Immunogenicity and Safety Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Given at 6, 7.5 and 9 Months of Age in Co-administration With Measles, Rubella and Yellow Fever Vaccines Followed by a Booster of the Malaria Vaccine.
Phase: PHASE3
Conditions: Malaria, Malaria Vaccines
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart
Belgium
Primary study vaccine and 
number

GlaxoSmithKline (GSK) Biologicals’ candidate 
Plasmodium falciparummalaria vaccine 
RTS,S/AS01E(SB257049)
Other study products

Licensed measles and rubella vaccine (live), MR-
VAC™ (Serum Institute of India)

Licensed World Health Organization (WHO)
prequalified yellow fever vaccine

Vitamin A
eTrack study number and 
Abbreviated Title
200596(MALARIA-073)
Date of protocol
FinalVersion 1: 03 June 2015
Date of protocol 
amendment
Amendment 1 Final:09 August 2016
Title
Immunogenicity and safety study of GSK Biologicals’ 
candidate malaria vaccine (SB257049) given at 6, 7.5 
and 9 months of age in co-administration with 
measles, rubella and yellow fever vaccines followed 
by a booster of the malaria vaccine.
Detailed Title
Phase IIIb randomized, open, controlled, multi-center 
study to evaluate the immunogenicity and safety of the 
RTS,S/AS01Ecandidate malaria vaccine, when 
administered as primary vaccination at 6, 7.5 and 9 
months of age with or without co-administration of 
measles, rubellaand yellow fever vaccines followed 
by an RTS,S/AS01
Ebooster vaccination 18 months 
post Dose 3, to children living in sub-Saharan Africa.
Co-ordinating author

 (Scientific Writer; Keyrus 
Biopharma contractorfor GSK Biologicals)
Contributing authors

 (Clinical Research and 
Development Lead, Director)

 (Lead Statistician)

 (Director, Biometrics)

 (Project Delivery Lead)
 
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eTrack study number and 
Abbreviated Title
200596(MALARIA-073)
Detailed Title
Phase IIIb randomized, open, controlled, multi-center 
study to evaluate the immunogenicity and safety of the 
RTS,S/AS01Ecandidate malaria vaccine, when 
administered as primary vaccination at 6, 7.5 and 9 
months of age with or without co-administration of 
measles, rubella and yellow fever vaccines followed 
by an RTS,S/AS01
Ebooster vaccination 18 months 
post Dose 3, to children living in sub-Saharan Africa.
Contributing authors
(continues)(Amended: 09 
August 2016)

 
(Study Delivery Leads)

 (Study Delivery Manager)

 (Clinical Readout Team Leader)

 (GVCL, Study Manager)

 (Clinical Laboratory Sciences 
Senior Lab Study Manager)

 (Clinical Regulatory 
Affairs representative)

 (Clinical Safety representative)

 (Safety and Pharmacovigilance)

(Study 
Data Managers; TCS contractor for GSK 
Biologicals)

,
and 
(Project Data Managers)

 (Vaccine Supply Coordinator)

 (Global Patents 
representative)

(Clinical Research and 
Development Lead)
GSK Biologicals’ Protocol DS v 14.1.1
Copyright 2015-2016the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited.
 
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Protocol Amendment 1 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
200596(MALARIA-073)
Date of protocol amendment
Amendment 1 Final: 09 August 2016
Detailed Title 
Phase IIIb randomized, open, controlled, multi-center 
study to evaluate the immunogenicity and safety of 
the RTS,S/AS01
Ecandidate malaria vaccine, when 
administered as primary vaccination at 6, 7.5 and 9 
months of age with or without co-administration of 
measles, rubella and yellow fever vaccines followed 
by an RTS,S/AS01
Ebooster vaccination 18 months 
post Dose 3, to children living in sub-Saharan Africa.
Sponsor signatory
François P Roman
Clinical and Epidemiology R&D Project Lead
Malaria vaccine
GlaxoSmithKline Biologicals, SA.
Signature
Date
 
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Protocol Amendment 1 Rationale
Amendment number:
Amendment 1
Rationale/background for changes: 
The protocol was amendedfor the following reasons:
The volumes of whole blood collected from subjects wereconsidered insufficient. 
To ensure that an adequate blood volume is obtained for the analysis, the volumes 
of whole blood to be collected specifiedin the protocol were increased to take into 
account the dead volume due to aliquoting,and also to enable repeat testing of 
samples in case of invalid results.
It has been clarified that confirmatory testing for any subject showing clinical 
presentations compatible with yellow fever, rubella or measles will be performed 
only to identify cases of vaccine failure.

Clarification about the eCRF pages required to be filled in for pIMDs and seizures 
was provided.

The names and address of the laboratories performing the biological assays and 
study personnel at GSK were updated.Details of the safety lab testswere also 
added.
The Ghana FDA recommendedthat screening and vaccination should not be 
performed on the same day, so the screening will be performed up until one day 
before vaccination (Day -28 to Day -1).
 
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ProtocolAmendment 1Investigator 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 locallyand, 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 writteninformed 
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 aboutthe investigator’s ownership interest in 
the sponsor or the investigational product(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
200596(MALARIA-073)
Date of protocol amendment
Amendment 1 Final: 09 August 2016
Detailed Title
Phase IIIb randomized, open, controlled, multi-center 
study to evaluate the immunogenicity and safety of 
the RTS,S/AS01
Ecandidate malaria vaccine, when 
administered as primary vaccination at 6, 7.5 and 9 
months of age with or without co-administration of 
measles, rubella and yellow fever vaccines followed 
by an RTS,S/AS01
Ebooster vaccination 18 months 
post Dose 3, to children living in sub-Saharan 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 tothe 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 toprotocol 
Section 8.3.2.
 
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SYNOPSIS
Detailed Title
Phase IIIb randomized, open, controlled, multi-center study to 
evaluate the immunogenicity and safety of the RTS,S/AS01
E
candidate malaria vaccine, when administered as primary 
vaccination at 6, 7.5 and 9 months of age with or without co-
administration of measles, rubella and yellow fever vaccines 
followed by an RTS,S/AS01Ebooster vaccination 18 months 
post Dose 3, to children living in sub-Saharan Africa.
Indication
Primary immunization against malaria disease caused by 
Plasmodium falciparumin children.
Rationale for the 
study and study 
design
Rationale for the study vaccine and vaccination schedule
In sub-Saharan Africa, most of the Expanded Program on 
Immunization (EPI) vaccines are given in early infancy while 
measles, rubella and yellow fever (YF) vaccines are given at 9 
months of age. Between the first EPI vaccines and the 
measles, rubella and YF vaccines, children receive Vitamin A 
supplementation at6 months of age as recommended by the 
World Health Organization (WHO) [UNICEF, 1998]. To limit 
the number of clinic visits for young children and to optimize 
vaccine implementation, it would be more efficient to 
administer the first dose of RTS,S/AS01
Eduring the EPI visit 
at 6 months of age when Vitamin A is given and to administer 
the third dose of RTS,S/AS01
Eon the same day as the YF, 
measles and rubella vaccines at 9 months of age according to 
the EPI schedule.This proposed schedule (0, 1.5, 3-month)is 
longer than the schedule currently evaluated in Phase III 
studies (0, 1, 2-month).
Recent results from the phase IIIstudy MALARIA-055PRI
(110021) showed a decline in efficacy against clinical and 
severe malaria with time in both children and infants who did 
not receive a booster dose of the RTS,S/AS01Evaccine. 
Administration of a booster dose enhanced protection against 
clinical malaria in infants and children as well as the efficacy 
against severe malaria in the children. Vaccination with 
RTS,S/AS01Ealso significantly reduced the overall hospital 
admissions, admissions due to malaria, severe anemia, and the 
need for blood transfusion. These protective effects were more 
marked in children who received a booster dose [RTS,S 
Clinical Trials Partnership; 2015]. In order to provide the 
greatest benefit to children enrolled inthis study, a booster 
dose of RTS,S/AS01Ewill be given 18 months post Dose 3.
In this study, to ensure the same protection as the children 
vaccinated with RTS,S/AS01E, children from the Control 
 
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group will also receive RTS,S/AS01E.
Rationale for non-inferiorityassessment
Non-inferiority of the immune response to measles and YF 
when the third dose of RTS,S/AS01Ewas co-administered 
with measles and YF vaccines compared to measles and YF 
vaccines given alone was demonstrated in study MALARIA-
050 in infants 6 to10 weeks of age at the time of first 
vaccination [Agnandji, 2010]. There are however no data of 
theanti-circumsporozoite protein of Plasmodium falciparum
(anti-CS)immune response induced by RTS,S/AS01Ewhen 
given in co-administration with measles, rubella and YF, in a 
0, 1.5, 3-month schedule starting at an older age (5-17 
months).Considering that the implementation of 
RTS,S/AS01Evaccine in EPI could occur in children aged 5-
17 months, this study intends to demonstrate that anti-CS 
immune response of the candidate malaria vaccine 
RTS,S/AS01Eis not inferior when RTS,S/AS01
Eis 
administered at 6, 7.5 and 9 months of age with the third dose 
given alone or in co-administration with a YF vaccine and a 
combined measles and rubella vaccine.
A secondary objective will assess the non-inferiority of the 
immune responses to YF vaccine and a combined measles and 
rubella vaccine when they are given in co-administration with 
RTS,S/AS01E.
Rationale for safety follow-up
Safety and reactogenicity for the RTS,S/AS01
Ehave 
previously been evaluated, alone or in co-administration with 
EPI vaccines given between 6-12 weeks of age. However, 
safety has not been evaluated in co-administration with 
measles, rubella and YF in a 0, 1.5, 3-month schedule starting 
at 6 months of age. This study will therefore provide safety 
information when RTS,S/AS01
Eis administered at 6, 7.5 and 
9 months of age alone or in co-administration with YF
vaccine and a combined measles and rubella vaccine.
A 12-month safety follow-up after the last dose of 
RTS,S/AS01Evaccine will be applied to all study groups.
Contrary to the 7-day follow-up period after RTS,S/AS01E
vaccinationin other malaria clinical studies, a 14-day follow-
up safety period will be applied in this study following the 
study vaccines administered at 9 months of age (Visit 4) 
because,in combined measles and rubella vaccines,the peak 
of fever usually occurs between 5-12 days post-vaccination 
[Shinefield, 2005].
 
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Objectives
Primary

To demonstrate the non-inferiority of the antibody 
response to the CS antigen when RTS,S/AS01
Eis co-
administered with YF vaccine and a combined measles 
and rubella vaccine versus RTS,S/AS01
Eadministered 
alone.
Criteria for non-inferiority: one month post Dose 3 of 
RTS,S/AS01E, the upper limit (UL) of the 2-sided 95% 
confidence interval (CI) on the geometric mean titer 
(GMT) ratio (RTS,S group/Coad group) of the anti-CS, is 
below alimit of 2.
Secondary
Immunogenicity
To describe the antibody response to the CS antigen when 
RTS,S/AS01Eis administered at 6, 7.5 and 9 months of 
age in co-administration with YF vaccine and a combined 
measles and rubella vaccine versus RTS,S/AS01E
administered alone.
To describe the antibody response to the hepatitis B 
surface (HBs) antigen when RTS,S/AS01
Eis 
administered at 6, 7.5 and 9 months of age in co-
administration with YF vaccine and a combined measles 
and rubella vaccine versus RTS,S/AS01Eadministered 
alone.
To demonstrate the non-inferiority of the antibody 
response to the measles vaccine antigen when YF vaccine 
and a combined measles and rubella vaccine are co-
administered with RTS,S/AS01
Eversus administration 
without RTS,S/AS01E.
Criteria for non-inferiority: one month post-vaccination 
with the combined measles and rubella vaccine, the UL of 
the 95% CI on the difference in seroconversion rates of 
the anti-measles antibody (anti-Me), is below 10% 
(Control group minus Coad group).
To describe the antibody response to the measles vaccine 
antigen when YF vaccine and a combined measles and 
rubella vaccine are co-administered with RTS,S/AS01
E
versus administration without RTS,S/AS01E.

To demonstrate the non-inferiority of the antibody 
response to the rubella vaccine antigen when YF vaccine 
and a combined measles and rubella vaccine are co-
administered with RTS,S/AS01
Eversus administration 
 
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without RTS,S/AS01E.
Criteria for non-inferiority: one month post-vaccination 
with the combined measles and rubella vaccine, the UL of 
the 95% CI on the difference in seroconversion rates of 
the anti-rubella antibody (anti-Ru), is below 10% 
(Control group minus Coad group).

To describe the antibody response to the rubella vaccine 
antigen when YF vaccine and a combined measles and 
rubella vaccine are co-administered with RTS,S/AS01
E
versus administration without RTS,S/AS01E.
To demonstrate the non-inferiority of the antibody 
response to the YF vaccine antigen when YF vaccine and 
a combined measles and rubella vaccine are co-
administered with RTS,S/AS01E versus administration 
without RTS,S/AS01E.
Criteria for non-inferiority: one month post-vaccination 
with the YF vaccine, the UL of the 95% CI on the 
difference in seropositivity rates of the anti-yellow fever 
antibody (anti-YF), is below 10% (Control group minus 
Coad group).

To describe the antibody response to the YF vaccine 
antigen when YF vaccine and a combined measles and 
rubella vaccine are co-administered with RTS,S/AS01
E
versus administration without RTS,S/AS01
E.
Safety

Evaluation of the safety profile of RTS,S/AS01Ewhen 
administered at 6, 7.5 and 9 months of age in co-
administration with YF vaccine and a combined measles 
and rubella vaccine versus RTS,S/AS01
Eadministered 
alone.
Tertiary
Immunogenicity
To describe the antibody response to the human catalase 
after administration of a 3-dose course of RTS,S/AS01E.
Study design

Experimental design: Phase IIIB, open, randomized, 
controlled, multi-centricstudy with three parallel groups.
Duration of the study:Approximately 33 months per 
participant in the Coad or the RTS,S group and 36 
months in the Control group.

Epoch001: Primary starting at Visit 1(Screening) 
and ending at Visit 15(Month 36).
 
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
Study groups:
Coad group: Children randomized to receive 
Vitamin A at 6 months of age, RTS,S/AS01Evaccine 
at 6, 7.5 and 9 months of age, and YF vaccine and a 
combined measles and rubella vaccine at 9 months of 
age. Children will receive a booster dose of 
RTS,S/AS01Evaccine 18 months post Dose 3 (i.e. at 
27 months of age).
RTS,S group: Children randomized to receive 
Vitamin A at 6 months of age, RTS,S/AS01Evaccine 
at 6, 7.5 and 9 months of age, and YF vaccine and a 
combined measles and rubella vaccine at 10.5 
months of age. Children will receive a booster dose 
of RTS,S/AS01Evaccine 18 months post Dose 3 (i.e. 
at 27 months of age).
Control group: Children randomized to receive 
Vitamin A at 6 months of age and YF vaccine and a 
combined measles and rubella vaccine at 9 months of 
age. These children will receive RTS,S/AS01
E
vaccine at 10.5, 11.5 and 12.5 months of age plus a 
booster dose 17.5 months post Dose 3 (i.e. at 30 
months of age), so they can benefit from the same 
protection as children from the Coad and the RTS,S 
groups.
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Number of subjects
Age (Min)
Epoch 001
Coad group
233
6months*
x
RTS,S group
233
6months*
x
Contro
l group
233
6months*
x
* For c
lar
ity th
is corresponds from the day the ch
i
ld becomes6 months of age unt
i
l the day before the ch
i
ld ach
ieves 7 
months of age.
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/Product name
Study groups
Coad group
RTS,S group
Control group
RTS,S/AS01E
RTS,S
x
x
x
AS01E
x
x
x
Ye
l
low fever
WHO prequa
l
if
iedYe
l
low 
Fever
x
x
x
Meas
les and 
Rube
l
la
MR-VAC
x
x
x
V
itam
in A
V
itam
in A
x
x
x
MR-VAC: L
ive attenuated meas
les v
irus and rube
l
la v
irus vacc
ine(Serum Inst
itute of Ind
ia)
Control: active control(Group receiving the EPI 
 
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interventions alone [Vitamin A at 6 months and YF 
vaccine and a combined measles and rubella vaccine at 9 
months of age]).Children from this group will receive a 3-
dose course (0, 1, 2-month) and a booster dose (17.5
months post Dose 3) of RTS,S/AS01Efrom Visit 6 
onwards (10.5 months of age) so they can benefit from the 
same protection as the children from the Coad and the 
RTS,S groups.

Vaccination schedules:

For the Coad group, children will receive Vitamin A 
and RTS,S/AS01
Evaccine on Day 0 (Visit 2 [6 
months of age]), RTS,S/AS01Ealone at Visit 3 (7.5 
months of age), co-administration of RTS,S/AS01
E,
YF vaccine and a combined measles and rubella 
vaccine at Visit 4 (9 months of age), and a booster 
dose of RTS,S/AS01Eat Visit 10 (27 months of age).

For the RTS,S group, children will receive Vitamin 
A and RTS,S/AS01Evaccine on Day 0 (Visit 2 [6 
months of age]), RTS,S/AS01Ealone at Visit 3 and 4 
(7.5 and 9 months of age), YF vaccine and a 
combined measles and rubella vaccine at Visit 6 
(10.5 months of age), and a booster dose of 
RTS,S/AS01Eat Visit 10 (27 months of age).

For the Control group, children will receive 
Vitamin A on Day 0 (Visit 2 [6 months of age]) and 
YF vaccine and a combined measles and rubella 
vaccine at Visit 4 (9 months of age).These children 
will also receive RTS,S/AS01Evaccine at Visit 6, 7 
and 8 (10.5, 11.5 and 12.5 months of age) and a 
booster dose of RTS,S/AS01Evaccine at Visit 12 (30 
months of age).
Treatment allocation: randomized in a 1:1:1 ratio to each 
study group.

Blinding: open
Synopsis Table 3
Blinding of study epochs
Study Epoch
Blinding
Epoch 001
open
 
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
Sampling schedule:

For the Coad group, blood samples will be taken on 
Day 0, on the day of co-administration of 
RTS,S/AS01Ewith the YF vaccine and the combined 
measles and rubella vaccine (Month 3) and at one 
month post co-administration (Month 4).

For the RTS,S group, blood samples will be taken on 
Day 0 and at one month post Dose 3 of RTS,S/AS01
E
(Month 4).
For the Control group, blood samples will be taken on 
Day 0, on the day of administration of the YF vaccine 
and the combined measles and rubella vaccine (Month 
3) and at one month post-vaccination with the YF 
vaccine and the combined measles and rubella vaccine 
(Month 4).

Type of study: self-contained.
Data collection: Electronic Case Report Form (eCRF).

Safety monitoring:
For theCoad group and the RTS,S group,there will be:

A 7-day follow-up period (day of vaccination and 6 
subsequent days) following vaccines administered at 6 
and 7.5 months of age (Visits 2 and 3) for recording of 
solicited local and general adverse events (AEs). On 
the day of vaccination the evaluation willbe carried-
out by the study physician at the study center. On Days 
1, 2, 3, 4, 5 and 6 after vaccination, trained study 
personnel will visit the children to record solicited AEs 
on diary cards.

A 14-day follow-up period (day of vaccination and 13 
subsequent days) following vaccines administered at 9 
months of age (Visit 4) for recording of solicited local 
and general AEs. On the day of vaccination the 
evaluation will be carried-out by the study physician at 
the study center. On Days 1 to 13 after vaccination, 
trained study personnel will visit the children to record 
solicited AEs on diary cards.
Unsolicited AEs will be collected from the day of first 
vaccine administration (Visit 2)until 42 days after 
Visit 4.On the daysof vaccinations (Visits 2, 3 and 4)
the evaluation will be carried-out by the study 
physician at the study center. Unsolicited AEs will be 
captured through passive surveillance at inpatient and 
 
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outpatient facilitiesand during study visits. In addition 
on Days 1 to 6 after vaccinations atVisits 2 and 3 and 
on Days 1 to 13 after Visit 4, trained study personnel 
will visit the children to record any unsolicited AEs on 
diary cards.

A 30-day follow-up period (day of vaccinationand 29 
subsequent days) after booster dose of RTS,S/AS01
E
vaccines administered at 27 months of age (Visit 10) 
for reporting unsolicited AEs. Unsolicited AEs will be 
captured through passive surveillance at inpatient and 
outpatient facilitiesand during study visits.
For the Control group, there will be:

A 7-day follow-up period (day of administrationand 6 
subsequent days) following Vitamin A administered at 
6 months of age (Visit 2)and a 7-day follow-up period 
following Visit 3 (7.5 months of age)for recording of 
solicited general AEs. On the day of Visits 2 and 3the 
evaluation will be carried-out by the study physician at 
the study center. On Days 1, 2, 3, 4, 5 and 6 after 
Visits 2 and 3, trained study personnel will visit the 
children to record solicited general AEs on diary cards.

A 14-day follow-up period (day ofvaccination and 13 
subsequent days) following vaccines administered at 9 
months of age (Visit 4) for recording of solicited local 
and general AEs. On the day of vaccination the 
evaluation will be carried-out by the study physician at 
the study center. On Days 1 to 13 after vaccination, 
trained study personnel will visit the children to record 
solicited AEs on diary cards.
Unsolicited AEs will be collected from the day of 
Vitamin A administration (Visit 2) until 42 days after 
Visit 4. On the day of Visits 2, 3 and 4 the evaluation 
will be carried-out by the study physician at the study 
center. Unsolicited AEs will be captured through 
passive surveillance at inpatient and outpatient 
facilities and during study visits. In addition on Days 1 
to 6 after vaccinations at Visits 2 and 3 and on Days 1 
to 13 after Visit 4, trained study personnel will visit the 
children to record any unsolicited AEs on diary cards.
Unsolicited AEs will be collected from the day of the 
first dose of RTS,S/AS01
E(Visit 6) until 30 days after 
Visit 8 and from the day of the booster dose of 
RTS,S/AS01Eadministered at 30 months of age (Visit 
12) until 30 days after the booster dose. Onthe day of 
vaccination the evaluation will be carried-out by the 
 
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study physicianat the study center. Unsolicited AEs 
will be captured through passive surveillance at 
inpatient and outpatient facilitiesand during study 
visits.
For all groups (Coad group, RTS,S groupand Control 
group):

Each subject will be observed for at least 60 minutes 
after vaccination to evaluate and treat any acute AEs.

All serious adverse events (SAEs) will be reported 
until study end (Month 33 for Coad and RTS,S groups 
and Month 36 for the Control group).

All AEs of specific interest will be reported until study 
end (Month 33 for Coad and RTS,S groups and Month 
36 for the Control group). AEs of specific interest 
include seizure (occurring within 30 days post-
vaccination for vaccine doses administered at 6 and 7.5 
months of age or 42 days post-vaccination for vaccine 
doses administered at 9 months of age), meningitis and 
potential immune-mediated diseases (pIMDs).

This study will be overseen by a formally constituted 
Independent Data Monitoring Committee (IDMC) 
operating under a charter.Information about the rescue 
plan for measles and rubella can be found in Section 
5.7.5.1.

Immunogenicity monitoring:
Immune response to the CS antigen will be assessed 
before vaccination (Day 0) and one month post Dose 3 
of RTS,S/AS01Evaccine (Month 4) (i.e. in the Coad 
group and RTS,S group).
Immune response to the HBs antigen will be assessed 
before vaccination (Day 0) and one month post Dose 3 
of RTS,S/AS01Evaccine (Month 4) (i.e. in the Coad 
group and RTS,S group).

