Extension to Study MALARIA-055 PRI (NCT00866619) for Evaluation of Long-term Efficacy, Safety and Immunogenicity of GSK Biologicals' Candidate Malaria Vaccine (SB257049) in Infants and Children in Africa
Phase: PHASE3
Conditions: Malaria
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart
Belgium
Primary Study vaccines

GlaxoSmithKline (GSK) Biologicals’ candidate 
Plasmodium falciparum malaria vaccine 
RTS,S/AS01E (SB257049).
Other Study vaccines

Purified Vero cell culture rabies vaccine (Sanofi 
Pasteur).

GSK Biologicals’ DTPwHepB/Hib vaccine: 
Tritanrix HepB™/Hib.

GSK Biologicals’ oral polio vaccine: Polio 
Sabin™.

Meningococcal C conjugate vaccine: 
Menjugate™ (Novartis).
eTrack study number and 
Abbreviated Title
200599 (MALARIA-076)
Date of protocol
Final Version 1: 15 July 2013
Date of protocol amendment
Amendment 1 Final: 18 February 2014
Amendment 2 Final: 15 April 2015
Title
Extension to study MALARIA-055 PRI (110021) for 
evaluation of long-term efficacy, safety and 
immunogenicity of GSK Biologicals’candidate 
malaria vaccine (SB257049) in infants and children 
in Africa
Detailed Title
An open extension to the phase III, multi-center 
study MALARIA-055 PRI (110021) to evaluate 
long-term efficacy, safety and immunogenicity of the 
RTS,S/AS01E candidate vaccine against malaria 
disease caused by Plasmodium falciparum in infants 
and children in Africa
Co-ordinating author
 (Scientific Writer, Keyrus Biopharma 
consultant for GSK Biologicals)
 
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eTrack study number and 
Abbreviated Title
200599 (MALARIA-076) 
Detailed Title
An open extension to the phase III, multi-center 
study MALARIA-055 PRI (110021) to evaluate 
long-term efficacy, safety and immunogenicity of the 
RTS,S/AS01E candidate vaccine against malaria 
disease caused by Plasmodium falciparum in infants 
and children in Africa
Contributing authors

 (Clinical Research and 
Development Lead)

 (Lead Statistician)

(Study Delivery 
Manager)

 (Study Delivery Manager, 
SynteractHCR consultant for GSK Biologicals)

(Study Delivery Manager)

 (Local Delivery Lead)

 (Study Delivery Lead, Novellas 
Healthcare consultant for GSK Biologicals)

 (Clinical Regulatory 
Affairs representative)

 (Clinical Immunology 
representative)

 (Clinical Safety representative)

 (Safety and Pharmacovigilance)

 (Project Data Manager)

 (Study Data Manager)

 (Vice President, Clinical 
Development Malaria, TB & Adjuvant support)

 (Director, Biometrics)
(Amended 15 April 2015)
GSK Biologicals’ Protocol DS v 14.0
Copyright 2013-2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized 
copying or use of this information is prohibited.
 
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Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
200599 (MALARIA-076)
Date of protocol amendment
Amendment 2 Final: 15 April 2015
Detailed Title 
An open extension to the phase III, multi-center study 
MALARIA-055 PRI (110021) to evaluate long-term 
efficacy, safety and immunogenicity of the 
RTS,S/AS01E candidate vaccine against malaria 
disease caused by Plasmodium falciparum in infants 
and children in Africa
Sponsor signatory
Didier Lapierre (Vice President, Clinical 
Development Malaria, TB & Adjuvant support)
Signature
Date
 
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Protocol Amendment 2 Rationale
Amendment number:
Amendment 2
Rationale/background for changes:
In order to maximize and harmonize the clinical information available during the gap 
period the following information will be documented retrospectively and prospectively 
in the eCRF:

Results of clinical diagnoses of malaria.

Rapid diagnostic test (RDT).

Blood slides read to guide treatment at the time of presentation.
In Appendix E, text describing “Determination of parasitemia” was removed because 
“Determination of Plasmodium falciparum asexual parasite density” is detailed in 
Appendix C.
 
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Protocol Amendment 2 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccine(s) and other study-related duties and 
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine(s), and more generally about his/her 
financial ties with the sponsor. GSK Biologicals will use and disclose the 
information solely for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
200599 (MALARIA-076)
Date of protocol amendment
Amendment 2 Final: 15 April 2015
Detailed Title
An open extension to the phase III, multi-center study 
MALARIA-055 PRI (110021) to evaluate long-term 
efficacy, safety and immunogenicity of the 
RTS,S/AS01E candidate vaccine against malaria 
disease caused by Plasmodium falciparum in infants 
and children in Africa
Investigator name
Signature
Date
 
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart (Belgium)
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 9.3.2.
 
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SYNOPSIS
Detailed Title
An open extension to the phase III, multi-center study 
MALARIA-055 PRI (110021) to evaluate long-term efficacy, 
safety and immunogenicity of the RTS,S/AS01E candidate 
vaccine against malaria disease caused by Plasmodium 
falciparum in infants and children in Africa
Indication
Primary immunization against malaria disease caused by 
Plasmodium falciparum in infants and children.
Rationale for the 
study and study 
design
It is possible that vaccination with RTS,S/AS01E in infancy 
and early childhood may affect the rate of acquisition of 
natural immunity to malaria and there is a concern that 
vaccinees would have enhanced susceptibility to malaria 
relative to unvaccinated children of the same age. We intend 
to conduct long-term surveillance for malaria disease in 
participants to randomized controlled trial of RTS,S/AS01E. 
We will describe the patterns of clinical and severe forms in 
the long-term under different conditions of transmission.
In total we will provide in children aged 5-17 months at first 
vaccination, approximately 7 years of follow-up post-Dose 1 
(mean: 85 months; range: 77-91 months), and in infants aged 
6-12 weeks at first vaccination, 6 years of follow-up post-
Dose 1 (mean: 77 months; range: 68-84 months).
Objectives
Primary

To describe the incidence of severe malaria in the long-
term over a 3-year period (from January 2014 to 
December 2016) of follow-up pooled across transmission 
settings, in both age categories.

In children enrolled in the 5-17 months age category, 
starting on average 4 years post primary vaccination.

In children enrolled in the 6-12 weeks age category, 
starting on average 3.5 years post primary 
vaccination.
Secondary efficacy objectives
In each age category (i.e. 5-17 months and 6-12 weeks) over 3 
years of follow-up (from January 2014 to December 2016):

To describe the incidence of clinical malaria in recipients 
of the RTS,S/AS01E candidate malaria vaccine and in 
controls.

To describe the incidence of hospitalization due to 
 
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malaria in recipients of the RTS,S/AS01E candidate 
malaria vaccine and in controls.

To describe the prevalence of malaria infection at annual 
cross sectional timepoints in recipients of the 
RTS,S/AS01E candidate malaria vaccine and in controls.

To describe the hemoglobin level and the prevalence of 
anemia at annual cross sectional timepoints in recipients 
of the RTS,S/AS01E candidate malaria vaccine and in 
controls.
In each age category since the start of the primary study 
(MALARIA-055 PRI [110021]) until December 2016:

To describe the incidence of severe malaria in recipients 
of the RTS,S/AS01E candidate malaria vaccine and in 
controls.

To describe the incidence of clinical malaria in recipients 
of the RTS,S/AS01E candidate malaria vaccine and in 
controls.

To describe the incidence of hospitalization due to 
malaria in recipients of the RTS,S/AS01E candidate 
malaria vaccine and in controls.
Secondary safety objective

To describe the incidence of the following reported 
serious adverse events (SAEs): fatalities, related SAEs
(related to vaccine administration in the primary study 
MALARIA-055 PRI [110021] and to study participation), 
malaria hospitalization, potential Immune-Mediated 
Disease (pIMDs), and meningitis from January 2014 to 
December 2016.
Secondary immunogenicity objective

To describe anti-circumsporozoite protein of Plasmodium 
falciparum (anti-CS) antibodies response over the 3-year 
follow-up period, in each age category.
Study design

Experimental design: extension to the phase III, 
randomized, controlled, multi-centric study MALARIA-
055 PRI (110021) that comprised 3 parallel groups

Duration of the study: approximately 3 years

Epoch 001: starting at Visit 39, including and ending 
at Visit 41 (December 2014).

Epoch 002: starting at Visit 42, including and ending 
 
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at Visit 43 (December 2015).

Epoch 003: starting at Visit 44, including and ending 
at Visit 45 (December 2016).

Study groups: same study groups as in the primary study 
MALARIA-055 PRI (110021). Subjects enrolled in each 
of the 2 age categories (5-17 months and 6-12 weeks at 
first vaccination) were randomized in 3 study groups:

R3C: infants/children randomized to receive 3 doses 
of RTS,S/AS01E on a 0-, 1-, 2-month schedule with a 
dose of comparator vaccine at Month 20 during the 
primary study MALARIA-055 PRI (110021).

R3R: infants/children randomized to receive 3 doses 
of RTS,S/AS01E on a 0-, 1-, 2-month schedule with 
an RTS,S/AS01E booster dose at Month 20 during 
the primary study MALARIA-055 PRI (110021).

C3C: infants/children randomized to receive 3 doses 
of a comparator vaccine on a 0-, 1-, 2-month 
schedule with a dose of comparator vaccine at Month 
20 during the primary study MALARIA-055 PRI 
(110021).
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Estimated number 
of subjects
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
R3C
600
6 weeks - 12 weeks*
x
x
x
600
5 months -17 months*
x
x
x
R3R
600
6 weeks - 12 weeks*
x
x
x
600
5 months -17 months*
x
x
x
C3C
600
6 weeks - 12 weeks*
x
x
x
600
5 months -17 months*
x
x
x
R3C: RTS,S/AS01E: primary schedule without booster
R3R: RTS,S/AS01E: primary schedule with booster
C3C: controls
* Age at first vaccination in the primary study MALARIA-055 PRI (110021).

Control: active comparator administered in the primary 
study MALARIA-055 PRI (110021; rabies vaccine in the 
5-17 months age category and Meningococcal C 
conjugate vaccine in the 6-12 weeks age category).

Vaccination schedule: not applicable, all vaccinations 
were performed in the primary study MALARIA-055 PRI
(110021).

Treatment allocation: follow-up of a randomized study 
(Randomization performed in the primary study 
MALARIA-055 PRI will be kept for this extension. 
 
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Subjects will remain in the same group as the one of the 
primary study MALARIA-055 PRI [110021]).

Blinding: open
Synopsis Table 2
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
open
Epoch 002
open
Epoch 003
open

Sampling schedule: blood samples will be taken at annual 
intervals during the extension (maximum 3 blood samples).

Type of study: extension of other protocol(s) (MALARIA-
055 PRI [110021]). Data of the MALARIA-076 study will 
be analyzed with those of the primary study MALARIA-055 
PRI [110021]). Endpoints of the MALARIA-076 study are 
pooled with those of the primary study.

Data collection: electronic Case Report Form (eCRF).
Case definition
Clinical malaria
Synopsis Table 3
Case definition for clinical malaria
1definition
Plasmodium falciparum asexual parasitemia > 5000 parasites/L 
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
OR
A case of malaria meeting the primary case definition of severe malaria (refer to Synopsis Table 4)
2definition 1 Plasmodium 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
2definition 2 Plasmodium falciparum asexual parasitemia > 500 parasites/L
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
2definition 3 Plasmodium falciparum asexual parasitemia > 20 000 parasites/L
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
 
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Severe malaria
Severe malaria will be diagnosed based on symptoms and signs occurring at presentation 
or developing during admission according to the case definitions below.
Synopsis Table 4
Primary case definition for severe malaria
Plasmodium falciparum asexual parasitemia > 5000 parasites/L 
AND with one or more marker of disease severity:
- Prostration.
- Respiratory distress.
- Blantyre score 2.
- Seizures 2 or more.
- Hypoglycemia < 2.2 mmol/L.
- Acidosis BE -10.0 mmol/L.
- Lactate 5.0 mmol/L.
- Anemia < 5.0 g/dL.
AND without diagnosis of co-morbidity:
- Radiographically proven pneumonia.
- Meningitis on cerebrospinal fluid (CSF) examination.
- Positive blood culture.
- Gastroenteritis with dehydration.
Prostration is defined as, in an acutely sick child, the inability to perform previously-acquired motor function: in a child 
previously able to stand, inability to stand; in a child previously able to sit, inability to sit and in a very young child, 
inability to suck.
Respiratory distress is defined as lower chest wall indrawing or abnormally deep breathing.
2 or more seizures occurring in the total time period including 24 h prior to admission to the emergency room and the 
hospitalization.
Radiographically proven pneumonia is a consolidation or pleural effusion as defined by World Health Organization 
[WHO; 2001a] on a chest x-ray (CXR) taken within 72 h of admission.
Meningitis on CSF examination is defined as white cells 50 x 106/L or positive culture of compatible organism or 
latex agglutination positive for Haemophilus influenzae type b, pneumococci or meningococci [Berkley, 2001].
Positive blood culture as defined by WHO [WHO, 1999] on a blood culture taken within 72 h of admission.
Gastroenteritis with dehydration is defined as a history of 3 or more loose or watery stools in previous 24 h and an 
observed watery stool with decreased skin turgor (> 2 seconds for skin to return following skin pinch).
Secondary case definitions of severe malaria are given below.
Synopsis Table 5
Secondary case definition for severe malaria
2definition 1
“with co-morbidity”
Plasmodium falciparum asexual parasitemia > 5000 parasites/L
AND with one or more marker(s) of disease severity
2definition 2
“without a density threshold”
Plasmodium falciparum asexual parasitemia > 0
AND with one or more marker(s) of disease severity
AND without diagnosis of a co-morbidity
 
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Malaria hospitalization
Synopsis Table 6
Case definitions for malaria hospitalization
Definition 1
A medical hospitalization with confirmed Plasmodium falciparum asexual parasitemia > 5000
parasites/L 
(excludes planned admissions for medical investigation/care or elective surgery and trauma)
Definition 2
A hospitalization for which, in the judgment of the principal investigator, Plasmodium falciparum
infection was the sole or a major contributing factor to the presentation
Prevalent anemia
Synopsis Table 7
Case definitions of prevalent anemia
Prevalent severe anemia
A documented hemoglobin < 5.0 g/dL identified at an annual visit
Prevalent moderate anemia
A documented hemoglobin < 8.0 g/dL identified at an annual visit
Prevalent parasitemia
Synopsis Table 8
Case definitions for prevalent parasitemia
Prevalent parasitemia
A documented Plasmodium falciparum asexual parasite density > 0 identified at an annual 
visit
Number of subjects
Approximately 3000 to 4000 children who were vaccinated 
during the primary study MALARIA-055 PRI (110021) will be 
enrolled in the MALARIA-076 study.
Endpoints
Primary

The occurrence of severe malaria meeting the primary case 
definition analyzed over the time period starting January 
2014 until the end of the 3-year follow-up period (Visit 45).
Secondary efficacy endpoints

The occurrence of clinical malaria meeting the primary and 
secondary case definitions analyzed over the time period 
starting January 2014 until the end of the 3-year follow-up 
period (Visit 45).

The occurrence of malaria hospitalization meeting each of 
the case definitions analyzed over the time period starting 
January 2014 until the end of the 3-year follow-up period 
(Visit 45).
 
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
The prevalence of parasitemia at 3 annual timepoints (Visit 
41, 43 and 45), in both age categories (6-12 weeks and 5-17 
months).

The prevalence of anemia at 3 annual timepoints (Visit 41, 
43 and 45), in both age categories (6-12 weeks and 5-17 
months).

The level of hemoglobin at 3 annual timepoints (Visit 41, 
43 and 45), in both age categories (6-12 weeks and 5-17 
months).

The occurrence of severe malaria meeting the primary and 
secondary case definitions analyzed over the time period 
starting at the beginning of the primary study (MALARIA-
055 PRI [110021]; Visit 2) until the end of the follow-up 
period (Visit 45), in both age categories (6-12 weeks and 5-
17 months).

The occurrence of clinical malaria meeting the primary and 
secondary case definitions analyzed over the time period 
starting at the beginning of the primary study (MALARIA-
055 PRI [110021]; Visit 2) until the end of the follow-up 
period (Visit 45), in both age categories (6-12 weeks and 5-
17 months).

