Immunogenicity of the Hepatitis B Antigen of the GSK Biologicals' Candidate Malaria Vaccine (257049)
Phase: PHASE3
Conditions: Malaria, Malaria Vaccines
Sponsor: GlaxoSmithKline

Protocol and Protocol Amendments
 
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22-NOV-2011
Primary Study vaccine an
number
Other Study vaccines
eTrack study number and
Abbreviated Title
Date of protocol
Date of administrative 
change
Title
Detailed Title
Co-ordinating authors
Contributing authors
Copyright 2010 the GlaxoSmit
copying or use of this informat
CONFIDENTIAL
113681
Administr
1
Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensa
Belgium
nd 
GlaxoSmithKline (GSK) Biologicals’ cand
Plasmodium falciparum malaria vaccine R
(257049)

GSK Biologicals’ hepatitis B vaccine (

GSK Biologicals’ 10-valent pneumoco
conjugate vaccine (SynflorixTM)

GSK Biologicals’ oral live attenuated h
rotavirus vaccine (RotarixTM)

GSK Biologicals’ oral polio vaccine (P

DTPa/Hib vaccine (InfanrixTMHib)
d 
113681 (Malaria-063)
Final: 27 August 2010
Administrative change 1 Final, 22 Novem
Immunogenicity of the hepatitis B antigen
Biologicals’ candidate malaria vaccine (25
Phase III randomized, open, controlled stu
evaluate the immune response to the hepat
antigen of the RTS,S/AS01E candidate vac
administered as primary vaccination integr
EPI regimen to infants living in sub-Sahar
cientific writer
 Project Manager Scientific W

Global Study Mana

 Manager Safety Physici
Clinical Safety and Pharmacovigiliance

Global Study Manager

Clinical Immunology Read 
Manager, R&D

 Director, Global Clinical

 Bio-Statistician Manager, 
Global Clinical R&D

WHO/TDR fellow

Clinical Data Management
List con
GSK Biologicals’ Proto
thKline group of companies. All rights reserved. Unau
tion is prohibited.
1 (Malaria-063)
ative change 1
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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2
Contributing authors

 Senior Scientist, 
Clinical Regulatory, Clinical Reg. & Labelling

 Clinical Development Manager
 
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PPD
PPD

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Protocol Administrative change 1 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
113681(Malaria-063)
Date of administrative 
change
Administrative change 1 Final, 22 November 2011
Detailed Title 
Phase III randomized, open, controlled study to 
evaluate the immune response to the hepatitis B 
antigen of the RTS,S/AS01E candidate vaccine, when 
administered as primary vaccination integrated into 
an EPI regimen to infants living in sub-Saharan 
Africa.
Sponsor signatory
Johan Vekemans, Director, 
Clinical Development, Malaria Vaccines
Signature
Date
 
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Protocol Administrative Change 1 Rationale
Administrative change 
number:
Administrative change 1
Rationale/background for changes:
Some typographical errors were corrected for clarity:

In Synopsis table 1 and in Table 3: the footnote of Rotarix in the RE[RoP]s group 
was corrected (should be footnote b and not c)

The volume of the reconsitued Rotarix is 1.0 ml. It was errouneously recorded as 
1.5 ml in table 15 and in the heading of section 6.3.5. and has been corrected.

Infanrix is administered in the right deltoid as described in table 16. In section 
6.3.4. this was mistakenly mentioned in the left deltoid and has been corrected.
Corrected text has been indicated in bold italics, deletions are indicated by 
strikethrough.
 
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Protocol Administrative change 1 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, and with any other study 
conduct procedures and/or study conduct documents provided by GlaxoSmithKline 
Biologicals (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 product(s) and other study-related duties and 
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally authorised representative.

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s).

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the Sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the Sponsor or the investigational product, 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 1 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
113681(Malaria-063)
Date of administrative 
change
Administrative change 1 Final, 22 November 2011
Detailed Title
Phase III randomized, open, controlled study to 
evaluate the immune response to the hepatitis B 
antigen of the RTS,S/AS01E candidate vaccine, when 
administered as primary vaccination integrated into 
an EPI regimen to infants living in sub-Saharan 
Africa.
Investigator name
Signature
Date
 
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SYNOPSIS
Detailed Title
Phase III randomized, open, controlled study to evaluate the 
immune response to the hepatitis B antigen of the 
RTS,S/AS01E candidate vaccine, when administered as 
primary vaccination integrated into an EPI regimen to infants 
living in sub-Saharan Africa.
Indication
(Study population)
Primary immunization of healthy male and female infants 
aged 8 to 12 weeks against P. falciparum malaria and hepatitis 
B, if eligible according to inclusion and exclusion criteria.
Rationale for the 
study and study 
design
The RTS,S/AS01E candidate malaria vaccine is being 
developed for the routine immunization of infants and 
children living in malaria-endemic areas as part of the WHO 
Expanded Program on Immunization (EPI). The candidate 
vaccine consists of sequences of the Plasmodium falciparum
circumsporozoite (CS) protein and hepatitis B surface antigen 
(HBsAg) adjuvanted with AS01E (containing proprietary 
liposomes, MPL and QS21 immunostimulants). This vaccine 
would provide protection against both malaria disease due to 
the malaria parasite P. falciparum, and hepatitis B. This study 
therefore aims to support the indication of RTS,S/AS01E
candidate vaccine for primary immunization of infants against 
the hepatitis B virus infection.
This study is designed to:

Evaluate the immune response to the hepatitis B antigen 
in recipients of RTS,S/AS01E versus recipients of a 
licensed hepatitis B vaccine, including memory response 
and the quality of the immune response.