Immune responseto the catalase antigen will be 
assessed at Day 0 for the Control and the Coad groups, 
one month post Dose 3 of RTS,S/AS01Evaccine for 
the Coad group (Month 4) and before the first 
RTS,S/AS01Evaccine dose for the Control group 
(Month 4).
Immune responseto the YF vaccine will be assessed 
one month post-vaccination with the YF vaccine and 
the combined measles and rubella vaccines when 
administered at 9 months of age (Month 4) (i.e. in the 
 
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Coad group and Control group).

Immune response to the combined measles and rubella 
vaccine will be assessed before vaccination at Month 3 
and one month post-vaccination with the YF vaccine 
and the combined measles and rubella vaccines when 
administered at 9 months of age (Month 4) (i.e. in the 
Coad group and Control group).
Number of subjects Approximately 700subjects (233 subjects per group) will be 
enrolled in this study.
Endpoints
Primary

Non-inferiority of the antibody response to the CS antigen 
(RTS,S group/Coad group):

Anti-CS antibody titers at one month post Dose 3 of 
RTS,S/AS01E(Month 4).
Secondary
Immunogenicity

Antibody response to the candidate vaccine RTS,S/AS01
E
(RTS,S group and Coad group):

Anti-CS antibody titers and seropositivity at Day 0 and 
at one month post Dose 3 of RTS,S/AS01
E(Month 4).

Anti-HBs antibody titers and seroprotection at Day 0 
and at one month post Dose 3 of RTS,S/AS01
E(Month 
4).
Non-inferiority of the antibody response to the measles 
vaccine antigen in the combined measles and rubella 
vaccine (Control group minus Coad group):

Seroconversion for anti-Me at one month post-
vaccination with the combined measles and rubella 
vaccine (Month 4). Seroconversion is defined as 
children with an anti-Me pre-vaccination titer below 
150 mIU/ml and a post-vaccination titer ≥ 150 
mIU/ml.
Antibody response to the measles vaccine antigen in the 
combined measles and rubella vaccine (Control group and 
Coad group):

Anti-Me antibody titers and seropositivity (≥150 
mIU/ml) pre-vaccination (Month 3) and one month 
post-vaccination with the combined measles and 
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
Non-inferiority of the antibody response to the rubella 
vaccine antigen in the combined measles and rubella 
vaccine (Control group minus Coad group):

Seroconversion for anti-Ru at one month post-
vaccination with the combined measles and rubella 
vaccine (Month 4). Seroconversion is defined as 
children with an anti-Ru pre-vaccination titer below 4 
IU/ml and a post-vaccination titer ≥ 4 IU/ml.
Antibody response to the rubella vaccine antigen in the 
combined measles and rubella vaccine (Control group and 
Coad group):

Anti-Ru antibody titers and seropositivity (≥ 4 IU/ml) 
pre-vaccination (Month 3) and one month post-
vaccination with the combined measles and rubella 
vaccine (Month 4).

Non-inferiority of the antibody response to the YF vaccine 
antigen (Control group minus Coad group):

Seropositivity (≥10 ED50) for anti-YF at one month 
post-vaccination with the YF vaccine (Month 4).

Antibody response to the YF vaccine antigen (Control
group and Coad group):
Anti-YF antibody titers and seropositivity (≥ 10 ED50) 
one month post-vaccination with the YF vaccine 
(Month 4).
Safety

Solicited local and general AEs.

For the Coad and the RTS,S groups, the occurrence of 
solicited local andgeneral AEs over a 7-day follow-up 
period (day of administration and 6 subsequent days) 
after administration of Vitamin A and study vaccines 
at 6 months of age (Visit 2).
For the Control group, the occurrence of solicited 
general AEs over a 7-day follow-up period (day of 
administration and 6 subsequent days) after 
administration of Vitamin A at 6 months of age (Visit 
2).

For the Coad and the RTS,S groups, the occurrence of 
solicited local and general AEs over a 7-day follow-up 
period (day of vaccination and 6 subsequent days) after 
dose of study vaccines administered at 7.5 months of 
age (Visit 3).
For the Control group, the occurrence of solicited 
 
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general AEs over a 7-day follow-up period (day of 
visit and 6 subsequent days) after Visit 3 (7.5 months 
of age).
For all groups, the occurrence of solicited general and 
local AEs over a 14-day follow-up period (day of 
vaccination and 13 subsequent days) after dose of 
study vaccines administered at 9 months of age (Visit 
4).

Unsolicited AEs.

For allgroups, the occurrence of unsolicited AEs over 
a 30-day follow-up period (day of administration and 
29 subsequent days) after administration of Vitamin A 
and study vaccines at 6 months of age (Visit 2).
For the Coad and the RTS,S groups, the occurrence of 
unsolicited AEs over a 30-day follow-up period (day 
of vaccination and 29 subsequent days) after dose of 
study vaccines administered at 7.5 months of age 
(Visit 3).

For the Control group, the occurrence of unsolicited 
AEs over a 30-day follow-up period (day of visit and 
29 subsequent days) after Visit 3 (7.5 months of age).

For all groups, the occurrence of unsolicited AEs over 
a 42-day follow-up period (day of vaccination and 41 
subsequent days) after dose of study vaccines 
administered at 9 monthsof age (Visit 4).

For the Coad and the RTS,S groups, the occurrence of 
unsolicited AEs over a 30-day follow-up period (day 
of vaccination and 29 subsequent days) after the 
booster dose of study vaccine administered at 27 
months of age (Visit 10).
For the Control group, the occurrence of unsolicited 
AEs over a 30-day follow-up period (day of 
vaccination and 29 subsequent days) after dose of 
study vaccines administered at 10.5, 11.5, 12.5 and 30 
months of age (Visit 6, 7, 8 and 12).
SAEs: all, fatal and related SAEs.

The occurrence of SAEs occurring within 30 days (day 
of vaccination and 29 subsequent days) after each 
administrations.
The occurrence of SAEs from Screening visit (Visit 1) 
until Month 4.5.

The occurrence of SAEs from Screening visit (Visit 1) 
 
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until study end (Month 33 for Coad and RTS,S groups 
and Month 36 for the Control group).
The occurrence of pIMDs from Day 0 until Month 4.5.

The occurrence of pIMDsfrom Day 0 until study end 
(Month33 for Coad and RTS,S groups and Month 36 
for the Control group).

The occurrence of meningitis from Day 0 until Month 
4.5.

The occurrence of meningitis from Day 0 until study 
end (Month 33 for Coad and RTS,S groups and Month 
36 for the Control group).
The occurrence of seizure (occurring within 30 days 
post-vaccination for vaccine doses administered at 6 
and 7.5 months of age [Visits 2 and 3] or 42 days post-
vaccination for vaccine doses administered at 9 months 
of age [Visit 4]) from Day 0 until Month 4.5.

The occurrence of seizure occurring within 30 days 
post-vaccination for vaccine doses administered at 6, 
7.5 and 27 months of age (Visits 2, 3 and 10 for Coad 
and RTS,S group) and at 10.5, 11.5, 12.5 and 30 
months of age (Visits 6, 7, 8 and 12for Control group) 
or 42 days post-vaccination for vaccine doses 
administered at 9 months of age (Visit 4 for all 
groups).
The occurrence of generalized convulsive seizure 
occurring within 7 days after vaccines administered at 
Visit 2 and 3 (Coad and RTS,S groups) and 14days 
after vaccines administered at Visit 4 (all groups).
Tertiary
Immunogenicity
Antibody response tocomponent ofthe candidate vaccine 
RTS,S/AS01E(Coad groupand Control group):

Anti-catalase antibody concentrations and 
seropositivity at Day 0 and before administration of 
RTS,S/AS01E(Month 4) for the Control group and at 
Day 0 and at one month post Dose 3 of RTS,S/AS01
E
(Month 4) for the Coad group.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS (AMENDED: 09 AUGUST 2016)........................................28
GLOSSARY OF TERMS...............................................................................................31
TRADEMARKS.............................................................................................................35
1. INTRODUCTION....................................................................................................36
1.1.
Background................................................................................................36
1.2.
Rationale for the study and study design....................................................36
1.2.1.
Rationale for the study vaccine and vaccination schedule...........36
1.2.2.
Rationale for non-inferiority assessment......................................36
1.2.3.
Rationale for safety follow-up.......................................................37
1.3.
Benefit : Risk Assessment..........................................................................37
1.3.1.
Risk Assessment.........................................................................37
1.3.2.
Benefit Assessment.....................................................................39
1.3.3.
Overall Benefit : Risk Conclusion.................................................39
2. OBJECTIVES.........................................................................................................40
2.1.
Primary objective........................................................................................40
2.2.
Secondary objectives..................................................................................40
2.3.
Tertiary objective........................................................................................41
3. STUDY DESIGN OVERVIEW ................................................................................42
4. STUDY COHORT...................................................................................................47
4.1.
Number of subjects/centers........................................................................47
4.1.1.
Overview of the recruitment plan..................................................47
4.2.
Inclusion criteria for enrolment....................................................................47
4.3.
Exclusion criteria for enrolment...................................................................48
5. CONDUCT OF THE STUDY..................................................................................49
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................49
5.2.
Subject identification and randomization of treatment.................................50
5.2.1.
Subject identification....................................................................50
5.2.2.
Randomization of treatment.........................................................50
5.2.2.1.
Randomization of supplies..........................................50
5.2.2.2.
Treatment allocation to the subject.............................51
5.2.2.2.1.
Study group and treatment 
numberallocation...................................51
5.2.2.2.2.
Treatment number allocation for 
subsequent doses..................................51
5.2.3.
Allocation of subjects to assay subsets........................................51
5.3.
Method of blinding......................................................................................51
 
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5.4.
General study aspects................................................................................52
5.4.1.
Independent Data Monitoring Committee (IDMC) oversight.........52
5.4.2.
Standard of care provided to the subjects during the study..........52
5.5.
Outline of study procedures........................................................................53
5.6.
Detailed description of study procedures....................................................59
5.6.1.
Informed consent.........................................................................59
5.6.2.
Check inclusion and exclusion criteria.........................................59
5.6.3.
Collect demographic data............................................................60
5.6.4.
Medical history.............................................................................60
5.6.5.
Physical examination...................................................................60
5.6.6.
Measure/record length and weight...............................................60
5.6.7.
Issuing subject identification card.................................................60
5.6.8.
Study group and treatment number allocation..............................60
5.6.9.
Check contraindications, warnings and precautions to 
vaccination...................................................................................61
5.6.10. Assess pre-vaccination body temperature...................................61
5.6.11. Study Vaccines/product administration........................................61
5.6.12. Sampling......................................................................................61
5.6.12.1. Blood sampling for anti-HBs and anti-CS 
immune response assessments (Amended: 09 
August 2016)..............................................................62
5.6.12.2. Blood sampling for anti-catalase immune 
response assessments (Amended: 09 August 
2016)..........................................................................62
5.6.12.3. Blood sampling for anti-Me and anti-Ru 
immune response assessments (Amended: 09 
August 2016)..............................................................62
5.6.12.4. Blood sampling for anti-YF immune response 
assessments (Amended: 09 August 2016).................62
5.6.13. Check and record concomitant medication/vaccination and 
cases of measles and rubella.......................................................63
5.6.14. Recording of AEs, SAEs, and AEs of specific interest..................63
5.6.15. Study conclusion..........................................................................64
5.7.
Biological sample handling and analysis.....................................................64
5.7.1.
Use of specified study materials..................................................65
5.7.2.
Biological samples.......................................................................66
5.7.3.
Laboratory assays.......................................................................66
5.7.4.
Biological samples evaluation......................................................67
5.7.4.1.
Immunological read-outs............................................67
5.7.5.
Immunological correlates of protection.........................................68
5.7.5.1.
Rescue Plan...............................................................68
6. STUDY VACCINES/PRODUCT AND ADMINISTRATION......................................69
6.1.
Description of study vaccines/product.........................................................69
6.2.
Storage and handling of study vaccines/product.........................................69
6.3.
Dosage and administration of study vaccines/product.................................71
6.3.1.
RTS,S/AS01E(0.5 ml dose).........................................................71
6.3.2.
Combined measles and rubella vaccine (MR-VAC) (0.5 ml 
dose)...........................................................................................72
6.3.3.
Licensed WHO prequalified yellow fever vaccine (0.5 ml 
dose)...........................................................................................72
6.3.4.
Vitamin A(100000 IU dose).........................................................72
 
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6.4.
Replacement of unusable vaccine/product doses.......................................72
6.5.
Contraindications to subsequent vaccination..............................................72
6.6.
Warnings and precautions..........................................................................73
6.7.
Concomitant medications/products and concomitant vaccinations..............73
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................73
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses........................74
6.8.
Capture of cases of measles and rubella (Amended: 09 August 
2016)..........................................................................................................74
7. HEALTH ECONOMICS..........................................................................................75
8. SAFETY.................................................................................................................75
8.1.
Safety definitions........................................................................................75
8.1.1.
Definition of an adverse event......................................................75
8.1.2.
Definition of a serious adverse event...........................................76
8.1.3.
Solicited adverse events..............................................................77
8.1.3.1.
Solicited local (injection-site) adverse events..............77
8.1.3.2.
Solicited general adverse events................................77
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events............................................................................77
8.1.5. 
Adverse events of specific interest...............................................78
8.1.5.1.
Potential immune-mediated diseases.........................78
8.1.5.2.
Seizures within 30 or 42 days of vaccination 
(Amended: 09 August 2016).......................................80
8.1.5.3.
Meningitis (Amended: 09 August 2016)......................80
8.2.
Detecting and recording adverse events and serious adverse events.........80
8.2.1.
Time period for detecting and recording adverse events 
and serious adverse events.........................................................80
8.2.2.
Post-Study adverse events and serious adverse events..............83
8.2.3.
Evaluation of adverse events and serious adverse events...........83
8.2.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................83
8.2.3.2.
Assessment of adverse events...................................84
8.2.3.2.1.
Assessment of intensity..........................84
8.2.3.2.2.
Assessment of causality.........................85
8.2.3.3.
Assessment of outcomes............................................86
8.2.3.4.
Medically attended visits.............................................86
8.3.
Reporting of serious adverse events and other events................................87
8.3.1.
Prompt reporting of serious adverse events and other 
events to GSK Biologicals............................................................87
8.3.2.
Contact information for reporting serious adverse events 
and AEs of specific interest..........................................................88
8.3.3.
Completion and transmission of SAE reports to GSK 
Biologicals...................................................................................88
8.3.3.1.
Back-up system in case the electronic reporting 
system does not work.................................................88
8.3.4.
Reporting of AEs of specific interest to GSK Biologicals 
(Amended: 09 August 2016)........................................................89
 
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8.3.5. 
Updating of SAE and AEs of specific interest information 
after removal of write access to the subject’s eCRF.....................89
8.3.6.
Regulatory reporting requirements for serious adverse 
events..........................................................................................89
8.4.
Follow-up of adverse events and serious adverse events...........................90
8.4.1.
Follow-up of adverse events and serious adverse events............90
8.4.1.1.
Follow-up during the study..........................................90
8.4.1.2.
Follow-up after the subject is discharged from 
thestudy.....................................................................90
8.5.
Treatment of adverse events......................................................................90
8.6.
Subject card................................................................................................90
9. SUBJECT COMPLETION AND WITHDRAWAL.....................................................91
9.1.
Subject completion.....................................................................................91
9.2.
Subject withdrawal......................................................................................91
9.2.1.
Subject withdrawal from the study................................................91
9.2.2.
Subject withdrawal from investigational vaccine...........................92
9.3.
Extension study..........................................................................................92
9.4.
Screen and baseline failures.......................................................................92
10.STATISTICAL METHODS......................................................................................93
10.1. Primary endpoints.......................................................................................93
10.2. Secondary endpoints..................................................................................93
10.3. Tertiary endpoints.......................................................................................95
10.4. Determination of sample size......................................................................96
10.5. Cohorts for analyses...................................................................................96
10.5.1. Total vaccinated cohort................................................................96
10.5.2. According-to-protocol cohort for analysis of 
immunogenicity (ATP immunogenicity)........................................96
10.6. Derived and transformed data.....................................................................96
10.7. Analysis of demographics...........................................................................97
10.8. Analysis of immunogenicity.........................................................................97
10.9. Analysis of safety........................................................................................98
10.10.Interpretation of analyses............................................................................99
10.11.Conduct of analyses...................................................................................99
10.11.1. Sequence of analyses..................................................................99
10.11.2. Statistical considerations for interim analyses............................100
11.ADMINISTRATIVE MATTERS.............................................................................100
11.1. electronic Case Report Form instructions.................................................100
11.2. Study Monitoring by GSK Biologicals........................................................100
11.3. Record retention.......................................................................................101
11.4. Quality assurance.....................................................................................101
11.5. Posting of information on publicly available clinical trial registers and 
publication policy......................................................................................102
11.6. Provision of study results to investigators.................................................102
12.COUNTRY SPECIFIC REQUIREMENTS.............................................................102
13.REFERENCES.....................................................................................................102
SAFETY LABORATORY TESTING: CLS South Africa (Amended 09 
August 2016)............................................................................................105
 
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SAFETY LABORATORY TESTING: CLS South Africa.........................................116
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................43
Table 2
Study groups and treatment foreseen in the study.................................44
Table 3
Blinding of study epoch..........................................................................44
Table 4
List of study procedures for the Coad group (Amended: 09 
August 2016)..........................................................................................53
Table 5
List of study procedures for the RTS,S group (Amended: 09 
August 2016)..........................................................................................55
Table 6
List of study procedures for the Control group (Amended: 09 
August 2016)..........................................................................................57
Table 7
Intervals between study visits (Amended: 09 August 2016)....................59
Table 8
Biological samples (Amended: 09 August 2016)....................................66
Table 9
Humoral Immunity (Antibody determination) (Amended: 09 
August 2016)..........................................................................................67
Table 10
Immunological read-outs........................................................................68
Table 11
Study products.......................................................................................69
Table 12
Dosageand administration.....................................................................71
Table 13
Solicited local adverse events................................................................77
Table 14
Solicited general adverse events............................................................77
Table 15
List of potential immune-mediated diseases...........................................79
Table 16
Reporting periods for adverse events and serious adverse 
events (Amended: 09 August 2016).......................................................82
Table 17
Intensity scales for solicited symptoms in infants....................................84
Table 18
Timeframes for submitting serious adverse event and other 
events reports to GSK Biologicals..........................................................87
Table 19
Sample size and power..........................................................................96
Table 20
GSK Biologicals’ laboratories (Amended: 09 August 2016)..................109
Table 21
Outsourced laboratories.......................................................................109
 
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LIST OF FIGURES
PAGE
Figure 1
Study design (Amended: 09 August 2016).............................................42
LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS.....................................................................104
APPENDIX B CLINICAL LABORATORIES................................................................109
APPENDIX CAMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................110
 
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LIST OF ABBREVIATIONS(AMENDED: 09 August 2016)
AE:
Adverse event
Anti-CS:
Antibody to the Plasmodium falciparum
circumsporozoite (CS) repeat domain
Anti-HBs:
Antibody to the hepatitis B surface antigen
Anti-Me:
Anti-measles antibody
Anti-Ru:
Anti-rubella antibody
Anti-YF:
Anti-yellow fever antibody
AS01E:
GSK’s proprietary Adjuvant System containing MPL, 
QS-21 Stimulon®and liposome (25 g MPL and 25 g 
QS-21Stimulon®)
ATP:
According-to-protocol
CEVAC:
Center for Vaccinology
CI:
Confidence interval
CLIA:
Chemiluminescence enzyme immunoassay
CLS:
Clinical Laboratory Sciences
Coad:
Co-administration
CS:
Circumsporozoite protein of Plasmodium falciparum
DTPwHepB:
Diphtheria, tetanus, whole-cell pertussis; hepatitis B 
vaccine
eCRF:
Electronic case report form
ED50:
End point Dilution 50
ELISA:
Enzyme-linked immunosorbent assay
EPI:
Expanded Program on Immunization
eTDF:
Electronic Temperature excursion DecisionForm
FDA:
Food and Drug Administration, United States of America
GCP:
Good Clinical Practice
 
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GMT:
Geometric mean titer
GSK:
GlaxoSmithKline
HIV:
Human immunodeficiency virus
ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
IDMC:
Independent Data Monitoring Committee
IEC:
Independent Ethics Committee
IM:
Intramuscular
IMP:
Investigational Medicinal Product
IRB:
Institutional Review Board
IU:
International units
LAR:
Legally acceptable representative
MedDRA:
Medical Dictionary for Regulatory Activities
MPL:
3-O-desacyl-4’-monophosphoryl lipid A (produced by 
GSK)
pIMD:
Potential immune-mediated disease 
PRN:
Plaque neutralization assay
QS-21Stimulon®:
Quillaja saponariaMolina, fraction 21 (Licensed by 
GSK from Antigenics Inc., a wholly owned subsidiary of 
Agenus Inc., Lexington, MA, USA)
RDE:
Remote Data Entry
RE:
Retinol equivalent
RTS,S:
Particulate antigen, containing both RTS and S (hepatitis 
B surface antigen) proteins
RTS,S/AS01E:
GSK Biologicals’ candidate Plasmodium falciparum
malaria vaccine adjuvanted with GSK Biologicals’ 
proprietary Adjuvant System AS01
E
SAE:
Serious adverse event
 
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SBIR:
Randomization system on internet
SC:
Subcutaneous
SDV:
Source Document Verification
SPM:
Study Procedures Manual
TVC:
Total vaccinated cohort
UL:
Upper limit
WHO:
World Health Organization
YF:
Yellow fever
 
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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 incase 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.
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 
 
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safety.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Sections 6.7.2and 10.5for details on criteria for 
evaluability).
Immunological correlate 
of protection:
The defined immuneresponse 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 authorizationwhen 
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. 
Legally acceptable 
representative
(The terms legal 
representative or legally 
authorized 
representative are used 
in some settings.)
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject
's participation in the clinical trial.
Potential immune-
mediated disease:
Potential immune-mediated diseases (pIMDs) are a subset 
of AEsthat 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.
Randomization:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Self-contained study:
Study with objectives not linked to the data of another 
study.
Serious adverse event:
A serious adverse event (SAE) 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 or blood dyscrasias.
In this study, the following AEs of specific interest
(pIMDs, meningitis and seizure within 30 or 42 days of 
vaccination) will be reported as SAEs.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuringproper conduct of clinical studies at one or 
more investigational sites.
Solicited adverse event:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period.
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 
randomizationor treatment allocation.
Treatment number:
A number identifying a treatment to a subject, according 
to the study randomizationor 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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TRADEMARKS
The following trademarks are used in the present protocol.
Note: In the body of the protocol (including the synopsis), the names of the vaccines and 
medications will be written without the superscript symbol ™ or ® and in italics.
Trademarks not owned by the 
GlaxoSmithKline group of companies
Generic description
MR-VAC™ (Serum Inst
itute of Ind
ia)
L
ive attenuated meas
les v
irus and rube
l
la 
v
irus vacc
ine
QS-21St
imu
lon®(Qu
i
l
la
ja saponar
ia 
Mo
l
ina, fract
ion 21) (
l
icensed by GSK from 
Ant
igen
ics Inc, a who
l
ly owned subs
id
iary of 
Agenus Inc., Lex
ington, MA, USA)
Tr
iterpene g
lycos
ide 
immune enhancer
 