The occurrence of malaria hospitalization meeting all case 
definitions analyzed over the time period starting at the 
beginning of the primary study (MALARIA-055 PRI 
[110021]; Visit 2) until the end of the follow-up period 
(Visit 45), in both age categories (6-12 weeks and 5-17 
months).
Secondary safety endpoint

The occurrence of the following reported SAEs: fatalities, 
related SAEs (related to vaccine administration in the 
primary study MALARIA-055 PRI [110021] and to study 
participation), malaria hospitalization, pIMDs, and 
meningitis over the time period starting January 2014 until 
the end of the 3-year follow-up period (Visit 45).
Secondary immunogenicity endpoint

The annual anti-CS antibody titers (Visit 41, 43 and 45) for 
children of both age categories (6-12 weeks and 5-17 
months).
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................22
GLOSSARY OF TERMS ...............................................................................................25
1.
INTRODUCTION....................................................................................................29
1.1.
Background ................................................................................................29
1.2.
Rationale for the study and study design ....................................................30
2.
OBJECTIVES.........................................................................................................31
2.1.
Primary objective ........................................................................................31
2.2.
Secondary objectives..................................................................................31
2.2.1.
Efficacy objectives .......................................................................31
2.2.2.
Safety objective ...........................................................................32
2.2.3.
Immunogenicity objective.............................................................32
3.
STUDY DESIGN OVERVIEW ................................................................................33
4.
CASE DEFINITION ................................................................................................36
4.1.
Clinical malaria ...........................................................................................36
4.2.
Severe malaria ...........................................................................................36
4.3.
Malaria hospitalization ................................................................................37
4.4.
Prevalent anemia........................................................................................37
4.5.
Prevalent parasitemia .................................................................................38
5.
STUDY COHORT...................................................................................................38
5.1.
Number of subjects/centers ........................................................................38
5.2.
Overview of the recruitment plan ................................................................38
5.3.
Inclusion criteria for enrolment....................................................................39
5.4.
Exclusion criteria for enrolment...................................................................39
6.
CONDUCT OF THE STUDY ..................................................................................40
6.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................40
6.2.
Subject identification and randomization of treatment .................................41
6.2.1.
Subject identification....................................................................41
6.2.2.
Allocation of subjects to assay subsets........................................41
6.3.
Method of blinding ......................................................................................41
6.4.
General study aspects ................................................................................41
6.5.
Outline of study procedures ........................................................................42
6.6.
Detailed description of study procedures ....................................................43
6.6.1.
Recording reasons for non-participation ......................................43
6.6.2.
Informed consent.........................................................................43
6.6.3.
Check inclusion and exclusion criteria .........................................43
6.6.4.
Collect demographic data ............................................................43
 
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6.6.5.
Physical examination ...................................................................44
6.6.6.
Anthropometry .............................................................................44
6.6.7.
Issuing subject identification card ................................................44
6.6.8.
Screening conclusion...................................................................44
6.6.9.
Documentation of bednets and indoor residual spraying..............44
6.6.10.
Retrospective collection of efficacy and safety data.....................45
6.6.11.
Surveillance for efficacy...............................................................45
6.6.12.
Passive surveillance for safety.....................................................46
6.6.13.
Sampling......................................................................................47
6.6.13.1.
Blood sampling for surveillance of 
immunogenicity ..........................................................47
6.6.13.2.
Blood sampling for prevalent parasitemia and 
anemia .......................................................................47
6.6.14.
Study conclusion..........................................................................47
6.7.
Biological sample handling and analysis.....................................................48
6.7.1.
Use of specified study materials ..................................................48
6.7.2.
Biological samples.......................................................................49
6.7.3.
Laboratory assays .......................................................................49
6.7.4.
Biological samples evaluation......................................................49
6.7.4.1.
Immunological read-outs ............................................49
6.7.4.2.
Parasitemia and anemia.............................................50
6.7.5.
Immunological correlates of protection.........................................50
7.
STUDY VACCINE(S) AND ADMINISTRATION......................................................50
8.
HEALTH ECONOMICS ..........................................................................................50
9.
SAFETY.................................................................................................................50
9.1.
Safety definitions ........................................................................................51
9.1.1.
Definition of an adverse event......................................................51
9.1.2.
Definition of a serious adverse event ...........................................52
9.1.3.
Clinical laboratory parameters and other abnormal 
assessments qualifying as serious adverse events......................52
9.1.4.
Adverse events of specific interest...............................................53
9.1.4.1.
Potential immune-mediated diseases .........................53
9.1.4.2.
Meningitis ...................................................................55
9.2.
Detecting and recording serious adverse events.........................................55
9.2.1.
Time period for detecting and recording serious adverse 
events..........................................................................................55
9.2.2.
Post-Study serious adverse events..............................................56
9.2.3.
Evaluation of serious adverse events...........................................56
9.2.3.1.
Active questioning to detect serious adverse 
events.........................................................................56
9.2.3.2.
Assessment of adverse events...................................57
9.2.3.2.1.
Assessment of intensity..........................57
9.2.3.2.2.
Assessment of causality .........................57
9.2.3.3.
Assessment of outcomes............................................59
9.2.3.4.
Medically attended visits.............................................59
9.3.
Reporting of serious adverse events and other events................................59
9.3.1.
Prompt reporting of serious adverse events and other 
events to GSK Biologicals............................................................59
 
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9.3.2.
Contact information for reporting serious adverse events 
and other events to GSK Biologicals............................................60
9.3.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................60
9.3.3.1.
Back-up system in case the electronic SAE 
reporting system does not work..................................60
9.3.4.
Reporting of pIMDs to GSK Biologicals........................................60
9.3.5.
Updating of SAE and pIMD information after freezing of 
the subject’s eCRF ......................................................................61
9.3.6.
Regulatory reporting requirements for serious adverse 
events..........................................................................................61
9.4.
Follow-up of serious adverse events...........................................................61
9.4.1.
Follow-up of serious adverse events............................................61
9.4.1.1.
Follow-up during the study..........................................61
9.4.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................62
9.5.
Treatment of serious adverse events..........................................................62
9.6.
Subject card................................................................................................62
10. SUBJECT COMPLETION AND WITHDRAWAL.....................................................62
10.1.
Subject completion .....................................................................................62
10.2.
Subject withdrawal......................................................................................62
10.2.1.
Subject withdrawal from the study ...............................................63
10.3.
Screen and baseline failures.......................................................................63
11. STATISTICAL METHODS......................................................................................64
11.1.
Primary endpoint.........................................................................................64
11.2.
Secondary endpoints ..................................................................................64
11.2.1.
Efficacy endpoints........................................................................64
11.2.2.
Safety endpoint............................................................................65
11.2.3.
Immunogenicity endpoint.............................................................65
11.3.
Power of the trial.........................................................................................65
11.4.
Study populations .......................................................................................65
11.4.1.
Modified Intention-to-Treat (ITT) population.................................65
11.4.2.
According-to-Protocol population for efficacy...............................65
11.4.3.
According-to-Protocol population for immunogenicity ..................66
11.5.
Derived and transformed data.....................................................................66
11.6.
Analysis of demographics...........................................................................66
11.7.
Analysis of malaria disease incidence.........................................................66
11.7.1.
Clinical malaria ............................................................................66
11.7.2.
Severe malaria and malaria hospitalization..................................67
11.7.3.
Vaccine efficacy against prevalent parasitemia and 
prevalent anemia .........................................................................67
11.7.4.
Vaccine impact ............................................................................67
11.8.
Analysis of immunogenicity.........................................................................68
11.9.
Analysis of safety........................................................................................68
11.10. Interpretation of analyses............................................................................68
11.11. Conduct of analyses ...................................................................................68
11.11.1. Sequence of analyses..................................................................68
11.11.2. Statistical considerations for interim analyses..............................69
12. ADMINISTRATIVE MATTERS ...............................................................................69
 
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12.1.
Case Report Form/Remote Data Entry instructions ....................................69
12.2.
Study Monitoring by GSK Biologicals..........................................................69
12.3.
Record retention .........................................................................................70
12.4.
Quality assurance.......................................................................................71
12.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................71
12.6.
Provision of study results to investigators ...................................................71
13. COUNTRY SPECIFIC REQUIREMENTS...............................................................71
14. REFERENCES.......................................................................................................72
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................34
Table 2
Blinding of study epochs ........................................................................35
Table 3
Case definition for clinical malaria ..........................................................36
Table 4
Primary case definition for severe malaria..............................................36
Table 5
Secondary case definition for severe malaria.........................................37
Table 6
Case definitions for malaria hospitalization.............................................37
Table 7
Case definitions of prevalent anemia......................................................37
Table 8
Case definitions for prevalent parasitemia..............................................38
Table 9
Sub-cohorts............................................................................................38
Table 10
List of study procedures .........................................................................42
Table 11
Intervals between study visits.................................................................43
Table 12
Biological samples .................................................................................49
Table 13
Humoral Immunity (Antibody determination)...........................................49
Table 14
Immunological read-outs........................................................................49
Table 15
Parasitology and hemoglobin read-outs .................................................50
Table 16
List of potential immune-mediated diseases...........................................54
Table 17
Reporting periods for serious adverse events ........................................56
Table 18
Timeframes for submitting serious adverse event and other 
events reports to GSK Biologicals ..........................................................59
Table 19
Coma scale for young children...............................................................76
Table 20
Classification of quality of chest x-rays...................................................83
Table 21
Classification of findings of chest x-rays.................................................84
Table 22
Outsourced laboratories.........................................................................87
 
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LIST OF FIGURES
PAGE
Figure 1
Study design overview ...........................................................................33
Figure 2
Diagnosis of dehydration........................................................................77
Figure 3
Lower chest wall indrawing ....................................................................78
Figure 4
Determination of final result....................................................................82
Figure 5
Diagrams to support classification of findings of chest x-rays.................85
 
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LIST OF APPENDICES
PAGE
APPENDIX A Documentation of bednet usage and indoor residual spraying ...............74
APPENDIX B Assessment of a potential case of severe malaria..................................75
APPENDIX C Determination of Plasmodium falciparum asexual parasite 
density ...................................................................................................79
APPENDIX D Interpretation of chest x-rays..................................................................83
APPENDIX E Laboratory assays..................................................................................86
APPENDIX F Clinical laboratories................................................................................87
APPENDIX G AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL...........................................................................................88
 
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LIST OF ABBREVIATIONS
AE:
Adverse event
AS01E:
GSK’s proprietary liposome-based Adjuvant System containing 
MPL and QS21
ATP:
According-to-Protocol
BS:
Blood Sampling
C3C:
Infants/Children randomized to receive 3 doses of a comparator 
vaccine on a 0-, 1-, 2-month schedule with a dose of comparator 
vaccine at Month 20 in study MALARIA-055 PRI
CI:
Confidence Interval
CS:
Circumsporozoite protein of Plasmodium falciparum
CSF:
Cerebrospinal Fluid
CXR:
Chest X-Ray
eCRF:
electronic Case Report Form
ELISA:
Enzyme-Linked Immunosorbent Assay
EPI:
Expanded Program on Immunization
FWV:
Field Worker Visit
GCP:
Good Clinical Practice
GMT:
Geometric Mean Titers
GSK:
GlaxoSmithKline
HR:
Hazard Ratio
ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
IEC:
Independent Ethics Committee
IR:
Incidence Ratio
IRB:
Institutional Review Board
IRS:
Indoor Residual Spraying
 
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ITT:
Intention-to-Treat
LAR:
Legally Acceptable Representative
LP:
Lumbar Puncture
MedDRA:
Medical Dictionary for Regulatory Activities
MF:
Microscope Factor
MPL:
3-O-desacyl-4’-monophosphoryl lipid A
pIMD:
Potential Immune-Mediated Disease
PT:
Preferred Terms
QS21 (Quillaja 
saponaria 21):
A triterpene glycoside purified from the bark of the soap bark 
tree, Quillaja saponaria
RBC:
Red Blood Cells 
RDE:
Remote Data Entry
RDT:
Rapid diagnostic test
R3R:
Infants/Children randomized to receive 3 doses of RTS,S/AS01E
on a 0-, 1-, 2-month schedule with an RTS,S/AS01E booster dose 
at Month 20 in study MALARIA-055 PRI
R3C:
Infants/Children randomized to receive 3 doses of RTS,S/AS01E
on a 0-, 1-, 2-month schedule with a dose of comparator vaccine 
at Month 20 in study MALARIA-055 PRI
RR:
Risk Ratio
RTS:
Hybrid protein comprising S (hepatitis B surface antigen) and CS 
portions
RTS,S:
Particulate antigen, containing both RTS and S (hepatitis B 
surface antigen) proteins
RTS,S/AS:
GSK Biologicals’ candidate Plasmodium falciparum malaria 
vaccine adjuvanted with GSK Biologicals’ proprietary Adjuvant 
Systems
SAE:
Serious Adverse Event
SDV:
Source Document Verification
SPM:
Study Procedures Manual
 
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VE:
Vaccine Efficacy
WBC:
White Blood Cells
WHO:
World Health Organization
(Amended 15 April 2015)
 
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GLOSSARY OF TERMS
Adverse event:
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product. 
An adverse event (AE) can therefore be any unfavorable
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse.
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
open-label study, no blind is used. Both the investigator 
and the subject know the identity of the treatment 
assigned.
Child in care:
A child who has been placed under the control or 
protection of an agency, organization, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
 
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Epoch:
An epoch is a self-contained set of consecutive
timepoints or a single timepoint from a single protocol. 
Self-contained means that data collected for all subjects 
at all timepoints within that epoch allows to draw a 
complete conclusion to define or precise the targeted 
label of the product. Typical examples of epochs are 
primary vaccinations, boosters, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety.
eTrack:
GSK’s tracking tool for clinical trials.
Immunological correlate 
of protection:
The defined humoral antibody response above which 
there is a high likelihood of protection in the absence of 
any host factors that might increase susceptibility to the 
infectious agent.
Investigational 
vaccine/product:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorization when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
Passive case detection:
The passive case detection is the detection of malaria 
disease by self-presentation to health facility in the study 
area. If there is a history of fever within 24 hours or 
axillary temperature is 37.5C at presentation then a 
blood slide is taken and examined for parasitemia.
Potential Immune-
Mediated Disease:
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.
Primary completion date:
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated.
Protocol amendment:
The International Conference on Harmonization (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study.
 
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Protocol administrative 
change:
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study. 
Note: Any change that falls under the definition of a 
protocol amendment (e.g. a change that affects the safety 
of subjects, scope of the investigation, study design, or 
scientific integrity of the study) MUST be prepared as an 
amendment to the protocol. 
Randomization:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Serious Adverse Event:
A serious adverse event is any untoward medical 
occurrence that:
a.
Results in death,
b.
Is life-threatening,
c.
Requires hospitalization or prolongation of existing 
hospitalization,
d.
Results in disability/incapacity.
Medical or scientific judgment should be exercised in 
deciding whether reporting is appropriate in other 
situations, such as important medical events that may not 
be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such 
events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
Sub-cohort:
A group of subjects for whom specific study procedures 
are planned as compared to other subjects.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine(s)/product(s) or as a control.
 
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Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomization or treatment allocation.
Unsolicited adverse event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
 
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1.
INTRODUCTION
1.1.
Background
GlaxoSmithKline (GSK) Biologicals is developing the RTS,S/AS01 vaccine for 
prevention of malaria disease in children 6 to 12 weeks of age in co-administration with 
Expanded Program on Immunization (EPI) vaccines and in children 5 to 17 months of 
age. Phase III evaluation of the vaccine is ongoing.
Study MALARIA-055 PRI (110021) is a phase III, randomized, controlled, double-blind 
study conducted in 11 centers in 7 African countries with a range of malaria transmission 
intensities to support licensure. Approximately 9000 children 5 – 17 months of age and 
6000 infants 6 - 12 weeks have been enrolled. This study has reported the co-primary 
endpoints of efficacy to one year of follow-up post-Dose 3. In children 5–17 months of 
age at first vaccination, the vaccine efficacy (VE) was 55.8% (97.5% confidence interval 
[CI]: 50.6 to 60.4) and in infants aged 6-12 weeks in EPI co-administration VE was 
31.3% (97.5% CI: 23.6 to 38.3). All children enrolled in MALARIA-055 PRI are under 
continuous surveillance for efficacy, immunogenicity and safety until December 2013.
In parallel to the phase III evaluation, long-term follow-up of a phase II study was 
ongoing. This study examined children 5 to 17 months of age who were randomized to 
receive RTS,S/AS01E or control (MALARIA-059 [112902]). These children have now 
been followed for more than 5 years. Clinical malaria incidence in the 5th year of follow-
up was 1.4-fold higher in the vaccinees (95% CI: 0.97-2.04, p = 0.07) than in the control
group. The number of cases averted over the 5-year follow-up period was approximately 
55/100 children vaccinated. In the control group the incidence was 0.7 to 1 cases per 
child per year. This corresponds to a moderate to high transmission setting and it is an 
unexpected finding that incidence is rising in the controls in sequential years as the 
children age. These data suggested a waning efficacy over time up to 4 years and then in 
the 5th year an apparent reversal of disease incidence [Olotu, 2013].
This reversal of incidence may be due to a slower buildup of natural immunity to malaria 
in the vaccine recipients compared to controls. Theoretically, children who receive an 
intervention, may not develop natural immunity through exposure to infection. As a 
consequence when the intervention is withdrawn the intervention recipients have less 
immunity than children of the same age in the population. The delay in acquisition of 
natural immunity may also induce a clinical risk which may be specific to the age; in 
infants and young children severe malaria anemia is predominant, whereas in older 
children and adolescents it is cerebral malaria.
The heightened susceptibility is theoretically more likely to occur when:

The intervention is given early in life before natural immunity has been induced.