Evaluate the immune response to the antigens contained 
in a conjugate pneumococcal vaccine and in a rotavirus 
vaccine when administered concomitantly with 
RTS,S/AS01E, within the existing EPI schedules in 
African countries.

Demonstrate consistency of the hepatitis B response 
induced by RTS,S/AS01E candidate vaccine produced at 
the intended scale for commercial production of RTS,S 
bulk antigen.
 
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Objectives
Primary

To demonstrate in terms of antibody response to the HBs 
antigen, the non-inferiority of RTS,S/AS01E to a primary 
vaccination regimen of a licensed hepatitis B vaccine 
(Engerix-B) integrated into an EPI regimen.
Criteria for non-inferiority: one month post Dose 3, 
upper limit (UL) of the 2-sided 95% confidence interval 
(CI) on the difference in percent seroprotection below 5% 
between recipients of licensed hepatitis B vaccine 
(Engerix-B) and recipients of RTS,S/AS01E vaccine. 
Secondary
Immunogenicity

To demonstrate the non-inferiority of antibody responses 
to the pneumococcal conjugate vaccine when co-
administered with versus without RTS,S/AS01E as part of 
an EPI regimen.
Criteria for non-inferiority: one month post Dose 3, 
upper limit (UL) of the 2-sided 95% confidence interval 
(CI) on the GMC ratios of 10 pneumococcal serotypes 
titers (measured with an ELISA test), is below a limit of 2 
for the pneumococcal conjugate vaccine when co-
administered with versus without RTS,S/AS01E.

To describe the antibody responses to the 10 
pneumococcal serotypes (1, 4, 5, 6B, 7F, 9V, 14, 18C, 
19F and 23F), measured by ELISA and OPA, when the 
pneumococcal conjugate vaccine is co-administered with 
and without RTS,S/AS01E as part of an EPI-regimen.

To describe the antibody response to the Protein D (PD) 
component of the pneumococcal conjugate vaccine when 
co-administered with versus without RTS,S/AS01E as 
part of an EPI regimen.

To demonstrate the non-inferiority of antibody response 
to the rotavirus vaccine when co-administered with 
versus without RTS,S/AS01E as part of an EPI regimen.
Criteria for non-inferiority: one month post Dose 2, 
upper limit (UL) of the 2-sided 95% confidence interval 
(CI) on the geometric mean titers (GMT) ratios of 
rotavirus antibodies (IgA) titers is below 2 for the 
rotavirus vaccine when co-administered with versus 
without RTS,S/AS01E.

To describe the antibody response to the rotavirus antigen 
 
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when co-administered with and without RTS,S/AS01E as 
part of an EPI regimen.

To describe the antibody response to the HBs antigen, 
induced by RTS,S/AS01E when administered as a 3 doses 
schedule (0, 1, 2-month) integrated into an EPI regimen.

To describe the antibody response to the HBs RF1 
epitope, induced by RTS,S/AS01E when administered as 
a 3 doses schedule (0, 1, 2-month) integrated into an EPI 
regimen.

To describe the antibody response to the CS antigen when 
RTS,S/AS01E is co-administered with a pneumococcal 
conjugate vaccine as part of an EPI regimen.

To describe the antibody response to the CS antigen when 
RTS,S/AS01E is co-administered with a rotavirus vaccine 
as part of an EPI regimen.

To demonstrate the lot-to-lot consistency in terms of anti-
HBs immunogenicity between three commercial lots of 
the RTS,S/AS01E candidate malaria vaccine.
Criteria for consistency: one month post Dose 3 of 
RTS,S/AS01E, the two-sided 95% confidence interval (CI) 
of the geometric mean titer (GMT) ratio between all pairs 
of lots are within [0.5, 2].

To demonstrate the non-inferiority of antibody response 
to the acellular B pertussis antigens of the DTPa/Hib 
vaccine when co-administered with RTS,S/AS01E as part 
of an EPI regimen.
Criteria for non-inferiority: one month post Dose 3, 
upper limit (UL) of the 2-sided 95% confidence interval 
(CI) on the GMT ratios of anti-PT, anti-FHA, anti-PRN 
antibody titers, is below a limit of 2 for the DTPa/Hib 
vaccine when co-administered with versus without 
RTS,S/AS01E.

To describe the antibody response to acellular B pertussis 
antigens pre- and post-vaccination when a DTPa/Hib 
vaccine is co-administered with RTS,S/AS01E as part of 
an EPI-regimen.
Immunogenicity follow-up

To describe the long-term antibody response to the HBs 
antigen induced by RTS,S/AS01E, compared to a primary 
vaccination regimen of a licensed hepatitis B vaccine 
when administered as a 3 doses schedule (0, 1, 2-month) 
 
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integrated into an EPI regimen.

Evaluation of the antibody response to the HBs antigen 
induced by a booster dose of a licensed hepatitis B 
vaccine.

Evaluation of the antibody response to HBs RF1 like 
antigen induced by a booster dose of a licensed hepatitis 
B vaccine.

To describe the long-term antibody response to the CS 
antigen induced by RTS,S/AS01E, when administered as 
a 3 doses schedule (0, 1, 2-month) integrated into an EPI 
regimen.

Evaluation of the antibody response to the 10 
pneumococcal serotypes (1, 4, 5, 6B, 7F, 9V, 14, 18C, 
19F and 23F) induced by a booster dose of a licensed 
pneumococcal conjugate vaccine when co-administered 
with and without RTS,S/AS01E.
Safety

Evaluation of the safety profile of the RTS,S/AS01E
candidate malaria vaccine, when co-administered with a 
pneumococcal conjugate vaccine or a rotavirus vaccine 
integrated into an EPI regimen.
Study design

Experimental design: Phase III, multi-center, open, 
randomized, controlled trial with 11 study groups.

