JJ, Renom M, Leach A, Mandomando I, Lievens M, Bassat Q, Lafuente S, Macete E, Vekemans J, Guinovart C, Sigaúque B, Sillman M, Milman J, Dubois MC, Demoitié MA, Thonnard J, Menéndez C, Ballou WR, Cohen J, Alonso PL. Long-term safety and efficacy of the RTS,S/AS02A malaria vaccine in Mozambican children. J Infect Dis. 2009 Aug 1;200(3):329-36. doi: 10.1086/600119.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00323622
• Other Study ID Numbers: 104297
• First Posted: May 9, 2006
• Last Update Posted: Dec 9, 2016
• Last Verified: Oct 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Malaria; Pyrimethamine; Sulfadoxine; Fanasil, pyrimethamine drug combination; Amodiaquine; Vaccines

Study Results

Participant Flow

Recruitment Details	This current study NCT00323622, a follow-up (FU) study to the primary study NCT00197041, is aimed at vaccine safety assessment, and took place from Months 21 to 45 (Month 0 = Dose 1 administration of RTS,S/AS02A (GSK 257049) or comparator vaccine in the primary study).
Pre-assignment Detail	Once re-enrolled, subjects in this study were allocated to the same groups as in the NCT00197041 study, as well as the same cohorts, e. a. Cohorts 1 and 2 whose subjects were followed for analysis of, respectively, malaria infection and disease.

Arm/Group Title	Cohort 1-RTS,S/AS02A<24M Group	Cohort 1-RTS,S/AS02A≥24M Group	Cohort 2-RTS,S/AS02A<24M Group	Cohort 2-RTS,S/AS02A≥24M Group	Cohort 1-Prevnar-Hiberix <24M Group	Cohort 1-Engerix-B ≥24M Group	Cohort 2-Prevnar- Hiberix <24M Group	Cohort 2-Engerix-B ≥24M Group
Arm/Group Description	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 of the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study
Period Title: Overall Study
STARTED	176	515	42	134	159	528	43	140
COMPLETED	145	423	38	122	120	454	38	125
NOT COMPLETED	31	92	4	12	39	74	5	15

Baseline Characteristics

Arm/Group Title	Cohort 1-RTS,S/AS02A <24M Group	Cohort 1-RTS,S/AS02A ≥24M Group	Cohort 2-RTS,S/AS02A <24M Group	Cohort 2-RTS,S/AS02A ≥24M Group	Cohort 1-Prevnar-Hiberix <24M Group	Cohort 1-Engerix-B ≥24M Group	Cohort 2-Prevnar- Hiberix <24M Group	Cohort 2-Engerix-B ≥24M Group	Total
Arm/Group Description	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 of the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Total of all reporting groups
Overall Participants	176	515	42	134	159	528	43	140	1737
Age (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	38 (4.0)	62 (11.0)	39 (4.0)	62 (9.0)	38 (3.0)	62 (10.0)	38 (3.0)	61 (9.0)	50.0 (6.6)
Gender (Count of Participants)
Female	85 48.3%	240 46.6%	19 45.2%	67 50%	79 49.7%	252 47.7%	16 37.2%	78 55.7%	836 48.1%
Male	91 51.7%	275 53.4%	23 54.8%	67 50%	80 50.3%	276 52.3%	27 62.8%	62 44.3%	901 51.9%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Serious Adverse Events (SAEs)
Description	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	Throughout the entire study period: from Month 21 to Month 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).

Outcome Measure Data

Analysis Population Description

The analysis was performed on the Total Vaccinated cohort, which included all subjects vaccinated in the primary NCT00197041 study, and re- enrolled in this follow-up NCT 00323622 study, and for whom data were available.

Arm/Group Title	Cohort 1-RTS,S/AS02A <24M Group	Cohort 1-RTS,S/AS02A ≥24M Group	Cohort 2-RTS,S/AS02A <24M Group	Cohort 2-RTS,S/AS02A ≥24M Group	Cohort 1-Prevnar-Hiberix <24M Group	Cohort 1-Engerix-B ≥24M Group	Cohort 2-Prevnar- Hiberix <24M Group	Cohort 2-Engerix-B ≥24M Group
Arm/Group Description	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 of the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.
Measure Participants	176	515	42	134	159	528	43	140
Number [Subjects]	21	17	1	0	24	29	1	4

2. Secondary Outcome

Title	Anti-circumsporozoite Protein (CS) Antibody Concentrations.
Description	Concentrations for anti-CS antibodies are presented as Geometric Mean Concentrations (GMCs), expressed in Enzyme-Linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off of 0.5 EL.U/mL. Subjects were pooled across age ranges for this outcome measure.
Time Frame	At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).