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1.
INTRODUCTION
1.1.
Background
Measles vaccine, yellow fever (YF) vaccine and Vitamin A are part of the standard 
Expanded Program on Immunization (EPI) in several African countries and the rubella 
vaccine is currently being rolled-out in African countries and is expected to be part of the 
routine vaccination program in some countries when RTS,S/AS01Ewill be available.
Please refer to the current Investigator Brochure for information regarding the pre-clinical 
and clinical studies of RTS,S/AS01
E.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study vaccine andvaccination schedule
In sub-Saharan Africa, most of the EPI vaccines are given in early infancy while measles, 
rubella and YF vaccines are given at 9 months of age. Between the first EPI vaccines and 
the measles, rubella and YF vaccines, children receive Vitamin A supplementation at 6 
months of age as recommended by the World Health Organization (WHO)[UNICEF, 
1998]. To limit the number of clinic visits for young children and to optimize vaccine 
implementation, it would be more efficient to administer the first dose of RTS,S/AS01
E
during the EPI visit at 6 months of age when Vitamin A is given and to administer the 
third dose of RTS,S/AS01
Eon the same day as the YF, measles and rubella vaccines at 9 
months of age according to the EPI schedule.This proposed schedule (0, 1.5, 3-month) is 
longer than the schedule currently evaluated in Phase III studies (0, 1, 2-month). 
Recent results from the phase IIIstudy MALARIA-055 PRI (110021) showed a decline 
in efficacy against clinical and severe malaria with time in both children and infants who 
did not receive a booster dose of the RTS,S/AS01Evaccine. Administration of a booster 
dose enhanced protection againstclinical malaria in infants and children as well as the 
efficacy against severe malaria in the children. Vaccination with RTS,S/AS01
Ealso 
significantly reduced the overall hospital admissions, admissions due to malaria, severe 
anemia, and the need for blood transfusion. These protective effects were more marked in 
children who received a booster dose [RTS,S Clinical Trials Partnership,2015]. In order 
to provide the greatest benefit to children enrolled in this study, a booster dose of
RTS,S/AS01Ewill be given 18 months post Dose 3.
In this study, to ensure the same protection as the children vaccinated with RTS,S/AS01E,
children from the Control group will also receive RTS,S/AS01
E.
1.2.2.
Rationale for non-inferiorityassessment
Non-inferiority of the immune response to measles and YF when the third dose of 
RTS,S/AS01Ewas co-administered with measles and YF vaccines compared to measles 
and YF vaccines given alone was demonstrated in study MALARIA-050 in infants 6 to
10 weeks of age at the time of first vaccination [Agnandji, 2010]. There are however no 
data of theanti-circumsporozoite protein of Plasmodium falciparum(anti-CS)immune 
 
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response induced by RTS,S/AS01Ewhen given in co-administration with measles, rubella 
and YF, in a 0, 1.5, 3-month schedule starting at an older age (5-17 months). Considering 
that the implementation of RTS,S/AS01
Evaccine in EPI could occur in children aged 5-
17 months, this study intends to demonstrate that anti-CS immune response of the 
candidate malaria vaccine RTS,S/AS01
Eis not inferior when RTS,S/AS01
Eis 
administered at 6, 7.5 and 9 months of age with the third dose given alone or in co-
administration with a YF vaccine and a combined measles and rubella vaccine.
A secondary objective will assess the non-inferiority of the immune responses to YF 
vaccine and a combined measles and rubella vaccine when they are given in co-
administration with RTS,S/AS01
E.
1.2.3.
Rationale for safety follow-up
Safety and reactogenicity for the RTS,S/AS01
Ehave previously been evaluated, alone or 
in co-administration with EPI vaccines given between 6-12 weeks of age. However, 
safety has not been evaluated in co-administration with measles, rubella and YF in a 0, 
1.5, 3-month schedule starting at 6 months of age. This study will therefore provide 
safety information when RTS,S/AS01Eis administered at 6, 7.5 and 9 months of age 
alone or in co-administration with YF vaccine and a combined measles and rubella 
vaccine.
A 12-month safety follow-up after the last dose of RTS,S/AS01Evaccine will be applied
to all study groups.
Contrary to the 7-day follow-up period after RTS,S/AS01Evaccinationin other malaria 
clinical studies, a 14-day follow-up safety period will be applied in this study following 
the study vaccines administered at 9 months of age (Visit 4) because,in combined 
measles and rubella vaccines,the peak of fever usually occurs between 5-12 days post-
vaccination [Shinefield, 2005].
1.3.
Benefit: Risk Assessment
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of RTS,S/AS01E.
Please refer to the Prescribing Information for information regarding the summary 
potential risks and benefits of MR-VAC, YF vaccineand Vitamin A.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
1.3.1.
Risk Assessment
Important 
Potential/Identified 
Data/Rationale for Risk
Mitigation Strategy
Investigational study vaccine (RTS,S/AS01
E)
Important 
ident
if
ied r
isk: 
Febrile convulsion
The 
increased r
isk of febr
i
le convu
ls
ion w
ith
in 
sevendays post-vacc
inat
ion has been ident
if
ied.
Se
izure 
is an adverse event of 
spec
if
ic 
interest (see Sect
ion 
8.1.5).
 
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Important 
Potential/Identified 
Data/Rationale for Risk
Mitigation Strategy
A prev
ious h
istory of febr
i
le 
se
izures 
is not an exc
lus
ion 
cr
iter
ion for the study. Vacc
inees 
w
ith a h
istory of febr
i
le 
convu
ls
ions shou
ld be c
lose
ly 
fo
l
lowed up as vacc
ine re
lated 
fever may occur after 
vacc
inat
ion.
Important potent
ia
l r
isk: 
Meningitis
An 
imba
lance of men
ing
it
is cases of any et
io
log
ies 
(
i.e. 
inc
lud
ing cases w
ith conf
irmed et
io
logy and 
cases w
ith no et
io
logy found) has been 
ident
if
ied.
Men
ing
it
is 
is an adverse event of 
spec
if
ic 
interest (see Sect
ion 
8.1.5). 
A h
igh 
leve
l of med
ica
l 
superv
is
ion 
is 
in p
lace to detect 
and treat men
ing
it
is 
if 
it occurs. 
A
l
l centers part
ic
ipat
ing to th
is 
study have d
iagnost
ic 
m
icrob
io
log
ica
l fac
i
l
it
ies 
ava
i
lab
le.
Important potent
ia
l r
isk: 
Rebound effect
In the 
large phase III study, MALARIA-055PRI, an 
increased 
inc
idence of severe ma
lar
iare
lat
ive to 
contro
l grouphas been observed, start
ing around 
twoyears after RTS,S/AS01
Epr
imary vacc
inat
ion 
course, 
in ch
i
ldren 5-17 month of age at f
irst dose 
that d
id not rece
ive a RTS,S/AS01
Ebooster dose. 
Th
is h
igher r
isk of severe ma
lar
ia m
ight resu
lt from 
a rebound effect; a de
lay 
into the acqu
is
it
ion of 
natura
l 
immun
ity due to decreased exposure 
in 
vacc
ine re
lat
ive to contro
l.
A booster dose w
ith 
RTS,S/AS01Eis 
inc
luded 
in the 
vacc
inat
ion schedu
le.
Study data have shown that 
in 
those that rece
ived a booster 
there 
is no ev
idence of rebound
upto twoyears post booster.
Important potent
ia
l r
isk: 
Hypersensitivity 
(including anaphylaxis)
As w
ith other vacc
ines, anaphy
lax
is to one or 
severa
l components of the vacc
ine can rare
ly 
occur. 
Few cases of hypersens
it
iv
ity (3) have been 
reported w
ith
in 30 days fo
l
low
ing vacc
inat
ion w
ith 
RTS,S/AS01E. 
No case of hypersens
it
iv
ity has been reported after 
booster dose.
The sub
jects w
i
l
l be observed 
c
lose
ly for at 
least 60 m
inutes 
fo
l
low
ing the adm
in
istrat
ion of 
the vacc
ines, w
ith appropr
iate 
med
ica
l treatment read
i
ly 
ava
i
lab
le 
in case of anaphy
lax
is 
(see Sect
ion 5.6.11).
Prev
ious anaphy
lact
ic react
ion 
w
ith a vacc
ine 
is a 
contra
ind
icat
ion to vacc
inat
ion 
in 
th
is study (see Sect
ion 6.5)
Important potent
ia
l r
isk: 
potential immune-
mediated disease
(pIMD)
pIMDs 
is a theoret
ica
l concern w
ith ad
juvanted 
vacc
ines as no ev
idence of auto
immune d
isease 
caused by RTS,S/AS01
Ehas been observed.
pIMD 
is an adverse event of 
spec
if
ic 
interest (see Sect
ion 
8.1.5).
 
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Important 
Potential/Identified 
Data/Rationale for Risk
Mitigation Strategy
Other
Important 
ident
if
ied r
isk 
w
ith meas
les vacc
ine: 
Febrile convulsion
Febr
i
le convu
ls
ions have been reported assoc
iated 
w
ith the adm
in
istrat
ion of meas
les conta
in
ing 
vacc
ines.
Se
izure 
is an adverse event of 
spec
if
ic 
interest (see Sect
ion 
8.1.5). No preventab
i
l
ity 
measures are ava
i
lab
le so no 
part
icu
lar m
it
igat
ion strategy 
is 
deemed necessary.
Important 
ident
if
ied r
isk 
w
ith meas
les-rube
l
la 
vacc
ine and YF vacc
ine: 
Anaphylaxis
The meas
les and rube
l
la vacc
ine may conta
in 
traces of neomyc
in and YF vacc
ine 
is produced 
in 
spec
if
ied pathogen-free ch
ick embryos. 
Anaphy
lact
ic react
ion to neomyc
in, eggs, ch
icken 
prote
ins or any other components of the vacc
ine 
has been reported.
Anaphy
lact
ic or anaphy
lacto
id 
react
ions to neomyc
in,eggs, 
ch
icken prote
ins or any other 
component of the vacc
ine, 
h
istory of anaphy
lact
ic or 
anaphy
lacto
id react
ions are 
abso
lute contra
ind
icat
ions.
Important potent
ia
l r
isk 
w
ith meas
les-rube
l
la 
vacc
ine: 
Thrombocytopenia
Thrombocytopen
ia has been reported assoc
iated 
w
ith the adm
in
istrat
ion of meas
les conta
in
ing 
vacc
ines.
Most post-immun
izat
ion ep
isodes of 
thrombocytopen
ia reso
lve w
ith
in threemonths, 
a
lthough 
low p
late
let counts may rare
ly pers
ist for 
more than s
ixmonths [Farr
ington, 1995].
In case of thrombocytopen
ia 
fo
l
low
ing prev
ious vacc
inat
ion 
w
ith meas
les conta
in
ing 
vacc
ines, the r
isk-benef
it of 
furtherimmun
iz
ingw
ith meas
les 
vacc
ines shou
ld be carefu
l
ly 
eva
luated.
1.3.2.
Benefit Assessment
The results of the clinical trials showed a significant efficacy of RTS,S/AS01
Eagainst 
malaria disease caused by Plasmodium falciparum.
All the children in the study can benefit of the vaccine as they will all receive 
RTS,S/AS01E. The Control group will receive it later (start of primary vaccination at the 
age of 10.5months [Visit 6]) than the other groups.
1.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this
study, the potential or identified risks identified in association with RTS,S/AS01
E
(SB257049) are justified by the potential benefits (prevention / treatment) that may be 
afforded to subject(s) receiving primary immunization against malaria disease caused by 
Plasmodium falciparum.
 
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2.
OBJECTIVES
2.1.
Primary objective
To demonstrate the non-inferiority of the antibody response to the CS antigen when 
RTS,S/AS01Eis co-administered with YF vaccine and a combined measles and 
rubella vaccine versus RTS,S/AS01
Eadministered alone.
Criteria for non-inferiority: one month post Dose 3 of RTS,S/AS01
E, the upper 
limit (UL) of the 2-sided 95% confidence interval (CI) onthe geometric mean 
titer (GMT) ratio (RTS,S group/Coad group) of the anti-CS, is below a limit of 2.
Refer to Section 10.1for the definition ofthe primary endpoints.
2.2.
Secondary objectives
Immunogenicity
To describe the antibody response to the CS antigen when RTS,S/AS01
Eis 
administered at 6, 7.5 and 9 months of age in co-administration with YF vaccine and 
a combined measles and rubella vaccine versus RTS,S/AS01
Eadministered alone.
To describe the antibody response to the hepatitis B surface (HBs) antigen when 
RTS,S/AS01Eis administered at 6, 7.5 and 9 months of age in co-administration with 
YF vaccine and a combined measles and rubella vaccine versus RTS,S/AS01
E
administered alone.
To demonstrate the non-inferiority of the antibody response to the measles vaccine 
antigen when YF vaccine and a combined measles and rubella vaccine are co-
administered with RTS,S/AS01
Eversus administration without RTS,S/AS01E.
Criteria for non-inferiority: one month post-vaccination with the combined 
measles and rubella vaccine, the UL of the 95% CI on the difference in 
seroconversion rates of the anti-measles antibody (anti-Me), is below 10% 
(Control group minus Coad group).
To describe the antibody response to the measles vaccine antigen when YF vaccine 
and a combined measles and rubella vaccine are co-administered with RTS,S/AS01
E
versus administration without RTS,S/AS01E.
To demonstrate the non-inferiority of the antibody response to the rubella vaccine 
antigen when YF vaccine and a combined measles and rubella vaccine are co-
administered with RTS,S/AS01
Eversus administration without RTS,S/AS01E.
Criteria for non-inferiority: one month post-vaccination with the combined 
measles and rubella vaccine, the UL of the 95% CI on the difference in 
seroconversion rates of the anti-rubella antibody (anti-Ru), is below 10% 
(Control group minus Coad group).
To describe the antibody response to the rubella vaccine antigen when YF vaccine 
and a combined measles and rubella vaccine are co-administered with RTS,S/AS01
E
versus administration without RTS,S/AS01E.
 
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To demonstrate the non-inferiority of the antibody response to the YF vaccine 
antigen when YF vaccine and a combined measles and rubella vaccine are co-
administered with RTS,S/AS01E versus administration without RTS,S/AS01E.

Criteria for non-inferiority: one month post-vaccination with the YF vaccine, the 
UL of the 95% CI on the difference in seropositivity rates of the anti-yellow 
fever antibody (anti-YF), is below 10% (Control group minus Coad group).
To describe the antibody response to the YF vaccine antigen when YF vaccine and a 
combined measles and rubella vaccine are co-administered with RTS,S/AS01
E
versus administration without RTS,S/AS01E.
Safety

Evaluation of the safety profile of RTS,S/AS01Ewhen administered at 6, 7.5 and 9 
months of age in co-administration with YF vaccine and a combined measles and 
rubella vaccine versus RTS,S/AS01
Eadministered alone.
Refer to Section 10.2for the definition of the secondary endpoints.
2.3.
Tertiary objective
Immunogenicity

To describe the antibody response to the human catalase after administration of a 3-
dose course of RTS,S/AS01E.
Refer to Section 10.3for the definition of the tertiary endpoint.
 
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3.
STUDY DESIGN OVERVIEW
Figure 1 
Study design(Amended: 09 August 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 5.5), are essential and required for 
study conduct.
Experimental design: Phase IIIB, open, randomized, controlled, multi-centricstudy 
with three parallel groups.

Duration of the study: Approximately 33 months per participant in the Coad or the 
RTS,S group and 36 months in the Control group.
Epoch 001: Primary starting at Visit 1 (Screening) and ending at Visit 15
(Month 36).

Study groups:
Coad group: Children randomized toreceive Vitamin A at 6 months of age, 
RTS,S/AS01Evaccine at 6, 7.5 and 9 months of age, and YF vaccine and a 
combined measles and rubella vaccine at 9 months of age. Children will receive 
a booster dose of RTS,S/AS01
Evaccine 18 months post Dose 3 (i.e. at 27 
months of age).
RTS,S group: Children randomized to receive Vitamin A at 6 months of age, 
RTS,S/AS01Evaccine at 6, 7.5 and 9 months of age, and YF vaccine and a 
combined measles and rubella vaccine at 10.5months of age. Children will 
receive a booster dose of RTS,S/AS01
Evaccine 18months post Dose 3 (i.e. at 
27 months of age).
Control group: Children randomized to receive Vitamin A at 6 months of age 
and YF vaccine and a combined measles and rubella vaccine at 9 months of age. 
These children will receive RTS,S/AS01Evaccine at 10.5, 11.5and 12.5months 
of age plus a booster dose 17.5months post Dose 3 (i.e. at 30 months of age), so 
they can benefit fromthe same protection as children from the Coad andthe
RTS,S groups.
Table 1
Study groups and epochs foreseen in the study
Study groups
Number of subjects
Age (Min)
Epoch 001
Coad group
233
6months*
x
RTS,S group
233
6months*
x
Contro
l group
233
6months*
x
* For c
lar
ity th
is corresponds from the day the ch
i
ld becomes 6 months of age unt
i
l the day before the ch
i
ld ach
ieves 7 
months of age.
 
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Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/Product name
Study groups
Coad group
RTS,S group
Control group
RTS,S/AS01E
RTS,S
x
x
x
AS01E
x
x
x
Ye
l
low fever
WHO prequa
l
if
iedYe
l
low 
Fever
x
x
x
Meas
les and 
Rube
l
la
MR-VAC
x
x
x
V
itam
in A
V
itam
in A
x
x
x
MR-VAC: L
ive attenuated meas
les v
irus and rube
l
la v
irus vacc
ine (Serum Inst
itute of Ind
ia)
Control: active control(Group receiving the EPI interventions alone [Vitamin A at 6 
months and YF vaccine and a combined measles and rubella vaccine at 9 months of 
age]).Children from this group will receive a 3-dose course (0, 1, 2-month) and a 
booster dose (17.5months post Dose 3) of RTS,S/AS01Efrom Visit 6onwards (10.5
months of age) so they can benefit from the same protection as the children from the 
Coad and the RTS,S groups.

Vaccination schedules:
For the Coad group, children will receive Vitamin A and RTS,S/AS01
Evaccine 
on Day 0 (Visit 2 [6 months of age]), RTS,S/AS01
Ealone at Visit 3 (7.5 months 
of age), co-administration of RTS,S/AS01
E,YF vaccine and a combined measles 
and rubella vaccine at Visit 4 (9 months of age), and a booster dose of 
RTS,S/AS01Eat Visit 10(27 months of age).
For the RTS,S group, children will receive Vitamin A and RTS,S/AS01
E
vaccine on Day 0 (Visit 2 [6 months of age]), RTS,S/AS01
Ealone at Visit 3 and 
4 (7.5 and 9 months of age), YF vaccine and a combined measles and rubella 
vaccine at Visit 6(10.5months of age), and a booster dose of RTS,S/AS01Eat 
Visit 10(27 months of age).
For the Control group, children will receive Vitamin A on Day 0 (Visit 2 [6 
months of age]) and YF vaccine and a combined measles and rubella vaccine at 
Visit 4 (9 months of age).These children will also receive RTS,S/AS01Evaccine 
at Visit 6, 7and 8(10.5, 11.5and 12.5months of age) and a booster dose of 
RTS,S/AS01Evaccine at Visit 12(30 months of age).

Treatment allocation: randomized in a 1:1:1 ratio to each study group.
Blinding:open
Table 3
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
open
Sampling schedule:
For the Coad group,blood samples will be taken onDay 0, on the day of co-
administration of RTS,S/AS01Ewith the YFvaccine and the combined measles 
 
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and rubellavaccine (Month 3) and at one month post co-administration (Month 
4).

For the RTS,S group,blood samples will be taken onDay 0and at one month 
post Dose 3 of RTS,S/AS01E(Month 4).

For the Control group, blood samples will be taken on Day 0, on the day of
administration of the YFvaccine and the combined measles and rubellavaccine 
(Month 3) and at one month post-vaccination with the YFvaccine and the 
combined measles and rubellavaccine (Month 4).
Type of study: self-contained.
Data collection: Electronic Case Report Form (eCRF).
Safety monitoring:
For theCoad group and the RTS,S group,there will be:
A 7-day follow-up period (day of vaccination and 6 subsequent days) following 
vaccines administered at 6 and 7.5 months of age (Visits 2 and 3) for recording 
of solicited local and general adverse events (AEs). On the day of vaccination 
the evaluation will be carried-out by the study physician at the study center. On 
Days 1, 2, 3, 4, 5 and 6 after vaccination, trained study personnel will visit the 
children to record solicited AEs on diary cards.
A 14-day follow-up period (day of vaccination and 13 subsequent days) 
following vaccines administered at 9 months of age (Visit 4) for recording of 
solicited local and general AEs. On the day of vaccination the evaluation will be 
carried-out by the study physician at the study center. On Days 1 to 13 after 
vaccination, trained study personnel will visit the children to record solicited 
AEs on diary cards.

Unsolicited AEs will be collected from the day of first vaccine administration 
(Visit 2) until 42 days after Visit 4. On the days of vaccinations (Visits 2, 3 and 
4) the evaluation will be carried-out by the study physician at the study center. 
Unsolicited AEs will be captured through passive surveillance at inpatient and 
outpatient facilitiesand during study visits. In addition on Days 1 to 6 after 
vaccinations at Visits 2 and 3 and on Days 1 to 13 after Visit 4, trained study 
personnel will visit the children to record any unsolicited AEs on diary cards.
A 30-day follow-up period (day of vaccinationand 29 subsequent days) after 
booster dose of RTS,S/AS01Evaccines administered at 27 months of age (Visit 
10) for reporting unsolicited AEs. Unsolicited AEs will be captured through 
passive surveillance at inpatient and outpatient facilitiesand during study visits.
For the Control group, there will be:
A 7-day follow-up period (day of administrationand 6 subsequent days) 
following Vitamin A administered at 6 months of age (Visit 2) and a 7-day 
follow-up period following Visit 3 (7.5 months of age)for recording of solicited 
general AEs. On the day of Visits 2 and 3the evaluation will be carried-out by 
the study physician at the study center. On Days 1, 2, 3, 4, 5 and 6 after Visits 2 
 
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and 3, trained study personnel will visit the children to record solicited general 
AEs on diary cards.

A 14-day follow-upperiod (day of vaccination and 13 subsequent days) 
following vaccines administered at 9 months of age (Visit 4) for recording of 
solicited local and general AEs. On the day of vaccination the evaluation will be 
carried-out by the study physician at the study center. On Days 1 to 13 after 
vaccination, trained study personnel will visit the children to record solicited 
AEs on diary cards.
Unsolicited AEs will be collected from the day of Vitamin A administration 
(Visit 2) until 42 days after Visit 4. On the day of Visits 2, 3 and 4 the 
evaluation will be carried-out by the study physician at the study center. 
Unsolicited AEs will be captured through passive surveillance at inpatient and 
outpatient facilities and during study visits. In addition on Days 1 to 6after 
vaccinations at Visits 2 and 3 and on Days 1 to 13 after Visit 4, trained study 
personnel will visit the children to record any unsolicited AEs on diary cards.
Unsolicited AEs will be collected from the day of the first dose of RTS,S/AS01
E
(Visit 6)until 30 days after Visit 8 and from the day of the booster dose of 
RTS,S/AS01Eadministered at 30 months of age (Visit 12) until 30 days after the 
booster dose. Onthe day of vaccination the evaluation will be carried-out by the 
study physician at the study center. Unsolicited AEs will be captured through 
passive surveillance at inpatient and outpatient facilitiesand during study visits.
For all groups (Coad group, RTS,S groupand Control group):
Each subject will be observed for at least 60 minutes after vaccination to 
evaluate and treat any acute AEs.
All serious adverse events (SAEs) will be reported until study end (Month 33 for 
Coad and RTS,S groups and Month 36 for the Control group).
All AEs of specific interest will be reported until study end (Month 33 for Coad 
and RTS,S groups and Month 36 for the Control group). AEs of specific interest
include seizure (occurring within 30 dayspost-vaccination for vaccine doses 
administered at 6 and 7.5 months of age or 42 days post-vaccination for vaccine 
doses administered at 9 months of age), meningitis and potential immune-
mediated diseases(pIMDs).
This study will be overseen by a formally constituted Independent Data 
Monitoring Committee (IDMC) operating under a charter.Information about the 
rescue plan for measles and rubella can be found in Section 5.7.5.1.
Immunogenicity monitoring:
Immune response to the CS antigen will be assessed before vaccination (Day 0) 
and one month post Dose 3 of RTS,S/AS01
Evaccine (Month 4) (i.e. in the Coad 
group and RTS,S group).
Immune response to the HBs antigen will be assessed before vaccination (Day 
0) and one month post Dose 3 of RTS,S/AS01
Evaccine (Month 4) (i.e. in the 
Coad group and RTS,S group).
 