Study population: male and female infants, aged 8-12
weeks at the time of first vaccination, who are eligible 
based on inclusion and exclusion criteria.

Control: Engerix-B

Treatment allocation: Subjects will be randomized into 
11 study groups in a 1:1:1 : 1:1:1 : 1:1:1 :3:3 ratio [this 
means 5 treatment groups of which the 3 RTS,S/AS01E
groups will be randomized to receive 3 different lots].

Treatment groups and vaccination schedule:
The primary vaccination schedule for all treatment groups 
is presented in Synopsis Table 1. In the RTS,S arms, 3 
doses of RTS,S/AS01E will be administered on a 
0,1,2-month schedule. All groups will receive the measles 
vaccine 6 months post Dose 3 of RTS,S/AS01E or 
Engerix-B. Yellow fever vaccine will be given according 
to local treatment regulations, at 6 months post Dose 3 of 
RTS,S/AS01E or Engerix-B. All groups will receive 
Synflorix and Infanrix/Hib booster vaccinations at 
 
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approximately 18 months of age (Visit 11), and an 
Engerix-B booster vaccination at 48 months after the third 
dose in the primary vaccination schedule of Engerix-B.
Synopsis Table 1
Treatment groups
Treatment 
Group
Study Group
Primary vaccination schedule
Number of 
subjects
REP[Ro]s
REP[Ro]s lot 1
RTS,S/AS01Ea + CoAd (Infanrix/Hiba + Polio Sabina + 
Synflorixa) + Rotarixb staggered
141 
(47+47+47)
REP[Ro]s lot 2
REP[Ro]s lot 3
RERo[P]s  
RERo[P]s lot 1
RTS,S/AS01Ea + CoAd (Infanrix /Hiba + Polio Sabina + 
Rotarixc) + Synflorixd staggered
141
(47+47+47)
RERo[P]s lot 2
RERo[P]s lot 3
RE[RoP]s  
RE[RoP]s lot 1
RTS,S/AS01Ea + CoAd (Infanrix /Hiba + Polio Sabina) + 
staggered (Synflorixd + Rotarixb)
141
(47+47+47)
RE[RoP]s lot 2
RE[RoP]s lot 3
HEP[Ro]s  
HEP[Ro]s
Engerix-Ba+ CoAd (Infanrix /Hiba + Polio Sabina + Synflorixa) 
+ Rotarixb staggered
141
HERo[P]s  
HERo[P]s
Engerix-Ba + CoAd (Infanrix /Hiba + Polio Sabina + Rotarixc) + 
Synflorixd staggered
141
a. Administration at Visit 2, Visit 4 and Visit 6
b. Administration at Visit 5 and Visit 7
c. Administration at Visit 4 and Visit 6
d. Administration at Visit 3, Visit 5 and Visit 7

Type of study: self-contained

Data collection: Where technically possible, this study 
will use electronic case report form (eCRF) by remote data 
entry (RDE) in preference to conventional paper case 
report form (CRF).

Duration of the study: approximately 52 months per 
study participant, including a screening period and 49 
months of follow-up after the third vaccination of 
RTS,S/AS01E or Engerix-B.

Epochs:

Screening Epoch
starting Visit 1 and ending before Visit 2 (Day 0)

Primary vaccination Epoch
starting Visit 2 (Day 0) and ending at Visit 8 
(Week 12)

Safety follow-up Epoch
starting after Visit 8 (Week 12) and ending at Visit 9 
(Month 8)

Immunogenicity follow-up 1 Epoch
 
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starting after Visit 9 (Month 8); ending at Visit 13 
(Month 26)

Immunogenicity follow-up 2 Epoch
starting after Visit 13 (Month 26); ending at Visit 16 
(Month 51)
Screening of pregnant women

Pregnant women will be identified at antenatal clinics or in 
the community and will be informed about the study. If 
interested in participating they will be asked to sign a 
consent form for screening for hepatitis B or HIV 
infection.

Infants born to mothers who are HBsAg positive and are 
therefore at high risk of vertical transmission of hepatitis B 
infection will be excluded from this trial. These infants 
will be offered a licensed hepatitis B vaccine in a schedule 
beginning at birth. Women who are tested positive for 
HBsAg with symptoms will be referred to an appropriate 
health care center.

Infants born to mothers who are HIV positive will be 
excluded from this trial. Voluntary counselling and testing 
(VTC), highly active anti retroviral therapy (HAART) and 
prevention of mother-to-child transmission (PMCT) are 
available at the study center according to national policies.

The site study team will ensure that insecticide treated 
bednet use is optimized in the study population.
Screening of infants

Mothers who were screened negative for HBsAg and HIV 
and who agree to let their child participate in the study will 
be invited for the screening visit (Visit 1).

Prior to any other study procedures, the parents will be 
asked to sign/thumb-print a consent form to allow their 
child to participate in the trial.
Surveillance for safety

Each subject will be observed for at least 60 minutes after 
vaccination to evaluate and treat any acute adverse events 
(AEs).

There will be a 7-day follow-up period (day of vaccination 
and 6 subsequent days) after each dose of RTS,S/AS01E or 
Engerix-B co-administered with EPI vaccines for 
 
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recording of solicited AEs (+ any unsolicited AEs). On 
day of vaccination (day 0) 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 personnels 
will visit the children to record solicited AEs and any 
unsolicited AEs.

There will be a 30-day follow-up period (day of 
vaccination and 29 subsequent days) after each dose of 
RTS,S/AS01E or Engerix-B co-administered with EPI 
vaccines for reporting unsolicited adverse events.

All SAEs will be reported until 8 months post Dose 1 of 
RTS,S/AS01E or Engerix-B.