The intervention is highly efficacious preventing natural exposure.

The intervention is removed or efficacy wanes abruptly.
 
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This has been demonstrated experimentally when a group of Mozambican children were 
randomized to receive highly effective malaria chemoprophylaxis during the first year of 
life. During the period of chemoprophylaxis there was a marked reduction in the 
incidence of disease, but in the subsequent 2 years these children were at higher risk 
compared to the comparator group who received no intervention. By 4 years of age, rates 
were similar in both groups and over the complete time period there was a slight benefit 
of the intervention [Aponte, 2007].
Results from the MALARIA-059 (112902) study, a long-term follow-up in 450 Kenyan 
children, are suggestive of greater susceptibility to clinical malaria in the vaccine 
recipients occurring 5 years after vaccination in a moderate to high transmission area. 
However, no increase in the incidence of severe malaria has been observed with the 
available safety data. In order to get additional data on the question of enhanced 
susceptibility to malaria disease following a primary vaccination series, GSK proposes to 
extend the follow-up of MALARIA-055 PRI for an additional 3 years from January 2014 
to December 2016 at multiple study sites.
Please refer to the current Investigator Brochure for information regarding the pre-
clinical and clinical studies, the epidemiological information and the potential risks and 
benefits of GSK Biologicals’ candidate Plasmodium falciparum malaria vaccine 
RTS,S/AS01E (SB257049).
1.2.
Rationale for the study and study design
Extending the ongoing study MALARIA-055 PRI (110021) is the fastest and most robust 
way to have additional data on the question of enhanced susceptibility to malaria disease 
following a primary vaccination series. Given the strong benefit shown over one year of 
follow-up, any new study is likely to be unable to have an unvaccinated control group. 
Therefore this is a unique opportunity to obtain important long-term data relative to a 
control group. This study design will also allow evaluating in parallel whether giving a 
booster 18 months after the primary series changes the long-term experience.
Extending for an additional 3 years will permit to get sufficient follow-up time in both 
age categories (children aged 5–17 months and infants aged 6-12 weeks at first 
vaccination) to detect changes in malaria susceptibility as it has been previously observed 
in a long-term follow-up phase II study (i.e. MALARIA-059 [112902]).
In total we will provide in children aged 5-17 months at first vaccination approximately 7 
years of follow-up post-Dose 1 (mean: 85 months; range: 77-91 months), and in infants 
aged 6-12 weeks at first vaccination, 6 years of follow-up post-Dose 1 (mean: 77 months; 
range: 68-84 months).
 
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2.
OBJECTIVES
2.1.
Primary objective

To describe the incidence of severe malaria in the long-term over a 3-year period 
(from January 2014 to December 2016) of follow-up pooled across transmission 
settings, in both age categories.

In children enrolled in the 5-17 months age category, starting on average 4 years 
post primary vaccination.

In children enrolled in the 6-12 weeks age category, starting on average 3.5 
years post primary vaccination.
Refer to Section 11.1 for the definition of the primary endpoints.
2.2.
Secondary objectives
2.2.1.
Efficacy objectives
In each age category (i.e. 5-17 months and 6-12 weeks) over 3 years of follow-up (from 
January 2014 to December 2016)::

To describe the incidence of clinical malaria in recipients of the RTS,S/AS01E
candidate malaria vaccine and in controls.

To describe the incidence of hospitalization due to malaria in recipients of the 
RTS,S/AS01E candidate malaria vaccine and in controls.

To describe the prevalence of malaria infection at annual cross sectional timepoints 
in recipients of the RTS,S/AS01E candidate malaria vaccine and in controls.

To describe the hemoglobin level and the prevalence of anemia at annual cross 
sectional timepoints in recipients of the RTS,S/AS01E candidate malaria vaccine and 
in controls.
In each age category since the start of the primary study (MALARIA-055 PRI [110021]) 
until December 2016:

To describe the incidence of severe malaria in recipients of the RTS,S/AS01E
candidate malaria vaccine and in controls.

To describe the incidence of clinical malaria in recipients of the RTS,S/AS01E
candidate malaria vaccine and in controls.

To describe the incidence of hospitalization due to malaria in recipients of the 
RTS,S/AS01E candidate malaria vaccine and in controls.
 
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2.2.2.
Safety objective

To describe the incidence of the following reported serious adverse events (SAEs): 
fatalities, related SAEs (related to vaccine administration in the primary study 
MALARIA-055 PRI [110021] and to study participation), malaria hospitalization, 
potential Immune-Mediated Disease (pIMDs), and meningitis from January 2014 to 
December 2016.
2.2.3.
Immunogenicity objective

To describe anti-circumsporozoite protein of Plasmodium falciparum (anti-CS) 
antibodies response over the 3-year follow-up period, in each age category.
Refer to Section 11.2 for the definition of the secondary endpoints.
 
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3.
STUDY DESIGN OVERVIEW
Figure 1
Study design overview
* Subjects that had their last contact in the primary trial phase (Visit 34) BEFORE (and including) 30-Jun-2012, had 3 clinic visits and one field workers visit in the extension part of 
MALARIA-055 PRI.
** Subjects that had their last contact in the primary trial phase (Visit 34) BETWEEN 01-Jul-2012 and 30-Sep-2013 had 2 clinic visits and  one field workers visit in the extension part of 
MALARIA-055 PRI.
*** Subjects that had their last contact in the primary trial phase (Visit 34) AFTER 30-Sep-2013 were not enrolled in the extension part of MALARIA-055 PRI.
BS: blood sampling; FWV: Field Worker Visit.
Visit 2
Dose 1
Visit 34
Before
30-Jun-2012*
Visit 35
Visit 36
BS
Visit 38
BS
Visit 39
Screening visit
Visit 41
BS
Visit 43
BS
Visit 45
BS
32 months
INITIAL STUDY
EXTENSION
3-YEAR EXTENSION
MALARIA-055
MALARIA-076
Visit 2
Dose 1
Visit 34
Before
30-Sep-2013**
Visit 35
Visit 38
BS
Visit 2
Dose 1
Visit 34
After
30-Sep-2013***
Dec-2014
Dec-2015
Dec-2016
Visit 42
FWV
Visit 44
FWV
Visit 37
FWV
Visit 37
FWV
Visit 40
FWV
Visit 39
Screening visit
Visit 41
BS
Visit 43
BS
Visit 45
BS
Visit 42
FWV
Visit 44
FWV
Visit 40
FWV
Visit 39
Screening visit
Visit 41
BS
Visit 43
BS
Visit 45
BS
Visit 42
FWV
Visit 44
FWV
Visit 40
FWV
Dec-2013
Dec-2014
Dec-2015
Dec-2016
Dec-2013
Dec-2014
Dec-2015
Dec-2016
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Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 6.5), are essential and required for 
study conduct. 

Experimental design: extension to the phase III, randomized, controlled, multi-
centric study MALARIA-055 PRI (110021) that comprised 3 parallel groups

Duration of the study: approximately 3 years

Epoch 001: starting at Visit 39, including and ending at Visit 41 (December
2014).

Epoch 002: starting at Visit 42, including and ending at Visit 43 (December 
2015).

Epoch 003: starting at Visit 44, including and ending at Visit 45 (December 
2016).

Study groups: same study groups as in the primary study MALARIA-055 PRI 
(110021). Subjects enrolled in each of the 2 age categories (5-17 months and 6-12 
weeks at first vaccination) were randomized in 3 study groups:

R3C: infants/children randomized to receive 3 doses of RTS,S/AS01E on a 0-, 
1-, 2-month schedule with a dose of comparator vaccine at Month 20 during the 
primary study MALARIA-055 PRI (110021).

R3R: infants/children randomized to receive 3 doses of RTS,S/AS01E on a 0-, 1-
, 2-month schedule with an RTS,S/AS01E booster dose at Month 20 during the 
primary study MALARIA-055 PRI (110021).

C3C: infants/children randomized to receive 3 doses of a comparator vaccine on 
a 0-, 1-, 2-month schedule with a dose of comparator vaccine at Month 20 
during the primary study MALARIA-055 PRI (110021).
Table 1
Study groups and epochs foreseen in the study
Study groups
Estimated number 
of subjects
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
R3C
600
6 weeks - 12 weeks*
x
x
x
600
5 months -17 months*
x
x
x
R3R
600
6 weeks - 12 weeks*
x
x
x
600
5 months -17 months*
x
x
x
C3C
600
6 weeks - 12 weeks*
x
x
x
600
5 months -17 months*
x
x
x
R3C: RTS,S/AS01E: primary schedule without booster
R3R: RTS,S/AS01E: primary schedule with booster
C3C: controls
* Age at first vaccination in the primary study MALARIA-055 PRI (110021).

Control: active comparator administered in the primary study MALARIA-055 PRI 
(110021) (rabies vaccine in the 5-17 months age category and Meningococcal C 
conjugate vaccine in the 6-12 weeks age category).
 
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
Vaccination schedule: not applicable, all vaccinations were performed in the primary 
study MALARIA-055 PRI (110021).

Treatment allocation: follow-up of a randomized study (Randomization performed in 
the primary study MALARIA-055 PRI [110021] will be kept for this extension. 
Subjects will remain in the same group as the one of the primary study MALARIA-
055 PRI [110021]).

Blinding: open
Table 2
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
open
Epoch 002
open
Epoch 003
open

Sampling schedule: blood samples will be taken at annual intervals during the 
extension (maximum 3 blood samples).

Type of study: extension of other protocol(s) (MALARIA-055 PRI [110021]). Data 
of the MALARIA-076 study will be analyzed with those of the primary study 
MALARIA-055 PRI [110021]). Endpoints of the MALARIA-076 study are pooled 
with those of the primary study.

Data collection: electronic Case Report Form (eCRF).
 
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4.
CASE DEFINITION
4.1.
Clinical malaria
Table 3
Case definition for clinical malaria
1definition
Plasmodium falciparum asexual parasitemia > 5000 parasites/L 
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
OR
A case of malaria meeting the primary case definition of severe malaria (refer to Table 4)
2definition 1 Plasmodium 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
2definition 2 Plasmodium falciparum asexual parasitemia > 500 parasites/L
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
2definition 3 Plasmodium falciparum asexual parasitemia > 20 000 parasites/L
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
4.2.
Severe malaria
Severe malaria will be diagnosed based on symptoms and signs occurring at presentation 
or developing during admission according to the case definitions in Table 4.
Table 4
Primary case definition for severe malaria
Plasmodium falciparum asexual parasitemia > 5000 parasites/L 
AND with one or more marker of disease severity:
- Prostration.
- Respiratory distress.
- Blantyre score 2.
- Seizures 2 or more.
- Hypoglycemia < 2.2 mmol/L.
- Acidosis BE -10.0 mmol/L.
- Lactate 5.0 mmol/L.
- Anemia < 5.0 g/dL
AND without diagnosis of co-morbidity:
- Radiographically proven pneumonia.
- Meningitis on cerebrospinal fluid (CSF) examination.
- Positive blood culture
- Gastroenteritis with dehydration.
 
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Prostration is defined as, in an acutely sick child, the inability to perform previously-acquired motor function: in a child 
previously able to stand, inability to stand; in a child previously able to sit, inability to sit and in a very young child, 
inability to suck.
Respiratory distress is defined as lower chest wall indrawing or abnormally deep breathing.
2 or more seizures occurring in the total time period including 24 h prior to admission to the emergency room and the 
hospitalization.
Radiographically proven pneumonia is a consolidation or pleural effusion as defined by World Health Organization 
[WHO; 2001a] on a chest x-ray (CXR) taken within 72 h of admission (see APPENDIX D).
Meningitis on CSF examination is defined as white cells 50 x 106/L or positive culture of compatible organism or 
latex agglutination positive for Haemophilus influenzae type b, pneumococci or meningococci [Berkley, 2001].
Positive blood culture as defined by WHO [WHO, 1999] on a blood culture taken within 72 h of admission.
Gastroenteritis with dehydration is defined as a history of 3 or more loose or watery stools in previous 24 h and an 
observed watery stool with decreased skin turgor (> 2 seconds for skin to return following skin pinch).
Secondary case definitions of severe malaria are given in Table 5.
Table 5
Secondary case definition for severe malaria
2definition 1
“with co-morbidity”
Plasmodium falciparum asexual parasitemia > 5000 parasites/L
AND with one or more marker(s) of disease severity
2definition 2
“without a density threshold”
Plasmodium falciparum asexual parasitemia > 0
AND with one or more marker(s) of disease severity
AND without diagnosis of a co-morbidity
4.3.
Malaria hospitalization
Table 6
Case definitions for malaria hospitalization
Definition 1
A medical hospitalization with confirmed Plasmodium falciparum asexual parasitemia > 5000
parasites/L 
(excludes planned admissions for medical investigation/care or elective surgery and trauma)
Definition 2
A hospitalization for which, in the judgment of the principal investigator, Plasmodium falciparum
infection was the sole or a major contributing factor to the presentation
4.4.
Prevalent anemia
Table 7
Case definitions of prevalent anemia
Prevalent severe anemia
A documented hemoglobin < 5.0 g/dL identified at an annual visit
Prevalent moderate anemia
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4.5.
Prevalent parasitemia
Table 8
Case definitions for prevalent parasitemia
Prevalent parasitemia
A documented Plasmodium falciparum asexual parasite density > 0 identified at an annual 
visit
5.
STUDY COHORT
5.1.
Number of subjects/centers
This study will be conducted at multiple centers in malaria-endemic countries of sub-
Saharan Africa. Approximately 3000 to 4000 children who were vaccinated during the 
primary study MALARIA-055 PRI (110021) will be enrolled in the present study. Refer 
to Section 11.3 for the determination of sample size.
In the primary study (MALARIA-055 PRI [110021]), the first 200 subjects in each age 
category at each site had multiple blood samples to assess the immunological vaccine 
response. Subjects who previously belonged to the immunogenicity sub-cohort in the 
primary study and who consented to participate in this extension study will be again part 
of the immunogenicity sub-cohort in the present study.
Table 9
Sub-cohorts
Sub-cohort name
Description
Estimated number of subjects
Immunogenicity
Blood sample for immunological vaccine response (anti-
CS antibodies)
1200*
* The immunogenicity sub-cohort will comprise subjects that were included in the immunogenicity sub-cohort of the 
primary study (MALARIA-055 PRI [110021]) and who were enrolled in this extension study. There will be a maximum 
of 200 subjects from each age category in each site in the immunogenicity sub-cohort. Assuming 4 sites and a 25% 
dropout rate of the primary study (MALARIA-055 PRI [110021]).
5.2.
Overview of the recruitment plan
In the participating sites, the parent(s)/ Legally Acceptable Representative(s) (LAR[s]) of 
the subjects who fulfill inclusion/exclusion criteria described in Section 5.3, will be 
contacted for this extension study.

If subjects’ parent(s)/LAR(s) agree to let their child participate in the MALARIA-076 
study, they will need to sign an Informed Consent Form (ICF) before or at the start of 
the screening visit of the MALARIA-076 (Visit 39) and their child will be enrolled in 
this study. Once the child is enrolled in this study, a retrospective collection of 
efficacy and safety data will be performed as stated in Section 6.6.10.

For subjects who will not be enrolled in the study, the following reasons for non-
participation will be collected:

Parent(s)/LAR(s) do not agree to let their child participate in the MALARIA-
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
Subjects are lost to follow-up.

Subject died before the start of MALARIA-076. In addition, these subjects’ 
parent(s)/LAR(s) will be asked if for the purpose of safety monitoring of the 
vaccine, they allow reporting of the event leading to the death of their child in 
the MALARIA-076 database. If the parent(s)/LAR(s) agree, they will be asked 
to sign an ICF.
5.3.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subjects’ parent(s)/LAR(s) who, in the opinion of the investigator, can and will 
comply with the requirements of the protocol (e.g. return for follow-up visits).

Subjects who were enrolled and who received at least one vaccine dose in the 
primary study MALARIA-055 PRI (110021) and who did not withdraw consent 
(except those who moved away from the area) during the primary study MALARIA-
055 PRI (110021).

Written informed consent obtained from the parent(s)/LAR(s) of the subject.
5.4.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care
Please refer to the glossary of terms for the definition of child in care.

Use of any investigational or non-registered product (drug or vaccine) or planned use 
during the study period.
 
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6.
CONDUCT OF THE STUDY
6.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the International Conference on 
Harmonization (ICH) Guideline for Good Clinical Practice (GCP), all applicable subject 
privacy requirements and the guiding principles of the Declaration of Helsinki. 
The study has been designed and will be conducted in accordance with the ICH 
Harmonized Tripartite Guideline for clinical investigation of medicinal products in the 
pediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favorable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favorable opinion/approval of study protocol and any subsequent amendments.