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Immune response to the catalase antigen will be assessed at Day 0 for the 
Control and the Coad groups, one month post Dose 3 of RTS,S/AS01Evaccine 
for the Coad group (Month 4) and before the first RTS,S/AS01
Evaccine dose 
for the Control group (Month 4).
Immune response to the YF vaccine will be assessed one month post-
vaccination with the YF vaccine and the combined measles and rubella vaccines 
whenadministered at 9 months of age (Month 4) (i.e. in the Coad group and 
Control group).
Immune response to the combined measles and rubella vaccine will be assessed 
before vaccination at Month 3 and one month post-vaccination with the YF 
vaccine and the combined measles and rubella vaccines when administered at 9 
months of age (Month 4) (i.e. in the Coad group and Control group).
4.
STUDY COHORT
4.1.
Number of subjects/centers
Approximately 700subjects (233 subjects per group) will be enrolled in this study. Refer 
to Section 10.4for the determination of sample size.
4.1.1.
Overview of the recruitment plan
Upon completion of all screening procedures (Referto Table 4, Table 5and Table 6), the 
investigator, or designee, will review the inclusion/exclusion criteria for each subject. 
Subjects meeting all eligibility criteria will beenrolled in the study. Their screening 
information will be recorded on the appropriate screen of eCRF.
If the investigator believes there is a reasonable reason to do so, screening procedures 
may be repeated once only.
4.2.
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)/Legally Acceptable Representative(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).
A male or female 6 months of age (from the day the child becomes 6 months of age 
until the day before the child achieves 7 months of age) at the time of the first 
vaccination.
Signed or thumb-printed informed consent obtained from the parent(s)/LAR(s) of the 
subject. Where parent(s)/LAR(s) are illiterate, the consent form will be 
countersigned by an independent witness.
 
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Healthy subjects as established by medical history and clinical examination before 
entering into the study.

Previously received three documented doses of diphtheria, tetanus, and whole-cell 
pertussis, hepatitis B vaccine (DTPwHepB), and a 3-dose course of oral polio 
vaccine and,if locally recommended, pneumococcal and rotavirus vaccines.
4.3.
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 ANYexclusion 
criterion applies, the subject must not be included in the study:
Child in care
Please refer to the glossary of termsfor the definition of child in care.
Use of a drug or vaccine that is not approved for that indication (by one of the 
following regulatory authorities: Food and Drug Administration [FDA; United 
States] or European Union member state or WHO [with respect to prequalification]) 
other than the study vaccines within 30 days preceding the first dose of study 
vaccine, or planned use during the study period.
Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs within six months prior to 
the first vaccine dose. For corticosteroids, this will mean prednisone ( 0.5 mg/kg/day, 
or equivalent. Inhaled and topical steroids are allowed.
Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting sevendays before the first dose of RTS,S/AS01
E/ 
measles, rubella and YF vaccines and ending 42 days after the last dose of vaccines 
given at 9 months of age (Visit 4), with the exception of oral polio vaccine which 
could be given for unforseen public health threat.
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device).
Previous vaccination against measles, YF or rubella.
Previous administration of Vitamin A.
Moderate or severe malnutrition at screening defined as weight for age Z-score < -2 
(by WHO growth standard)[WHO, 2006].
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

Family history of congenital or hereditary immunodeficiency.
 
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History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine(s).See also Section 1.3.
Major congenital defects or serious chronic illness.
History of any neurological disorders or seizures.
Acute disease and/or fever at the time of enrolment.
Fever is defined as temperature ≥ 37.5°C /99.5°F for oral, axillary or tympanic 
route, or ≥ 38.0°C /100.4°F on rectal route. The preferred route for recording 
temperature in this study will be axillary.
Subjects with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may, be enrolled at the discretion of the investigator.
Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the first dose of study vaccine or planned administration during the study 
period.
Same sex twin (to avoid misidentification).
Maternal death.
Previous participation in any other malaria study.
5.
CONDUCT OF THE STUDY
5.1.
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 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 
HarmonizedTripartite Guideline for clinical investigation of medicinal products in the 
pediatricpopulation (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favorableopinion/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.
 
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Conduct of the study includes, but is not limited to, the following:
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favorableopinion/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 writtenor 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 Informed Consent Form (ICF) which willembody 
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 ICFgenerated 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.
5.2.
Subject identification and randomizationof treatment
5.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study center. Study subjects will receive study identification 
cards with their picturewith their parents/LAR(s)and subject number.
5.2.2.
Randomization of treatment
5.2.2.1.
Randomization of supplies
The randomization of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS
®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centers /warehouse(s).
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centers in this multi-centerstudy and to thus reduce the overall 
studyrecruitment period, an over-randomization of supplies will be prepared.
 
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5.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
5.2.2.2.1. Study group and treatment number allocation
The target will be to enroll approximately 700eligible subjects who will be randomly 
assigned to three study groups in a (1:1:1) ratio (approximately 233 subjects in each 
group).
Allocation of the subject to a study group at the investigator site will be performed using 
a randomizationsystem on internet (SBIR). The randomizationalgorithm will use a 
minimization procedure accounting for center.
After obtaining the signed and dated ICF from the subject’s parents/LAR(s)and having 
checked the eligibility of the subject, the site staff will access SBIR. Upon providing the 
subject identification number, the randomizationsystem will determine the study group 
and will provide the treatment number for the products to be administered at Visit 2 (Day 
0).
The number of each administered vaccines must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
5.2.2.2.2. Treatment number allocation for subsequent doses
For eachvisit where vaccines are administered, the studystaff will access SBIR, provide 
the subject identification number, and the system will provide treatment numbers
consistent with the allocated study group.
The number of each administered vaccines must be recorded in the eCRF on the Vaccine 
Administration screen.
5.2.3.
Allocation of subjects to assay subsets
There will be no subsets of subjects.
5.3.
Method of blinding
This study is an open-label study.
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.
 
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5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying 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.
5.4.1.
Independent Data Monitoring Committee (IDMC) oversight
This study will be overseen by IDMC operating under a charter and assisted by a Local 
Safety Monitor at each site. Overall, the role of the IDMC includes the review and 
protection of data integrity and rights and safety of study participants throughout the 
study period. It will provide initial, regular, and closing advice to GSK Biologicals on 
medical, ethical, scientific and safety-related issues. Its advice will be based on the 
interpretation of study data with reference to the study protocol.
The IDMC will review the Protocol and Statistical Analysis Plan. Meetings will be 
documented and minutes of open sessions of the IDMC meetings made available to the 
sponsor. The IDMC may, if deemed necessary, convene a meeting with, or request 
further information from the Principal Investigators, the Medical Monitor/Local Safety 
Monitorand GSK Biologicals’ designated project representatives at any stage of the 
study.
The IDMC may recommend to the sponsor to suspend the enrollment to the study and/or 
vaccination based on their review of safety data arising in this study or other relevant 
study of the same product.
The IDMC will receivethe following safety data:

Periodic safety reports.
In addition, theIDMC will receive from the sponsor, GSK Biologicals:
New information that may adversely affect the safety of the subjects or the conduct 
of the study.
All subsequent protocol amendments, informed consent changes or revisions or other 
documents originally submitted for review.

All subsequent protocol administrative changes (for information).
5.4.2.
Standard of care provided to the subjects during the study
During the study, subjects will receive standard medical care according to national 
guidelines.
 
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5.5.
Outline of study procedures
Table 4
List of study procedures for the Coad group(Amended: 09 August 2016)
Epoch
Epoch 001
Type of contact
Visit 1 
(Screening)* 
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 10
Visit 11
Visit 14
Timepoints
Day -28 to -1
Day 0
Month 1.5
Month 3
Month 4
Month 4.5
Month 21
Month 22
Month 33
Children age (Months)
6
7.5
9
10
10.5
27
28
39
Informed consent
●
Check 
inc
lus
ion/exc
lus
ion cr
iter
ia
●
O
Co
l
lect demograph
ic data
●
Check med
ica
l h
istory
●
Phys
ica
l exam
inat
ion
●
O
O
O
O
O
O
O
O
Measure/record 
length and we
ight
●
Issu
ing 
ident
if
icat
ion card
O
Check 
ident
if
icat
ion card
O
O
O
O
O
O
O
O
Random
izat
ion
●
Treatment number a
l
locat
ion
O
O
O
O
Record
ing of adm
in
istered vacc
ine treatment number
●
●
●
●
Check contra
ind
icat
ions and warn
ings and precaut
ions
●
●
●
●
Pre-vacc
inat
ion body temperature
●
●
●
●
V
itam
in A adm
in
istrat
ion
●
RTS,S/AS01Evacc
ine adm
in
istrat
ion
●
●
●
●
YF vacc
ine and meas
les and rube
l
la vacc
ine 
adm
in
istrat
ion
●
B
lood samp
l
ing for ant
i-HBs and ant
i-CS ant
ibody 
determ
inat
ion
●
●
B
lood samp
l
ing for ant
i-Me and ant
i-Ru ant
ibody 
determ
inat
ion
● 
●
B
lood samp
l
ing for ant
i-cata
lase ant
ibody 
determ
inat
ion
●
●
B
lood samp
l
ing for ant
i-YF ant
ibody determ
inat
ion
●
Record of so
l
ic
ited symptoms (Days 0-6)
●a
●a
Record of so
l
ic
ited symptoms (Days 0-13)
●b,c
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Epoch
Epoch 001
Type of contact
Visit 1 
(Screening)* 
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 10
Visit 11
Visit 14
Timepoints
Day -28 to -1
Day 0
Month 1.5
Month 3
Month 4
Month 4.5
Month 21
Month 22
Month 33
Children age (Months)
6
7.5
9
10
10.5
27
28
39
Record of unso
l
ic
ited AEs
●a
●a
●b
●
●
●
●
Record any concom
itant med
icat
ion/vacc
inat
ion
●
●
●
●
●
●
●
●
Record any case of meas
les and rube
l
la †
●
●
●
●
●
●
●
●
Record of SAEs re
lated to study part
ic
ipat
ion or to a 
concurrent GSK med
icat
ion/vacc
ine
● 
● 
● 
● 
● 
● 
● 
● 
●
Record of SAEs (a
l
l, fata
l, SAEs re
lated to 
invest
igat
iona
l vacc
ine)
● 
● 
● 
● 
● 
● 
● 
●
Record AEs of spec
if
ic 
interest (
inc
lud
ing se
izure 
occurr
ing w
ith
in 30 or 42 days post-vacc
inat
ion, 
men
ing
it
isand pIMDs)
d
● 
● 
● 
● 
● 
● 
● 
●
Study Conc
lus
ion
●
aStudy personne
l w
i
l
l v
is
it the ch
i
ldren on Days 1, 2, 3, 4, 5 and 6 after each vacc
inat
ionto record so
l
ic
itedand unso
l
ic
itedAEs on d
iary cards.
bStudy personne
l w
i
l
l v
is
it the ch
i
ldren on Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 after vacc
inat
ion to record so
lic
ited and unso
l
ic
ited AEs on d
iary cards.
cCo
l
lect
ion of so
l
ic
ited 
loca
l AE for the three 
in
ject
ion s
ites.
dSe
izures occurr
ing w
ith
in 30 days post-vacc
inat
ion for vacc
ine doses adm
in
istered at 6 and 7.5 months of age (V
is
its 2 and 3) or 42 days post-vacc
inat
ion for vacc
ine doses 
adm
in
istered at 9 months of age (V
is
it 4).
Note: The doub
le-l
ine border fo
l
low
ing M
onth 4.5(V
is
it 6) 
ind
icates the ana
lyses wh
ich w
i
l
l be performed on a
l
l data (
i.e. data that are as c
lean as poss
ib
le) obta
ined up to Month 4.5.
* If the 
invest
igator be
l
ieves there 
is a reasonab
le reason to do so, screen
ing procedures may on
ly be repeated once.
†Conf
irmatory sero
logy tests shou
ld be performed to 
ident
ify cases of vacc
ine fa
i
lure.
● 
is used to 
ind
icate a study procedure that requ
ires documentat
ion 
in the 
ind
iv
idua
l eCRF.
○ 
is used to 
ind
icate a study procedure that does not requ
ire documentat
ion 
in the 
ind
iv
idua
l eCRF.
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Table 5
List of study procedures for the RTS,S group(Amended: 09 August 2016)
Epoch
Epoch 001
Type of contact
Visit 1 
(Screening)* 
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 10
Visit 11
Visit 14
Timepoints
Day -28 to -1
Day 0
Month 1.5
Month 3
Month 4
Month 4.5
Month 21
Month 22
Month 33
Children age (Months)
6
7.5
9
10
10.5
27
28
39
Informed consent
●
Check 
inc
lus
ion/exc
lus
ion cr
iter
ia
●
O
Co
l
lect demograph
ic data
●
Check med
ica
l h
istory
●
Phys
ica
l exam
inat
ion
●
O
O
O
O
O
O
O
O
Measure/record 
length and we
ight
●
Issu
ing 
ident
if
icat
ion card
O
Check ident
if
icat
ion card
O
O
O
O
O
O
O
O
Random
izat
ion
●
Treatment number a
l
locat
ion
O
O
O
O
O
Record
ing of adm
in
istered vacc
ine treatment number
●
●
●
●
●
Check contra
ind
icat
ions and warn
ings and precaut
ions  
●
●
●
●
●
Pre-vacc
inat
ion body temperature
●
●
●
●
●
V
itam
in A adm
in
istrat
ion
●
RTS,S/AS01Evacc
ine adm
in
istrat
ion
●
●
●
●
YF vacc
ine and meas
les and rube
l
la vacc
ine 
adm
in
istrat
ion
●
B
lood samp
l
ing for ant
i-HBs and ant
i-CS ant
ibody 
determ
inat
ion
●
●
Record of so
l
ic
ited symptoms (Days 0-6)
●a
●a
Record of so
l
ic
ited symptoms (Days 0-13)
●b
Record of unso
l
ic
ited AEs
●a
●a
●b
●
●
●
●
Record any concom
itant med
icat
ion/vacc
inat
ion
●
●
●
●
●
●
●
●
Record any case of meas
les and rube
l
la †
●
●
●
●
●
●
●
●
Record of SAEs re
lated to study part
ic
ipat
ion or to a 
concurrent GSK med
icat
ion/vacc
ine
● 
● 
● 
● 
● 
● 
● 
● 
●
Record of SAEs (a
l
l, fata
l, SAEs re
lated to 
invest
igat
iona
l vacc
ine)
● 
● 
● 
● 
● 
● 
● 
●
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Epoch
Epoch 001
Type of contact
Visit 1 
(Screening)* 
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 10
Visit 11
Visit 14
Timepoints
Day -28 to -1
Day 0
Month 1.5
Month 3
Month 4
Month 4.5
Month 21
Month 22
Month 33
Children age (Months)
6
7.5
9
10
10.5
27
28
39
Record AEs of spec
if
ic 
interest (
inc
lud
ing se
izure 
occurr
ing w
ith
in 30 or 42 days post-vacc
inat
ion, 
men
ing
it
is and pIMDs)c
● 
● 
● 
● 
● 
● 
● 
●
Study Conc
lus
ion
●
aStudy personne
l w
i
l
l v
is
it the ch
i
ldren on Days 1, 2, 3, 4, 5 and 6 after each vacc
inat
ionto record so
l
ic
ited and unso
l
ic
ited AEs on d
iary cards.
bStudy personne
l w
i
l
l v
is
it the ch
i
ldren on Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 after vacc
inat
ionto record so
l
ic
ited and unso
l
ic
ited AEs on d
iary cards.
cSe
izures occurr
ing w
ith
in 30 days post-vacc
inat
ion for vacc
ine doses adm
in
istered at 6 and 7.5 months of age (V
is
its 2 and 3) or 42 days post-vacc
inat
ion for vacc
ine doses 
adm
in
istered at 9 months of age (V
is
it 4).
Note: The doub
le-l
ine border fo
l
low
ing 
Month 4.5 (V
is
it 6) ind
icates the ana
lyse
s wh
ich w
i
l
l be performed on a
l
l data (
i.e. data that are as c
lean as poss
ib
le) obta
ined up to Month 4.5.
* If the 
invest
igator be
l
ieves there 
is a reasonab
le reason to do so, screen
ing procedures may on
ly be repeated once.
†Conf
irmatory sero
logy tests shou
ld be performed to 
ident
ify cases of vacc
ine fa
i
lure.
● 
is used to 
ind
icate a study procedure that requ
ires documentat
ion 
in the 
ind
iv
idua
l eCRF.
○ 
is used to 
ind
icate a study procedure that does not requ
ire documentat
ion 
in the 
ind
iv
idua
l eCRF.
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Table 6
List of study procedures for the Control group(Amended: 09 August 2016)
Epoch
Epoch 001
Type of contact
Visit 1 
(Screening)* 
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit8
Visit 9
Visit 12
Visit 13 Visit 15
Timepoints
Day -28 to -1 Day 0 Month 1.5 Month 3 Month 4 Month 4.5Month 5.5Month 6.5Month 7.5Month 24 Month 25 Month 36
Children age (Months)
6
7.5
9
10
10.5
11.5
12.5
13.5
30
31
42
Informed consent
●
Check 
inc
lus
ion/exc
lus
ion cr
iter
ia
●
O
Co
l
lect demograph
ic data
●
Check med
ica
l h
istory
●
Phys
ica
l exam
inat
ion
●
O
O
O
O
O
O
O
O
O
O
O
Measure/recordlength and we
ight
●
Issu
ing 
ident
if
icat
ion card
O
Check 
ident
if
icat
ion card
O
O
O
O
O
O
O
O
O
O
O
Random
izat
ion
●
Treatment number a
l
locat
ion
O
O
O
O
O
O
Record
ing of adm
in
istered vacc
ine treatment 
number
●
● 
● 
●
●
Check contra
ind
icat
ions and warn
ings and 
precaut
ions
●
● 
● 
●
●
Pre-vacc
inat
ion body temperature
●
●
●
●
●
●
●
V
itam
in A adm
in
istrat
ion
●
YF vacc
ine and meas
les and rube
l
la vacc
ine 
adm
in
istrat
ion
●
RTS,S/AS01Evacc
ine adm
in
istrat
ion
●
●
●
●
B
lood samp
l
ing for ant
i-Me and ant
i-Ru 
ant
ibody determ
inat
ion
● 
●
B
lood samp
l
ing for ant
i-YF ant
ibody 
determ
inat
ion
●
B
lood samp
l
ing for ant
i-cata
lase ant
ibody 
determ
inat
ion
●
●
Record of so
l
ic
ited symptoms (Days 0-6)
●a
●a
Record of so
l
ic
ited symptoms (Days 0-13)
●b,c
Record of unso
l
ic
ited AEs
●a
●a
●b
●
●
●
●
●
●
●
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Epoch
Epoch 001
Type of contact
Visit 1 
(Screening)* 
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit8
Visit 9
Visit 12
Visit 13 Visit 15
Timepoints
Day -28 to -1 Day 0 Month 1.5 Month 3 Month 4 Month 4.5Month 5.5Month 6.5Month 7.5Month 24 Month 25 Month 36
Children age (Months)
6
7.5
9
10
10.5
11.5
12.5
13.5
30
31
42
Record any concom
itant 
med
icat
ion/vacc
inat
ion
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●
Record any case of meas
les and rube
l
la †
●
●
●
●
●
●
●
●
●
●
●
Record of SAEs re
lated to study part
ic
ipat
ion 
or to a concurrent GSK med
icat
ion/vacc
ine
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●
Record of SAEs (a
l
l, fata
l, SAEs re
lated to 
invest
igat
iona
l vacc
ine)
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●
Record AEs of spec
if
ic 
interest (
inc
lud
ing 
se
izure occurr
ing w
ith
in 30 or 42 days post-
vacc
inat
ion, men
ing
it
is and pIMDs)
d
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●
Study Conc
lus
ion
●
aStudy personne
l w
i
l
l v
is
it the ch
i
ldren on Days 1, 2, 3, 4, 5 and 6 after V
itam
in A adm
in
istrat
ion (V
is
it 2) and after V
is
it 3 to record so
l
ic
ited genera
l and unso
l
ic
ited AEs on d
iary cards.
bStudy personne
l w
i
l
l v
is
it the ch
i
ldren on Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 after vacc
inat
ionto record so
l
ic
ited and unso
l
ic
ited AEs on d
iary cards.
cCo
l
lect
ion of so
l
ic
ited 
loca
l AE for the two 
in
ject
ion s
ites.
dSe
izures occurr
ing w
ith
in 30 days post-vacc
inat
ion for vacc
ine doses adm
in
istered at 6 and 7.5 months of age (V
is
its 2 and 3) or 42 days post-vacc
inat
ion for vacc
ine doses 
adm
in
istered at 9 months of age (V
is
it 4).
Note: The doub
le-l
ine border fo
l
low
ing 
Month 4.5 (V
is
it 6) i
nd
icates the ana
lyses wh
ich w
i
l
l be performed on a
l
l data (
i.e. data that are as c
lean as poss
ib
le) obta
ined up to Month 4.5.
* If the 
invest
igator be
l
ieves there 
is a reasonab
le reason to do so, screen
ing procedures may on
ly be repeated once.
†Conf
irmatory sero
logy tests shou
ld be performed to 
ident
ify cases of vacc
ine fa
i
lure.
● 
is used to 
ind
icate a study procedure that requ
ires documentat
ion 
in the 
ind
iv
idua
l eCRF.
○ 
is used to 
ind
icate a study procedure that does not requ
ire documentat
ion 
in the 
ind
ividua
l eCRF
.
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Table 7
Intervals between study visits(Amended: 09 August 2016)
Study visit
Timing of visita
Allowed intervalb
V
is
it 1 
(Screen
ing)
c
1-28daysbefore V
is
it 2
-
V
is
it 2
6 months of age
Ch
i
ld shou
ld be 6cmonths of age
V
is
it 3
7.5 months of age
Ch
i
ld shou
ld be 7dor 8
emonths of age but respect
ing a m
in
imum of 4
weeks(28 days) s
ince prev
ious dose (V
is
it 2)
V
is
it 4
9 months of age
Ch
i
ld shou
ld be 9fmonths of age but respect
ing a m
in
imum of 4weeks
(28 days) s
ince prev
ious dose (V
is
it 3)
V
is
it 5
4 weeks after V
is
it 4
M
in
imum 4weeks(28 days) -Max
imum 6weeks(42 days)
V
is
it 6
2 weeks after V
is
it 5
M
in
imum 2weeks(14 days) -Max
imum 3weeks(21 days)
V
is
it 7
4 weeks after V
is
it 6
M
in
imum 4weeks(28 days) -Max
imum 6weeks(42 days)
V
is
it 8
4 weeks after V
is
it 7
M
in
imum 4weeks(28 days) -Max
imum 6weeks(42 days)
V
is
it 9
4 weeks after V
is
it 8
M
in
imum 4weeks(28 days) -Max
imum 6weeks(42 days)
V
is
it 10
18 months after V
is
it 4
17months(516 days) after V
is
it 4 –19months(577 days) after V
is
it 4
V
is
it 11
4 weeks after V
is
it 10
M
in
imum 4weeks(28 days) -Max
imum 6weeks(42 days)
V
is
it 12
17.5months after V
is
it 8 17months(516 days) after V
is
it 8 –19months(577 days) after V
is
it 8
V
is
it 13
4 weeks after V
is
it 12
M
in
imum 4weeks(28 days) -Max
imum 6weeks(42 days)
V
is
it 14
12 months after V
is
it 10 11months(334 days) after V
is
it 10 -13months(396 days) after V
is
it 10
V
is
it 15
12 months after V
is
it 12 11months(334 days) after V
is
it 12 -13months(396 days) after V
is
it 12
aWhenever poss
ib
le the 
invest
igator shou
ld arrange study v
is
its w
ith
in th
is 
interva
l.
bSub
jects w
i
l
l not be e
l
ig
ib
le for 
inc
lus
ion 
in the ATP cohortfor ana
lys
is of 
immunogen
ic
ity 
if they make the study v
is
it 
outs
ide th
is 
interva
l.
cFor c
lar
ity th
is corresponds from the day the ch
i
ld becomes 6 months of age unt
i
l the day before the ch
i
ld ach
ieves 7 
months of age.
dFor c
lar
ity th
is corresponds from the day the ch
i
ld becomes 7 months of age unt
i
l the day before the ch
i
ld ach
ieves 8 
months of age.
eFor c
lar
ity th
is corresponds from the day the ch
i
ld becomes 8 months of age unt
i
l the day before the ch
i
ld ach
ieves 9 
months of age.
fFor c
lar
ity th
is corresponds from the day the ch
i
ld becomes 9 months of age unt
i
l the day before the ch
i
ld ach
ieves 
10 months of age.
5.6.
Detailed description of study procedures
5.6.1.
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 5.1for the requirements on 
how to obtain informed consent and assent, as appropriate.
5.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2and 4.3before 
enrolment.
 