Outcome Measure Data

Analysis Population Description

The Long Term According-to-Protocol (ATP) cohort for immunogenicity included all enrolled subjects from the primary study ATP cohort for immunogenicity who did not receive any additional vaccine dose containing circumsporozoite protein or hepatitis B antigens, with blood sample within protocol-defined time limits and available antibody measurements

Arm/Group Title	Cohort 1-RTS,S/AS02A Group	Cohort 1-Engerix-B/Prevnar-Hiberix Group	Cohort 2-RTS,S/AS02A Group	Cohort 2-Engerix-B/Prevnar-Hiberix Group
Arm/Group Description	Subjects, male and female, aged between 12 and 48 months at the time of the first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-RTS,S/AS02A Cohort 1-RTS,S/AS02A <24M and Cohort 1-RTS,S/AS02A ≥24M groups.	Subjects, male and female, aged 12 up to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects, male and female, aged between 24 and 48 months first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-Engerix-B ≥24M and Cohort 1-Prevnar-Hiberix <24M groups.	Subjects, male and female, aged between 12 and 48 months at the time of the first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. This group is part of the Cohort 2 of the study, which was followed for analysis of malaria disease, and pools subjects from the Cohort 2-RTS,S/AS02A <24M and Cohort 2-RTS,S/AS02A ≥24M groups. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. This group is part of the Cohort 2 of the study, which was followed for analysis of malaria disease, and pools subjects from the Cohort 2-Engerix-B ≥24M and Cohort 2-Prevnar-Hiberix <24M groups. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.
Measure Participants	490	487	150	149
Month 33 [N = 490, 487, 149, 149]	10.1	NA	16.2	0.6
Month 45 [N = 452, 447, 150, 145]	8.9	NA	15.4	0.4

3. Secondary Outcome

Title	Anti-hepatitis B (HBs) Antibody Concentrations.
Description	Concentrations are presented as geometric mean concentrations (GMCs), expressed in milli-international units per milliliter (mIU/mL). Anti-HBs antibody concentration levels were measured in blood samples from Cohort 2 only.
Time Frame	At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).

Outcome Measure Data

Analysis Population Description

The Long Term According-to-Protocol (ATP) cohort for immunogenicity included all enrolled subjects from the primary study ATP cohort for immunogenicity who did not receive any additional vaccine dose containing circumsporozoite protein or hepatitis B antigens,with blood sample within protocol-defined time limits and available antibody measurements.

Arm/Group Title	Cohort 2-RTS,S/AS02A <24M Group	Cohort 2-RTS,S/AS02A ≥24M Group	Cohort 2-Prevnar- Hiberix <24M Group	Cohort 2-Engerix-B ≥24M Group
Arm/Group Description	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 of the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.	Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.
Measure Participants	35	116	34	115
Month 33 [N = 33, 116, 34, 115]	4008.6	1842.5	20.3	67.4
Month 45 [N = 35, 115, 32, 113]	3323.8	1557.0	26.6	99.4

4. Secondary Outcome

Title	Time to First or Only Clinical Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Primary Case Definition
Description	Malaria infection by Plasmodium falciparum was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges.
Time Frame	From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041

Outcome Measure Data

Analysis Population Description

The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).

Arm/Group Title	Cohort 1-RTS,S/AS02A Group	Cohort 1-Engerix-B/Prevnar-Hiberix Group
Arm/Group Description	Subjects, male and female, aged between 12 and 48 months at the time of the first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-RTS,S/AS02A Cohort 1-RTS,S/AS02A <24M and Cohort 1-RTS,S/AS02A ≥24M groups.	Subjects, male and female, aged 12 up to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects, male and female, aged between 24 and 48 months first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-Engerix-B ≥24M and Cohort 1-Prevnar-Hiberix <24M groups.
Measure Participants	650	645
RPFMI - PCD - M21-33 (N=650;645)	0.330	0.375
RPFMI - PCD - M33-45 (N=638;629)	0.140	0.149