Subject’s parent(s)/LAR(s) informed consent, as appropriate.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written informed consent, or witnessed, thumb printed informed consent
must be obtained from each subject’s parent(s)/LAR(s), as appropriate, prior to 
participation in the study.
GSK Biologicals will prepare a model ICF which will embody the ICH GCP and GSK 
Biologicals required elements. While it is strongly recommended that this model ICF is to 
be followed as closely as possible, the informed consent requirements given in this 
document are not intended to pre-empt any local regulations which require additional 
information to be disclosed for informed consent to be legally effective. Clinical 
judgment, local regulations and requirements should guide the final structure and content 
of the local version of the ICF. 
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
 
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6.2.
Subject identification and randomization of treatment
6.2.1.
Subject identification
Subject identification numbers will be the same as the ones assigned in the primary study 
MALARIA-055 PRI (110021). Study subjects will receive study identification cards with
their picture and subject number.
6.2.2.
Allocation of subjects to assay subsets 
Serum samples taken at annual clinic visit (see Section 6.5) will be tested for anti-CS 
antibody on an immunogenicity sub-cohort (see Table 9). The immunogenicity sub-
cohort will comprise subjects that were included in the immunogenicity sub-cohort of the 
primary study (MALARIA-055 PRI [110021]) and who were enrolled in this extension 
study. There will be a maximum of 200 subjects from each age category in each site in 
the immunogenicity sub-cohort.
6.3.
Method of blinding
This study is an open-label study.
6.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM provides the 
investigator and the site personnel with administrative and detailed technical information 
that does not impact the safety of the subjects.
 
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6.5.
Outline of study procedures
Table 10
List of study procedures
Epoch
Epoch 001
Epoch 002
Epoch 003
Type of contact
Screening
Visit (Visit 
39)
Visit 
401
Visit 
41
Visit 
421
Visit 
43
Visit 
441
Visit 
45
Timepoints
Day 0
Within 
30 
days
before 
Year 1
Year 
1
Within 
30 
days 
before 
Year 2
Year 
2
Within 
30 
days 
before 
Year 3
Year 
3
Recording reasons for non-participation
●
Informed consent2
●
Issuing identification card
O
Check identification card
O
O
O
O
O
O
Check inclusion/exclusion criteria
●
Collect demographic data3
●
Physical examination
O
O
O
O
Anthropometry4
●
●
●
●
Screening conclusion
●
Documentation of bednets and indoor residual spraying5
●
●
●
Retrospective collection of safety and efficacy data since the 
last contact of the primary study (MALARIA-055)
●
Surveillance for clinical malaria and severe malaria10
●6
●6
●6
Surveillance for safety: recording of SAEs7,11
●6
●6
●6
Blood sampling for anti-CS antibodies measurement 
(approximately 0.5 mL)8
●
●
●
Blood sampling for parasite density measurement9 and 
hemoglobin level (approximately 0.5 mL)
●
●
●
Interim analysis
O
O
Final analysis
O
Study Conclusion
●
1 Field worker visits
2 ICF to be signed by all subjects’ parents/LARs who consent to let their child participate in this study and by subjects’ 
parents/LARs who consent to allow reporting of the event leading to the death of their child before the start of 
MALARIA-076 in the MALARIA-076 database.
3Demographic data include age and gender
4 Anthropometry consists of height, weight and mid upper arm circumference
5Use of bednets and indoor residual spraying will be checked between 1 and 30 days before the annual visits (see 
APPENDIX A).
6 Retrospective collection since the last visit.
7SAEs: fatalities, related SAEs (related to vaccine administration in the primary study MALARIA-055 PRI [110021] and 
to study participation), malaria hospitalization, pIMDs, and meningitis (see Section 9).
8 Only for subjects that were included in the immunogenicity sub-cohort of the primary study (MALARIA-055 PRI 
[110021]) and who were enrolled in this extension study. There will be a maximum of 200 subjects from each age 
category in each site in the immunogenicity sub-cohort.
9 A volume of 16 L is required for this test.
10Note that passive surveillance for clinical and severe malaria is ongoing throughout the study (see Section 6.6.11) 
11 Note that passive surveillance for safety is ongoing throughout the study (see Section 6.6.12)
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
 
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Table 11
Intervals between study visits
Interval
Timing of visit1
Allowed interval2
Screening Visit (Visit 39)3
Study start at the center
Not applicable
Visit 40 (Field Worker Visit)4
November 2014
October 2014 to December 2014
Visit 41 (Annual Visit)
December 2014
November 2014 to January 2015
Visit 42 (Field Worker Visit)4
November 2015
October 2015 to December 2015
Visit 43 (Annual Visit)
December 2015
November 2015 to January 2016
Visit 44 (Field Worker Visit)4
November 2016
October 2016 to December 2016
Visit 45 (Annual Visit)
December 2016
November 2016 to January 2017
1 Whenever possible the investigator should arrange study visits within this interval.
2 Subjects will not be eligible for inclusion in the According-to-Protocol (ATP) population for analysis of immunogenicity 
if they make the study visit outside this interval.
3 Visit 39 should be performed as soon as the center is initiated. However, if the timing of Visit 39 is delayed beyond 
the allowed interval for Visit 40 or Visit 41, then those visits will be skipped.
4Field Worker Visits should be conducted between 1 and 30 days before Annual Visits.
6.6.
Detailed description of study procedures
6.6.1.
Recording reasons for non-participation
For subjects who will not be enrolled in the study, the following reasons for non-
participation will be collected:

Parent(s)/LAR(s) do not agree to let their child participate in the MALARIA-076 
study.

Subjects are lost to follow-up.

Subject died between the end of the primary study (MALARIA-055 PRI [110021]) 
and the beginning of MALARIA-076 (see Section 5.2).
6.6.2.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject’s parent(s)/LAR(s) 
must be obtained before study participation. Refer to Section 6.1 for the requirements on
how to obtain informed consent.
6.6.3.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 5.3 and 5.4 before 
enrolment. 
6.6.4.
Collect demographic data
Record demographic data such as date of birth and gender in the subject’s eCRF.
 
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6.6.5.
Physical examination
Perform physical examination of the subject, if deemed necessary by the investigator (at 
the screening visit [Visit 39] and at annual clinic visits [Visits 41, 43 and 45]).
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
6.6.6.
Anthropometry
Perform anthropometric measurements of the subject (height, weight and mid upper arm 
circumference) at the screening visit (Visit 39) and at annual clinic visits (Visits 41, 43 
and 45). Collected information needs to be recorded in the eCRF.
The methodologies used for height, weight and mid upper arm circumference 
measurements have been adapted from Cogill [Cogill, 2003] and are based on guidelines 
of the United Nations [United Nations, 1986]. These procedures are fully described in the 
SPM.
6.6.7.
Issuing subject identification card
At the screening visit (Visit 39), take a picture of the subject to make an identification 
card with subject’s picture and number. Give this identification card to the subject’s 
parent(s)/LAR(s). 
At each subsequent visits (Visit 40 to 45), check this identification card.
6.6.8.
Screening conclusion
Screening conclusion will be completed in the eCRF for all subjects who participate to 
this extension study.
6.6.9.
Documentation of bednets and indoor residual spraying
Bednets usage and indoor residual spraying (IRS) will be assessed during field worker 
visits (Visits 40, 42 and 44) at subjects’ house between 1 and 30 days before the annual 
visits.
The parent(s)/LAR(s) will be asked if the house has been sprayed with a residual 
insecticide and if so when (yes/no). In addition it will be asked if the child sleeps under a 
bednet and whether or not the net is impregnated with insecticide.
The response to these questions will be documented in the eCRF.
These procedures are fully described in APPENDIX A.
 
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6.6.10.
Retrospective collection of efficacy and safety data
During Visit 39, all subjects for whom the parents/LARs gave their consent to let their 
child participate in this study, will have a retrospective collection of efficacy data (cases 
of clinical, severe or malaria hospitalization) and safety data (SAEs: fatalities, related 
SAEs [related to vaccine administration in the primary study MALARIA-055 PRI and to 
study participation], malaria hospitalization, pIMD, and meningitis) since their last 
contact in the primary study MALARIA-055 PRI (110021). Retrospective data will be 
collected, for example by questioning subject's parents/LARs and by reviewing available 
medical records. Collected information needs to be recorded in the eCRF.
For subjects who will not be enrolled in the study, because they died before the start of 
MALARIA-076, subjects’ parent(s)/LAR(s) will be asked if they consent to allow 
reporting of the event leading to the death of their child in the MALARIA-076 database. 
If the parent(s)/LAR(s) agree, they will be asked to sign an ICF. This event will be 
reported as SAE in the MALARIA-076 database and any available information 
captured in the inpatient module of the eCRF or any other specific section as 
applicable.
(Amended 15 April 2015)
6.6.11.
Surveillance for efficacy
Retrospective data since the previous visit will be collected by questioning subject's 
parents/LARs and by reviewing available medical record during annual clinic visit (Visits 
41, 43, and 45). Collected information needs to be recorded in the eCRF. For clarity, if 
available the following data will be collected: history of fever, temperature, parasite 
density, treatment administered, any clinical diagnoses of malaria, rapid diagnostic test 
(RDT) and blood slides read to guide treatment at the time of presentation will be 
captured.
Passive surveillance for clinical malaria
All subjects presenting to health facilities in the study area will be evaluated as potential 
cases of clinical malaria. A blood sample for the evaluation of malaria parasites will be 
taken for all children who are reported to have had a fever within 24 hours of presentation 
or have a measured axillary temperature of 37.5C.
Data points that will be captured in the eCRF for all cases of suspected clinical malaria 
are: history of fever; temperature; parasite density; treatment administered. To 
supplement this information, any clinical diagnoses of malaria, RDT and blood slides 
read to guide treatment at the time of presentation will be captured.
Note that the data on all subjects investigated for malaria will be captured in the eCRF 
regardless of whether the case was confirmed.
 
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Passive surveillance for severe malaria
All subjects presenting for admission through the outpatient and emergency departments 
of hospitals in the study areas will be evaluated as potential cases of severe malaria 
following an algorithm (see APPENDIX B).
During the hospitalization, the subject's course will be monitored to capture the signs and 
blood parameters indicative of severe malaria. If the subject's condition changes from 
admission and he/she meets one of the criteria for additional investigations, these will be 
performed.
Harmonization of case evaluation across centers will be assured by training of clinicians 
in the assessment of clinical signs and the standardization of equipment and processes 
used for laboratory investigations. On all admissions, data will be captured to support the 
endpoints of this study. In addition RDT and blood slides read to guide treatment at the 
time of presentation will be captured.
Note that measurement of creatinine and total bilirubin were not specified per algorithm. 
If performed for case management these will be captured in the eCRF.
Prevalent parasitemia and anemia
Evaluation of prevalent parasitemia (see APPENDIX C) and prevalent anemia will be 
performed annually (see also Section 6.6.13.2, for the sampling method).
All slides will be made in duplicate and stored locally in the clinical center. For each 
slide, the parasite density will be determined, independently by two readers and in the 
case of non-concordance a third read will be carried out (see APPENDIX C).
Children who are symptomatic will be assessed by a clinician and managed as 
appropriate. Collected information needs to be recorded in the eCRF.
(Amended 15 April 2015)
6.6.12.
Passive surveillance for safety
Retrospective data since the previous visit will be collected by questioning subject's 
parents/LARs and by reviewing available medical record during annual clinic visit (Visits 
41, 43, and 45). Collected information needs to be recorded in the eCRF.
The following SAEs: fatalities, related SAEs (related to vaccine administration in the 
primary study MALARIA-055 PRI [110021] and to study participation), malaria 
hospitalization, pIMDs, and meningitis will be collected for all subjects presenting to 
health facilities in the study area and through annual clinic visits.
Verbal autopsy will be performed on all cases of mortality occurring outside hospital and 
where it adds value to ascribe the cause of a fatal event. The questionnaire used will be 
based on the INDEPTH standard and adapted to be locally appropriate [WHO, 2007]. For 
children who died before study start and whose parents consent, the death will be 
 
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reported as an SAE. If there is uncertainty of cause of death based on the review of 
available medical records, a verbal autopsy should be performed.
Refer to Section 9.2 for procedures for the investigator to record SAEs and pIMDs. Refer 
to Section 9.3 for guidelines on how to submit SAE and pIMD reports to GSK
Biologicals.
The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subjects manifest any signs or symptoms they perceive as serious.
6.6.13.
Sampling
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
6.6.13.1.
Blood sampling for surveillance of immunogenicity
Blood samples will be taken during annual clinic visits (Visits 41, 43 and 45).
A volume of at least 0.5 mL of whole blood (to provide at least 200 L of serum) for 
anti-CS antibodies measurement should be drawn from all subjects who were previously 
included in the immunogenicity sub-cohort in the primary study MALARIA-055 PRI 
(110021). After centrifugation, serum samples should be kept at –20°C/ –4°F or below 
until shipment. Refer to the SPM for more details on sample storage conditions.
6.6.13.2.
Blood sampling for prevalent parasitemia and anemia
Blood samples will be taken during annual clinic visits (Visits 41, 43 and 45).
A volume of at least 0.5 mL of whole blood for parasite density (16 L needed for this 
test) and haemoglobin level measurement should be drawn from all subjects.
For prevalent parasitemia one out of two blood slide reading methods which were 
approved by GSK Biologicals and collaborating partners and contributors should be used.
The first method counts parasites relative to a concomitantly measured white blood cell 
count [Greenwood, 1991] and the second method counts parasites relative to a fixed 
measured blood volume [Planche, 2001]. These two methodologies are well established 
and used as gold-standards in the field. Slides are always taken in duplicate.
These procedures are fully described in the APPENDIX C.
6.6.14.
Study conclusion
The investigator will:

review collected data to ensure accuracy and completeness.

complete the Study Conclusion screen in the eCRF.
 
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6.7.
Biological sample handling and analysis
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment).
Samples will not be labeled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number). 
Under the following circumstances, additional testing on the samples may be performed 
by GSK Biologicals outside the scope of this protocol:

Collected samples may be used in other assays, for test improvement or development 
of analytical methods related to the study vaccine(s) and its constituents or the 
disease under study. 

Collected samples may be used for purposes related to the quality assurance of data 
generated linked to the study vaccine(s) or the disease under study, such as for 
maintenance of assays described in this protocol and comparison between analytical 
methods and/or laboratories.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s). 
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
6.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 11.4 for the definition of 
study cohorts/ data sets to be analyzed). The investigator must ensure that his/her 
personnel and the laboratory(ies) under his/her supervision comply with this requirement. 
However, when GSK Biologicals does not provide material for collecting and storing 
clinical samples, appropriate materials from the investigator’s site must be used. Refer to 
the Module on Clinical Trial Supplies in the SPM.
 
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6.7.2.
Biological samples
The different biological samples collected in the study, the quantity needed, the unit and 
the timepoints are described in Table 12.
Table 12
Biological samples
Sample type
Quantity Unit
Timepoint
Sub-cohort Name*
Blood for anti-CS antibodies
0.5
ml
Visit 41
Visit 43
Visit 45
Immunogenicity sub-cohort
Blood sampling for parasite density and hemoglobin level
0.5
ml
Visit 41
Visit 43
Visit 45
All subjects
* Refer to Section 5.1 for sub-cohort description
6.7.3.
Laboratory assays
Please refer to APPENDIX E for a detailed description of the assays performed in the 
study. Please refer to APPENDIX F for the address of the clinical laboratories used for 
sample analysis.
Serological assays for the determination of anti-CS antibodies will be performed by 
enzyme-linked immunosorbent assay (ELISA) at a laboratory designated by GSK 
Biologicals using standardized and validated procedures (refer to Table 13).
Table 13
Humoral Immunity (Antibody determination)
System
Component
Method
Kit / 
Manufacturer
Unit
Cut-
off
Laboratory
Serum
Plasmodium 
falciparum.Circumsporozoite 
Protein.R32LR Ab.IgG
ELISA
NA
EU/ml
0.5
CEVAC*
* Centre for Vaccinology, Ghent University, Belgium (Refer to APPENDIX F for the laboratory address).
CS = Circumsporozoite protein of Plasmodium falciparum; ELISA: enzyme-linked immunosorbent assay; EU/mL: 
ELISA units per milliliter; NA: not applicable.
6.7.4.
Biological samples evaluation
6.7.4.1.
Immunological read-outs
The plan for immunogenicity testing on samples obtained is shown in Table 14.
Table 14
Immunological read-outs
Blood sampling timepoint
Estimated No. subjects
Component
Type of contact and timepoint
Sampling timepoint
Visit 41
Year 1
1200
anti-CS antibodies
Visit 43
Year 2
1200
anti-CS antibodies
Visit 45
Year 3
1200
anti-CS antibodies
 
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6.7.4.2.
Parasitemia and anemia
The plan for parasitemia and anemia testing on samples obtained is shown in Table 15.
Table 15
Parasitology and hemoglobin read-outs
Blood sampling timepoint
Estimated No. subjects
Component
Type of contact and timepoint
Sampling timepoint
Visit 41
Year 1
3600
Parasite density
Hemoglobin
Visit 43
Year 2
3600
Parasite density
Hemoglobin
Visit 45
Year 3
3600
Parasite density
Hemoglobin
Additionally, blood samples for parasitology will be taken at each presentation to a health 
facility with a febrile illness (documented or history of fever; refer to Section 6.6.11).
6.7.5.
Immunological correlates of protection
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigen (CS) used in the candidate vaccine.
7.
STUDY VACCINE(S) AND ADMINISTRATION
This section is not applicable since no vaccine is administered in this study. Vaccines
were administered in the study MALARIA-055 PRI (110021) and the current study is a 
long-term follow-up of the MALARIA-055 PRI study.
8.
HEALTH ECONOMICS
Not applicable.
9.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or SAE as 
provided in this protocol. 
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subject manifest any signs or symptoms they perceive as serious.
 