This study will be overseen by a formally constituted 
IDMC operating under a charter.
Blood sampling

Groups RERo[P]s, RE[RoP]s and HERo[P]s will have a 
total of 7 blood samples taken: at Visit 1 (screening) and 
Visit 8, 10, 13, 14, 15, 16 (post Dose 3 of RTS,S/AS01E or 
Engerix-B).

Groups REP[Ro]s and HEP[Ro]s will have a total of 8 
blood samples taken: at Visit 1 (screening) and Visit 8, 10, 
12, 13, 14, 15, 16 (post Dose 3 of RTS,S/AS01E or 
Engerix-B).

Blood for safety evaluation will be collected at screening 
(Visit 1) to ensure healthy children are recruited.
Surveillance for immunogenicity

Immune responses to the HBs antigen will be assessed at 
screening (Visit 1), at Visit 8 (one month post Dose 3 of 
RTS,S/AS01E or Engerix-B), at Visit 10 (Month 14), at 
Visit 13 (Month 26), at Visit 14 (Month 38), at Visit 15 
(Month 50) and at Visit 16 (Month 51).

Immune responses to the CS antigen will be assessed at 
screening (Visit 1), at Visit 8 (one month post Dose 3 of 
RTS,S/AS01E or Engerix-B), at Visit 10 (Month 14), at 
Visit 13 (Month 26), at Visit 14 (Month 38) and at Visit 15 
(Month 50).

Immune response to the 10 pneumococcal serotypes will
be assessed at one month post Dose 3 of pneumococcal 
conjugate vaccine with RTS,S/AS01E co-administration 
(Visit 8) and one month post booster dose of 
 
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pneumococcal conjugate vaccine (Visit 12).

Immune response to rotavirus antigen will be assessed at 
one month post Dose 2 of rotavirus vaccine with 
RTS,S/AS01E co-administration (Visit 8).
Statistical analysis

The primary analysis will be performed on data collected 
up to Visit 8 (1 month post Dose 3 of RTS,S/AS01E or 
Engerix-B) and will include primary and secondary 
immunogenicity and safety endpoints. Results will be 
reported in a final study report.

A safety analysis will be performed on data (SAEs) 
collected until 8 months post Dose 1 of RTS,S/AS01E or 
Engerix-B (Visit 9) and will be reported in an annex 
report.

An immunogenicity analysis based on data collected until 
Visit 13 (Month 26) will include anti-CS and anti-HBs 
antibody responses and will be reported in an annex report.

The final analysis will be performed on further safety and 
immunogenicity data collected up to the last study visit 
(Visit 16), 51 months following the administration of the 
first dose of study vaccine. Results will be presented in an 
annex report.
Number of subjects
A total of 705 subjects will be enrolled (141 per group), in 
order to have at least 600 evaluable subjects (approximately 
120 per group).
Endpoints
Primary: immunogenicity

Non-inferiority of the immune response to the hepatitis B 
antigen induced by RTS,S/AS01E vaccine versus a 
licensed hepatitis B vaccine.

Anti-HBs antibody titers one month post Dose 3 of 
RTS,S/AS01E or Engerix-B.
Secondary
Immunogenicity

Non-inferiority of the immune response to the 10 
pneumococcal serotype antigens when pneumococcal 
conjugate vaccine is given as part of an EPI regimen with 
and without RTS,S/AS01E co-administration.
 
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
Anti-pneumococcal serotypes (1, 4, 5, 6B, 7F, 9V, 14, 
18C, 19F and 23F) antibody concentrations one month 
post Dose 3 of pneumococcal conjugate vaccine.

Immune response to the 10 pneumococcal serotype 
antigens of the pneumococcal conjugate vaccine, when 
given as part of an EPI regimen with and without 
RTS,S/AS01E co-administration.

Anti-pneumococcal serotypes (1, 4, 5, 6B, 7F, 9V, 14, 
18C, 19F and 23F) antibody concentrations one month 
post Dose 3 of pneumococcal conjugate vaccine.

Opsonophagocytic titers to each of the 10 
pneumococcal serotypes one month post Dose 3 of 
pneumococcal conjugate vaccine.

Immune response against the protein D (PD) component of 
the pneumococcal antigen.

Anti-PD antibody titers one month post Dose 3 of 
pneumococcal conjugate vaccine.

Non-inferiority of the immune response to the rotavirus 
antigen when the rotavirus vaccine is given as part of an 
EPI regimen with and without RTS,S/AS01E co-
administration.

Anti-rotavirus antibody (IgA) titers one month post 
Dose 2 of rotavirus vaccine.

Immune response to the rotavirus antigen of the rotavirus 
vaccine, when given as part of an EPI regimen with and 
without RTS,S/AS01E co-administration.

Anti rotavirus antibody (IgA) titers one month post 
Dose 2 of rotavirus vaccine.

Immune response to hepatitis B antigen of the 
investigational vaccine RTS,S/AS01E or a licensed 
hepatitis B vaccine.

Anti-HBs antibody titers one month post Dose 3 of 
RTS,S/AS01E or Engerix-B.

Anti-HBs RF1 like antibody titers one month post 
Dose 3 of RTS,S/AS01E or Engerix-B.

Immune response to the CS antigen of the investigational 
vaccine RTS,S/AS01E when given as part of an EPI 
regimen with and without pneumococcal conjugate 
vaccine co-administration.

Anti-CS antibody titers one month post Dose 3 of 
 
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RTS,S/AS01E.

Immune response to the CS antigen of the investigational 
vaccine RTS,S/AS01E when given as part of an EPI 
regimen with and without rotavirus co-administration.

Anti-CS antibody titers one month post Dose 3 of 
RTS,S/AS01E.