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-RTS,S/AS02A <24M Group, Cohort 1-RTS,S/AS02A ≥24M Group
	Comments	The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 21-33 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) [Hazard Ratio (HR) in Cohort 1 - GSK RTS,S/AS02A Group [HR1]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group [HR2])], i. e. 1 - (HR1/HR2).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments	The p-value presented is the Wald Chi-square p-value from the Cox regression model.
	Method	Regression, Cox
	Comments	Point estimate of efficacy was adjusted for age, geographical area of residence, bednet use and distance from health center.
Method of Estimation	Estimation Parameter	1 - (HR1/HR2)
	Estimated Value	16.8
	Confidence Interval	(2-Sided) 95%; -2.50 to 32.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-RTS,S/AS02A <24M Group, Cohort 1-RTS,S/AS02A ≥24M Group
	Comments	The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 33-45 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) [Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group [HR1]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group [HR2])], i. e. 1 - (HR1/HR2).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments	The p-value presented is the Wald Chi-square p-value from the Cox regression model
	Method	Regression, Cox
	Comments	Point estimate of efficacy was adjusted for age, geographical area of residence, bednet use and distance from health center.
Method of Estimation	Estimation Parameter	1 - (HR1/HR2)
	Estimated Value	11.8
	Confidence Interval	(2-Sided) 95%; -20.11 to 35.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 1
Description	PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 1 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges.
Time Frame	From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041

Outcome Measure Data

Analysis Population Description

The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).

Arm/Group Title	Cohort 1-RTS,S/AS02A Group	Cohort 1-Engerix-B/Prevnar-Hiberix Group
Arm/Group Description	Subjects, male and female, aged between 12 and 48 months at the time of the first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-RTS,S/AS02A Cohort 1-RTS,S/AS02A <24M and Cohort 1-RTS,S/AS02A ≥24M groups.	Subjects, male and female, aged 12 up to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects, male and female, aged between 24 and 48 months first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-Engerix-B ≥24M and Cohort 1-Prevnar-Hiberix <24M groups.
Measure Participants	650	645
RPFMI - SCD 1 - M21-33 (N=650;645)	0.365	0.409
RPFMI - SCD 1 - M33-45 (N=638;629)	0.161	0.174

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-RTS,S/AS02A <24M Group, Cohort 1-RTS,S/AS02A ≥24M Group
	Comments	The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 21-33 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) [Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group [HR1]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group [HR2])], i. e. 1 - (HR1/HR2).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments	The p-value presented is the Wald Chi-square p-value from the Cox regression model.
	Method	Regression, Cox
	Comments	Point estimate of efficacy was adjusted for age, geographical area of residence, bednet use and distance from health center.
Method of Estimation	Estimation Parameter	1 - (R1/R2)
	Estimated Value	14.90
	Confidence Interval	(2-Sided) 95%; -3.88 to 30.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-RTS,S/AS02A <24M Group, Cohort 1-RTS,S/AS02A ≥24M Group
	Comments	The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 33-45 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) [Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group [HR1]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group [HR2])], i. e. 1 - (HR1/HR2).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments	The p-value presented is the Wald Chi-square p-value from the Cox regression model.
	Method	Regression, Cox
	Comments	Point estimate of efficacy was adjusted for age, geographical area of residence, bednet use and distance from health center.
Method of Estimation	Estimation Parameter	1 - (R1/R2)
	Estimated Value	12.79
	Confidence Interval	(2-Sided) 95%; -16.27 to 34.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 2
Description	PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 2 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films in an unwell child brought for treatment with a history of fever (axillary temperature equal or above 37.5 degrees Celsius) within 24 hours or documented fever. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was performed on Cohort 1 subjects, with groups pooled across age ranges.
Time Frame	From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041

Outcome Measure Data

Analysis Population Description

The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).