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9.1.
Safety definitions
9.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
Examples of an AE include:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after investigational vaccine(s)/product(s) 
administration even though they may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational vaccine(s)/product(s) or a concurrent medication (overdose per se 
should not be reported as an AE/SAE).

Signs, symptoms temporally associated with vaccine administration.

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen).
Examples of an AE DO NOT include:

Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF.
 
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9.1.2.
Definition of a serious adverse event 
A serious adverse event is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalization or prolongation of existing hospitalization,
Note: In general, hospitalization signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalization are also considered AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity.
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza like illness, and accidental trauma (e.g. sprained ankle) 
which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization.
9.1.3.
Clinical laboratory parameters and other abnormal assessments 
qualifying as serious adverse events 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
hematology, urinalysis) or other abnormal assessments that are judged by the investigator 
to be clinically significant will be recorded as SAE if they meet the definition of an SAE 
(refer to Section 9.1.2). Clinically significant abnormal laboratory findings or other 
 
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abnormal assessments that are present at baseline and significantly worsen following the 
start of the study will also be reported as SAEs.
The investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
9.1.4.
Adverse events of specific interest
All adverse events of specific interest described below will be reported as SAEs.
9.1.4.1.
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. AEs that need to be recorded and reported as pIMDs include those listed in 
Table 16.
However, the investigator will exercise his/her medical and scientific judgment in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.
 
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Table 16
List of potential immune-mediated diseases
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve disorders, including 
paralyses/paresis (e.g. Bell’s palsy) 

Optic neuritis

Multiple sclerosis

Transverse myelitis

Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants

Acute disseminated encephalomyelitis, 
including site specific variants: e.g. 
non-infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculomyelitis

Myasthenia gravis, including Lambert-
Eaton myasthenic syndrome 

Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with 
monoclonal gammopathy).

Narcolepsy

Systemic lupus erythematosus 

Scleroderma, including diffuse 
systemic form and CREST 
syndrome

Systemic sclerosis

Dermatomyositis 

Polymyositis 

Antisynthetase syndrome

Rheumatoid arthritis, 

Juvenile chronic arthritis, 
(including Still’s disease)

Polymyalgia rheumatic

Spondyloarthritis, including 
ankylosing spondylitis, 
reactive arthritis (Reiter's 
Syndrome) and 
undifferentiated 
spondyloarthritis 

Psoriatic arthropathy

Relapsing polychondritis

Mixed connective tissue 
disorder

Psoriasis

Vitiligo

Erythema nodosum

Autoimmune bullous 
skin diseases 
(including pemphigus, 
pemphigoid and 
dermatitis 
herpetiformis)

Cutaneous lupus 
erythematosus

Alopecia areata

Lichen planus

Sweet’s syndrome

Morphoea
Liver disorders
Gastrointestinal disorders
Metabolic diseases

Autoimmune hepatitis

Primary biliary cirrhosis

Primary sclerosing 
cholangitis

Autoimmune cholangitis

Crohn’s disease 

Ulcerative colitis 

Ulcerative proctitis 

Celiac disease

Autoimmune thyroiditis (including 
Hashimoto thyroiditis)

Grave's or Basedow’s disease

Diabetes mellitus type I

Addison’s disease
Vasculitides
Others

Large vessels vasculitis including: giant 
cell arteritis such as Takayasu's arteritis 
and temporal arteritis. 

Medium sized and/or small vessels 
vasculitis including: polyarteritis nodosa, 
Kawasaki's disease, microscopic 
polyangiitis, Wegener's granulomatosis, 
Churg–Strauss syndrome (allergic 
granulomatous angiitis), Buerger’s 
disease (thromboangiitis obliterans), 
necrotizing vasculitis and anti-neutrophil 
cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-
Schonlein purpura, Behcet's syndrome, 
leukocytoclastic vasculitis.

Autoimmune hemolytic anemia

Autoimmune thrombocytopenia

Antiphospholipid syndrome

Pernicious anemia

Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous 
glomerulonephritis, membranoproliferative 
glomerulonephritis, and mesangioproliferative 
glomerulonephritis)

Uveitis

Autoimmune myocarditis/cardiomyopathy

Sarcoidosis

Stevens-johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary fibrosis

Goodpasture syndrome

Raynaud’s phenomenon
When there is enough evidence to make any of the above diagnoses, the event must be 
reported as a pIMD. Regardless of it being considered an AE or an SAE, it should be 
reported per the SAE reporting rules.
 
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In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start.
9.1.4.2.
Meningitis
For the further evaluation of the safety signal of meningitis all the cases occurring during 
the study will be reported as SAE and medical documentation of the events will be 
reported in appropriate targeted follow-up forms included in the eCRF.
9.2.
Detecting and recording serious adverse events
SAEs that will be reported under this protocol are: those that are fatal, those that are 
related to vaccine administration in the primary study MALARIA-055 PRI (110021), 
those that are related to study participation, malaria hospitalization, pIMDs, and
meningitis. SAEs will be captured at the health facilities in the study area or by direct 
questioning at the Annual Visits (Visits 41, 43 and 45).
9.2.1.
Time period for detecting and recording serious adverse events
The time period for collecting and recording SAEs will begin at the first study visit (i.e. 
Visit 39) and will end at the last study visit (i.e. Visit 45) for each subject. See Section 
9.3 for instructions on reporting of SAEs.
In addition, at Visit 39, a retrospective collection of SAEs (fatalities, related SAEs, 
malaria hospitalization, pIMDs, and meningitis) since the last study contact of the 
primary study (MALARIA-055 PRI [110021]) will be performed.
In addition to the above-mentioned reporting requirements and in order to fulfill
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study.
The time period for collecting and recording of pIMDs will begin at the first study visit 
(i.e. Visit 39) and will end at the last study visit (i.e. Visit 45). See section 9.3 for 
instructions on reporting of pIMDs.
An overview of the protocol-required reporting periods for SAEs (fatalities, related 
SAEs, malaria hospitalization, pIMDs, and meningitis) is given in Table 17.
 
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Table 17
Reporting periods for serious adverse events
Event
From Visit 39* to Visit 45
Fatalities
Related SAEs
Malaria hospitalization
pIMDs
Meningitis
* A retrospective collection of safety data (SAEs: fatalities, related SAEs [related to vaccine administration in the 
primary study MALARIA-055 PRI and to study participation], malaria hospitalization, pIMD, and meningitis) since the 
last contact in the primary study MALARIA-055 PRI (110021) will be performed at Visit 39.
Additional, safety data could also be collected as required to support the further 
evaluation of a safety signal.
9.2.2.
Post-Study serious adverse events
A post-study SAE is defined as any event that occurs outside of the SAE reporting period 
defined in Table 17. Investigators are not obligated to actively seek SAEs in former study 
participants. However, if the investigator learns of any SAE at any time after a subject 
has been discharged from the study, and he/she considers the event reasonably related to 
the investigational vaccine/product, the investigator will promptly notify the Study 
Contact for Reporting SAEs.
9.2.3.
Evaluation of serious adverse events
9.2.3.1.
Active questioning to detect serious adverse events
As a consistent method of collecting SAEs, the subject or the subject’s parent(s)/LAR(s)
should be asked a non-leading question such as:
‘Has your child acted differently or felt different in any way since receiving the vaccine 
or since the last visit?’
When an SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an SAE 
in the eCRF. The investigator is not allowed to send photocopies of the subject’s medical 
records to GSK Biologicals instead of appropriately completing the eCRF. However, 
there may be instances when copies of medical records for certain cases are requested by 
 
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GSK Biologicals. In this instance, all subject identifiers will be blinded on the copies of 
the medical records prior to submission to GSK Biologicals.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the SAE and not the individual signs/symptoms.
9.2.3.2.
Assessment of adverse events
9.2.3.2.1.
Assessment of intensity
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgment.
The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities (in a young 
child, such an AE would, for example, prevent attendance at 
school/kindergarten/a day-care center and would cause the 
parent(s)/LAR(s) to seek medical advice.
Grade 3 is a category used for rating the intensity of an event; and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 9.1.2.
9.2.3.2.2.
Assessment of causality
The definitions for ‘NO’ and ‘YES’ have been written in such a way that all events that 
have been attributed a ‘NO’ can be pooled with events which in the primary vaccination 
study were determined to be ‘not related’ or ‘unlikely to be related’ to vaccination. Those 
events that are attributed a ‘YES’ can be pooled with those events that in the past were 
determined to have a ‘suspected’ or ‘probable’ relationship to vaccination in the primary 
vaccination study.
The investigator is obligated to assess the relationship between investigational 
vaccine/product and the occurrence of each SAE. The investigator will use clinical 
judgment to determine the relationship. Alternative plausible causes, such as natural 
history of the underlying diseases, concomitant therapy, other risk factors, and the 
temporal relationship of the event to the investigational vaccine/product will be 
considered and investigated. The investigator will also consult the IB to determine his/her 
assessment.
 
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There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the SAE report to GSK Biologicals. The investigator may change 
his/her opinion of causality in light of follow-up information and update the SAE 
information accordingly. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements.
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of SAEs to the individual vaccines administered. The 
investigator should, therefore, assess whether the SAE could be causally related to 
vaccination rather than to the individual vaccines.
Causality of SAEs should be assessed by the investigator using the following question:
Is there a reasonable possibility that the SAE may have been caused by the 
investigational vaccine/product?
YES
:
There is a reasonable possibility that the vaccine(s) contributed to 
the SAE. 
NO
:
There is no reasonable possibility that the SAE is causally related 
to the administration of the study vaccine(s). There are other, more 
likely causes and administration of the study vaccine(s) is not 
suspected to have contributed to the SAE.
If an event meets the criteria to be determined as ‘serious’ (see Section 9.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccine(s), if applicable.

Erroneous administration.

Other cause (specify).
 
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9.2.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
9.2.3.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in in the 
eCRF.
9.3.
Reporting of serious adverse events and other events
9.3.1.
Prompt reporting of serious adverse events and other events to 
GSK Biologicals
SAEs that occur in the time period defined in Section 9.2 will be reported promptly to 
GSK within the timeframes described in Table 18, once the investigator determines that 
the event meets the protocol definition of a SAE.
pIMDs that occur in the time period defined in Section 9.2 will be reported promptly to 
GSK within the timeframes described in Table 18, once the investigator becomes aware 
of the pIMD.
Table 18
Timeframes for submitting serious adverse event and other events 
reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
Fatalities
24 hours*
electronic SAE report
24 hours*
electronic SAE report
Related SAEs**
24 hours*
electronic SAE report
24 hours*
electronic SAE report
Malaria hospitalization
24 hours*
electronic SAE report
24 hours*
electronic SAE report
pIMDs
24 hours*
electronic SAE report
24 hours*
electronic SAE report
Meningitis
24 hours*
electronic SAE report
24 hours*
electronic SAE report
* Timeframe allowed after receipt or awareness of the information.
** Related to vaccine administration in the primary study MALARIA-055 PRI (110021) and to study participation.
 
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9.3.2.
Contact information for reporting serious adverse events and 
other events to GSK Biologicals
Back-up Study Contact for Reporting SAEs
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: +
 or +
9.3.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic SAE report 
WITHIN 24 HOURS. The SAE report will always be completed as thoroughly as 
possible with all available details of the event. Even if the investigator does not have all 
information regarding a SAE, the report should still be completed within 24 hours. Once 
additional relevant information is received, the report should be updated WITHIN 24 
HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report.
9.3.3.1.
Back-up system in case the electronic SAE reporting system does not 
work
If the electronic SAE reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper SAE report and fax it to the GSK Biologicals 
Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic SAE reporting system is not 
working and NOT if the system is slow. As soon as the electronic SAE reporting system 
is working again, the investigator (or designate) must complete the electronic SAE report 
within 24 hours. The final valid information for regulatory reporting will be the 
information reported through the electronic SAE reporting system. 
9.3.4.
Reporting of pIMDs to GSK Biologicals
Once onset of a new pIMD or exacerbation of a pre-existing pIMD is diagnosed (serious
or non-serious) in a study subject, the investigator (or designate) must complete the 
information in the electronic SAE report WITHIN 24 HOURS after he/she becomes 
aware of the diagnosis. A field on the SAE report allows to specify that the event is a 
pIMD and whether it is serious or non-serious. The SAE report will always be completed 
as thoroughly as possible with all available details of the event, in accordance with the 
pIMD standard questionnaire provided. Even if the investigator does not have all 
information regarding a pIMD, the report should still be completed within 24 hours. Once 
additional relevant information is received, the report should be updated WITHIN 24 
HOURS.
 
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The investigator will always provide an assessment of causality at the time of the initial 
report.
Refer to Section 9.3.3.1 for back-up system in case the electronic SAE reporting system 
does not work.
9.3.5.
Updating of SAE and pIMD information after freezing of the 
subject’s eCRF
When additional SAE or pIMD information is received after freezing of the subject’s 
eCRF, new or updated information should be recorded on a paper report, with all changes 
signed and dated by the investigator. The updated report should be faxed to the GSK 
Biologicals Clinical Safety and Pharmacovigilance department or to the Study Contact 
for Reporting SAEs (refer to the Sponsor Information Sheet) within the designated 
reporting time frames specified in Table 18. 
9.3.6.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 9.3.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccine/product and unexpected. 
The purpose of the report is to fulfill specific regulatory and GCP requirements, 
regarding the product under investigation.
9.4.
Follow-up of serious adverse events
9.4.1.
Follow-up of serious adverse events 
9.4.1.1.
Follow-up during the study
After the initial SAE report, the investigator is required to proactively follow each subject 
and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 18).
All SAEs and pIMDs (serious or non-serious) documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the end of the study.
 
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9.4.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects with SAEs, pIMDs, or subjects withdrawn from the 
study as a result of an SAE, until the event has resolved, subsided, stabilized, 
disappeared, or until the event is otherwise explained, or the subject is lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper SAE report as 
applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the SAE. The investigator is obliged to assist. If a subject 
dies during participation in the study or during a recognized follow-up period, GSK 
Biologicals will be provided with any available post-mortem findings, including 
histopathology.
9.5.
Treatment of serious adverse events
Treatment of any SAE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an SAE should 
be recorded in the subject’s eCRF.
9.6.
Subject card
Subjects’ parent(s)/LAR(s) must be provided with the address and telephone number of 
the main contact for information about the clinical study.
The investigator (or designate) must therefore provide a “subject card” to each subject’s 
parent(s)/LAR(s). In an emergency situation this card serves to inform the responsible 
attending physician that the subject is in a clinical study and that relevant information 
may be obtained by contacting the investigator.
Subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times.
10.
SUBJECT COMPLETION AND WITHDRAWAL
10.1.
Subject completion
A subject who returns for the concluding visit/is available for the concluding contact 
foreseen in the protocol is considered to have completed the study.
10.2.
Subject withdrawal
Withdrawals will not be replaced.
 
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10.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit/was not available for the concluding contact 
foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subjects who do not return for
scheduled visits or follow-up.
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject’s parent(s) or LAR(s), or by the investigator, as well as which of the 
following possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because he/she/the subject’s parent(s) has 
withdrawn consent, the investigator will document the reason for withdrawal of consent, 
if specified by the subject, in the CRF.
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 9.4.1.2).
10.3.
Screen and baseline failures
Screening failures are defined as subjects who are withdrawn from the study after giving 
informed consent, but who do not meet the inclusion and exclusion criteria. The 
following information will be collected for screening failures: 

Informed consent.
 
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
Inclusion/exclusion criteria.

Demographic data.

SAEs related to study participation, to concomitant use of GSK products or any fatal 
SAEs.

Screening conclusion.
11.
STATISTICAL METHODS
11.1.
Primary endpoint

The occurrence of severe malaria meeting the primary case definition analyzed over 
the time period starting January 2014 until the end of the 3-year follow-up period 
(Visit 45).
11.2.
Secondary endpoints
11.2.1.
Efficacy endpoints

The occurrence of clinical malaria meeting the primary and secondary case 
definitions analyzed over the time period starting January 2014 until the end of the 3-
year follow-up period (Visit 45).

The occurrence of malaria hospitalization meeting each of the case definitions 
analyzed over the time period starting January 2014 until the end of the 3-year 
follow-up period (Visit 45).