Lot-to lot consistency for immunogenicity of three lots of 
the investigational vaccine RTS,S/AS01E.

Anti-HBs antibody titers one month post Dose 3 of 
RTS,S/AS01E.

Non-inferiority of the immune response to the acellular B 
pertussis antigens of the DTPa/Hib vaccine when given 
with and without RTS,S/AS01E co-administration.

Anti-acellular B pertussis (BPT) antibody titers (anti-
PT, anti-FHA, anti-PRN) at screening and one month 
post Dose 3 of the DTPa/Hib vaccine.

Immune response to the acellular B pertussis antigens of 
the DTPa/Hib vaccine (anti-PT, anti-FHA, anti-PRN) 
when given with RTS,S/AS01E.

Anti-acellular B-Pertussis (BPT) antibody titers (anti-
PT, anti-FHA, anti-PRN) at screening and one month 
post Dose 3 of the DTPa/Hib vaccine.
Immunogenicity follow-up

Immune response (on a long-term) to the hepatitis B 
antigen after a primary course of investigational vaccine 
RTS,S/AS01E or a licensed hepatitis B vaccine.

Anti-HBs antibody titers assessed at 12, 24, 36 and 48 
months post Dose 3 of RTS,S/AS01E or Engerix-B.

Immune response to a booster dose of a licensed hepatitis 
B vaccine.

Anti-HBs antibody titers one month post booster dose 
of Engerix-B.

Anti-HBs RF1 like antibody titers one month post 
booster dose of Engerix-B.

Immune response (on a long-term) to the CS-antigen after 
a primary course of the investigational vaccine 
RTS,S/AS01E.

Anti-CS antibody titers assessed 12, 24, 36 and 48 
 
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months post Dose 3 of RTS,S/AS01E.

Immune response to a booster dose of pneumococcal 
conjugate vaccine when primary vaccination is given as 
part of an EPI regimen with and without RTS,S/AS01E co-
administration.

Anti- pneumococcal serotypes (1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F and 23F) antibody concentrations one 
month post booster dose of pneumococcal conjugate 
vaccine.

Opsonophagocytic titers to each of the 10 
pneumococcal serotypes one month post booster dose 
of pneumococcal conjugate vaccine.

Anti-protein D antibody titers one month post booster 
dose of pneumococcal conjugate vaccine.
Safety

For each of the 5 vaccination regimens corresponding to the 
5 treatment groups (REP[Ro]s, RERo[P]s, RE[RoP]s, 
HEP[Ro]s and HERo[P]s), to describe the occurrence of 
solicited general and local adverse events (AEs) over a 7-
day follow-up period (day of vaccination and 6 subsequent 
days) after the first, second and third doses of RTS,S/AS01E
or a licensed hepatitis B vaccine.

For each of the 5 vaccination regimens corresponding to the 
5 treatment groups (REP[Ro]s, RERo[P]s, RE[RoP]s, 
HEP[Ro]s and HERo[P]s), to describe the occurrence of 
unsolicited AEs over a 30-day follow-up period (day of 
vaccination and 29 subsequent days) after the first, second 
and third doses of RTS,S/AS01E or a licensed hepatitis B 
vaccine.

To describe the occurence of serious adverse events 
(SAEs).

SAEs from the time of first vaccination until 3 month 
post Dose 1 (Visit 8) of RTS,S/AS01E or a licensed 
hepatitis B vaccine.

SAEs from the time of first vaccination until 8 month 
post Dose 1 (Visit 9) of RTS,S/AS01E or a licensed 
hepatitis B vaccine.

Fatal SAEs from study start until study end.

Immune mediated disorders (IMDs) from study start 
until study end.
 
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TABLE OF CONTENTS
PAGE
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS...........................................................................................24
GLOSSARY OF TERMS ...............................................................................................27
TRADEMARKS .............................................................................................................30
1.
INTRODUCTION....................................................................................................31
1.1.
Background ................................................................................................31
1.2.
Rationale for the study and study design ....................................................32
1.2.1.
Rationale for the study.................................................................32
1.2.2.
Rationale for the hepatitis B vaccination in Africa.........................32
1.2.2.1.
Evaluation of memory response to the HBs 
antigen .......................................................................32
1.2.3.
Rationale for the evaluation of co-administration with a 
conjugate pneumococcal vaccine ................................................33
1.2.4.
Rationale for the evaluation of co-administration with a 
rotavirus vaccine..........................................................................33
2.
OBJECTIVES.........................................................................................................33
2.1.
Primary objective: immunogenicity..............................................................33
2.2.
Secondary objectives..................................................................................34
3.
STUDY DESIGN OVERVIEW ................................................................................36
4.
STUDY COHORT...................................................................................................41
4.1.
Number of subjects/centres ........................................................................41
4.2.
Overview of the recruitment plan.................................................................41
4.3.
Inclusion criteria for enrolment....................................................................41
4.4.
Exclusion criteria for enrolment...................................................................42
5.
CONDUCT OF THE STUDY ..................................................................................43
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................43
5.2.
Subject identification and randomisation of treatment .................................44
5.2.1.
Subject identification....................................................................44
5.2.2.
Randomisation of treatment.........................................................45
5.2.2.1.
Randomisation of supplies..........................................45
5.2.2.2.
Treatment allocation to the subject.............................45
5.3.
Method of blinding ......................................................................................45
5.4.
General study aspects ................................................................................45
5.4.1.
Safety Monitoring Plan.................................................................45
5.4.1.1.
Independent data monitoring committee 
(IDMC)........................................................................45
5.4.1.2.
Data Reviewed by the IDMC ......................................46
5.4.1.3.
Local Safety Monitor (LSM) ........................................46
 