Arm/Group Title	Cohort 1-RTS,S/AS02A Group	Cohort 1-Engerix-B/Prevnar-Hiberix Group
Arm/Group Description	Subjects, male and female, aged between 12 and 48 months at the time of the first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-RTS,S/AS02A Cohort 1-RTS,S/AS02A <24M and Cohort 1-RTS,S/AS02A ≥24M groups.	Subjects, male and female, aged 12 up to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects, male and female, aged between 24 and 48 months first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-Engerix-B ≥24M and Cohort 1-Prevnar-Hiberix <24M groups.
Measure Participants	650	645
RPFMI - SCD 2 - M21-33 (N=650;645)	0.540	0.630
RPFMI - SCD 2 - M33-45 (N=638;629)	0.260	0.270

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-RTS,S/AS02A <24M Group, Cohort 1-RTS,S/AS02A ≥24M Group
	Comments	The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 21-33 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) [Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group [HR1]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group [HR2])], i. e. 1 - (HR1/HR2).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments	The p-value presented is the Wald Chi-square p-value from the Cox regression model.
	Method	Regression, Cox
	Comments	Point estimate of efficacy was adjusted for age, geographical area of residence, bednet use and distance from health center.
Method of Estimation	Estimation Parameter	1 - (R1/R2)
	Estimated Value	19.42
	Confidence Interval	(2-Sided) 95%; 4.62 to 31.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-RTS,S/AS02A <24M Group, Cohort 1-RTS,S/AS02A ≥24M Group
	Comments	The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 33-45 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) [Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group [HR1]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group [HR2])], i. e. 1 - (HR1/HR2).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments	The p-value presented is the Wald Chi-square p-value from the Cox regression model.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	1 - (R1/R2)
	Estimated Value	7.08
	Confidence Interval	(2-Sided) 95%; -17.37 to 26.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 3
Description	PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 3 was defined as the presence of P. falciparum asexual parasitaemia above 15000 per microliter (µL) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.
Time Frame	From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041

Outcome Measure Data

Analysis Population Description

The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).

Arm/Group Title	Cohort 1-RTS,S/AS02A Group	Cohort 1-Engerix-B/Prevnar-Hiberix Group
Arm/Group Description	Subjects, male and female, aged between 12 and 48 months at the time of the first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-RTS,S/AS02A Cohort 1-RTS,S/AS02A <24M and Cohort 1-RTS,S/AS02A ≥24M groups.	Subjects, male and female, aged 12 up to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects, male and female, aged between 24 and 48 months first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-Engerix-B ≥24M and Cohort 1-Prevnar-Hiberix <24M groups.
Measure Participants	650	645
RPFMI - SCD 3 - M21-33 (N=650;645)	0.288	0.329
RPFMI - SCD 3 - M33-45 (N=638;629)	0.122	0.122

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-RTS,S/AS02A <24M Group, Cohort 1-RTS,S/AS02A ≥24M Group
	Comments	The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 21-33 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) [Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group [HR1]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group [HR2])], i. e. 1 - (HR1/HR2).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments	The p-value presented is the Wald Chi-square p-value from the Cox regression model.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	1 - (R1/R2)
	Estimated Value	16.79
	Confidence Interval	(2-Sided) 95%; -3.75 to 33.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-RTS,S/AS02A <24M Group, Cohort 1-RTS,S/AS02A ≥24M Group
	Comments	The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 33-45 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) [Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group [HR1]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group [HR2])], i. e. 1 - (HR1/HR2).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments	The p-value presented is the Wald Chi-square p-value from the Cox regression model.
	Method	Regression, Cox
	Comments	Point estimate of efficacy was adjusted for age, geographical area of residence, bednet use and distance from health center.
Method of Estimation	Estimation Parameter	1 - (R1/R2)
	Estimated Value	6.31
	Confidence Interval	(2-Sided) 95%; -31.00 to 32.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Primary Case Definition Clinical Episodes of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI)
Description	PFMI was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The number of PFMI episodes (EPFMI) per person-year (pyr) was tabulated, using as unit EPFMI episode per pyr. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.
Time Frame	From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041

Outcome Measure Data

Analysis Population Description

The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).