The prevalence of parasitemia at 3 annual timepoints (Visit 41, 43 and 45), in both 
age categories (6-12 weeks and 5-17 months).

The prevalence of anemia at 3 annual timepoints (Visit 41, 43 and 45), in both age 
categories (6-12 weeks and 5-17 months).

The level of hemoglobin at 3 annual timepoints (Visit 41, 43 and 45), in both age 
categories (6-12 weeks and 5-17 months).

The occurrence of severe malaria meeting the primary and secondary case definitions 
analyzed over the time period starting at the beginning of the primary study 
(MALARIA-055 PRI [110021]; Visit 2) until the end of the follow-up period (Visit 
45), in both age categories (6-12 weeks and 5-17 months).

The occurrence of clinical malaria meeting the primary and secondary case 
definitions analyzed over the time period starting at the beginning of the primary 
study (MALARIA-055 PRI [110021]; Visit 2) until the end of the follow-up period 
(Visit 45), in both age categories (6-12 weeks and 5-17 months).

The occurrence of malaria hospitalization meeting all case definitions analyzed over 
the time period starting at the beginning of the primary study (MALARIA-055 PRI 
 
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[110021]; Visit 2) until the end of the follow-up period (Visit 45), in both age 
categories (6-12 weeks and 5-17 months).
11.2.2.
Safety endpoint

The occurrence of the following reported SAEs: fatalities, related SAEs (related to 
vaccine administration in the primary study MALARIA-055 PRI [110021] and to 
study participation), malaria hospitalization, pIMDs, and meningitis over the time 
period starting January 2014 until the end of the 3-year follow-up period (Visit 45).
11.2.3.
Immunogenicity endpoint

The annual anti-CS antibody titers (Visit 41, 43 and 45) for children of both age 
categories (6-12 weeks and 5-17 months).
11.3.
Power of the trial
The incidence of severe malaria and clinical malaria following a primary RTS,S/AS01E
vaccination given in 2 different age categories, with or without booster, across different 
transmission settings will be described. If 600 subjects per group in each category are 
enrolled with an attack rate of 24 episodes over 3 years in controls (4% over 3 years [or 
1.3% per year]) of severe malaria this sample size will allow to detect a 2-fold increase in 
the incidence of severe malaria between the recipients of primary vaccination only (R3C 
versus C3C) or primary vaccination + booster (R3R versus C3C) over the 3-year 
additional follow-up, with 80% power.
The projected attack rates of severe malaria have been calculated using attack rates over 
the first year of observation and the transmission intensity at each center and projected 
according to the expected variations over time and by transmission intensity as described 
by Carneiro [Carneiro, 2010].
11.4.
Study populations
11.4.1.
Modified Intention-to-Treat (ITT) population
The modified Intention-to-Treat (ITT) population will include all subjects that consented 
to the trial. The analyses on the modified ITT population will be performed per treatment 
assignment.
11.4.2.
According-to-Protocol population for efficacy
The According-to-Protocol (ATP) population for efficacy will include all subjects 
included in the ITT who were in the ATP population for efficacy of the primary study 
(MALARIA-055 PRI) and who have follow-up data available in the current study.
 
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11.4.3.
According-to-Protocol population for immunogenicity
The ATP population for immunogenicity will include all subjects who were in the ATP 
population for immunogenicity of the primary study (MALARIA-055 PRI) and that 
attended all annual follow-up visits within specified intervals.
11.5.
Derived and transformed data
The cut-off of the anti-CS assay is 0.5 EU/mL (see Section 6.7.3). The Geometric 
Mean Titer (GMT) calculations are performed by taking the anti-log of the mean of the 
log transformations (base 10). Antibody titers below the cut-off of the assay will be given 
an arbitrary value of half the cut-off for the purpose of GMT calculation. All available 
immunogenicity data will be analyzed. Missing data will not be imputed.
11.6.
Analysis of demographics
For both age categories (6-12 weeks and 5-17 months), demographic characteristics (age 
and gender) will be tabulated per study group.
For both age categories, the distribution of subjects enrolled among the study sites will be 
tabulated as a whole and per study group.
11.7.
Analysis of malaria disease incidence
All analyses will be performed on the ATP population for efficacy and modified ITT 
population.
VE will be calculated on the entire follow-up period. Incidence comparison, using the 
same formula and analytic methodology will be calculated for time period breakdown.
Disease incidence will be estimated over the following time-period:
i.
Over the 3-year extension period.
ii.
Over the complete time at risk (including primary study [MALARIA-055 PRI] and 
follow-up).
iii. By yearly and 6-monthly breakdown periods covering the 3-year period.
11.7.1.
Clinical malaria
For both age categories (6-12 weeks and 5-17 months), VE/ incidence comparison 
against all episodes of clinical malaria will be estimated as 1-incidence ratio (IR; total 
number of events/follow-up time in the RTS,S/AS01E groups [R3R/R3C] over the total 
number of events/follow-up time in the control group [C3C]) calculated by negative 
binomial regression allowing for interdependence between episodes within the same 
subject (mixed model with over-dispersion parameter estimated from the random effect) 
and will be presented together with 95% CI and p-values calculated from this model.
Results will be analyzed per site and overall.
 
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For both age categories (6-12 weeks and 5-17 months), VE against first or only episodes 
of clinical malaria will be estimated as 1-hazard ratio (HR; log survival in the 
RTS,S/AS01E groups [R3R/R3C] over log survival in the control group [C3C]) 
calculated by Cox regression models and will be presented together with 95% CI and p-
values (likelihood ratio test). Results will be analyzed per site and overall.
Schoenfeld residuals and models with time-varying covariates will be evaluated on Cox 
models on first or only episodes and including multiple episodes of clinical malaria for 
each site and overall.
11.7.2.
Severe malaria and malaria hospitalization
For both age categories (6-12 weeks and 5-17 months), severe malaria and malaria 
hospitalization will be analyzed by the proportion of children affected. VE will be 
estimated as 1-the risk ratio (RR; proportion of subjects reporting events in the 
RTS,S/AS01E groups [R3R/R3C] over the proportion in controls [C3C]) over the entire 
follow-up period, and will be presented together with 95% CIs and p-values. Results will 
be analyzed per site and overall.
11.7.3.
Vaccine efficacy against prevalent parasitemia and prevalent 
anemia
For both age categories (6-12 weeks and 5-17 months), VE against prevalent endpoints 
(parasitemia, moderate and severe anemia) assessed annually will be estimated as 1-RR 
where RR is the risk ratio (proportion of subjects reporting events in the RTS,S/AS01E
groups [R3R/R3C] over the proportion in controls [C3C]) and will be presented together 
with 95% CIs and p-values. Results will be analyzed per site and overall. The geometric 
mean parasite density and arithmetic mean hemoglobin level will be calculated per site 
and overall. The effect of the group will be evaluated using the t-test.
11.7.4.
Vaccine impact
For both age categories (6-12 weeks and 5-17 months), each site and overall, the number 
of cases of clinical malaria, severe malaria, and malaria hospitalizations averted will be 
calculated (difference between incidences, expressed per 1000 population vaccinated) for 
each 6-monthly time period and totaled over the entire follow-up time. Graphical
presentations will be generated showing the cumulative number of averted cases over 
time (breakdown of follow-up period).
To evaluate effect on growth, the height for age, weight for age and mid arm 
circumference z-scores and absolute height measurements annually will be tabulated for 
each site and overall and the mean values will be compared between study groups using a 
t-test.
 
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11.8.
Analysis of immunogenicity
All analyses will be performed on the ATP population immunogenicity and modified ITT 
population.
For both age categories (6-12 weeks and 5-17 months), the percentage of subjects with 
seropositive levels of anti-CS (proportion of subjects with anti-CS antibody titers 0.5 
EU/mL) with 95% CI will be determined at each blood sampling timepoint. Antibody 
titers will be summarized by GMT with 95% CI at all timepoints at which serological 
samples are taken.
11.9.
Analysis of safety
The primary analysis will be performed on the modified ITT population.
For both age categories (6-12 weeks and 5-17 months), safety will be evaluated by 
examining SAEs (fatalities, related SAEs [related to vaccine administration in the 
primary study MALARIA-055 PRI and to study participation], malaria hospitalization, 
pIMDs, and meningitis) from study start (MALARIA-076). All safety analyses will be 
performed separately for both age categories.
The proportion of subjects with SAEs, classified by the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term level, will be tabulated by group with 
exact 95% CI.
11.10.
Interpretation of analyses
All analyses will be descriptive with respect to malaria disease incidence, safety and 
immunogenicity.
11.11.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
11.11.1.
Sequence of analyses
All analyses (including interim analyses) will be conducted on data as clean as possible.
Two interim analyses of efficacy, immunogenicity and safety data will be performed 
when all data up to and including the end of Year 1 (i.e. Visit 41) and end of Year 2 (i.e. 
Visit 43) will be available.
The final analysis of efficacy, immunogenicity and safety data will be performed when 
all data up to and including the end of the 3-year follow-up (i.e. Visit 45) will be 
available. Annual study reports will be written after each analyses.
 
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11.11.2.
Statistical considerations for interim analyses
Two interim analyses will be performed. As all analyses are descriptive, p-values will be 
informatory and not confirmatory. No alpha-adjustment will be planned.
12.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
12.1.
Case Report Form/Remote Data Entry instructions
Remote Data Entry (RDE), a validated computer application, will be used as the method 
for data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data.
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties.
12.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a RDE review and a Source Document 
 
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Verification (SDV). By SDV we understand verifying RDE entries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the RDE. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the RDE will serve as the source must be identified, agreed and 
documented in the source documentation agreement form. 
For RDE, the monitor will mark completed and approved screens at each visit.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
12.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures; otherwise, 
the minimum retention period will default to 15 years. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
 
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12.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
12.5.
Posting of information on publicly available clinical trial 
registers and publication policy
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within 12 months of the primary completion date for 
studies of authorized vaccines and 18 months for studies of non-authorized vaccines. 
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit.
12.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
13.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
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14.
REFERENCES
Aponte JJ, Menendez C, Schellenberg D, et al. Age interactions in the development of 
naturally acquired immunity to Plasmodium falciparum and its clinical presentation. 
PLOS med. 2007: 4(7); 1259-1267.
Berkley JA, Mwangi I, Ngetsa CJ, Mwarumba S, Lowe BS et al. Diagnosis of acute 
bacterial meningitis in children at a district hospital in sub-Saharan Africa. The Lancet. 
2001: 357; 1753-1757.
Berkley JA, Ross A, Mwangi I et al. Prognostic indicators of early and late death in 
children admitted to district hospital in Kenya: cohort study. BMJ 2003; 326: 361-366.
Carneiro I, Roca-Feltrer A, Griffin JT, et al. Age-patterns of malaria vary with severity, 
transmission intensity and seasonality in sub-Saharan Africa: a systematic review and 
pooled analysis. PLOS One. 2010: 5(2).
Clement F, Dewar V, Van Braeckel E, et al. Validation of an enzyme-linked 
immunosorbent assay for the quantification of human IgG directed against the repeat 
region of the circumsporozoite protein of the parasite Plasmodium falciparum. Malaria 
Journal 2012, 11 (article 384).
Cogill B. Anthropometric Indicators Measurement Guide. Food and Nutrition Technical 
Assistance Project, Academy for Educational Development - Chapter 5: Taking 
Measurements. Washington, DC, 2003.
Greenwood BM, Armstrong JR. Comparison of two simple methods for determining 
malaria parasite density. Trans R Soc Trop Med Hyg. 1991; 85: 186-188.
Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic 
indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J 
Med. 1989; 71: 441-59.
Olotu A, Fegan G, Wambua J, et al. Four-Year Efficacy of RTS,S/AS01E and Its 
Interaction with Malaria Exposure. N Engl J Med. 2013; 368(12):1111-1120.
Planche T, Krishna S, Kombila M et al. Comparison of methods for the rapid laboratory 
assessment of children with malaria. Am J Trop Med Hyg. 2001; 65: 599-602.
United Nations. How to Weigh and Measure Children: Assessing the Nutritional Status 
of Young Children. 1986.
WHO Young Infants Study Group. Bacterial etiology of serious infections in young 
infants in developing countries: results of a multicenter study. Pediatr Infect Dis J. 
1999;18 (Suppl): S17-22.
WHO. Communicable Diseases Cluster. Severe falciparum malaria. Trans R Soc Trop 
Med Hyg. 2000a; 94 Suppl 1: S1-90.
 
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WHO. Management of the Child with a Serious Infection or Severe Malnutrition: 
Guidelines for Care at the first-referral level in developing countries. 2000b. 
http://www.who.int/maternal_child_adolescent/documents/fch_cah_00_1/en/ Accessed 
on 03 June 2013.
WHO. Standardization of interpretation of chest radiographs for the diagnosis of 
pneumonia in children. World Health Organization, Geneva, 2001a. 
http://www.who.int/vaccine_research/diseases/ari/www616.pdf ; Accessed on 03 June 
2013.
WHO. Model Chapter for Textbooks: IMCI, Integrated Management of Childhood 
Illness. 2001b. http://www.who.int/maternal_child_adolescent/documents/imci/en/
Accessed on 03 June 2013.
WHO. Pocket book of hospital care for children; Guidelines for the management of 
common illnesses with limited resources. 2005. 
http://www.who.int/maternal_child_adolescent/documents/9241546700/en/ Accessed on 
03 June 2013.
WHO. Verbal autopsy standards : ascertaining and attributing cause of death. World 
Health Organization, Geneva, 2007.
 
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APPENDIX A
Documentation of bednet usage and indoor 
residual spraying
Bednet usage and IRS will be assessed at three home visits (field worker visits) at Visit 
40, 42 and 44.

Bednets
The parent(s)/LAR(s) will be asked if the child sleeps under a bednet and whether or not 
the net is impregnated with insecticide. The child’s bednet will be inspected and the 
integrity of the net (i.e. whether or not the net has holes) documented. Net usage will be 
classified in the eCRF according to the following choices: 
1:
No bednet
2:
Impregnated bednet with no hole large enough to admit three fingers
3:
Impregnated bednet with at least one hole large enough to admit three fingers
4:
Untreated bednet with no hole large enough to admit three fingers
5:
Untreated bednet with at least one hole large enough to admit three fingers

Indoor residual spraying
The parent(s)/LAR(s) will be asked if the house has been sprayed with a IRS and if so 
when.
The question asked at Visit 40, 42 and 44 will be
‘Has indoor residual spraying been performed since last visit?’
The response to these questions (yes/no) will be documented in the eCRF.
The investigator will endeavor to find out what chemical was used from the malaria 
control programs in the study area and if the information is available, the investigator will 
record it in the eCRF.
 
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APPENDIX B
Assessment of a potential case of severe 
malaria
Algorithm for the evaluation of a hospital admission as a potential 
case of severe malaria
For all acute hospital admissions (i.e. except planned admissions for medical 
investigation/care or elective surgery and trauma admissions), an eCRF module will be 
filled in and a blood sample will be taken for evaluation of:

Malaria parasite density.

Blood culture.

Hemoglobin.

Blood glucose, lactate and base excess determination.
Lumbar Puncture (LP) is indicated by:

Seizure except simple febrile seizure (simple febrile seizure is defined as associated 
with fever, lasts for 5 minutes or less, generalized as opposed to focal, not followed 
by transient or persistent neurological abnormalities, occurring in a child 6 months 
of age, with full recovery within 1 hour).

Level of consciousness < 5 (or in children ≤ 9 months of age level < 4 [in association 
with best motor response of 1]).

Prostration in child < 3 year of age.

Meningism stiff neck/bulging fontanelle.

Clinician’s judgment: note that this list is not an exhaustive list of indications for 
lumbar puncture in clinical practice.
NB: LP can be delayed until child is stable.
Chest X-ray (CXR) is indicated by:

Tachypnea (50 breaths per minute in a child < 1 year and 40 breaths per minute 
in a child 1 year) [Berkley, 2003].

Lower chest wall indrawing.

Abnormally deep breathing.

Clinician’s judgment: note that this list is not an exhaustive list of indications for 
CXR in clinical practice.
 