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5.4.1.4.
Data Reviewed by the LSM ........................................46
5.4.1.5.
Process if the trial is suspended .................................47
5.4.1.6.
Safety Review Team (SRT)........................................47
5.5.
Outline of study procedures ........................................................................47
5.6.
Detailed description of study procedures ....................................................51
5.6.1.
Procedures prior to study participation.........................................51
5.6.1.1.
Informed consent of pregnant women.........................51
5.6.1.2.
Informed consent of infants ........................................51
5.6.2.
Procedures prior to the first vaccination .......................................52
5.6.2.1.
Assign subject number ...............................................52
5.6.2.2.
Collect demographic data...........................................52
5.6.2.3.
Medical history ...........................................................52
5.6.2.4.
Check inclusion and exclusion criteria ........................52
5.6.2.5.
Physical examination..................................................52
5.6.2.6.
Blood sampling for safety or immune response 
assessments ..............................................................52
5.6.3.
Procedures during the primary vaccination epoch........................52
5.6.3.1.
Check and record concomitant 
medication/vaccination and intercurrent 
medical conditions......................................................53
5.6.3.2.
Check contraindications, warnings and 
precautions to vaccination ..........................................53
5.6.3.3.
Assess pre-vaccination body temperature..................53
5.6.3.4.
Randomization ...........................................................53
5.6.3.5.
Vaccine number assignment ......................................53
5.6.3.6.
Vaccination.................................................................53
5.6.3.7.
Recording of non-serious AEs and SAEs ...................54
5.6.3.8.
Conclusion of the primary epoch ................................54
5.6.4.
Procedures during follow-up epochs............................................55
5.6.4.1.
Study conclusions.......................................................55
5.7.
Biological sample handling and analysis.....................................................55
5.7.1.
Use of specified study materials ..................................................56
5.7.2.
Biological samples.......................................................................56
5.7.3.
Laboratory assays .......................................................................57
5.7.4.
Biological samples evaluation......................................................59
5.7.4.1.
Immunological read-outs ............................................59
5.7.5.
Immunological correlates of protection.........................................64
6.
STUDY VACCINES AND ADMINISTRATION ........................................................65
6.1.
Description of study vaccines......................................................................65
6.1.1.
Vaccines given according to local policy ......................................67
6.1.1.1.
Measles......................................................................67
6.1.1.2.
Yellow fever................................................................67
6.2.
Storage and handling of study vaccines......................................................67
6.3.
Dosage and administration of study vaccines .............................................68
6.3.1.
RTS,S/AS01E (0.5 ml dose) .........................................................68
6.3.2.
Engerix-B (0.5 ml dose) ...............................................................69
6.3.3.
Polio Sabin ..................................................................................69
6.3.4.
Infanrix/Hib (0.5 ml dose).............................................................69
6.3.5.
Rotarix (1.5 1.0 ml dose)..............................................................70
6.3.6.
Synflorix (0.5 ml dose) .................................................................70
6.3.7.
Measles .......................................................................................70
 
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6.3.8.
Yellow fever.................................................................................70
6.4.
Replacement of unusable vaccine doses....................................................70
6.5.
Contraindications to subsequent vaccination ..............................................70
6.5.1.
Absolute contraindications to further vaccination .........................70
6.5.2.
Indications for deferral of vaccination...........................................71
6.6.
Warnings and precautions ..........................................................................71
6.7.
Concomitant medication/vaccination...........................................................71
6.7.1.
Medications/products that may lead to the elimination of a 
subject from ATP analyses ..........................................................72
6.7.2.
Time window for recording concomitant 
medication/vaccination in the CRF/eCRF.....................................72
6.8.
Intercurrent medical conditions that may lead to elimination from an 
ATP cohort..................................................................................................73
7.
HEALTH ECONOMICS ..........................................................................................73
8.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.....................................73
8.1.
Safety definitions ........................................................................................73
8.1.1.
Definition of an adverse event......................................................73
8.1.2.
Definition of a serious adverse event ...........................................75
8.1.3.
Solicited adverse events..............................................................76
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................76
8.2.
Detecting and recording adverse events and serious adverse events.........77
8.2.1.
Time period for detecting and recording adverse events, 
serious.........................................................................................77
8.2.2.
Evaluation of adverse events and serious adverse events...........78
8.2.2.1.
Active questioning to detect adverse events 
and serious adverse events........................................78
8.2.2.2.
Assessment of adverse events...................................78
8.2.2.2.1.
Assessment of intensity..........................78
8.2.2.2.2.
Assessment of causality .........................80
8.2.2.3.
Assessment of outcomes............................................81
8.2.2.4.
Medically attended visits.............................................81
8.2.2.5.
AEs of specific interest ...............................................82
8.2.2.6.
Rashes and mucocutaneous lesions ..........................83
8.3.
Reporting and follow-up of adverse events and serious adverse 
events.........................................................................................................83
8.3.1.
Prompt reporting of serious adverse events and other 
events to GSK Biologicals............................................................83
8.3.2.
Regulatory reporting requirements for serious adverse 
events..........................................................................................83
8.3.3.
Completion and transmission of SAEs reports to GSK 
Biologicals ...................................................................................84
8.3.3.1.
Studies using the paper CRF......................................84
8.3.3.2.
Studies using RDE .....................................................84
8.3.4.
Follow-up of adverse events and serious adverse events............85
8.4.
Treatment of adverse events ......................................................................86
8.5.
Unblinding...................................................................................................86
8.6.
Emergency unblinding ................................................................................86
8.7.
Subject card................................................................................................87
 