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5.6.3.
Collect demographic data
Record demographic data such as date of birth, gender, and ethnicity in the subject’s 
eCRF.
5.6.4.
Medical history
Obtain the subject’s medical history by interview of subject’s parent(s)/LAR(s) and/or 
review of the subject’s medical records and record any pre-existing conditions or signs 
and/or symptoms present in a subject prior to the firststudy vaccinationin the eCRF.
5.6.5.
Physical examination
Perform a physical examination of the subject, including assessment of body temperature, 
heart rate and respiratory rate. Collected information needs to be recorded in the eCRF
(Visit 1 only).
Physical examination at each studyvisit subsequent to the first vaccination visit, will be 
performed only if the subject indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the Investigator or delegate.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
5.6.6.
Measure/record length and weight
Perform anthropometric measurements of the subject (length andweight) at the 
Screening visit (Visit 1). Collected information needs to be recorded in the eCRF.
The methodologies used for length and weight 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.
5.6.7.
Issuing subject identification card
At the Screening visit (Visit 1), take a picture of the subject and his/her parent(s)/LAR(s)
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, check this identification card.
5.6.8.
Study group and treatment number allocation
Study group and treatment number allocation will be performed as described in Section 
5.2.2. The number of each administered vaccines must be recorded in the eCRF.
 
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5.6.9.
Check contraindications, warnings and precautions to 
vaccination
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 6.5and 6.6for more details.
5.6.10.
Assess pre-vaccination body temperature
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be 
measured prior to any study vaccine/ product administration. The preferred route for 
recording temperature in this study will be axillary. If the subject has fever [fever is 
defined as temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 
38.0°C/100.4°F for rectal route] on the day of vaccination, the vaccination visit will be 
rescheduled within the allowed interval for this visit (see Table 7).
5.6.11.
Study Vaccines/product administration

After completing all prerequisite procedures prior to vaccination, study vaccines will 
be administered (refer to Section 6.3for detailed description of the vaccines/product 
administration procedure). If the investigator or delegate determines that the 
subject’s health on the day of administration temporarily precludes vaccines/product 
administration, the visit will be rescheduled within the allowed interval for this visit 
(refer to Table 7).
The subjects will be observed closely for at least 60 minutes following the 
administration of the vaccines, with appropriate medical treatment readily available 
in case of anaphylaxis.
Vaccination will take place at the vaccination center. All vaccinations will be given 
by a qualified person: a nurse or a doctor. A staff member experienced in the 
resuscitation of children will be available at all vaccination sessions.
5.6.12.
Sampling
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
 
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5.6.12.1.
Blood sampling for anti-HBsand anti-CS immune response 
assessments(Amended: 09 August 2016)
Blood samples will be taken during certain study visits as specified in Section 5.5List of 
Study Procedures.
A volume of at least 1.2ml of whole blood (to provide at least 500l of serum for 
anti-CS and anti-HBs) should be drawn from all subjects from the Coad groupand 
the RTS,S groupfor each analysis of humoral immune response at each pre-defined 
timepoint. 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.
5.6.12.2.
Blood sampling for anti-catalase immune response assessments
(Amended: 09 August 2016)
Blood samples will be taken during certain study visits as specified in Section 5.5List of 
Study Procedures.
A volume of at least 600l of whole blood (to provide at least 250l of serum) 
should be drawn from all subjects from the Coadand the Control groupsfor 
analysis of anti-catalase immune response at each pre-defined timepoint. 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.
5.6.12.3.
Blood sampling for anti-Me and anti-Ru immune response 
assessments(Amended: 09 August 2016)
Blood samples will be taken during certain study visits as specified in Section 5.5List of 
Study Procedures.
A volume of at least 600lof whole blood (to provide at least 250 l of serum for 
anti-Me and anti-Ru) should be drawn from all subjects from the Coad groupand 
the Control groupfor each analysis of humoral immune response at each pre-
defined timepoint. 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.
5.6.12.4.
Blood sampling for anti-YF immune response assessments(Amended: 
09 August 2016)
Blood samples will be taken during certain study visits as specified in Section 5.5List of 
Study Procedures.
A volume of at least600µl of whole blood (to provide at least 250 l of serum for 
anti-YF) should be drawn from all subjects from the Coad groupand the Control 
groupfor each analysis of humoral immune response at each pre-defined timepoint. 
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.
 
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5.6.13.
Check and record concomitant medication/vaccination and cases 
of measles and rubella
Concomitant medication/vaccination must bechecked and recorded in the eCRF as
described in Section 6.7.
Capture of cases of measles and rubella is described in Section 6.8.
5.6.14.
Recording ofAEs, SAEs, and AEs of specific interest

Refer to Section 8.2for procedures for the investigator to record AEs, SAEs and AEs 
of specific interest(pIMDs, meningitis and seizure within 30 or 42 days of 
vaccination). Refer to Section 8.3for guidelines on how to submit SAE and AEs of 
specific interestreports 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.
For theCoad group and the RTS,S group,there will be:
A 7-day follow-up period (day of vaccination and 6 subsequent days) following 
vaccines administered at 6 and 7.5 months of age (Visits 2 and 3) for recording 
of solicited local and general AEs. On the day of vaccination the evaluation will 
be carried-outby the study physician at the study center. On Days 1, 2, 3, 4, 5 
and 6 after vaccination, trained study personnel will visit the children to record 
solicited AEs on diary cards.

A 14-day follow-up period (day of vaccination and 13 subsequent days) 
following vaccines administered at 9 months of age (Visit 4) for recording of 
solicited local and general AEs. On the day of vaccination the evaluation will be 
carried-out by the study physician at the study center. On Days 1 to 13 after 
vaccination, trained study personnel will visit the children to record solicited 
AEs on diary cards.
Unsolicited AEs will be collected from the day of first vaccine administration 
(Visit 2) until 42 days after Visit 4. On the days of vaccinations (Visits 2, 3 and 
4) the evaluation will be carried-out by the study physician at the study center. 
Unsolicited AEs will be captured through passive surveillance at inpatient and 
outpatient facilitiesand during study visits. In addition on Days 1 to 6 after 
vaccinations at Visits2 and 3 and on Days 1 to 13 after Visit 4, trained study 
personnel will visit the children to record any unsolicited AEs on diary cards.

A 30-day follow-up period (day of vaccinationand 29 subsequent days) after 
booster dose of RTS,S/AS01Evaccines administered at 27 months of age (Visit 
10) for reporting unsolicited AEs. Unsolicited AEs will be captured through 
passive surveillance at inpatient and outpatient facilitiesand during study visits.
For the Control group, there will be:
A 7-day follow-up period (day of administrationand 6 subsequent days) 
following Vitamin A administered at 6 months of age (Visit 2) and a 7-day 
 
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follow-up period following Visit 3 (7.5 months of age)for recording of solicited 
general AEs. On the day of Visits 2 and 3the evaluation will be carriedout by 
the study physician at the study center. On Days 1, 2, 3, 4, 5 and 6 after Visits 2 
and 3, trained study personnel will visit the children to record solicited general 
AEs on diary cards.
A 14-day follow-up period (day of vaccination and 13 subsequent days) 
following vaccines administered at 9 months of age (Visit 4) for recording of 
solicited local and general AEs. On the day of vaccination the evaluation will be 
carried-out by the study physician at the study center. On Days 1 to 13 after 
vaccination, trained study personnel will visit the children to record solicited 
AEs on diary cards.

Unsolicited AEs will be collected from the day of Vitamin A administration 
(Visit 2) until 42 days after Visit 4. On the day of Visits 2, 3 and4 the 
evaluation will be carried-out by the study physician at the study center. 
Unsolicited AEs will be captured through passive surveillance at inpatient and 
outpatient facilities and during study visits. In addition on Days 1 to 6 after 
vaccinations atVisits 2 and 3 and on Days 1 to 13 after Visit 4, trained study 
personnel will visit the children to record any unsolicited AEs on diary cards.
Unsolicited AEs will be collected from the day of the first dose of RTS,S/AS01
E
(Visit 6) until 30 days after Visit 8 and from the day of the booster dose of 
RTS,S/AS01Eadministered at 30 months of age (Visit 12) until 30 days after the 
booster dose. Onthe day of vaccination the evaluation will be carried-out by the 
study physician at the study center. Unsolicited AEs will be captured through 
passive surveillance at inpatient and outpatient facilitiesand during study visits.
For all groups (Coad group, RTS,S groupand Control group):

All SAEs will be reported until study end (Month 33 for Coad and RTS,S 
groups and Month 36 for the Control group).
All AEs of specific interest will be reported until study end (Month 33 for Coad 
and RTS,S groups and Month 36 for the Control group). AEs of specific interest 
include seizure (occurring within 30 days post-vaccination for vaccine doses 
administered at 6 and 7.5 months of age or 42 days post-vaccination for vaccine 
doses administered at 9 months of age), meningitis and pIMDs.
5.6.15.
Study conclusion
The investigator will:
Review data collected to ensure accuracy and completeness

Complete the Study Conclusion screen in the eCRF.
5.7.
Biological sample handling and analysis
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment).
 
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Samples will not be labeledwith information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).
Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed, will be asked to give a specific 
consentto allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to the laws and regulations in the respective countries 
and will only be performed once an independent Ethics Committee or Review Board 
has approved this research.
Information on further investigations and their rationale can beobtained 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). 
If additional testing is performed, the marker priority ranking given in Section 5.7.4may 
be changed.
Collected samples will bestored 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.
5.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORYthat 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 10.5for the definition of 
cohortsto be analyzed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision complywith 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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5.7.2.
Biological samples
Details of the quantity of blood to be taken at each timepoint during the study are 
provided in Table 8.
Table 8
Biological samples(Amended: 09 August 2016)
Timepoint
Group
Sample type
Quantity
Unit
V
is
it 2(Day 0)
Coad group
B
lood
1.8
m
l
RTS,S group
B
lood
1.2
m
l
Contro
l group
B
lood
0.6
m
l
V
is
it 4(Month 3)
Coad group
B
lood
0.6
m
l
Contro
l group
B
lood
0.6
m
l
V
is
it 5(Month 4)
Coad group
B
lood
3.5
m
l
RTS,S group
B
lood
1.2
m
l
Contro
l group
B
lood
1.8
m
l
5.7.3.
Laboratory assays
Please refer to APPENDIX Afor a detailed description of the assays performed in the 
study. Please refer to APPENDIX Bfor 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 9). 
Serological assays for the determination of anti-HBs antibodies will be performed by 
chemiluminescence enzyme immunoassay (CLIA) at a GSK Biologicals laboratory using 
standardized and validated procedures (refer to Table 9).
Serological assays for the determination of anti-catalase antibodies will be performed by 
ELISA at a GSK Biologicals laboratory using optimized procedures (refer to Table 9).
Serological assays for the determination of anti-Me and anti-Ru antibodies will be 
performed by ELISA at a GSK Biologicals laboratory using standardized and qualified 
procedures (refer to Table 9).
Serological assays for the determination of anti-YF antibodies will be performed by 
plaque neutralization assay (PRN) at a laboratory designated by GSK Biologicals using 
standardized and validated procedures (refer to Table 9).
 
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Table 9
Humoral Immunity (Antibody determination)(Amended: 09 August 
2016)
System
Component
Method
Kit/ 
Manufacturer
Unit
Cut-off
Laboratory
SERUM 
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
ELISA
Not 
App
l
icab
le
EU/m
l
0.5
CEVAC
SERUM 
Hepat
it
is B V
irus.Surface Ab CLIA
ADVIA 
Centaur ant
i-
HBs2 
(S
iemens 
Hea
lthcare)
mIU/m
l
6.2
GSK 
B
io
log
ica
ls*
SERUM 
cata
lase Ab.IgG
ELISA 
In house
ng/m
l
65
GSK 
B
io
log
ica
ls*
SERUM 
Meas
les V
irus Ab.IgG
ELISA
Dade Behr
ing 
Enzygnost 
Ant
i-meas
les 
v
irus IgG
mIU/m
l
150
GSK 
B
io
log
ica
ls*
SERUM
Ye
l
lowFever V
irus Ab
PRN
in house
ED50
10
Focus 
D
iagnost
ics
SERUM
Rube
l
la V
irus Ab.IgG
ELISA
Dade Behr
ing 
Enzygnost 
Ant
i-rube
l
la 
v
irus IgG
IU/m
l
4
GSK 
B
io
log
ica
ls*
*GSK B
io
log
ica
ls 
laboratory refers to the Clinical Laboratory Sciences(CLS) 
in R
ixensart, Be
lg
ium; Wavre, Be
lg
ium; 
NEOMED-LABSInc, Canada.
CEVAC: Center for Vacc
ino
logy, Ghent, Be
lg
ium
Focus D
iagnost
ics, Inc.: 5785 Corporate Avenue; Cypress, CA 90630, Un
ited States
CLIA: chem
i
lum
inescence enzyme 
immunoassay
ELISA: Enzyme l
inked 
immunosorbent assay
PRN: P
laque neutra
l
izat
ion assay
ED50: End po
int D
i
lut
ion50
EU/m
l: ELISA un
it per m
i
l
l
i
l
iter
mIU/m
l: m
i
l
l
i-
internat
iona
l un
it per m
i
l
l
i
l
iter
IU/m
l: Internat
iona
lun
it per m
i
l
l
i
l
iter
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
Blood samples will be collected for assessment of serology.
 
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Table 10
Immunological read-outs
Blood sampling timepoint
study group
No. 
subjects Component
Components
priority rank
Type of contact 
and timepoint
Sampling 
timepoint
V
is
it 2
Day 0
Coad groupand RTS,S group
466
ant
i-CS
1
Coad groupand RTS,S group
466
ant
i-HBs
2
Coad groupand Contro
l group
466
ant
i-cata
lase
3
V
is
it 4
Month 3
Coad groupand Contro
lgroup
466
ant
i-Me
1
Coad groupand Contro
l group
466
ant
i-Ru
2
V
is
it 5
Month 4
Coad groupand RTS,S group
466
ant
i-CS
1
Coad groupand RTS,S group
466
ant
i-HBs
5
Coad groupand Contro
l group
466
ant
i-cata
lase
6
Coad groupand Contro
l group
466
ant
i-Me
2
Coad groupand Contro
l group
466
ant
i-Ru
3
Coad groupand Contro
l group
466
ant
i-YF
4
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analyzed according to priority ranking provided inTable 10.
5.7.5.
Immunological correlates of protection
No correlate of protection has been demonstrated so far for the CS and YF antigens.
For the hepatitis B surface antigen, the conventional correlate of protection is anti-HBs 
antibody titers above 10 mIU/ml [European Consensus Group on Hepatitis B Immunity, 
2000].
Anti-Me and anti-Ru antibodytiters will be determined using ELISA kits. The 
seroprotection threshold is 150 mIU/ml and 10 IU/ml for anti-Me and anti-Ru antibodies, 
respectively.
5.7.5.1.
Rescue Plan
Assessment of the protection level for measles and rubella will be done one month post-
vaccination (Visit 5 for the Coad and Control groups). The results of the immunological 
assay will be communicated to the investigator as soon as they become available and in 
any case no later than 12 months after the visit date at which sampling allows the 
assessment of protection.Children with antibodies below the seroprotection thresholds of 
150 mIU/ml (anti-Me antibodies) and 10IU/ml (anti-Ru antibodies) will be considered as 
non-responders. The list of non-responders will be provided to the IDMC and 
investigators. Investigatorsbased on their clinical judgment will decide whether families 
should be offered additional measles or rubella vaccine doses.
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects/subjects’ parent(s)/LAR(s).
 
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For the subjects identified as non-responders, it remains the responsibility of the 
investigator in charge of the subject’s clinical management to determine the medical need 
for re-vaccination and to re-vaccinate the subjects as per local/regional practices.
6.
STUDY VACCINES/PRODUCT AND ADMINISTRATION
6.1.
Description of study vaccines/product
The candidate RTS,S/AS01Evaccine has been developed by GSK Biologicals.
The Quality Control Standards and Requirements for the candidate vaccineare described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained. 
The vaccines/productare labelled and packed according to applicable regulatory 
requirements.
Commercial vaccines/productare assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics.
Table 11
Study products
Treatment 
name
Vaccine/product 
name
Formulation
Presentation
Volume to 
be 
administered
Number of 
doses
RTS,S/AS01E*
RTS,S
RTS,S=25µg
Lyoph
i
l
ized pe
l
let 
in 
a two-dose g
lass v
ia
l
0.5m
l
4
AS01E
MPL=25µg; 
QS21=25µg; 
L
iposomes
L
iqu
id so
lut
ion 
in a 
two-dose g
lass v
ia
l
Ye
l
low fever
WHO 
prequa
l
if
ied
Ye
l
low Fever
17D
Lyoph
i
l
ized w
ith 
d
i
luent
0.5 m
l
1
Meas
les and 
Rube
l
la
MR-VAC
Edmonston-Zagreb 
meas
les 
v
irus=1000CCID₅₀; 
W
istar RA 27/3 
rube
l
la 
v
irus=1000CCID₅₀
Lyoph
i
l
ized w
ith 
d
i
luent
0.5m
l
1
V
itam
in A 
V
itam
in A
-
Capsu
les
100000 IU 
(30 mg RE)
1
IU: internat
iona
l un
its; MPL:3-O-desacy
l-4
’-monophosphory
l 
l
ip
id A; QS-21St
imu
lon®: Qu
i
l
la
ja saponar
iaMo
l
ina, 
fract
ion 21; RE: ret
ino
l equ
iva
lent
MR-VAC: L
ive attenuated meas
les v
irus and rube
l
la v
irus vacc
ine (Serum Inst
itute of Ind
ia)
* In th
is study the commerc
ia
l presentat
ionof RTS,S/AS01
Ew
i
l
l be used, 
i.e. a two-doses g
lass v
ia
l of 
lyoph
i
l
ized 
RTS,S ant
igen (50 µg) to be reconst
ituted w
ith 1.0 m
l of AS01 Ad
juvant System (MPL = 50 µg; QS-21 St
imu
lon®= 
50 µg; L
iposome). From the reconst
ituted vacc
ine v
ia
l,0.5-m
l w
i
l
l be w
ithdrawn to adm
in
ister to each ch
i
ldren a 
dose of 25 µg RTS,S and 25 µg QS-21St
imu
lon®, 25 µg MPL and 
l
iposome, a
lso ca
l
led AS01
E.
6.2.
Storage and handling of study vaccines/product
The study vaccines/productmust be stored at the respective label storage temperature 
conditions in a safe and locked place. Access to the storage space should be limited to 
 
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authorized study personnel. The storage conditions will be assessed during pre-study 
activities under the responsibility of the sponsor study contact. The storage temperature 
should be continuously monitored with calibrated (if not validated) temperature 
monitoring device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the 
SPM for more details on storage of the study vaccines/product.
Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 0.0 to +8.0C(for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor.
In case of temperature excursion below +2.0°C down to 0.0°Cimpacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°Flabel storage temperatureconditions.The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion.
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take.
Non-IMPs that are impacted by a temperature excursion may not be used and must be 
quarantined at label storage conditions until usage approval has been obtained from/via 
the local study contact (e.g. Site Monitor). There is no need for reporting via the eTDF.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines/product.
 