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Methodologies for the assessment of clinical signs
Level of consciousness (Blantyre Score)
Conscious level will be scored using the Blantyre coma scale [Molyneux, 1989] (see 
Table 19). To obtain the coma score, add the scores for each section; the maximum coma 
score is 5, the minimum is 0.
Table 19
Coma scale for young children
Score
Best motor response
Localizes painful stimulus*
2
Withdraws limb from painful stimulus†
1
No response or inappropriate response
0
Best verbal response
Cries appropriately with painful stimulus* or, if verbal, speaks
appropriately
2
Moan or abnormal cry with painful stimulus or inappropriate speech
1
No vocal response to painful stimulus
0
Eye movement
Watches or follows (e.g. mother’s face)
1
Fails to watch or follow
0
* Pressure with blunt end of pencil on sternum or supraorbital ridge
† Pressure with horizontal pencil on nailbed of finger or toe
Guidance on the application of the scale is given by WHO [WHO, 2000a]. ‘Testing 
should begin with a minimal stimulus which should be increased only to a point where a 
clear response is obtained. A localizing response must be distinguished from a brisk 
flexion response which brings the hand into coincidental proximity to the stimulus. The 
interpretation of ‘verbal cry’ is difficult, some children are stoical and the appropriateness 
of verbal response needs to be considered in the light of other responses and the age of 
the child. It is best to test orientation by asking the mother to move her face across the 
child’s field of vision as the child may be less interested in looking at a strangers’face.
The coma score will be assessed at presentation. If it is depressed, it will be re-assessed 
after initial resuscitation; approximately one hour after correction of hypoglycemia and 
control of fits. This value will be recorded in the eCRF (if anticonvulsants were given 
prior to the assessment this will be documented in the eCRF). The intention is to avoid 
diagnosing cerebral malaria in a child with post-ictal coma [WHO, 2000a]. A child with 
persistent seizure activity despite optimal therapy should have the coma scale recorded 1 
hour after the treatment is optimized.
A normal coma score in a child of > 9 months of age is 5. In children 9 months of age, 
because localization of pain is difficult to assess, a normal coma score is 4 (in association 
with a best motor response of 1).
 
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Skin Turgor
Dehydration will be assessed by skin pinch test. The standard procedures are:

Locate the area on the child’s abdomen halfway between the umbilicus and the side 
of the abdomen. The hand should be placed so that when the skin is pinched, the fold 
of skin will be in a line up and down the child’s body and not across the child’s 
body.

Pinch the skin using the thumb and first finger. It is important to firmly pick up all of 
the layers of skin and the tissue under them for one second and then release it.

When released, the skin pinch goes back either very slowly (longer than 2 seconds), 
or slowly (skin stays up even for a brief instant), or immediately. In a child with 
marasmus (severe malnutrition), the skin may go back slowly even if the child is not 
dehydrated. In an overweight child, or a child with edema, the skin may go back 
immediately even if the child is dehydrated. [WHO, 2000b; WHO, 2001b; WHO, 
2005] (see Figure 2).
Figure 2
Diagnosis of dehydration
Left: pinching the child’s abdomen to test for decreased skin turgor Right: Slow return of skin pinch in severe 
dehydration [WHO, 2005].
Prostration
Prostration will be defined as, in an acutely sick child, the inability to perform 
previously-acquired motor function: in a child previously able to stand, inability to stand; 
in a child previously able to sit, inability to sit and in a very young child, inability to 
suck.
Guidance on the assessment of prostration is given by the WHO [WHO, 2000a].
‘Prostration must always be recorded directly and not based on history. Many children 
who are pyrexial and feel unwell prefer to lie or be carried but are capable of sitting if 
gently encouraged to do so.’
 
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Respiratory signs
Respiratory signs will be assessed in line with the guidance on the assessment of 
respiratory signs by WHO [WHO, 2005].
‘Respiratory signs should be looked for while the child is calm; (usually before the child 
is disturbed by hands on clinical examination). Ask the mother or caretaker to cautiously 
reveal part of the chest to look for lower chest wall indrawing or to count the respiratory 
rate. If a child is distressed or crying, it might need to be left for a brief time with its 
mother in order to settle, or the mother could be ask to breastfeed, before key signs such 
as respiratory rate can be measured. Then proceed to signs which require touching the 
child but are little disturbing.’

Rate: The respiratory rate will be counted over one full minute while the child is 
calm [WHO, 2005].

Lower chest wall indrawing: Lower chest wall indrawing will be defined as the 
inward movement of the bony structure of the chest wall with inspiration [WHO, 
2001b] (see Figure 3).
Note: chest indrawing should only be considered present if it is consistently present 
in a calm child. Agitation, a blocked nose or breastfeeding can all cause temporary 
chest indrawing [WHO, 2001b].
Note: lower chest wall indrawing occurs when the lower chest wall goes in when the 
child breathes in; if only the soft tissue between the ribs or above the clavicle goes in 
when the child breathes, this is not lower chest wall indrawing [WHO, 2005].
Figure 3
Lower chest wall indrawing
With inspiration, the lower chest wall moves in [WHO, 2005]

Acidotic or Kussmaul respiration: Abnormally deep breathing will be defined as 
breathing that is deep and labored while the chest is clear [WHO, 2005]. The key 
component is increased inspiratory and expiratory excursion of the chest [WHO, 
2000a].
 
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APPENDIX C
Determination of Plasmodium falciparum 
asexual parasite density
Slide reading methodology
Two blood slide reading methods for the determination of Plasmodium falciparum
asexual parasitemia density were approved by GSK Biologicals and collaborating 
partners and contributors.
The first method counts parasites relative to a concomitantly measured white blood cell 
count [Greenwood, 1991] and the second method counts parasites relative to a fixed 
measured blood volume [Planche, 2001]. These two methodologies are well established 
and used as gold-standards in the field. Slides are always taken in duplicate.
A positive parasitemia identified on any thick blood film must always be identified to 
species. This will be done on thin blood film except in case of low parasitemia. This 
section relates only to the determination of Plasmodium falciparum parasite density
results.
Method 1: Counting against known blood cell concentration
This method follows the principles described by Greenwood and Armstrong [Greenwood, 
1991].

A contemporaneous measure of white and red blood cell count is determined and 
used in parasite density calculation.

6 L of blood for the thick smear and 2 L of blood for the thin smear are put on the 
same slide with a standard template. All slides are prepared in duplicate.

Negative result: 100 fields on the thick blood smear free of parasites are to be read 
before a slide is declared negative.

Positive result:

High parasitemia: If 100 parasites or more are seen on the first field of the thick 
smear, the parasites are counted on the thin film. Red blood cells (RBC) and 
parasitized RBC are counted on the thin film until a minimum of 20 parasitized 
RBC are counted. If 20 parasitized RBC are counted before all the parasitized 
RBC in a field are counted, finish counting all parasitized RBCs and 
non-parasitized RBC in that field.

Medium parasitemia: If less than 100 parasites are seen on the first field of the 
thick smear, parasites are counted up to when 200 white blood cells (WBC) are 
counted, on the thick smear. If 200 WBC are counted before finishing a field, 
finish counting all parasites and WBC in that field.

Low parasitemia: If less than 10 parasites are counted per 200 WBC on the thick 
smear, the parasite counting is extended up to when 500 WBC have been 
 
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counted. If 500 WBC are counted before finishing a field, finish counting all 
parasites and WBC in that field.
Method 2: Counting against known blood volume
This method follows the principles described by Planche et al. [Planche, 2001].

10 L of blood are spread with a pipette on an area of 1x1.8 cm, using a template on 
which the slide is set.

Negative result: 100 fields free of parasites are to be read before a slide is declared 
negative.

Positive result:

If there are 1 to 9 parasites per field, 100 fields are counted.

If there are 10 to 99 parasites per field, 10 fields are counted.

If there are 100 to 999 parasites per field, 1 field is counted.

The parasitemia count will be calculated on the basis of the following formula:
Parasites/L = parasites/field  x  Microscope Factor (MF)

The Microscope Factor (MF) is the assumed blood volume per microscope high 
power field. To calculate the MF:

Make a thick blood film with 10 L of blood.

Calculate the mean number of WBC per high power field, after counting WBC 
across 10 fields. (X)

Count the number of WBC in 10 L of blood using a computerized blood 
analyzer. (Y)

The microscope factor is calculated as follows:
MF = Y / X
X = Mean WBC number per high power field (microscopy)
Y = WBC in 10 L of blood (automated analyzer)

For each microscope, this predetermination of the MF is done once.
 
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Criteria for concordance for double reading of slides
All slides are read twice, by two independent readers to quantify the Plasmodium 
falciparum parasite density. A third independent reader will examine the slides if the 
following discrepancies are observed between the first two readings:
A.
The result from one reader is negative and the one from the other reader is 
positive.
B.
For high and medium parasitemia (parasitemia > 400 parasites/L), the higher 
count divided by the lower count is > 2.
C.
For low parasitemia (parasitemia 400 parasites/L), the highest reading density 
is more than one log10 higher than the lowest reading.
If parasitemia result is high or medium and one is low, i.e. one is > 400/L and the other 
is 400/L, parasitemia, criteria (C) will be applied.
Determination of final result
If there are two concordant results, the final result is the geometric mean of the two 
readings.
If the first two readings are discordant, then the final result follows the following 
principles:

For cases of positive/negative discrepancy (A), the majority decision following the 
reading by the third reader is adopted. If the decision is positive, the final result is the 
geometrical mean of the two positives.

For cases of three positive readings (B and C), the final result is the geometric mean 
of the two geometrically closest readings (see Figure 4).
 
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Figure 4
Determination of final result
Identification of Plasmodium species
Positive parasitemia identified on any thick blood film must always be identified to
species. This will be done on thin blood film except in case of low parasitemia. Only 
Plasmodium falciparum results will be accounted for in the efficacy analyses.
 
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APPENDIX D
Interpretation of chest x-rays
All x-rays will be classified for quality and findings according to the scales in Table 20
and Table 21. For more details about these definitions, please refer to [WHO, 2001a]. 
Note that for ‘uninterpretable’ chest x-rays, no further reading will be made. 
Table 20
Classification of quality of chest x-rays
Uninterpretable:
an image is classified as “uninterpretable” if the features of the image are not interpretable 
without additional images. No further reading should be made for such images.
Suboptimal:
an image is classified as “suboptimal” if the features allow interpretation of primary end-
point but not of other infiltrates or findings. No entries should be made for other infiltrates 
for such images
Adequate:
an image is classified as “adequate” if the features allow confident interpretation of end-
point as well as other infiltrates
 
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Table 21
Classification of findings of chest x-rays
Consolidation or 
pleural effusion
where consolidation is defined as a dense opacity that may be a fluffy consolidation of a 
portion or whole of a lobe or of the entire lung, often containing air bronchograms* and 
where pleural effusion is defined if it occurs in the lateral pleural space (and not just in the 
minor or oblique fissure) and is spatially associated with a pulmonary parenchymal 
infiltrate (including other infiltrate) or if the effusion obliterates enough of the hemithorax 
to obscure an opacity
* atelectasis of an entire lobe that produces a dense opacity and a positive silhouette sign 
with the mediastinal border will be considered to be an endpoint consolidation
Other infiltrate
linear and patchy densities (interstitial infiltrate) in a lacy pattern involving both lungs, 
featuring peribronchial thickening and multiple areas of atelectasis. Lung inflation is 
normal to increased. It also includes minor patchy infiltrates that are not of sufficient 
magnitude to constitute primary end-point consolidation, and small areas of atelectasis 
which in children can be difficult to distinguish from consolidation.
No consolidation, 
infiltrate or effusion
Definitions of terms: for the purposes of this study. (See Figure 5, below)
1) Infiltrate: any pathologic density in the lung.
2) Alveoli: tiny air-filled spaces where oxygen and C02 are exchanged (see diagram B)
3) Bronchi: tubes leading from the trachea to the alveoli
4) Interstitium: lung tissue outside the air-containing spaces: includes support tissues, blood vessels, bronchial 
walls, lymphatics
5) Alveolar infiltrate: alveoli filled with fluid (pus, edema, etc.)
6) Heart and diaphragm borders: (see diagram A).
7) Air bronchogram: branching linear lucent structure representing air still present in bronchi after the alveoli 
around them have consolidated; not to be confused with peribronchial thickening (an interstitial infiltrate)
8) Consolidation: especially dense, often homogeneous, confluent alveolar infiltrate sometimes may encompass 
an entire lobe or large segment, fluffy, mass-like, cloud-like density, erases heart and diaphragm borders 
(silhouette sign); often contains air bronchograms
9) Atelectasis: volume loss as air is absorbed from lung tissue, usually distal to an airway obstruction (e.g. a 
mucous plug). The lung tissue collapses like a Japanese fan, leaving a dense streak on the film that radiates 
outward from the hilum (see diagram D).
10) Interstitial infiltrate: includes peribronchial thickening and tiny areas of atelectasis (thought to be typical of 
viral infection).
11) Pleural effusion: fluid collecting in the pleural space around the lung, seen as a dense rim (the same density 
as the chest-wall muscles) interposed between the lung and the ribs (see diagram C)
12) Peribronchial thickening or cuffing: increased density of the walls of the smaller bronchi (away from the 
immediate hilar area) so that they become visible as circles or parallel lines (see diagram E)
 
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Figure 5
Diagrams to support classification of findings of chest x-rays
1) Right diaphragm: erased by a right lower lobe infiltrate. 
2) Right heart (right atrium): erased by a right middle lobe infiltrate. 
3) Minor fissure: divides the right upper lobe from the right middle lobe; seen as a line when there is fluid in it; seen 
as a border when there is infiltrate in the lobe adjacent to it. 
4) Left heart (left ventricle): erased by an infiltrate in the lingula (homolog of the right middle lobe; actually a part of 
the left upper lobe). 
5) Left diaphragm: erased by an infiltrate in the left lower lobe, often behind the heart shadow. 
6) & 7) Right hilum and left hilum: contain large blood vessels, lymph nodes, and main bronchi; bronchial walls 
may be normally visible here, but should disappear quickly just outside the immediate hilar area. 
8) Thymus: bi-lobed semi-lucent structure in the upper mid chest with defined borders, may resemble an upper lobe 
infiltrate but often shrinks when the child is sick. 
9) Heart: from the spine to the left heart border should be the same density.
 
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APPENDIX E
Laboratory assays
Determination of hemoglobin level
Quantification of hemoglobin level will be made at the investigator’s sites according to 
laboratory standard operating procedures at the timepoints listed in Table 10.
Antibody titers against the CS repeat region
Blood for analysis of humoral immune response will be obtained at timepoints listed in 
Table 10. After centrifugation, serum samples should be kept at -20C until shipment.
Antibody levels against Plasmodium falciparum CS-repeat region will be measured at 
CEVAC by a standard ELISA methodology using plate adsorbed recombinant R32LR 
antigen, as described by Clement [Clement, 2012]. Anti-CS antibody titers will be 
determined relative to a standard reference antibody as a control according to standard 
operating procedures from the laboratory. Results will be reported in EU/mL.
(Amended 15 April 2015)
 
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APPENDIX F
Clinical laboratories
Table 22
Outsourced laboratories
Laboratory
Address
Center For Vaccinology (CEVAC) - Ghent University and Hospital
De Pintelaan, 185
Building A - 1st floor
9000 Ghent (Belgium)
 
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APPENDIX G
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
200599 (MALARIA-076)
Amendment number:
Amendment 1
Amendment date:
Amendment 1 Final: 18 February 2014
Co-ordinating author:
 (Scientific Writer, Keyrus Biopharma 
consultant for GSK Biologicals)
Rationale/background for changes: 

Name and function title of contributing authors have been updated on the Title 
page.

The procedure for “passive case detection” was corrected.

Central nervous system infections was removed from the secondary safety 
objective and only meningitis was kept as meningitis is the safety signal observed 
in malaria studies. This modification was done in the relevant sections of the 
protocol. Information on meningitis reporting was added in the section “adverse 
events of specific interest”.

The blood volume collected for parasite density and hemoglobin level was 
mistakenly set to 2.0 ml while it should have been 0.5 ml. This has been corrected.

Clarification of the timing for passive surveillance for clinical malaria and severe 
malaria as well as for safety was brought to the list of study procedures.

The timing for the study visits have been clarified in the event that the first study 
visit (Visit 39) occurs after the allowed interval for the subsequent visits.

A note regarding the collection of creatinine and total bilirubin was added because 
disease manifestation of severe malaria at the later age are renal and liver 
dysfunctions.

It was clarified that children who died before the study start of MALARIA-076 
and whose parents consent will be reported as serious adverse events. If there is 
uncertainty on the cause of death based on the review of available medical records, 
a procedure for verbal autopsy should be performed. This was added in the passive 
surveillance for safety.

All adverse events of specific interest (i.e. potential immune-mediated disease and 
meningitis) occurring during this study will be reported as serious adverse events. 
Clarification was performed in the relevant sections of the protocol.

Clarification of the serious adverse events to be recorded during the study was 
brought in Section 9.2.1.
 
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
An adaptation in the wording of the Blantyre coma scale was performed in order to 
clarify the best verbal response for the age range of the children enrolled in the 
present study (4 to 9 years).