Arm/Group Title	Cohort 1-RTS,S/AS02A Group	Cohort 1-Engerix-B/Prevnar-Hiberix Group
Arm/Group Description	Subjects, male and female, aged between 12 and 48 months at the time of the first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-RTS,S/AS02A Cohort 1-RTS,S/AS02A <24M and Cohort 1-RTS,S/AS02A ≥24M groups.	Subjects, male and female, aged 12 up to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects, male and female, aged between 24 and 48 months first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-Engerix-B ≥24M and Cohort 1-Prevnar-Hiberix <24M groups.
Measure Participants	650	645
EPFMI - PCD - M21-33 (N=650;645)	252	291
EPFMI - PCD - M33-45 (N=638;629)	99	100

9. Secondary Outcome

Title	Number of Subjects With Anemia.
Description	Anemia was indicated by a hematocrit level (HL) below (<) 25%. The numbers of subjects with HL below (<) and above or equal (≥) 25 %, and with missing HL results were tabulated. In the tabulation below, the number of subjects falling into the "HL ≥25%" category corresponds to the number of subjects with anemia as asked per outcome. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.
Time Frame	At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).

Outcome Measure Data

Analysis Population Description

The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).

Arm/Group Title	Cohort 1-RTS,S/AS02A Group	Cohort 1-Engerix-B/Prevnar-Hiberix Group
Arm/Group Description	Subjects, male and female, aged between 12 and 48 months at the time of the first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-RTS,S/AS02A Cohort 1-RTS,S/AS02A <24M and Cohort 1-RTS,S/AS02A ≥24M groups.	Subjects, male and female, aged 12 up to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects, male and female, aged between 24 and 48 months first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-Engerix-B ≥24M and Cohort 1-Prevnar-Hiberix <24M groups.
Measure Participants	650	645
HL <25%, Month 33 (N = 650, 645)	2	2
HL ≥25%, Month 33 (N = 650, 645])	584	593
Missing Results, Month 33 (N = 650;645)	64	50
HL <25%, Month 45 (N = 638, 629)	0	0
HL ≥25%, Month 45 (N = 638, 629)	540	543
Missing Results, Month 45 (N = 638;629)	98	86

10. Secondary Outcome

Title	Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) Parasitemia
Description	Subjects prevalent for P. falciparum parasitemia were defined as subjects with the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films.Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.
Time Frame	At Months 33 (M33) and 45 (M45) (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).

Outcome Measure Data

Analysis Population Description

The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).

Arm/Group Title	Cohort 1-RTS,S/AS02A Group	Cohort 1-Engerix-B/Prevnar-Hiberix Group
Arm/Group Description	Subjects, male and female, aged between 12 and 48 months at the time of the first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-RTS,S/AS02A Cohort 1-RTS,S/AS02A <24M and Cohort 1-RTS,S/AS02A ≥24M groups.	Subjects, male and female, aged 12 up to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects, male and female, aged between 24 and 48 months first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. This group is part of the Cohort 1 of the study, which was followed for analysis of malaria infection, and pools subjects from the Cohort 1-Engerix-B ≥24M and Cohort 1-Prevnar-Hiberix <24M groups.
Measure Participants	590	596
Subjects prevalent for parasitemia, M33[N=590,590]	93	121
Subjects prevalent for parasitemia, M45[N=541,547]	66	101