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6.3.
Dosage and administrationof study vaccines/product
Table 12
Dosage and administration
Type of contact 
and timepoint
Doseto be 
administered
Study Group Treatment name Route 1
Site
Side
V
is
it 2
100000IU
Coad group
V
itam
in A
O
Not app
l
icab
le
Not app
l
icab
le
0.5m
l
Coad group
RTS,S/AS01E
IM
De
lto
id
Left
100000IU
RTS,S group
V
itam
in A
O
Not app
l
icab
le
Not app
l
icab
le
0.5m
l
RTS,S group
RTS,S/AS01E
IM
De
lto
id
Left
100000IU
Contro
l group
V
itam
in A
O
Not app
l
icab
le
Not app
l
icab
le
V
is
it 3
0.5m
l
Coad group
RTS,S/AS01E
IM
De
lto
id
Left
0.5m
l
RTS,S group
RTS,S/AS01E
IM
De
lto
id
Left
V
is
it 4
0.5m
l
Coad group
RTS,S/AS01E
IM
De
lto
id
Left
0.5m
l
Coad group
Ye
l
low fever
IM
Antero
latera
l th
igh
R
ight
0.5m
l
Coad group
Meas
les and 
Rube
l
la
SC
Antero
latera
l th
igh
Left
0.5m
l
RTS,S group
RTS,S/AS01E
IM
De
lto
id
Left
0.5m
l
Contro
l group
Ye
l
low fever
IM
Antero
latera
l th
igh
R
ight
0.5m
l
Contro
l group
Meas
les and 
Rube
l
la
SC
Antero
latera
l th
igh
Left
V
is
it 6
0.5m
l
RTS,S group
Ye
l
low fever
IM
Antero
latera
l th
igh
R
ight
0.5m
l
RTS,S group
Meas
les and
Rube
l
la
SC
Antero
latera
l th
igh
Left
0.5m
l
Contro
l group
RTS,S/AS01E
IM
De
lto
id
Left
V
is
it 7
0.5m
l
Contro
l group
RTS,S/AS01E
IM
De
lto
id
Left
V
is
it 8
0.5m
l
Contro
l group
RTS,S/AS01E
IM
De
lto
id
Left
V
is
it 10
0.5m
l
Coad group
RTS,S/AS01E
IM
De
lto
id
Left
0.5m
l
RTS,S group
RTS,S/AS01E
IM
De
lto
id
Left
V
is
it 12
0.5m
l
Contro
l group
RTS,S/AS01E
IM
De
lto
id
Left
1IM: Intramuscu
lar; O: Ora
l; SC: Subcutaneous
The subjects will be observed closely for at least 60 minutes following the administration 
of the vaccines, with appropriate medical treatment readily available in case of 
anaphylaxis.
6.3.1.
RTS,S/AS01E(0.5 ml dose)
The commercial presentation will be a two-doses glass vial of lyophilized RTS,S antigen 
to be reconstituted with a two-doses glass vial of AS01EAdjuvant System. The final 
product for administration will be prepared by reconstitution of the lyophilized antigen 
with the liquid adjuvant to deliver two doses (1.0 ml). A single dose consists of 0.5 ml of 
RTS,S/AS01Efinal preparation. All vials of vaccine provided in this study are intended 
for single use only.
Disinfect top of vaccine vial (pellet) and adjuvant vial with alcohol swabs and let dry. 
Withdraw the contents of the adjuvant vial in a syringe and inject adjuvant into the vial of 
lyophilized antigen. The pellet is then dissolved by gently shaking the vial. Wait for one
minute to ensure complete dissolution of vial contents before withdrawing one dose of 
RTS,S/AS01E(0.5 ml). The reconstituted vaccine should be administered by slow IM 
 
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injection, using a fresh 25G needle with length of one inch (25 mm),in the left deltoid.
Vaccine should be injected within four hours of reconstitution (storage at +2°C to +8°C).
6.3.2.
Combined measles and rubella vaccine (MR-VAC) (0.5 ml dose)
The combined measles and rubella vaccine will be used according to manufacturer 
instructions and the Summary of Product Characteristics. The vaccine will be 
administered as a SC injection into the left anterolateral thigh.
6.3.3.
Licensed WHO prequalified yellow fever vaccine(0.5 ml dose)
The YF vaccine will be used according to manufacturer instructions and the Summary of 
Product Characteristics. The vaccine will be administered as an IM injection into the right 
anterolateral thigh.
6.3.4.
Vitamin A(100000 IU dose)
The Vitamin A will be used according to manufacturer instructions and the Summary of 
Product Characteristics. Vitamin A will be administered orally.
6.4.
Replacement of unusable vaccine/productdoses
In addition to the vaccine/productdoses provided for the planned number of subjects 
(including over-randomizationwhen applicable), at least 10%additional vaccine/product
doses will be supplied to replace those that are unusable.
6.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of 
study vaccines. If any of these events occur during the study, the subject must not receive 
additional doses of vaccinesbut may continue other study procedures at the discretion of 
the investigator (see Section 8.4).

Anaphylaxis following the administration of vaccines.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including human immunodeficiency virus (HIV) infection.
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe.
Failure to thrive.
Any other findings that the investigator feels would increase the risk of having an 
adverse outcome from participation in the trial.
Administration of a dose of measles, rubella or YF vaccines outside of this study 
protocol.
The following events constitute contraindications to administration of study vaccinesat 
that point in time; if any of these events occur at the time scheduled for vaccination, the 
subject may be vaccinated at a later date, within the time window specified in the 
 
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protocol (see Section 5.5), or the subject may be withdrawn at the discretion of the 
investigator (see Section 8.4).
Acute disease and/or fever at the time of vaccination.

Fever is defined as temperature 37.5°C/99.5°F for oral, axillary or tympanic 
route, or 38.0°C/100.4°F for rectal route. The preferred route for recording 
temperature in this study will be axillary.
Subjects with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever can be administered all vaccines/.
A lesion that would prevent injection.
Administration of a vaccine not foreseen by the study protocol within sevendays of 
any dose of RTS,S/AS01
E, YF vaccine and the combined measles and rubella 
vaccine.
6.6.
Warnings and precautions
Refer to the approved product label/package insert.
6.7.
Concomitant medications/productsand concomitant 
vaccinations
At each study visit/contact, the investigator should question the subject’s 
parent(s)/LAR(s) about any medications/productstaken and vaccinationsreceived by the 
subject.
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s)must be recorded in 
the eCRF.
Anti-inflammatory, analgesics, anti-pyretic, and systemic antibiotics administered 
starting 30 days before and following each dose of study vaccine.

Any concomitant vaccination administered in the period starting sevendays before 
the first dose of study vaccine and ending at Visit 5 (Month 4).

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring (fever is defined as 
temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 
38.0°C/100.4°F for rectal route).
Any concomitant medications/products/vaccines listed in Section 6.7.2.
Any concomitant medication/product/vaccinerelevant to a SAE
*or administered at 
any time during the study period for the treatment of a SAE
*.
 
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*SAEs that are required to be reported per protocol.

Any concomitant medications/products/vaccinesrelevant to a SAE/pIMDto be 
reported as per protocol or administered at any time during the study period for the 
treatment of a SAE/pIMD.In addition, concomitant medications relevant to SAEs 
and pIMD need to be recorded on the expedited Adverse Event report.
6.7.2.
Concomitant medications/products/vaccines that maylead to the
elimination of a subject from ATP analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analysis. See Section10.5for cohorts to be analyzed.
Use of a drug or vaccine that is not approved for that indication (by one of the 
following regulatory authorities: FDA or European Union member state or WHO
[with respect to prequalification]) other than the study vaccines during the study 
period.
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) during the study period. For corticosteroids, this will mean 
prednisone 0.5 mg/kg/day or equivalent. Inhaled and topical steroids are allowed.
A vaccine not foreseen by the study protocol administered during the period starting 
from sevendays before each dose of vaccine(s)and ending 42 days after.*
* In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic or polio control) is organized by the public health authorities, outside the 
routine immunization program, the time period described above can be reduced if 
necessary for that vaccine provided it is licensed and used according to its Summary 
of Product Characteristics or Prescribing Information and according to the local 
governmental recommendations and provided a written approval of the Sponsor is 
obtained.
Immunoglobulins and/or any blood products administered during the study period.
Administration of a dose of measles, rubella or YF vaccines from sevendays before 
the first dose of study vaccine and ending at the first birthday of the subject.
6.8.
Capture of cases of measles and rubella(Amended: 09 
August 2016)
At each study visit subsequent to the first vaccination, it must be verified if the subject 
has experienced or is experiencing measles or rubella. If it is the case, the condition(s) 
must be recorded in the eCRF.
During the course of the study, any clinical presentation compatible with measles, rubella
or YF will be captured as AE or SAE as appropriate and confirmatory serology tests 
should be performed to identify cases of vaccine failure.
 
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7.
HEALTH ECONOMICS
Not applicable.
8.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAEas provided in 
this protocol.
Each subject’s parent(s)/LAR(s)will be instructed to contact the investigator immediately 
should they/the subject manifest any signs or symptoms they perceive as serious.
8.1.
Safety definitions
8.1.1.
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 unfavorableand 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. lackof 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 vaccineadministration.

Significant failure of expected pharmacological or biological action. 

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).
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
 
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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 
firststudy vaccination. These events will be recorded in the medical history section 
of the eCRF.
8.1.2.
Definition of a serious adverse event 
A SAEis 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 hospitalizationor prolongation of existing hospitalization,
Note: In general, hospitalizationsignifies that the subject has been admitted at the 
hospital or emergencyward 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 hospitalizationare also considered AEs. If a complication prolongs 
hospitalizationor fulfils 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.
Hospitalizationfor 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, OR
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 judgmentshould 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 hospitalizationbut may jeopardizethe 
subject or may require medical or surgical intervention to prevent one of the other 
 
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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.
In this study, the following AEs of specific interest(pIMDs,meningitis and seizure
within 30 or 42 days of vaccination) will be reported as SAEs(see also Section 8.1.5).
8.1.3.
Solicited adverse events
8.1.3.1.
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 13 
Solicited local adverse events
Pa
in at 
in
ject
ion s
ite
Redness* at 
in
ject
ion s
ite
Swe
l
l
ing at 
in
ject
ion s
ite
* In case the pr
inc
ipa
l 
invest
igator or des
ignate 
is 
unab
le to determ
ine the extent of redness on 
dark
ly p
igmented sk
in, 
it w
i
l
l be reported as 
un
interpretab
le 
in the eCRF
8.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 14
Solicited general adverse events
Drows
iness
Fever
Irr
itab
i
l
ity/Fuss
iness
Loss of appet
ite
Meas
les/rube
l
la-l
ike rash*
* To be conf
irmed by phys
ic
ian
Note: Temperature will be recorded daily. Should additional temperature measurements 
be performed at other times of day, the highest temperature will be recorded in the eCRF.
8.1.4.
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 definitionof an 
AE or SAE (refer to Sections8.1.1and 8.1.2). 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.
 
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The investigator will exercise hisor her medical and scientific judgmentin deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
8.1.5.
Adverse events of specific interest
All adverse events of specific interest described below will be reported as SAEs.
8.1.5.1.
Potential immune-mediated diseases
pIMDs are a subset of AEsthat 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 15.pIMD will be reported as SAEs.
However, the investigator will exercise his/her medical and scientific judgmentin 
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 15 
List of potential immune-mediated diseases
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cran
ia
l nerve d
isorders, 
inc
lud
ing 
para
lyses/pares
is (e.g. Be
l
l
’s pa
lsy) 

Opt
ic neur
it
is

Mu
lt
ip
le sc
leros
is

Transverse mye
l
it
is

Gu
i
l
la
in-Barré syndrome, 
inc
lud
ing 
M
i
l
ler F
isher syndrome and other 
var
iants

Acute d
issem
inated 
encepha
lomye
l
it
is, 
inc
lud
ing s
ite 
spec
if
ic var
iants: e.g. non-infect
ious 
encepha
l
it
is, encepha
lomye
l
it
is, 
mye
l
it
is, mye
lorad
icu
loneur
it
is

Myasthen
ia grav
is, 
inc
lud
ing 
Lambert-Eaton myasthen
ic 
syndrome 

Immune-med
iated per
iphera
l 
neuropath
ies and p
lexopath
ies, 
(
inc
lud
ing chron
ic 
inf
lammatory 
demye
l
inat
ing po
lyneuropathy, 
mu
lt
ifoca
l motor neuropathy and 
po
lyneuropath
ies assoc
iated w
ith 
monoc
lona
l gammopathy).

Narco
lepsy

System
ic 
lupus erythematosus 
and assoc
iated cond
it
ions

System
ic sc
leroderma
(System
ic sc
leros
is), 
inc
lud
ing 
d
iffuse system
ic form and 
CREST syndrome
Id
iopath
ic 
inf
lammatory 
myopath
ies, 
inc
lud
ing 
dermatomyos
it
is 

Po
lymyos
it
is 

Ant
isynthetase syndrome

Rheumato
id arthr
it
is, and 
assoc
iated cond
it
ions 
inc
lud
ing 
j
uven
i
le chron
ic arthr
it
isand 
St
i
l
l
’s d
isease

Po
lymya
lg
ia rheumat
ica

Spondy
loarthr
it
is, 
inc
lud
ing 
anky
los
ing spondy
l
it
is, react
ive 
arthr
it
is (Re
iter
's Syndrome) 
and und
ifferent
iated 
spondy
loarthr
it
is 

Psor
iat
ic arthropathy

Re
laps
ing po
lychondr
it
is

M
ixed connect
ive t
issue 
d
isorder

Psor
ias
is

V
it
i
l
igo

Erythema nodosum

Auto
immune bu
l
lous 
sk
in d
iseases (
inc
lud
ing 
pemph
igus, pemph
igo
id 
and dermat
it
is 
herpet
iform
is)

A
lopec
ia areata

L
ichen p
lanus

Sweet
’s syndrome

Loca
l
ised Sc
leroderma 
(Morphoea)
Vasculitides
Blood disorders
Others

Large vesse
ls vascu
l
it
is 
inc
lud
ing: 
g
iant ce
l
l arter
it
is such as 
Takayasu
's arter
it
is and tempora
l 
arter
it
is. 

Med
ium s
ized and/or sma
l
l vesse
ls 
vascu
l
it
is 
inc
lud
ing: po
lyarter
it
is 
nodosa, Kawasak
i
's d
isease, 
m
icroscop
ic po
lyang
i
it
is, Wegener
's 
granu
lomatos
is, Churg–Strauss 
syndrome (a
l
lerg
ic granu
lomatous 
ang
i
it
is), Buerger
’s d
isease 
(thromboang
i
it
is ob
l
iterans), 
necrot
iz
ing vascu
l
it
is and ant
i-
neutroph
i
l cytop
lasm
ic ant
ibody 
(ANCA) pos
it
ive vascu
l
it
is (type 
unspec
if
ied), Henoch-Schon
le
in 
purpura, Behcet
's syndrome, 
leukocytoc
last
ic vascu
l
it
is.

Auto
immune 
hemo
lyt
ic anem
ia

Auto
immune 
thrombocytopen
ia

Ant
iphospho
l
ip
id 
syndrome

Pern
ic
ious anem
ia

Auto
immune 
ap
last
ic anaem
ia

Auto
immune 
neutropen
ia 

Auto
immune 
pancytopen
ia

Auto
immune g
lomeru
lonephr
it
is 
(
inc
lud
ing IgA nephropathy, 
g
lomeru
lonephr
it
is rap
id
ly 
progress
ive, membranous 
g
lomeru
lonephr
it
is, 
membranopro
l
iferat
ive 
g
lomeru
lonephr
it
is, and 
mesang
iopro
l
iferat
ive 
g
lomeru
lonephr
it
is)
Ocu
lar auto
immune d
iseases
(
inc
lud
ing auto
immune uve
it
is and 
auto
immune ret
inopathy)

Auto
immune 
myocard
it
is/card
iomyopathySarco
id
os
is

Stevens-Johnson syndrome

S
jögren
’s syndrome

Id
iopath
ic pu
lmonary f
ibros
is

Goodpasture syndrome

Raynaud
’s phenomenon
 
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Liver disorders
Gastrointestinal disorders
Endocrine disorders

Auto
immune hepat
it
is

Pr
imary b
i
l
iary c
irrhos
is

Pr
imary sc
leros
ing 
cho
lang
it
is

Auto
immune cho
lang
it
is

Inf
lammatory Bowe
l d
isease, 
inc
lud
ingCrohn
’s d
isease, 
u
lcerat
ive co
l
it
is,m
icroscop
ic 
co
l
it
is, u
lcerat
ive proct
it
is 

Ce
l
iac d
isease

Auto
immune pancreat
it
is

Auto
immune thyro
id
it
is (
inc
lud
ing 
Hash
imoto thyro
id
it
is)

Grave
's or Basedow
’s d
isease

D
iabetes me
l
l
itus type I

Add
ison
’s d
isease

Po
lyg
landu
lar auto
immune 
syndrome

Auto
immune hypophys
it
is
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as SAEs 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.
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaireand a list of preferredterms and preferred termscodes corresponding to the 
above diagnoseswill be available to investigators at study start.
8.1.5.2.
Seizures within 30 or 42 days of vaccination(Amended: 09 August 
2016)
All seizures occurring within 30 days of vaccination for vaccine doses administered at 6 
and 7.5 months of age (Visits 2 and 3) and within 42 days for vaccine doses administered 
at 9 months of age (Visit 4) will be reported as SAEsandin specific eCRF screens. Key 
information pertaining to seizures occurring within sevendays of vaccination for vaccine 
doses administered at 6 and 7.5 months of age (Visits 2 and 3) and within 14days for 
vaccine doses administered at 9 months of age (Visit 4) will be documented in the eCRF 
[refer to Bonhoeffer, 2004].
8.1.5.3.
Meningitis(Amended: 09 August 2016)
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 inspecific eCRF screens.Cerebrospinal fluid will be frozen for future testing 
for infectious agents if applicable (this procedure is fully described in the SPM).
8.2.
Detecting and recording adverse eventsandserious 
adverse events
8.2.1.
Time period for detecting and recording adverse eventsand
serious adverse events
In the Coad and the RTS,S group, all AEs starting after the first vaccine administration 
(Visit 2) until 42 daysfollowing administration of study vaccine at 9 months of age (Visit 
4) and AEs starting within 30 daysfollowing administration of study vaccine at 27 
months of age (Visit 10) must be recorded into the appropriate section of the eCRF,
irrespective of intensity or whether or not they are considered vaccination-related.
 
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In the Control group, all AEs starting after the Vitamin A administration (Visit 2) until 42 
daysfollowing administration of study vaccine at 9 months of age(Visit 4),AEs starting 
from the day of the first dose of RTS,S/AS01
E(Visit 6) until 30 days after Visit 8and 
from the day of the booster dose of RTS,S/AS01
Eadministered at 30 months of age (Visit 
12) until 30 days after the booster dose must be recorded into the appropriate section of 
the eCRF, irrespective of intensity or whether or not they are considered vaccination-
related.
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine and will end 12 monthsfollowing administration of the last dose of study vaccine 
(Month 33 for Coad and RTS,S groups and Month 36 for the Control group)for each 
subject. See Section 8.3for instructions on reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine.
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 AEs of specific interestwill begin at the 
first receipt of study vaccine and will end 12 monthsfollowing administration of the last 
the dose of study vaccine (Month 33 for Coad and RTS,S groups and Month 36 for the 
Control group). See section 8.3for instructions on reporting of AEs of specific interest.
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 16.
 
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Table 16
Reporting periods for adverse eventsandserious adverse events(Amended: 09 August 2016)
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Children age 
(Months)
6
7.5
9
10
10.5 
11.5 12.5 13.5
27 
28 
30 
31 
39 
42
Study Month
M0
M1.5
M3
M4
M4.5
M5.5
M6.5
M7.5
M21
M22
M24
M25
M33
M36
D-28 
to -1
D0 D6 D29
M1.5 M1.5 
+6d
M1.5
+29d
M3
M3
+13d
M3
+41d
So
l
ic
ited 
loca
l 
and genera
l AEs
Xa Xa
Xa
Xa
Xa
Unso
l
ic
ited AEs
Xb Xb Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb,c
Xc
Xc
Xc
Xd
Xd
Xe
Xe
SAEs re
lated to 
study 
part
ic
ipat
ion or 
concurrent GSK 
med
icat
ion/vacc
i
ne
SAEs (A
l
l, fata
l, 
re
lated to the 
invest
igat
ion
a
l 
vacc
ine)
AEs of spec
if
ic 
interest**
M: study month; d: day
** AEs of spec
if
ic 
interestinc
lude se
izure(occurr
ing w
ith
in 30 days post-vacc
inat
ion for vacc
ine doses adm
inistered at 6 and 7.5 months of age [V
is
its 2 and 3] or 42 days post-
vacc
inat
ion for vacc
ine doses adm
in
istered at 9 months of age [V
is
it 4]), men
ing
it
is and pIMDs.
a In the Contro
l group, on
ly so
l
ic
ited genera
l AE w
i
l
l be co
l
lected. In the Coad andtheRTS,S groups, so
l
ic
ited 
loca
l and genera
l AEs w
i
l
l be co
l
lected.
bUnso
l
ic
ited AEs w
i
l
l be co
l
lected from V
is
it 2 unt
i
l 42 days after V
is
it 4 for ch
i
ldren 
in Coad,RTS,S and Contro
l groups.
cUnso
l
ic
ited AEs w
i
l
l be co
l
lected from V
is
it 6 unt
i
l 30 days after V
is
it 8on
lyfor ch
i
ldren from the Contro
l group.
dUnso
l
ic
ited AEs w
i
l
l be co
l
lected over a 30-day fo
l
low-up per
iod after vacc
inat
ion on
lyfor ch
i
ldren from the Coad and the RTS,S groups.
eUnso
l
ic
ited AEs w
i
l
l be co
l
lected over a 30-day fo
l
low-up per
iod after vacc
inat
ion on
lyfor ch
i
ldren from the Contro
lgroup.
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8.2.2.
Post-Study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 16. Investigators are not obligated toactively seek AEs 
or 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 vaccines/product, the investigator will 
promptly notify the Study Contact for Reporting SAEs.
8.2.3.
Evaluation of adverse events and serious adverse events
8.2.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, 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 AE/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 
AE/SAE on the in the eCRF.The investigator is not allowed tosend 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 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 AE/SAE and not the individual signs/symptoms.
 
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8.2.3.2.
Assessment of adverse events
8.2.3.2.1. Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 17
Intensity scales for solicited symptoms in infants
Infants
Adverse Event
Intensity grade
Parameter
Pa
in at 
in
ject
ion s
ite
0
None
1
M
i
ld: M
inor react
ion to touch
2
Moderate: Cr
ies/protests on touch
3
Severe: Cr
ies when 
l
imb 
is moved/spontaneous
lypa
infu
l
Redness at 
in
ject
ion s
ite
Record greatest surface d
iameter 
in mm
Swe
l
l
ing at 
in
ject
ion s
ite
Record greatest surface d
iameter 
in mm
Fever*
Record temperature 
in °C/°F
Irr
itab
i
l
ity/Fuss
iness
0
Behav
ior as usua
l
1
M
i
ld: Cry
ing more than usua
l/no effect on norma
l act
iv
ity
2
Moderate: Cry
ing more than usua
l/
interferes w
ith norma
l act
iv
ity
3
Severe: Cry
ing that cannot be comforted/prevents norma
l 
act
iv
ity
Drows
iness
0
Behav
ior as usua
l
1
M
i
ld: Drows
iness eas
i
ly to
lerated
2
Moderate:Drows
iness that 
interferes w
ith norma
l act
iv
ity
3
Severe: Drows
iness that prevents norma
l act
iv
ity
Loss of appet
ite
0
Appet
ite as usua
l
1
M
i
ld: Eat
ing 
less than usua
l/no effect on norma
l act
iv
ity
2
Moderate: Eat
ing 
less than usua
l/
interferes w
ith norma
l act
iv
ity
3
Severe: Not eat
ing at a
l
l
Meas
les/rube
l
la-l
ike rash
0
No 
les
ion
1
1-50 
les
ions
2
51-150 
les
ions
3
>150 
les
ions
*Fever 
is def
ined as temperature 37.5°C / 99.5°F for ora
l, ax
i
l
lary or tympan
ic route, or 38.0°C / 100.4°F for recta
l 
route. The preferred route for record
ing temperature 
in th
is study w
i
l
l be ax
i
l
lary.
The maximum intensity of local injection site redness/swelling/fever will be scored at 
GSK Biologicals as follows:
0 :
None
1 :
< 5 mm
2 :
5 to 20 mm
3 :
> 20 mm
The maximum intensity of fever will be scored at GSK Biologicals as follows (the 
preferred route for recording temperature in this study will be axillary):
0 :
< 37.5°C
1 : 
37.5 –38.0°C
2 :
> 38 –39.0°C
3 :
> 39.0°C
 
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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 day-
care centerand would cause the parent(s)/LAR(s) to seek medical 
advice.)
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs 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 8.1.2.
8.2.3.2.2. Assessment of causality
The investigator is obligated to assess the relationship between investigational vaccine
and the occurrence of each AE/SAE. The investigator will use clinical judgmentto 
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 vaccinewill be considered and 
investigated. The investigator will also consult the IB or Prescribing Informationfor 
marketed productsto determine his/her assessment.
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 Expedited Adverse Events Reportto 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/products, it may not be 
possible to determine the causal relationship of general AEs to the individual 
vaccine/productadministered. The investigator should, therefore, assess whether the AE 
could be causally related to vaccination rather than to the individual vaccines/products.
 