Smear and polymerase chain reaction for detection and quantification of parasite 
were mistakenly mentioned in Appendix E. This was removed as no polymerase 
chain reaction will be performed in the present study.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
On the Title page

 (Lead Clinical Development ManagerClinical Research and 
Development Lead)

 (Study Delivery Manager, SynteractHCR consultant for GSK 
Biologicals)

 (Safety and Pharmacovigilance)
In Synopsis
Secondary safety objective

To describe the incidence of the following reported serious adverse events (SAEs): 
fatalities, related SAEs (related to vaccine administration in the primary study 
MALARIA-055 PRI [110021] and to study participation), malaria hospitalization, 
potential Immune-Mediated Disease (pIMDs), and meningitis, and central nervous 
system (CNS) infections, from January 2014 to December 2016. 
Secondary safety endpoint

The occurrence of the following reported SAEs: fatalities, related SAEs (related to 
vaccine administration in the primary study MALARIA-055 PRI [110021] and to 
study participation), malaria hospitalization, pIMDs, and meningitis, and CNS 
infections, over the time period starting January 2014 until the end of the 3-year 
follow-up period (Visit 45).
In List of abbreviations
CNS:
Central Nervous System
 
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PPD
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In Glossary of Terms
Passive case detection:
The passive case detection is the detection of malaria 
disease by self-presentation to health facility in the study 
area. If there is a history of fever within 24 hours or 
axillary temperature is 37.5C at presentation then a 
blood slide is taken and examined for parasitemia.
In Section 2.2.2 Safety objective

To describe the incidence of the following reported serious adverse events (SAEs): 
fatalities, related SAEs (related to vaccine administration in the primary study 
MALARIA-055 PRI [110021] and to study participation), malaria hospitalization, 
potential Immune-Mediated Disease (pIMDs), and meningitis, and central nervous 
system (CNS) infections, from January 2014 to December 2016.
In Section 6.5 Outline of study procedures
Table 10
List of study procedures
Epoch
Epoch 001
Epoch 002 Epoch 003 
Type of contact
Screening 
Visit (Visit 
39)
Visit 
401
Visit 
41 
Visit 
421
Visit 
43 
Visit 
441
Visit 
45 
Timepoints
Day 0
Within 
30 
days 
before 
Year 1
Year 
1
Within 
30 
days 
before 
Year 2
Year 
2
Within 
30 
days 
before 
Year 3
Year 
3
Recording reasons for non-participation
●
Informed consent2
●
Issuing identification card
O 
Check identification card
O
O
O
O
O
O
Check inclusion/exclusion criteria
●
Collect demographic data3
●
Physical examination
O
O
O
O
Anthropometry4
●
●
●
●
Screening conclusion
●
Documentation of bednets and indoor residual spraying5
●
●
●
Retrospective collection of safety and efficacy data since the 
last contact of the primary study (MALARIA-055)
●6
Surveillance for clinical malaria and severe malaria10
●76
●76
●76
Surveillance for safety: recording of SAEs7,11
●76
●76
●76
Blood sampling for anti-CS antibodies measurement 
(approximately 0.5 mL)8
●
●
●
Blood sampling for parasite density measurement9 and 
hemoglobin level (approximately 2.0 0.5 mL)
●
●
●
Interim analysis
O
O
Final analysis
O
Study Conclusion 
●
1 Field worker visits
 
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2 ICF to be signed by all subjects’ parents/LARs who consent to let their child participate in this study and by subjects’ 
parents/LARs who consent to allow reporting of the event leading to the death of their child before the start of 
MALARIA-076 in the MALARIA-076 database.
3 Demographic data include age and gender
4 Anthropometry consists of height, weight and mid upper arm circumference)
5 Use of bednets and indoor residual spraying will be checked between 1 and 30 days before the annual visits (see 
APPENDIX A).
6 Retrospective collection since the last contact of the primary study (MALARIA-055 PRI).
76 Retrospective collection since the last visit.
87SAEs: fatalities, related SAEs (related to vaccine administration in the primary study MALARIA-055 PRI [110021] 
and to study participation), malaria hospitalization, pIMDs, and meningitis and CNS infections (see Section 9).
98 Only for subjects that were included in the immunogenicity sub-cohort of the primary study (MALARIA-055 PRI 
[110021]) and who were enrolled in this extension study. There will be a maximum of 200 subjects from each age 
category in each site in the immunogenicity sub-cohort.
109 A volume of 16 L is required for this test.
10 Note that passive surveillance for clinical and severe malaria is ongoing throughout the study (see Section 
6.6.11) 
11 Note that passive surveillance for safety is ongoing throughout the study (see Section 6.6.12)
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
Table 11
Intervals between study visits
Interval
Timing of visit1
Allowed interval2
Screening Visit (Visit 39)3
Study start at the center
Earliest October 2013 Not 
applicable
Visit 40 (Field Worker Visit)34
November 2014
October 2014 to December 2014
Visit 41 (Annual Visit)
December 2014
November 2014 to January 2015
Visit 42 (Field Worker Visit) 34
November 2015
October 2015 to December 2015
Visit 43 (Annual Visit)
December 2015
November 2015 to January 2016
Visit 44 (Field Worker Visit) 34
November 2016
October 2016 to December 2016
Visit 45 (Annual Visit)
December 2016
November 2016 to January 2017
1 Whenever possible the investigator should arrange study visits within this interval.
2 Subjects will not be eligible for inclusion in the According-to-Protocol (ATP) population for analysis of immunogenicity 
if they make the study visit outside this interval.
3 Visit 39 should be performed as soon as the center is initiated. However, if the timing of Visit 39 is delayed 
beyond the allowed interval for Visit 40 or Visit 41, then those visits will be skipped.
34Field Worker Visits should be conducted between 1 and 30 days before Annual Visits.
In Section 6.6 Detailed description of study procedures
6.6.9 Documentation of bednets and indoor residual spraying
Bednets usage and indoor residual spraying (IRS) will be assessed during field worker 
visits (Visits 40, 42 and 44) at subjects’ house between 1 and 30 days before the annual 
visits (Visits 40, 42 and 44).
6.6.10 Retrospective collection of efficacy and safety data
During Visit 39, all subjects for whom the parents/LARs gave their consent to let their 
child participate in this study, will have a retrospective collection of efficacy data (cases 
of clinical, severe or malaria hospitalization) and safety data (SAEs: fatalities, related 
SAEs [related to vaccine administration in the primary study MALARIA-055 PRI and to 
study participation], malaria hospitalization, pIMD, and meningitis, and CNS infections)
since their last contact in the primary study MALARIA-055 PRI (110021). Retrospective 
 
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data will be collected, for example by questioning subject's parents/LARs and by 
reviewing available medical records. Collected information needs to be recorded in the 
eCRF.
For subjects who will not be enrolled in the study, because they died before the start of 
MALARIA-076, subjects’ parent(s)/LAR(s) will be asked if they consent to allow 
reporting of the event leading to the death of their child in the MALARIA-076 database. 
If the parent(s)/LAR(s) agree, they will be asked to sign an ICF. This event will be 
reported as SAE in the MALARIA-076 database.
6.6.11 Surveillance for efficacy
In Passive surveillance for severe malaria
Note that measurement of creatinine and total bilirubin were not specified per 
algorithm. If performed for case management these will be captured in the eCRF.
6.6.12 Passive surveillance for safety
The following SAEs: fatalities, related SAEs (related to vaccine administration in the 
primary study MALARIA-055 PRI [110021] and to study participation), malaria 
hospitalization, pIMDs, and meningitis, and CNS infections will be collected for all 
subjects presenting to health facilities in the study area and through annual clinic visits.
Verbal autopsy will be performed on all cases of mortality occurring outside hospital and 
where it adds value to ascribe the cause of a fatal event. as described in WHO (2007). 
The questionnaire used will be based on the INDEPTH standard and adapted to be 
locally appropriate [WHO, 2007]. For children who died before study start and whose 
parents consent, the death will be reported as an SAE. If there is uncertainty of cause 
of death based on the review of available medical records, a verbal autopsy should be 
performed.
6.6.13.2 Blood sampling for prevalent parasitemia and anemia
A volume of at least 2.0 0.5 mL of whole blood for parasite density (16 L needed for 
this test) and haemoglobin level measurement should be drawn from all subjects.
In Section 6.7 Biological samples
Table 12
Biological samples
Sample type
Quantity Unit
Timepoint
Sub-cohort Name*
Blood for anti-CS antibodies
0.5
ml
Visit 41
Visit 43
Visit 45
Immunogenicity sub-cohort
Blood sampling for parasite density and hemoglobin level
2 0.5
ml
Visit 41
Visit 43
Visit 45
All subjects
* Refer to Section 5.1 for sub-cohort description
 
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In Section 9 Safety
9.1.3 Clinical laboratory parameters and other abnormal assessments qualifying as 
adverse events or serious adverse events
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
hematology, urinalysis) or other abnormal assessments that are judged by the investigator 
to be clinically significant will be recorded as AE or SAE if they meet the definition of an 
AE or SAE (refer to Sections 9.1.1 and 9.1.2). Clinically significant abnormal laboratory 
findings or other abnormal assessments that are present at baseline and significantly 
worsen following the start of the study will also be reported as AEs or SAEs.
9.1.4 Adverse events of specific interest
All adverse events of specific interest described below will be reported as SAEs.
9.1.4.1 Potential immune-mediated diseases
When there is enough evidence to make any of the above diagnoses, the AEevent must be 
reported as a pIMD. Regardless of it being considered an AE or an SAE, it should be 
reported per the SAE reporting rules. Symptoms, signs or conditions which might (or 
might not) represent the above diagnoses, should be recorded and reported as AEs but not 
as pIMDs until the final or definitive diagnosis has been determined, and alternative 
diagnoses have been eliminated or shown to be less likely.
9.1.4.2 CNS infections and CNS inflammations Meningitis
For the further evaluation of the safety signal of meningitis all the cases occurring 
during the study will be reported as SAE and medical documentation of the events will 
be reported in appropriate targeted follow-up forms included in the eCRF.
9.2 Detecting and recording serious adverse events
SAEs that will be reported under this protocol are: those that are fatal, those that are 
related to vaccine administration in the primary study MALARIA-055 PRI (110021), 
those that are related to study participation, malaria hospitalization, pIMDs, and
meningitis, and CNS infections. SAEs will be captured at the health facilities in the study 
area or by direct questioning at the Annual Visits (Visits 41, 43 and 45).
9.2.1 Time period for detecting and recording serious adverse events
In addition, at Visit 39, a retrospective collection of SAEs (fatalities, related SAEs, 
malaria hospitalization, pIMDs, and meningitis) since the last study contact of the 
primary study (MALARIA-055 PRI [110021]) will be performed.
An overview of the protocol-required reporting periods for SAEs (fatalities, related 
SAEs, malaria hospitalization, pIMDs, and meningitis, and CNS infections) is given in 
Table 17.
 
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Table 17
Reporting periods for serious adverse events
Event
From Visit 39* to Visit 45
Fatalities
Related SAEs
Malaria hospitalization
pIMDs
Meningitis, and CNS infections
* A retrospective collection of safety data (SAEs: fatalities, related SAEs [related to vaccine administration in the 
primary study MALARIA-055 PRI and to study participation], malaria hospitalization, pIMD, and meningitis, and
CNS infections) since the last contact in the primary study MALARIA-055 PRI (110021) will be performed at Visit 39.
9.3 Reporting of serious adverse events and other events
Table 18
Timeframes for submitting serious adverse event and other events 
reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
Fatalities
24 hours*
electronic SAE report
24 hours*
electronic SAE report
Related SAEs**
24 hours*
electronic SAE report
24 hours*
electronic SAE report
Malaria hospitalization
24 hours*
electronic SAE report
24 hours*
electronic SAE report
pIMDs
24 hours*
electronic SAE report
24 hours*
electronic SAE report
Meningitis, and CNS infections
24 hours*
electronic SAE report
24 hours*
electronic SAE report
* Timeframe allowed after receipt or awareness of the information.
** Related to vaccine administration in the primary study MALARIA-055 PRI (110021) and to study participation.
9.4.1.2 Follow-up after the subject is discharged from the study
The investigator will follow subjects with SAEs, pIMDs (serious or non-serious), or 
subjects withdrawn from the study as a result of an SAE, until the event has resolved, 
subsided, stabilized, disappeared, or until the event is otherwise explained, or the subject 
is lost to follow-up.
In Section 11 Statistical methods
11.2.2 Safety endpoint

The occurrence of the following reported SAEs: fatalities, related SAEs (related to 
vaccine administration in the primary study MALARIA-055 PRI [110021] and to 
study participation), malaria hospitalization, pIMDs, and meningitis, and CNS 
infections, over the time period starting January 2014 until the end of the 3-year 
follow-up period (Visit 45).
 
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11.3 Power of the trial
The incidence of severe malaria and clinical malaria following a primary RTS,S/AS01E
vaccination given in 2 different age categories, with or without booster, across different 
transmission settings will be described. If 600 subjects per group in each category are 
enrolled with an attack rate of 24 episodes over 3 years in controls (4% over 3 years [or 
1.3% per year]) of severe malaria. T, this sample size will allow to detect a 2-fold 
increase in the incidence of severe malaria between the recipients of primary vaccination 
only (R3C versus C3C) or primary vaccination + booster (R3R versus C3C) over the 3-
year additional follow-up, with 80% power.
11.9 Analysis of safety
For both age categories (6-12 weeks and 5-17 months), safety will be evaluated by 
examining SAEs (fatalities, related SAEs [related to vaccine administration in the 
primary study MALARIA-055 PRI and to study participation], malaria hospitalization, 
pIMDs, and meningitis, and CNS infections) from study start (MALARIA-076). All 
safety analyses will be performed separately for both age categories.
In APPENDIX B Assessment of a potential case of severe malaria
Table 19
Coma scale for young children
Score
Best motor response
Localizes painful stimulus*
2
Withdraws limb from painful stimulus†
1
No response or inappropriate response
0
Best verbal response
Cries appropriately with painful stimulus* or, if verbal, speaks 
appropriately
2
Moan or abnormal cry with painful stimulus or inappropriate speech
1
No vocal response to painful stimulus
0
Eye movement
Watches or follows (e.g. mother’s face)
1
Fails to watch or follow
0
* Pressure with blunt end of pencil on sternum or supraorbital ridge
† Pressure with horizontal pencil on nailbed of finger or toe)
In APPENDIX E Laboratory assay
Determination of parasitemia and hemoglobin level
Blood samples for smear and polymerase chain reaction will be taken at the timepoints 
listed in Table 10. Detection and quantification of Plasmodium falciparum parasitemia 
and hemoglobin level will be made at the investigator’s sites according to laboratory 
standard operating procedures at the timepoints listed in Table 10.
 
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GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
200599 (MALARIA-076)
Amendment number:
Amendment 2
Amendment date:
Amendment 2 Final: 15 April 2015
Co-ordinating author:
 (Scientific Writer, Keyrus Biopharma 
contractor for GSK Biologicals)
Rationale/background for changes: 
In order to maximize and harmonize the clinical information available during the gap 
period the following information will be documented retrospectively and prospectively 
in the eCRF:

Results of clinical diagnoses of malaria.

Rapid diagnostic test (RDT).

Blood slides read to guide treatment at the time of presentation.
In Appendix E, text describing “Determination of parasitemia” was removed because 
“Determination of Plasmodium falciparum asexual parasite density” is detailed in 
Appendix C.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
On the Title page

(Study Delivery Manager)

 (Local Delivery Lead)

 (Project Data Manager)
In List of abbreviations
RDT:
Rapid diagnostic test
In Section 6.6 Detailed description of study procedures
6.6.10 Retrospective collection of efficacy and safety data
For subjects who will not be enrolled in the study, because they died before the start of 
MALARIA-076, subjects’ parent(s)/LAR(s) will be asked if they consent to allow 
reporting of the event leading to the death of their child in the MALARIA-076 database. 
If the parent(s)/LAR(s) agree, they will be asked to sign an ICF. This event will be 
 
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reported as SAE in the MALARIA-076 database and any available information 
captured in the inpatient module of the eCRF or any other  specific section as 
applicable.
6.6.11 Surveillance for efficacy
Retrospective data since the previous visit will be collected by questioning subject's 
parents/LARs and by reviewing available medical record during annual clinic visit (Visits 
41, 43, and 45). Collected information needs to be recorded in the eCRF. For clarity, if 
available the following data will be collected: history of fever, temperature, parasite 
density, treatment administered, any clinical diagnoses of malaria, rapid diagnostic test 
(RDT) and blood slides read to guide treatment at the time of presentation will be 
captured.
Passive surveillance for clinical malaria
Data points that will be captured in the eCRF for all cases of suspected clinical malaria 
are: history of fever; temperature; parasite density; treatment administered. To 
supplement this information, any clinical diagnoses of malaria, RDT and blood slides 
read to guide treatment at the time of presentation will be captured.
Passive surveillance for severe malaria
Harmonization of case evaluation across centers will be assured by training of clinicians 
in the assessment of clinical signs and the standardization of equipment and processes 
used for laboratory investigations. On all admissions, data will be captured to support the 
endpoints of this study. In addition RDT and blood slides read to guide treatment at the 
time of presentation will be captured.
In APPENDIX E Laboratory assay
Determination of parasitemia and hemoglobin level
Detection and qQuantification of Plasmodium falciparum parasitemia and hemoglobin
level will be made at the investigator’s sites according to laboratory standard operating 
procedures at the timepoints listed in Table 10.
 
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