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9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................87
9.1.
Subject completion .....................................................................................87
9.2.
Subject withdrawal......................................................................................88
9.2.1.
Subject withdrawal from the study................................................88
9.2.2.
Subject withdrawal from investigational vaccine...........................88
10. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES ...............89
10.1.
Primary endpoint: immunogenicity ..............................................................89
10.2.
Secondary endpoints ..................................................................................89
10.3.
Estimated sample size................................................................................91
10.4.
Study cohorts to be evaluated.....................................................................92
10.4.1.
Total vaccinated cohort (TVC) .....................................................92
10.4.2.
According-To-Protocol (ATP) cohort for analysis of safety...........93
10.4.3.
According-to-protocol (ATP) cohort for analysis of 
immunogenicity............................................................................93
10.5.
Derived and transformed data.....................................................................93
10.6.
Conduct of analyses ...................................................................................94
10.6.1.
Sequence of analyses..................................................................94
10.6.2.
Statistical considerations for interim analyses..............................95
10.7.
Statistical methods......................................................................................95
10.7.1.
Analysis of demographics/baseline characteristics ......................95
10.7.2.
Analysis of immunogenicity..........................................................95
10.7.2.1.
Statistical analysis for primary endpoint......................95
10.7.2.2.
Statistical analyses for secondary endpoints ..............95
10.7.2.2.1.
Analysis of immunogenicity.....................95
10.7.2.2.2.
Analysis of safety....................................97
11. ADMINISTRATIVE MATTERS ...............................................................................97
11.1.
Case Report Form/Remote Data Entry instructions ....................................98
11.2.
Monitoring by GSK Biologicals....................................................................98
11.3.
Archiving of data at study sites .................................................................100
11.4.
Audits .......................................................................................................100
11.5.
Posting of information on Clinicaltrials.gov................................................100
11.6.
Ownership, confidentiality and publication ................................................101
11.6.1.
Ownership .................................................................................101
11.6.2.
Confidentiality ............................................................................101
11.6.3.
Publication.................................................................................101
11.6.4.
Provision of study results to investigators, posting to the 
clinical trials registers and publication........................................102
12. COUNTRY SPECIFIC REQUIREMENTS.............................................................102
13. REFERENCES.....................................................................................................103
 
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LIST OF TABLES
PAGE
Table 1
Blinding of study epochs ........................................................................37
Table 2
Study groups and epochs foreseen in the study.....................................38
Table 3
Treatment groups...................................................................................38
Table 4
Treatment groups (primary vaccination) .................................................39
Table 5
List of study procedures .........................................................................48
Table 6
Intervals between study visits.................................................................51
Table 7
Biological samples .................................................................................56
Table 8
Humoral immunity (antibody determination) ...........................................57
Table 9
Hematology, Serum Chemistry...............................................................59
Table 10
Summary of blood sampling time points, immunological read-
outs and volumes to be collected for infants in treatment group 
REP[Ro]s................................................................................................60
Table 11
Summary of blood sampling time points, immunological read-
outs and volumes to be collected for infants in treatment group 
RERo[P]s................................................................................................61
Table 12
Summary of blood sampling time points, immunological read-
outs and volumes to be collected for infants in treatment group 
RE[RoP]s................................................................................................62
Table 13
Summary of blood sampling time points, immunological read-
outs and volumes to be collected for infants in treatment group 
HEP[Ro]s................................................................................................63
Table 14
Summary of blood sampling time points, immunological read-
outs and volumes to be collected for infants in treatment group 
HERo[P]s................................................................................................64
Table 15
Study vaccines.......................................................................................66
Table 16
Dosage and administration.....................................................................68
Table 17
Time window for recording concomitant medication/vaccination.............73
Table 18
Solicited local adverse events ................................................................76
Table 19
Solicited general adverse events............................................................76
 
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Table 20
Reporting periods for adverse events and serious adverse 
events ....................................................................................................77
Table 21
Intensity scales for solicited symptoms in infants/toddlers and 
children less than 6 years of age............................................................79
Table 22
Time frames for submitting SAEs and other events reports to 
GSK Biologicals .....................................................................................83
Table 23
Power for secondary non-inferiority endpoints........................................92
LIST OF FIGURES
PAGE
Figure 1
Study design diagram.............................................................................36
LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .....................................................................106
APPENDIX B AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................108
 
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
anti-CS
Antibody to the Plasmodium falciparum circumsporozoite (CS) 
repeat domain
anti-HBs
Antibody to the hepatitis B surface antigen
anti-HBs RF1
Antibody to the hepatitis B RF1 surface antigen
anti-BPT
Anti Bordetella Pertussis antibody
ATP
According To Protocol
BPT
Bordetella pertussis
CCID50
Median Cell Culture Infective Dose (quantity of virus causing 
infection in 50% of exposed cells)
CI
Confidence Interval
CRF/eCRF
Case Report Form/electronic Case Report Form
CS
Circumsporozoite protein of Plasmodium falciparum
DTPa/Hib
Diphtheria, Tetanus, Pertussis (acellular) and Haemophilus 
influenzae type b conjugate vaccine
ELISA
Enzyme-Linked Immunosorbent Assay
EMA
European Medicines Agency
EPI
Expanded Program on Immunization
EU/ml
ELISA Unit per milliliter
FDA
Food and Drug Administration, United States
GCP
Good Clinical Practice
GMC
Geometric Mean Concentration
GMT
Geometric Mean Titer
GSK
GlaxoSmithKline
HAART
Highly Active Anti Retroviral Therapy
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
Hep B
Hepatitis B
HEP[Ro]s
Children to receive 3 doses of licensed hepatitis B vaccine  with 
co-administration of DTPa/Hib and Polio Sabin EPI vaccines 
and co-administration of pneumococcal conjugate vaccine. 
Rotavirus vaccine will be given in a staggered way.
 