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All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine?
YES
: There is a reasonable possibility that the vaccinescontributed to the 
AE. 
NO
: There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccines. There are other, more 
likely causes and administration of the study vaccinesis not 
suspected to have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), 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 vaccines, if applicable.
Erroneous administration.
Other cause (specify).
8.2.3.3.
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).
8.2.3.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s)will be asked if the subjectreceived medical attention defined as 
 
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hospitalization, or an otherwise unscheduledvisit to or from medical personnel for any 
reason, including emergency room visits. Thisinformation will be recorded in the eCRF.
8.3.
Reporting of serious adverse eventsand other events
8.3.1.
Prompt reporting of serious adverse events and other events to 
GSK Biologicals
SAEs that occur in the time period defined in Section 8.2will 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.
AEs of specific interest(pIMDs, meningitis and seizure within 30 or 42 days of 
vaccination) that occur in the time period defined in Section 8.2will be reported 
promptly to GSK within the timeframes described in Table 18, once the investigator 
determines that the event meets the protocol definition of an AEs of specific interest
(pIMDs, meningitis and seizure within 30 or 42 days of vaccination).
Table 18
Timeframes for submitting serious adverse eventand other events 
reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours*
‡
e
lectron
icExped
ited 
Adverse Events Report
24 hours*
e
lectron
icExped
ited Adverse 
Events Report
AEs of spec
if
ic 
interest
**
24 hours*
‡
e
lectron
icExped
ited 
Adverse Events Report
24 hours*
e
lectron
icExped
ited Adverse 
Events Report
* T
imeframe a
l
lowed after rece
ipt or awareness of the 
informat
ion.
** AEs of spec
if
ic 
interestinc
lude se
izure(occurr
ing w
ith
in 30 days post-vacc
inat
ion for vacc
ine doses adm
in
istered at 
6 and 7.5 months of age [V
is
its 2 and 3] or 42 days post-vacc
inat
ion for vacc
ine doses adm
in
istered at 9 months of 
age [V
is
it 4]), men
ing
it
is and pIMDs.
‡ The 
invest
igator w
i
l
l be requ
ired to conf
irm rev
iew of the SAE/AEs of spec
if
ic 
interestcausa
l
ity by t
ick
ing the 
‘rev
iewed
’ box 
in the e
lectron
ic Exped
ited Adverse Events Report w
ith
in 72 hours of subm
iss
ion of the SAE/AEs of 
spec
if
ic 
interest.
 
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8.3.2.
Contact information for reporting serious adverse eventsand 
AEs of specific interest
Study Contact for Reporting SAEsand AEs of specific interest*
Refer to the localstudycontact information document.
Back-up Study Contact for Reporting SAEsand AEs of specific interest*
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US & Canadasites:
Fax: +
Email address: 
* AEs of spec
if
ic 
interestinc
lude se
izure(occurr
ing w
ith
in 30 days post-vacc
inat
ion for vacc
ine doses adm
in
istered at 6 
and 7.5 months of age [V
is
its 2 and 3] or 42 days post-vacc
inat
ion for vacc
ine doses adm
in
istered at 9 months of age 
[V
is
it 4]), men
ing
it
is and pIMDs.
8.3.3.
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 Expedited 
Adverse Events ReportWITHIN 24 HOURS. The 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.The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
8.3.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Reportand fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Reportwithin 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system. 
 
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8.3.4.
Reporting of AEs of specific interestto GSK Biologicals
(Amended: 09 August 2016)
Once anAE of specific interest(pIMDs, meningitis and seizure within 30 or 42 days of 
vaccination) is diagnosed in a study subject, the investigator (or designate) must complete 
the information in the electronic Expedited Adverse Events ReportWITHIN 24 HOURS 
after he/she becomes aware of the diagnosis. The report allows to specify that the event is 
a pIMD. The report will always be completed as thoroughly as possible with all available 
details of the event, in accordance with the pIMDstandard questionnaire provided. Even 
if the investigator does not have all information regardingan AEs of specific interest,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.The investigator will be required to confirmthe review of the AEs of specific 
interest causality by ticking the ‘reviewed’ box in the electronic Expedited Adverse 
Events Report within 72 hours of submission of the AEs of specific interest.
Refer to Section 8.3.3.1for back-up system in case the electronic reporting system does 
not work.
8.3.5.
Updating of SAEand AEs of specific interestinformation after 
removal of write access to the subject’seCRF
When additional SAE or AEs of specific interestinformation is received afterremoval of 
the write access tothe subject’s eCRF, new or updated information should be recorded on 
the appropriatepaper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified inTable 18.
8.3.6.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.3.1. 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 vaccines and unexpected. The 
purpose of the report is to fulfillspecific regulatory and GCP requirements, regarding the 
product under investigation.
 
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8.4.
Follow-up of adverse events andserious adverse events
8.4.1.
Follow-up of adverse events and serious adverse events 
8.4.1.1.
Follow-up during the study
After the initial AE/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 AEs of specific interest(pIMDs, meningitis and seizure within 30 or 42 
days of vaccination) 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.
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination.
8.4.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:
with SAEs, AEs of specific interestor subjects withdrawn from the study as a result 
of an AE, 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/ electronic 
Expedited Adverse Events Reportand/or pregnancy 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 AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognizedfollow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
8.5.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according tocurrent
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 6.7).
8.6.
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.
 
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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.
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
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.
9.2.
Subject withdrawal
Withdrawals will not be replaced.
9.2.1.
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 (phone and visit contacts) to contact those subjects 
who do not return forscheduled 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)/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.
 
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Other (specify).
*In case a subject is withdrawn from the study because the subject’s parent(s)/LAR(s)
has withdrawn consent, the investigator will document the reason for withdrawal of 
consent, if specified by the subject/subject’s parent(s)/LAR(s), in the eCRF.
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 8.4.1.2).
9.2.2.
Subject withdrawal from investigational vaccine
A ‘withdrawal’ from the investigational vaccinerefers to any subject who does not 
receive the complete treatment, i.e. when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational vaccinemay not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol. 
Information relative to premature discontinuation of the investigational vaccinewill be 
documented on the Vaccine Administration screenof the eCRF. The investigator will 
document whether the decision to discontinue further vaccination/treatment was made by 
the subject’s parent(s)/LAR(s), or bythe investigator, as well as which of the following 
possible reasons was responsible for withdrawal:
Serious adverse event.
Non-serious adverse event.
Other (specify).
9.3.
Extension study
At the end of the study (study conclusion visit/contact), the investigator will ask subject’s 
parent(s)/LAR(s)if they are interested to allow the subject to participate in a booster 
study/long-term study. If asubject’s parent(s)/LAR(s) is/are not interested in 
participating in the booster study/long-term studythe reason for refusal will be 
documented in the subject’s eCRF.
9.4.
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. Reason for 
screening failure will be collected.
 
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10.
STATISTICAL METHODS
10.1.
Primary endpoints
Non-inferiority of the antibody response to the CS antigen (RTS,S group/Coad 
group):
Anti-CS antibody titers at one month post Dose 3 of RTS,S/AS01
E(Month 4).
10.2.
Secondary endpoints
Immunogenicity
Antibody response to the candidate vaccine RTS,S/AS01
E(RTS,S group and Coad 
group):
Anti-CS antibody titers and seropositivity at Day 0 and at one month post Dose 
3 of RTS,S/AS01E(Month 4).
Anti-HBs antibody titers and seroprotection at Day 0 and at one month post 
Dose 3 of RTS,S/AS01E(Month 4).
Non-inferiority of the antibody response to the measles vaccine antigen in the 
combined measles and rubella vaccine (Control group minus Coad group):
Seroconversion for anti-Me at one month post-vaccination with the combined 
measles and rubella vaccine (Month 4). Seroconversion is defined as children 
with an anti-Me pre-vaccination titer below 150 mIU/ml and a post-vaccination 
titer ≥ 150 mIU/ml.

Antibody response to the measles vaccine antigen in the combined measles and 
rubella vaccine (Control group and Coad group):
Anti-Me antibody titers and seropositivity (≥150 mIU/ml) pre-vaccination 
(Month 3) and one month post-vaccination with the combined measles and 
rubella vaccine (Month 4).
Non-inferiority of the antibody response to the rubella vaccine antigen in the 
combined measles and rubella vaccine (Control group minus Coad group):
Seroconversion for anti-Ru at one month post-vaccination with the combined 
measles and rubella vaccine (Month 4). Seroconversion is defined as children 
with an anti-Ru pre-vaccination titer below 4 IU/ml and a post-vaccination titer 
≥ 4 IU/ml.
Antibody response to the rubella vaccine antigen in the combined measles and 
rubella vaccine (Control group and Coad group):
Anti-Ru antibody titers and seropositivity (≥ 4 IU/ml) pre-vaccination (Month 3) 
and one month post-vaccination with the combined measles and rubella vaccine 
(Month 4).
 
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Non-inferiority of the antibody response to the YF vaccine antigen (Control group 
minus Coad group):

Seropositivity (≥10 ED50) for anti-YF at one month post-vaccination with the 
YF vaccine (Month 4).

Antibody response to the YF vaccine antigen (Control group and Coad group):
Anti-YF antibody titers and seropositivity (≥ 10 ED50) one month post-
vaccination with the YF vaccine (Month 4).
Safety
Solicited local and general AEs.
For the Coad and the RTS,S groups, the occurrence of solicited local and 
general AEs over a 7-day follow-up period (day of administration and 6 
subsequent days) after administration of Vitamin A and study vaccines at 6 
months of age (Visit 2).

For the Control group, the occurrence of solicited general AEs over a 7-day 
follow-up period (day of administration and 6 subsequent days) after 
administration of Vitamin A at 6 months of age (Visit 2).

For the Coad and the RTS,S groups, the occurrence of solicited local and 
general AEs over a 7-day follow-up period (day of vaccination and 6 subsequent 
days) after dose of study vaccines administered at 7.5 months of age (Visit 3).
For the Control group, the occurrence of solicited general AEs over a 7-day 
follow-up period (day of visit and 6 subsequent days) after Visit 3 (7.5 months 
of age).
For all groups, the occurrence of solicited general and local AEs over a 14-day 
follow-up period (day of vaccination and 13 subsequent days) after dose of 
study vaccines administered at 9 months of age (Visit 4).

Unsolicited AEs.
For all groups, the occurrence of unsolicited AEs over a 30-day follow-up 
period (day of administration and 29 subsequent days) after administration of 
Vitamin A and study vaccines at 6 months of age (Visit 2).

For the Coad and the RTS,S groups, the occurrence of unsolicited AEs over a 
30-day follow-up period (day of vaccination and 29 subsequent days) after dose 
of study vaccines administered at 7.5 months of age (Visit 3).

For the Control group, the occurrence of unsolicited AEs over a 30-day follow-
up period (day of visit and 29 subsequent days) after Visit 3 (7.5 months of age).
For all groups, the occurrence of unsolicited AEs over a 42-day follow-up 
period (day of vaccination and 41 subsequent days) after dose of study vaccines 
administered at 9 months of age (Visit 4).
 
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For the Coad and the RTS,S groups, the occurrence of unsolicited AEs over a 
30-day follow-up period (day of vaccination and 29 subsequent days) after the 
booster dose of study vaccine administered at 27 months of age (Visit 10).

For the Control group, the occurrence of unsolicited AEs over a 30-day follow-
up period (day of vaccination and 29 subsequent days) after dose of study 
vaccines administered at 10.5, 11.5, 12.5 and 30 months of age (Visit 6, 7, 8 and 
12).
SAEs: all, fatal and related SAEs.
The occurrence of SAEs occurring within 30 days (day of vaccination and 29 
subsequent days) after each administrations.

The occurrence of SAEs from Screening visit (Visit 1) until Month 4.5.
The occurrence of SAEs from Screening visit (Visit 1) until study end (Month 
33 for Coad and RTS,S groups and Month 36 for the Control group).
The occurrence of pIMDs from Day 0 until Month 4.5.
The occurrence of pIMDsfrom Day 0 until study end (Month 33 for Coad and 
RTS,S groups and Month 36 for the Control group).

The occurrence of meningitis from Day 0 until Month 4.5.
The occurrence of meningitis from Day 0 until study end (Month 33 for Coad 
and RTS,S groups and Month 36 for the Control group).
The occurrence of seizure (occurring within 30 days post-vaccination for 
vaccine doses administered at 6 and 7.5 months of age [Visits 2 and 3] or 42 
days post-vaccination for vaccine doses administered at 9 months of age [Visit 
4]) from Day 0 until Month 4.5.
The occurrence of seizure occurring within 30 days post-vaccination for vaccine 
doses administered at 6, 7.5 and 27 months of age (Visits 2, 3 and 10 for Coad 
and RTS,S group) and at 10.5, 11.5, 12.5 and 30 months of age (Visits 6, 7, 8 
and 12 for Control group) or 42 days post-vaccination for vaccine doses 
administered at 9 months of age (Visit 4 for all groups).

The occurrence of generalized convulsive seizure occurring within 7 days after 
vaccines administered at Visit 2 and 3 (Coad and RTS,S groups) and 14days 
after vaccines administered at Visit 4 (all groups).
10.3.
Tertiary endpoints
Immunogenicity
Antibody response tocomponent ofthe candidate vaccine RTS,S/AS01
E(Coad 
groupand Control group):
Anti-catalase antibody concentrations and seropositivity at Day 0 andbefore 
administration of RTS,S/AS01
E(Month 4) for the Control group and at Day 0 
and at one month post Dose 3 of RTS,S/AS01
E(Month 4) for the Coad group.
 
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10.4.
Determination of sample size
For the primary endpoint, with 205 evaluable subjects per group the study has at least 
90% power to rule out a minimum 2-fold decrease in anti-CS GMTs in the Coad group 
versus the RTS,S group with a 2-sided 5% alpha level and an assumed anti-CS log 
standard deviation of ≤ 0.9 (see Table 19).
For the secondary endpoints, the power to demonstrate non-inferiority in terms of anti-
YF, anti-Ru and anti-Me with 205 evaluable subjects per group is presented in Table 19. 
Non-inferiority is defined as the UL of the 95% CI on the difference (Control group 
minus Coad group) in response <10%.
In order to account for drop-outs and subjects non-evaluable for immunogenicity 
endpoints (approximately 12%), 233 subjects per group will be enrolled for a total of 699 
subjects.
Table 19
Sample size and power
Antibody
Endpoint
Non-inferiority 
limit
Reference in 
control
Power
Ant
i-CS
GMT rat
io (RTS,S group / Coad group)
2-fo
ld decrease log SD 
≤ 0.9
90%
Ant
i-Ru
Seroconvers
ion
10%
90%*
90%
Ant
i-YF
Seropos
it
iv
ity
10%
95%**
99%
Ant
i-Me
Seroconvers
ion
10%
90%**
90%
Power of a non-infer
ior
ity test on 
seroconvers
ion/pos
it
iv
ity or means, 2-s
ided a
lpha 0.05, N=205 (Pass 2005).
* Adapted from Rube
l
la vacc
ines: WHO pos
it
ion paper [WHO, 2011].
** [G
laxoSm
ithK
l
ine B
io
log
ica
ls C
l
in
ica
l Study Report Amendment 1 -106369(MALARIA-050)].
10.5.
Cohorts for analyses
10.5.1.
Total vaccinated cohort
The total vaccinated cohort (TVC) will include all subjects who received treatment (i.e.
receiving at least one dose of study vaccineor VitaminA). The TVC analysis will be 
performed per treatment actually administered.
10.5.2.
According-to-protocol cohort for analysis of immunogenicity 
(ATP immunogenicity)
The ATP cohort for analysis of immunogenicity will include all evaluable subjects 
meeting all eligibility criteria, complying with the procedures defined in the protocol, 
with no elimination criteria during the study. Subjects with incomplete vaccination course 
or blood sampling performed outside the protocol defined windows will be eliminated.
10.6.
Derived and transformed data
A subject seropositive for anti-CS antibody will be a subject whose antibody titer 
will be greater than or equal to the cut-off value (anti-CS 0.5 EU/ml).
 
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Seroprotection rate for anti-HBs antibody is defined as the percentage of subjects 
with antibody titers greater than or equal to an established cut-off (anti-HBs 10 
mIU/ml).

Seroconversion rates for anti-Me is defined as children with an anti-Me pre-
vaccination titer below 150 mIU/ml and a post-vaccination titer ≥ 150 mIU/ml.
Seroconversion rates for anti-Ru is defined as children with an anti-Ru pre-
vaccination titer below 4 IU/ml and a post-vaccination titer ≥ 4 IU/ml.
A subject seropositive for anti-YF antibody will be a subject whose antibody titer 
will be greater than or equal to the cut-off value (anti-YF 10 ED50).
A subject seropositive for anti-catalase antibody will be a subject whose antibody 
concentrationis greater than or equal to 65 ng/ml.

The GMT calculations will be 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 halfthe cut-off for the purpose of GMT calculation. All 
available immunogenicity data will be analyzed. Missing data will not be imputed.
10.7.
Analysis of demographics
Demographic characteristics (age, gender, height for age Z-score, and weight for age Z-
score) of each cohort (TVC and ATP cohort for immunogenicity) will be tabulated per 
study group.
The mean age at first vaccination (in months) (plus range and standard deviation) of the 
vaccinated subjects, as a whole, and per group, will be calculated.
10.8.
Analysis of immunogenicity
The primary analysis will be based on the ATP cohort for immunogenicity.
For the primary endpoint, the 95% CIs of the anti-CS GMT ratio between the groups 
(RTS,S group over Coad group) at one month post Dose 3 of RTS,S/AS01Ewill be 
calculated. Non-inferiority of anti-CS immune response will be concluded if the UL of 
this CI is below 2.
For the secondary endpoints, the 95% CIs of the difference in anti-Me, anti-Ru and anti-
YF seroconversion/seropositivity rates between the groups (Control group minus Coad 
group) at one month post-vaccination will be calculated (standardized asymptotic). The 
seroconversion rate is defined as the percentage of initially seronegative that are 
seropositive post-vaccination. Non-inferiority will be concluded if the UL of this CI is 
below 10%.
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 Day 0 and 
one month post Dose 3 of RTS,S/AS01E in the RTS,S group and Coad group. Antibody 
titers will be summarized by GMT with 95% CI. Antibody titers at one month post Dose 
3 of RTS,S/AS01Ewill also be investigated using reverse cumulative curves.
 
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Seroprotection level for anti-HBs with 95% CI will be determined at Day 0 and one
month post Dose 3 of RTS,S/AS01E in the RTS,S group and Coadgroup. Anti-HBs titers 
will be summarized by GMT with 95% CI. Anti-HBs titers one month post Dose 3 of 
RTS,S/AS01E will also be investigated using reverse cumulative curves.
Seropositivity levels of anti-Ru (≥ 4 IU/ml) and seropositivity levels of anti-Me (≥ 150 
mIU/ml) with 95% CI will be determined pre-vaccination and one month post-
vaccination with the YF vaccine and the combined measles and rubella vaccine in the 
Control group and Coadgroup. Antibody titers will be summarized by GMT with 95% 
CI. Anti-Ru and anti-Me titers at one month post-vaccination with the YF vaccine and the 
combined measles and rubella vaccine will also be investigated using reverse cumulative 
curves.
Seropositivity levels of anti-YF (≥10 ED50) with 95% CI will be determined one month 
post-vaccination with the YF vaccine and the combined measles and rubella vaccine in 
the Control group and Coadgroup. Antibody titers will be summarized by GMT with 
95% CI. Anti-YF titers at one month post-vaccination with the YF vaccine and the 
combined measles and rubella vaccine will also be investigated using reverse cumulative 
curves.
For the tertiary endpoints, the anti-catalase concentrations will be summarized by 
seropositivity and geometric mean concentrationwith 95% CI at Day 0 (Control and 
Coad groups), at one month post Dose 3 of RTS,S/AS01E in the Coad group and before 
administration of the first dose of RTS,S/AS01
E in the Control group.
10.9.
Analysis of safety
The primary analysis will be based on the TVC.
The percentage of subjects with at least one local AE (solicited and unsolicited), with at 
least one general AE (solicited and unsolicited) and with any AE during the solicited 
follow-upperiod will be tabulated with exact 95% CI after each vaccine dose and overall. 
The percentage of doses followed by at least one local AE (solicited and unsolicited), by 
at least one general AE (solicited and unsolicited) and by any AE will be tabulated for the 
overall vaccination course, with exact 95% CI. Similar tables will be generated for Grade 
3 AEs and AEs considered as causally related to vaccination.
The percentage of subjects reporting each individual solicited local and general AE 
during the solicited follow-up period will be tabulated with exact 95% CI. The percentage 
of doses followed by each individual solicited local and general AE will be tabulated for 
each dose and for the overall vaccination course, with exact 95% CI. Similar tables will 
be generated for Grade 3 AEs, causal events and for fever, temperature in 0.5C 
increments.
The proportion of subjects reporting an AE (unsolicited) until 30 days (Days 0-29) post 
each dose of RTS,S/AS01
E, classified by the Medical Dictionary for Regulatory
Activities (MedDRA) preferred term level will be tabulated with exact 95% CI. The 
proportion of subjects reporting an AE (unsolicited) until 42 days (Days 0-41) after the 
administration of the YF vaccine and the combined measles and rubella vaccine 
 
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(restricted to the Coad group and Control group), classified by the MedDRA preferred 
term level will be tabulated with exact 95% CI.
The proportion of subjects reporting an SAE (all, fatal, related) occurring within 30 days 
(day of vaccination and 29 subsequent days) after each dose of study vaccines, classified 
by the MedDRA preferred term level will be tabulated with exact 95% CI.
The proportion of subjects reporting an SAE (all, fatal, related) from Day 0 to Month 4.5
and over the whole study duration (Day 0 to Month 33 for Coad and RTS,S groups and 
Month 36 for the Control group), classified by the MedDRA preferred term level will be 
tabulated with exact 95% CI.
The proportion of subjects reporting an AEs of specific interest(pIMDs, meningitis and 
seizures)from Day 0 to Month 4.5and over the whole study duration (Day 0 to Month 33 
for Coad and RTS,S groups and Month 36 for the Control group), classified by the 
MedDRA preferred term level will be tabulated with exact 95% CI.
For generalized convulsive seizures occurring within 7 days after vaccines administered 
at Visit 2 and 3 (Coad and RTS,S groups) and 15 days after vaccines administered at 
Visit 4 (all groups) an analysis will be performed based on the Brighton Collaborations 
guidelines [Bonhoeffer, 2004]. This includes descriptive tables of the time relationship of 
seizures to vaccination, the duration of seizures and the level of diagnostic certainty.
10.10.
Interpretation of analyses
Except for analyses on objectives with a pre-defined success criterion (see Section 2), 
comparative analyses will be descriptive with the aim to characterize the difference in 
immunogenicity and safety between groups.
10.11.
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.
10.11.1. Sequence of analyses
The primary analysis will be performed on data collected up to and including 42 days 
post-measles/rubella/YF vaccination and will include all immunogenicity data (primary 
secondary and tertiary endpoints) and safety data (secondary endpoints) up to Month 4.5
(Visit 6). A clinical study report will be written after this analysis.
An analysis with remaining safety data will be performed when all data up to and 
including the Month 33 for Coad and RTS,S groups (Visit 14) and Month 36 for the 
Control group (Visit 15) will be available. Additional safety information will be added to 
the clinical study report prepared after Visit 6.
All analyses will be conducted on data as clean as possible.
 