Adverse Events

Time Frame	SAE reports were collected from 21 to 45 months post Dose 1 of either vaccine.
Adverse Event Reporting Description	No reports of solicited symptoms or unsolicited AEs were collected during this study. Fatal SAEs were reported for a total of 11 subjects (1 in the Cohort 1-RTS,S/AS02A <24M Group, 1 in the Cohort 1-RTS,S/AS02A ≥24M Group, 7 in the Cohort 1-Prevnar-Hiberix <24M Group and 2 in the Cohort 2-Engerix-B ≥24M Group)
Arm/Group Title	Cohort 1-RTS,S/AS02A <24M Group		Cohort 1-RTS,S/AS02A ≥24M Group		Cohort 2-RTS,S/AS02A <24M Group		Cohort 2-RTS,S/AS02A ≥24M Group		Cohort 1-Prevnar-Hiberix <24M Group		Cohort 1-Engerix-B ≥24M Group		Cohort 2-Prevnar- Hiberix <24M Group		Cohort 2-Engerix-B ≥24M Group
Arm/Group Description	Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.		Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.		Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.		Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 of the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.		Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.		Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection.		Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.		Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study.
All Cause Mortality
	Cohort 1-RTS,S/AS02A <24M Group		Cohort 1-RTS,S/AS02A ≥24M Group		Cohort 2-RTS,S/AS02A <24M Group		Cohort 2-RTS,S/AS02A ≥24M Group		Cohort 1-Prevnar-Hiberix <24M Group		Cohort 1-Engerix-B ≥24M Group		Cohort 2-Prevnar- Hiberix <24M Group		Cohort 2-Engerix-B ≥24M Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1-RTS,S/AS02A <24M Group		Cohort 1-RTS,S/AS02A ≥24M Group		Cohort 2-RTS,S/AS02A <24M Group		Cohort 2-RTS,S/AS02A ≥24M Group		Cohort 1-Prevnar-Hiberix <24M Group		Cohort 1-Engerix-B ≥24M Group		Cohort 2-Prevnar- Hiberix <24M Group		Cohort 2-Engerix-B ≥24M Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/176 (11.9%)		17/515 (3.3%)		1/42 (2.4%)		0/134 (0%)		24/159 (15.1%)		29/528 (5.5%)		1/43 (2.3%)		4/140 (2.9%)
Blood and lymphatic system disorders
Anemia	12/176 (6.8%)		8/515 (1.6%)		1/42 (2.4%)		0/134 (0%)		14/159 (8.8%)		9/528 (1.7%)		0/43 (0%)		1/140 (0.7%)
Eye disorders
Conjunctivitis	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
General disorders
Death	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		1/140 (0.7%)
Hepatobiliary disorders
Hepatitis acute	1/176 (0.6%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Immune system disorders
Immunosuppression	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Infections and infestations
Ascariasis	1/176 (0.6%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Bronchopneumonia	1/176 (0.6%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Cellulitis	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		1/528 (0.2%)		0/43 (0%)		1/140 (0.7%)
Encephalitis viral	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Haemophilus sepsis	1/176 (0.6%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Malaria	1/176 (0.6%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		2/528 (0.4%)		0/43 (0%)		0/140 (0%)
Oral candidiasis	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Pneumococcal sepsis	2/176 (1.1%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Sepsis	1/176 (0.6%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Tinea capitis	0/176 (0%)		2/515 (0.4%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Upper respiratory tract infection	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Cellulitis orbital	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Cerebral malaria	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Fungal skin infection	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Gastroenteritis	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		2/159 (1.3%)		2/528 (0.4%)		0/43 (0%)		0/140 (0%)
Herpes simplex	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Otitis media	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Pulmonary tuberculosis	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Pyoderma	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Salmonella sepsis	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Streptococcal bacteremia	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Acquired immunodeficiency syndrome	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		2/159 (1.3%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
HIV Infection	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Plasmodium falciparum infection	20/176 (11.4%)		14/515 (2.7%)		1/42 (2.4%)		0/134 (0%)		18/159 (11.3%)		19/528 (3.6%)		1/43 (2.3%)		2/140 (1.4%)
Pneumonia	2/176 (1.1%)		2/515 (0.4%)		0/42 (0%)		0/134 (0%)		3/159 (1.9%)		3/528 (0.6%)		0/43 (0%)		0/140 (0%)
Injury, poisoning and procedural complications
Brain contusion	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Tibia fracture	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Forearm fracture	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Subcutaneous haematoma	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Thermal burn	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		1/140 (0.7%)
Investigations
Platelet count decreased	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Metabolism and nutrition disorders
Kwashiorkor	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Underweight	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		1/528 (0.2%)		0/43 (0%)		0/140 (0%)
Marasmus	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Nervous system disorders
Convulsion	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Febrile convulsion	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		5/159 (3.1%)		7/528 (1.3%)		1/43 (2.3%)		1/140 (0.7%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Skin and subcutaneous tissue disorders
Dermatitis	0/176 (0%)		1/515 (0.2%)		0/42 (0%)		0/134 (0%)		1/159 (0.6%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Urticaria	1/176 (0.6%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1-RTS,S/AS02A <24M Group		Cohort 1-RTS,S/AS02A ≥24M Group		Cohort 2-RTS,S/AS02A <24M Group		Cohort 2-RTS,S/AS02A ≥24M Group		Cohort 1-Prevnar-Hiberix <24M Group		Cohort 1-Engerix-B ≥24M Group		Cohort 2-Prevnar- Hiberix <24M Group		Cohort 2-Engerix-B ≥24M Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/176 (0%)		0/515 (0%)		0/42 (0%)		0/134 (0%)		0/159 (0%)		0/528 (0%)		0/43 (0%)		0/140 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.