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10.11.2. Statistical considerations for interim analyses
No interim analyses are planned.
11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled.
11.1.
electronic Case Report Forminstructions
A validated GSK defined electronic data collection tool 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 reportingwill 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 allcases, 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.
11.2.
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 aneCRFreviewand a Source Document 
Verification (SDV). By SDV we understand verifying eCRFentries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
 
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The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. 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 eCRFwill serve as the source must be identified, agreed and 
documented in the source documentation agreement form. 
For eCRF, the monitor freezescompleted 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.
11.3.
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 forretaining 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 meetthe strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures. 
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. 
11.4.
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.
 
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11.5.
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 6 months of the primary completion date for 
studies of authorizedvaccines and 18 months for studies of non-authorizedvaccines. 
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.At the time of publication, this protocol will be fully disclosed.
11.6.
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.
12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
13.
REFERENCES
Agnandji ST, Asante KP, Lyimo J, et al. Evaluation of the Safety and Immunogenicity of 
the RTS,S/AS01
EMalaria Candidate Vaccine When Integrated in the Expanded Program 
of Immunization. The Journal of Infectious Diseases2010; 202(7):1076–1087.
Bonhoeffer J, Menkes J, Gold, MS et al. Generalized convulsive seizure as an adverse 
event following immunization: case definition and guidelines for data collection, analysis 
and presentation. Vaccine. 2004;22:557-562.
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 
Journal2012;11:384.
Cogill B. Anthropometric Indicators Measurement Guide. Food and Nutrition Technical 
Assistance Project, Academy for Educational Development -Chapter 5: Taking 
Measurements. Washington, DC, 2003.
 
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European Consensus Group on Hepatitis B Immunity. Are booster immunisations needed 
for lifelong hepatitis B immunity? Lancet.2000;355(9203):561-565.
FarringtonP, Pugh S, Colville A, et al. A new method for active surveillance of adverse 
events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines. Lancet. 
1995;345(8949):567-9.
GlaxoSmithKline Biologicals Clinical Study Report Amendment 1 -106369
(MALARIA-050). A Phase II randomized, open, controlled study of the safety and 
immunogenicity ofGlaxoSmithKline Biologicalscandidate Plasmodium falciparum
malaria vaccine RTS,S/AS01E, when incorporated into an Expanded Program on 
Immunization (EPI) regimen that includes DTPwHepB/Hib, OPV, measles and yellow 
fever vaccination in infants living in malaria-endemic regions. 19 March 2014.
Osei-Kwasi M, Dunyo SK, Koram KA, et al. Antibody response to 17D yellow fever 
vaccine in Ghanaian infants. Bulletin of the World Health Organization2001; 79(11). 
http://www.who.int/bulletin/archives/79(11)1056.pdf (last access 09 August 2016)
RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine 
with or without a booster dose in infants andchildren in Africa: final results of a phase 3, 
individually randomised, controlled trial. Lancet.2015; Published online April 24, 2015 
http://dx.doi.org/10.1016/S0140-6736(15)60721-8(last access 09 August 2016).
Shinefield H, Black S, Digilio L, et al. Evaluation of a Quadrivalent Measles, Mumps, 
Rubella and Varicella Vaccine in Healthy Children. Pediatr Infect Dis J.Aug 2005;24(8): 
665–669.
United Nations. How to Weigh and Measure Children: Assessing the Nutritional Status 
of Young Children. 1986.
Integration of vitamin A supplementation with immunization: policy and programme 
implications Report of a meeting, 12-13 January 1998, UNICEF, New York. 
http://whqlibdoc.who.int/hq/1998/WHO_EPI_GEN_98.07.pdf (last access 09 August 
2016).
WHO Child Growth Standards (2006): 
http://www.who.int/childgrowth/standards/cht_wfa_girls_p_0_2.pdf and 
http://www.who.int/childgrowth/standards/cht_wfa_boys_p_0_2.pdf (last access 09 
August 2016).
Rubella vaccines: WHOposition paper. Weekly epidemiological record (2011); 
86(29):301–316. http://www.who.int/wer/2011/wer8629.pdf (last access 09 August 
2016).
 
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APPENDIX A
LABORATORY ASSAYS
Blood for analysis of humoral immune response will beobtained at timepoints listed in 
Table 8. After centrifugation, serum samples should be kept at -20°C/-4°Funtil shipment.
Antibody titers against theCS repeat region
Antibody levels against P.falciparumCS-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. The cut-off for the assay is 0.5 EU/ml. Results will be 
reported in EU/ml.
Antibody titers against the HB antigen
Anti-HBsantibody titers will be determined using commercially available CLIA kits 
ADVIA®Centaur anti-HBs2 manufactured by Siemens Healthcare. The cut-off for the 
assay is 6.2 mIU/ml. Results will be reported in mIU/ml.
Antibody titers against the catalase antigen
Anti-catalase antibody concentrationswill be determined using in house ELISA. The cut-
off for the assay is 65 ng/ml. Results will be reported in ng/ml.
Antibody titers against the measles antigen
Anti-measles antibody titers will be determined using commercially available ELISA kits 
Enzygnost™ manufactured by Dade Behring. The cut-off for the assay is 150 mIU/ml. 
Results will be reported in mIU/ml.
Antibody titers against the rubella antigen
Anti-rubella antibody titers will be determined using commercially available ELISA kits 
Enzygnost™ manufactured by Dade Behring. The cut-off for the assay is 4 IU/ml. 
Results will be reported in IU/ml.
Antibody titers against the YF antigen
Antibody levels against YF will be measured by a neutralization assay [Osei-Kwasi, 
2001]. The cut-off for the assay is 10 ED50. Results will be reported in ED50.
 
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SAFETY LABORATORY TESTING: CLS South Africa(Amended 09 
August 2016)
Cerebrospinal fluid (CSF) for meningitis testing
The recommended method for evaluation of meningitis will be through CSF analysis. 
The minimum acceptable volume for CSF should be 500 µl.
All CSF samples for suspected meningitis cases will be sent to CLS South Africa for 
CSF polymerase chain reaction (PCR) testing for selected common aetiological 
pathogens of meningitis as listed below. 
CSF: PCR testing
TEST
Bacteria
Haemophilus influenzae
Streptococcus pneumoniae
Neisseria meningitidis
Salmonella enterica
Mytobacterium tuberculosis
Viruses
Adenovirus
Cytomegalovirus
Enterovirus
Epstein Bar virus
Herpes simplex virus 1 & 2
HHV 6
Rabies
Mumps virus
Parasite
Plasmodium spp
The following additional tests are available at CLS South Africa andcan be requested 
by the treating clinician if required.
 
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CSF: Other possible PCR testing 
TEST
Bacteria
Borrelia burgdorferi*
Brucella spp*
Coxiella burnetii*
Ehrlichia spp*
Leptospira spp*
Rickettsia spp *
Viruses
Chikungunya*
Crimean-Congo haemorrhagic fever virus*
Dengue virus*
Flavivirus genus*
Hepatitis A virus* 
Hepatitis B virus *
JC virus *
Measles virus *
Rift valley fever virus*
Sindbis virus*
Rubella virus*
Varicella zoster virus* 
West Nile virus*
Parasite
Toxoplasmosis
*These tests are performed in a multiplex PCR.
An additional blood sample of approximately 5 ml whole blood may be taken at the 
discretion of the treating clinician to aid in the diagnosis of meningitis through serum 
PCR or serum serology.  The following tests will be available at CLS South Africa, if 
not available locally. 
 
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Serum: PCR
TEST
Viruses
Cytomegalovirus
Enterovirus
Haemophilus Influenza
Varicella
Parasite
Toxoplasmosis
Serum: Serology
TEST
Bacteria
Beta haemolytic streptococcus
Mycoplasma pneumoniae
Streptococcus pneumoniae
Viruses
CMV IgG & IgM
Epstein-Barr virus
HSV IgG
HSV IgM
Measles IgG/IgM
Mumps IgG/IgM
Rabies IgG/IgM
VZV IgG/IgM
Parasites
Cryptococcus
Analysis of potential Immune-Mediated Diseases (pIMDs)
The medical and scientific judgement of the investigator is required in deciding 
whether other disorders not mentioned in the list of pIMDs have enough evidence of 
an autoimmune origin. 
A volume of approximately 5 ml of whole blood will be required for testing. A list of 
potential serum autoimmune tests that can be performed at CLS South Africa is 
provided below. 
 
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Serum: Autoimmune tests
TEST
Anti-insulin autoantibodies (IA2)*
Anti-glutamic acid decarboxylase autoantibodies (anti-GAD65)
Anti-Tyrosine phosphatase-like IA2 antibodies
Anti-islet cell antibodies
Anti-smooth muscle antibodies (ASMA) 
Anti-liver-kidney microsomal antibodies (anti-LKM)
Anti-soluble liver antigens (anti-SLA)
Anti-mitochondrial antibodies (AMA)
Anti-nuclear antibodies (ANA)
Anti-double stranded DNA (anti-dsDNA)
Rheumatoid factor (RF)
Anti-Glomerular Basement Membrane antibodies (anti-GBM)
Anti-neutrophil cytoplasmic autoantibodies (ANCAs)
Anti-streptolysin O / Anti-DNAse
Serum C3, C4 complement 
Anti-cyclic citrullinated peptide antibodies (anti-CCP)
Anti-skin basement membrane protein
IgA endomysial antibodies
Anticardiolipin (ELISA) IgM, IgG
Anti-beta 2 glycoprotein I
Anti-prothrombin
Measles/Rubella confirmatory testing  
Confirmatory testing for measles and rubella may be required for suspected cases. A 
volume of approximately 5 ml of whole blood will be required for confirmatory 
serology to be sent to CLS South Africa. 
 
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APPENDIX B 
CLINICAL LABORATORIES
Table 20
GSK Biologicals’ laboratories(Amended: 09 August 2016)
Laboratory
Address
GSK B
io
log
ica
ls Clinical Laboratory 
Sciences, R
ixensart
B
iospec
imen Recept
ion -B7/44
Rue de 
l
'Inst
itut, 89 -B-1330 R
ixensart -Be
lg
ium
GSK B
io
log
ica
ls Clinical Laboratory 
Sciences, Wavre-Nord No
ir Ep
ine
Avenue F
lem
ing, 20 -B-1300 Wavre -Be
lg
ium
Table 21
Outsourced laboratories
Laboratory
Address
Focus D
iagnost
ics, Inc.
5785 Corporate Avenue
Cypress, CA90630
USA
CEVAC -Un
ivers
ity of Gent
De P
inte
laan, 185 Gent
Be
lg
ium
NEOMED-LABS Inc
525 Cartier blvd West-Laval-Quebec
Canada-H7V 3S8
Clinical Laboratory Sciences(CLS South 
Africa)
4th Floor Spencer Lister Building
Corner of Hospital and de Korte Streets
Braamfontein
Johannesburg 2000, South Africa
 
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APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES 
TO THE PROTOCOL
GlaxoSmithKline BiologicalsSA
Vaccines R &D
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
200596(MALARIA-073)
Amendment number:
Amendment 1
Amendment date:
09 August 2016
Co-ordinating author:
 Scientific Writer
Rationale/background for changes: 
The protocol was amended for the following reasons:
The volumes of whole blood collected from subjects wereconsidered insufficient. 
To ensure that an adequate bloodvolumeis obtained for the analysis, the volumes 
of whole blood to be collected specifiedin the protocol were increased to take into 
account the dead volumedue to aliquoting,and also to enable repeat testing of 
samples in case of invalid results.

It has been clarified that confirmatory testing for any subject showing clinical 
presentations compatible with yellow fever, rubella or measles will be performed 
only to identify cases of vaccine failure.
Clarification about the eCRF pages required to be filled in for pIMDs and seizures 
was provided.
The names and address of the laboratories performing the biological assays and 
study personnel at GSK were updated.Details of the safety lab testswere also 
added.
The Ghana FDA requested that screening and vaccination should not be performed 
on the same day, so the screening will be performed up until one day before 
vaccination (Day -28 to Day -1).
Amended text has been included in bold italicsand deleted text in strikethroughin 
the following sections:
Contributing authors:The list of contributing authors was updated.

(Study Delivery Leads; 
Novellas Healthcare contractor for GSK Biologicals)

 (Clinical Readout Team LeaderImmunology representative)

 (Clinical Laboratory Sciences Senior Lab Study Manager)

(Study Data Managers; TCS contractor 
for GSK Biologicals)

(Project Data 
Managers)
 
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PPD
PPD
PPD
PPD
PPD

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
(Clinical Research and Development Lead)
List of abbreviations: The list was updated:
CLS:
Clinical Laboratory Sciences
GVCL:
Global Vaccine Clinical Laboratories
 
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Figure 1: Study Design: The figure was updated.
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Tables4, 5 and 6: List of study procedures 
The following changes were made: 
Type of contact
Visit 1 
(Screening)* 
Timepoints
Day -28 to 0-1
†Conf
irmatory sero
logy tests shou
ld be performed to 
ident
ify pre-exposure wh
ich may 
lead to e
l
im
inat
ion from 
Accord
ing-to-Protoco
l (ATP) orcases of vacc
ine fa
i
lure.
Table 7: Intervals between study visits
The following changes were made:
Study visit
Timing of visita
Allowed intervalb
V
is
it 1 
(Screen
ing)
c
01-28 days before V
is
it 
2
-
cV
is
it 1 (Screen
ing v
is
it) can occur on the same day as V
is
it 2 (Day 0).
Section 5.6.12.1: Blood sampling for anti-HBs and anti-CS immune response 
assessments
A volume of at least 1.01.2ml of whole blood (to provide at least 50 500 l of serum for 
anti-CS and at least 250 l of serum foranti-HBs) should be drawn from all subjects 
from the Coad groupand the RTS,S groupfor each analysis of humoral immune 
response at each pre-defined timepoint.
Section 5.6.12.2:Blood sampling for anti-catalase immune response assessments
A volume of at least 500 600l of whole blood (to provide at least 150250l of serum) 
should be drawn from all subjects from the Coadand the Control groupsfor analysis of 
anti-catalase immune response at each pre-defined timepoint.
Section 5.6.12.3: Blood sampling for anti-Me and anti-Ru immune response 
assessments
A volume ofat least 500 µl600l of whole blood (to provide at least 250l of serum for 
anti-Me and anti-Ru) should be drawn from all subjects from the Coad groupand the 
Control groupfor each analysis of humoral immune response at each pre-defined 
timepoint.
Section 5.6.12.4: Blood sampling for anti-YF immune response assessments
A volume of at least600 750lof whole blood (to provide at least 250 l of serum for 
anti-YF) should be drawn from all subjects from the Coad groupand the Control group
for each analysis of humoral immune response at each pre-defined timepoint.
 
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Table 8: Biological Samples
Timepoint
Group
Sample type
Quantity
Unit
V
is
it 2(Day 0)
Coad group
B
lood
1.51.8
m
l
RTS,S group
B
lood
1.01.2
m
l
Contro
l group
B
lood
0.50.6
m
l
V
is
it 4(Month 3)
Coad group
B
lood
0.50.6
m
l
Contro
l group
B
lood
0.50.6
m
l
V
is
it 5(Month 4)
Coad group
B
lood
2.753.5
m
l
RTS,S group
B
lood
1.01.2
m
l
Contro
l group
B
lood
1.751.8
m
l
Table 9: Humoral Immunity (Antibody determination)
*GSK B
io
log
ica
ls 
laboratory refers to the G
loba
l Vacc
ines C
l
in
ica
l Laborator
iesClinical Laboratory Sciences 
(CLSGVCL) 
in R
ixensart, Be
lg
ium; Wavre, Be
lg
ium; Lava
l, CanadaNEOMED-LABS Inc, Canada.
Section 6.8: Capture of cases of measles and rubella
During the course of the study, any clinical presentation compatible with measles, rubella
or YF will be captured as AE or SAE as appropriate and confirmatory serology tests 
should be performed to identify pre-exposure which may lead to eliminationfrom ATP or
cases of vaccine failure.
Section 8.1.5.2: Seizures within 30 or 42 days of vaccination
All seizures occurring within 30 days of vaccination for vaccine doses administered at 6 
and 7.5 months of age (Visits 2 and 3) and within 42 days for vaccine doses administered 
at 9 months of age (Visit 4) will be reported as SAEs and in specific eCRF 
screensappropriate targeted follow-up forms included in the eCRF.
Section 8.1.5.3: 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 inspecific eCRF screens appropriate targeted follow-up forms included in the 
eCRF. Cerebrospinal fluid will be frozen for future testing for infectious agents if 
applicable (this procedure is fully described in the SPM).
Section 8.3.4: Reporting of AEs of specific interest to GSK Biologicals
Once an AEs of specific interest (pIMDs, meningitis and seizure within 30 or 42 days of 
vaccination) is diagnosed in a study subject, the investigator (or designate) must complete 
the information in the electronic Expedited Adverse Events ReportWITHIN 24 HOURS 
after he/she becomes aware of the diagnosis. The report allows to specify that the event is 
a pIMD. The report will always be completed as thoroughly as possible with all available 
details of the event, in accordance with the pIMDAEs of specific interest standard 
questionnaire provided.
 
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Table 16:Reporting periods for adverse events and serious adverse events
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Children age 
(Months)
6
7.5
9
10
10.5 
11.5 12.5 13.5
27 
28 
30 
31 
39 
42
Study Month
M0
M1.5
M3
M4
M4.5
M5.5
M6.5
M7.5
M21
M22
M24
M25
M33
M36
D-28 
to 
01
D0 D6 D29
M1.5 M1.5 
+6d
M1.5
+29d
M3
M3
+13d
M3
+41d
So
l
ic
ited 
loca
l 
and genera
l AEs
Xa Xa
Xa
Xa
Xa
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Appendix A: Laboratory assays: The following information has been added.
SAFETY LABORATORY TESTING: CLS South Africa
Cerebrospinal fluid (CSF) for meningitis testing
The recommended method for evaluation of meningitis willbe through CSF analysis. 
The minimum acceptable volume for CSF should be 500 µl.
All CSF samples for suspected meningitis cases will be sent to CLS South Africa for 
CSF polymerase chain reaction (PCR) testing for selected common aetiological 
pathogens of meningitis as listed below. 
CSF: PCR testing
TEST
Bacteria
Haemophilus influenzae
Streptococcus pneumoniae
Neisseria meningitidis
Salmonella enterica
Mytobacterium tuberculosis
Viruses
Adenovirus
Cytomegalovirus
Enterovirus
Epstein Bar virus
Herpes simplex virus 1 & 2
HHV 6
Rabies
Mumps virus
Parasite
Plasmodium spp
The following additional tests are available at CLS South Africa andcan be requested 
by the treating clinician if required.
 
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CSF: Other possible PCR testing 
TEST
Bacteria
Borrelia burgdorferi*
Brucella spp*
Coxiella burnetii*
Ehrlichia spp*
Leptospira spp*
Rickettsia spp *
Viruses
Chikungunya*
Crimean-Congo haemorrhagic fever virus*
Dengue virus*
Flavivirus genus*
Hepatitis A virus* 
Hepatitis B virus *
JC virus *
Measles virus *
Rift valley fever virus*
Sindbis virus*
Rubella virus*
Varicella zoster virus* 
West Nile virus*
Parasite
Toxoplasmosis
* These tests are performed in a multiplex PCR.
An additional blood sample of approximately 5 ml whole blood may be taken at the 
discretion of the treating clinician to aid in the diagnosis of meningitis through serum 
PCR or serum serology.  The following tests will be available at CLS South Africa, if 
not available locally. 
 
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Serum: PCR
TEST
Viruses
Cytomegalovirus
Enterovirus
Haemophilus Influenza
Varicella
Parasite
Toxoplasmosis
Serum: Serology
TEST
Bacteria
Beta haemolytic streptococcus
Mycoplasma pneumoniae
Streptococcus pneumoniae
Viruses
CMV IgG & IgM
Epstein-Barr virus
HSV IgG
HSV IgM
Measles IgG/IgM
Mumps IgG/IgM
Rabies IgG/IgM
VZV IgG/IgM
Parasites Cryptococcus
Analysis of potential Immune-Mediated Diseases (pIMDs)
The medical and scientific judgement of the investigator is required in deciding 
whether other disorders not mentioned in the list of pIMDs have enough evidence of 
an autoimmune origin. 
A volume of approximately 5 ml of whole blood will be required for testing. A list of 
potential serum autoimmune tests that can be performed at CLS South Africa is 
provided below. 
 
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Serum: Autoimmune tests
TEST
Anti-insulin autoantibodies (IA2)*
Anti-glutamic acid decarboxylase autoantibodies (anti-GAD65)
Anti-Tyrosine phosphatase-like IA2 antibodies
Anti-islet cell antibodies
Anti-smooth muscle antibodies (ASMA) 
Anti-liver-kidney microsomal antibodies (anti-LKM)
Anti-soluble liver antigens (anti-SLA)
Anti-mitochondrial antibodies (AMA)
Anti-nuclear antibodies (ANA)
Anti-double stranded DNA (anti-dsDNA)
Rheumatoid factor (RF)
Anti-Glomerular Basement Membrane antibodies (anti-GBM)
Anti-neutrophil cytoplasmic autoantibodies (ANCAs)
Anti-streptolysin O / Anti-DNAse
Serum C3, C4 complement 
Anti-cyclic citrullinated peptide antibodies (anti-CCP)
Anti-skin basement membrane protein
IgA endomysial antibodies
Anticardiolipin (ELISA) IgM, IgG
Anti-beta 2 glycoprotein I
Anti-prothrombin
Measles/Rubella confirmatory testing  
Confirmatory testing for measles and rubella may be required for suspected cases. A 
volume of approximately 5 ml of whole blood will be required for confirmatory 
serology to be sent to CLS South Africa. 
Table 20: GSK Biologicals’ laboratories
Laboratory
Address
GSK B
io
log
ica
ls Clinical Laboratory Sciences
G
loba
l Vacc
ine C
l
in
ica
l Laboratory, R
ixensart
B
iospec
imen Recept
ion -B7/44
Rue de 
l
'Inst
itut, 89 -B-1330 R
ixensart -Be
lg
ium
GSK B
io
log
ica
ls G
loba
l Vacc
ine C
l
in
ica
l 
Laboratory, North Amer
ica-Lava
l
B
iospec
imen Recept
ion -C
l
in
ica
l Sero
logy
525 Cart
ier b
lvd West -Lava
la -Quebec -Canada -H7V 3S8
GSK B
io
log
ica
ls Clinical Laboratory Sciences
G
loba
l Vacc
ine C
l
in
ica
l Laboratory, Wavre-Nord 
No
ir Ep
ine
Avenue F
lem
ing, 20 -B-1300 Wavre -Be
lg
ium
 
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Table 21: Outsourcedlaboratories
Laboratory
Address
Focus D
iagnost
ics, Inc.
5785 Corporate Avenue
Cypress, CA90630
USA
CEVAC -Un
ivers
ity of Gent
De P
inte
laan, 185 Gent
Be
lg
ium
NEOMED-LABS Inc
525 Cartier blvd West-Laval-Quebec
Canada-H7V 3S8
Clinical Laboratory Sciences(CLS South 
Africa)
4th Floor Spencer Lister Building
Corner of Hospital and de Korte Streets
Braamfontein
Johannesburg 2000, South Africa
 
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PPD
PPD