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HERo[P]s
Children to receive 3 doses of licensed hepatitis B vaccine with 
co-administration of DTPa/Hib and Polio Sabin EPI vaccines 
and co-administration of rotavirus vaccine. Pneumococcal 
conjugate vaccine will be given in a staggered way.
Hib
Haemophilus influenzae type b
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IM
Intramuscular
IMD
Immune-Mediated Disorders
IPD
Invasive Pneumococcal Disease
IRB
Institutional Review Board
IU
International Unit
kg
Kilogram
LAR
Legally Acceptable Representative
LSM
Local Safety Monitor
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
ml
Milliliter
MPL
3-deacylated Monophosphoryl Lipid A
OPA
Opsonophagocytic Assay
OPV
Oral Polio Vaccine
PCV
Pneumococcal Conjugate Vaccine
PD
Protein D, a 42 kD cell-surface lipoprotein which is highly 
conserved among capsulated and unencapsulated strains of 
Haemophilus influenzae
P. falciparum
Plasmodium falciparum
PFS
Pre-filled syringe
PI
Principal Investigator
PMCT
Prevention of mother-to-child transmission of HIV infection
 
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QS21
‘Quillaja saponaria 21’: a triterpene glycoside purified from 
the bark of the soap bark tree, Quillaja saponaria
RAP
Report and Analysis Plan
RCC
Reverse Cumulative Curves
RDE
Remote Data Entry
REP[Ro]s
Children to receive 3 doses of RTS,S/AS01E with co-
administration of DTPa/Hib and Polio Sabin EPI vaccines and 
co-administration of pneumococcal conjugate vaccine. 
Rotavirus vaccine will be given in a staggered way.
RERo[P]s
Children to receive 3 doses of RTS,S/AS01E with co-
administration of DTPa/Hib and Polio Sabin EPI vaccines and 
co-administration of rotavirus vaccine. Pneumococcal 
conjugate vaccine will be given in a staggered way.
RE[RoP]s
Children to receive 3 doses of RTS,S/AS01E with co-
administration of DTPa/Hib and Polio Sabin EPI vaccines. 
Rotavirus vaccine and pneumococcal conjugate vaccine will be 
given in a staggered way.
RF1 mAb
RF1 Monoclonal Antibody
RTS,S
Particulate antigen, containing both RTS and HBs proteins
SAE
Serious Adverse Event
SBIR
Internet Based Randomization System
SDV
Source Document Verification
SOP
Standard Operating Procedure
SP
Seropositive
SPM
Study Procedures Manual
TVC
Total Vaccinated Cohort
VCT
Voluntary Counselling and Testing
WBC
White blood cells
WHO
World Health Organization
 
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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 AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For 
marketed medicinal products, this also includes failure to 
produce expected benefits (i.e. lack of efficacy), abuse or 
misuse.
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event.
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.
Independent Data 
Monitoring Commitee:
The IDMC is an independent committee appointed to 
oversee ethical and safety aspects of the conduct of the 
study.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Epoch:
An epoch is a well defined part of a protocol that covers a 
set of consecutive time-points. Generally, an epoch is 
self-contained and allows to perform a data analysis to 
address some of the trial objectives (e.g. primary, booster, 
yearly follow-ups …).
 
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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.
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 authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
Local Safety Monitor:
The Local Safety Monitor is an experienced physician 
based in-country who will be of support to the study 
investigators and act as a link between the investigators
and the IDMC.
Medical Monitor:
An individual medically qualified to assume the 
responsibilities of the Sponsor (GSK Biologicals) 
especially in regards to the ethics, clinical safety of a 
study and the assessment of adverse events.
Randomisation:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
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;
e.
adverse events of specific interest
NB: AEs of specific interest include all seizures 
occurring within a 30-day period of vaccination 
and immune-mediated disorders. Key information
pertaining to seizures occurring within 7 days of 
vaccination will be documented in the CRF/eCRF 
[refer to Bonhoeffer, 2004]. AEs of specific interest 
to be reported as SAEs also include specific 
auto-immune diseases and other immune mediated 
disorders as listed in section 8.2.2.5.
Medical or scientific judgment should be exercised in 
deciding whether reporting is appropriate in other 
 
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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.
Site Monitor:
An individual assigned by the Sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
Solicited adverse event:
Adverse events (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 product(s) or as a control.
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 
randomisation or treatment allocation.
Unsolicited adverse 
event:
Any adverse event (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.
Vaccine number:
A number identifying a vaccine to a subject, according to 
the study randomization or treatment allocation.
 
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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/products and/or medications will be written without the subscript symbol ™ or 
®.
Trademarks 
of the GlaxoSmithKline group of 
companies
Generic description
Engerix-B™
Hepatitis B vaccine
Infanrix™Hib
Diphtheria, tetanus, acellular pertussis and Haemophilus 
Influenza type B vaccine
Polio Sabin™
Oral poliovirus vaccine
Rotarix™
Rotavirus vaccine
Synflorix™
10-valent pneumococcal conjugate vaccine with protein D, 
diphtheria toxoid and tetanus carriers and containing 
pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F 
and 23F
 
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1.
INTRODUCTION
1.1.
Background
GlaxoSmithKline (GSK) Biologicals is developing a pre-erythrocytic Plasmodium 
falciparum malaria vaccine (RTS,S/AS01E vaccine) for routine immunization of infants 
and children living in malaria-endemic areas as part of the Expanded Program of 
Immunization (EPI).
The RTS,S antigen is a hybrid antigen in which a portion of the circumsporozoite (CS) 
protein (repeat region (R) + T-cell epitopes (T)) is fused to a hepatitis B surface antigen 
(HBs Ag). This fused antigen, called RTS, is expressed together with an unfused HBs Ag 
in yeast. The RTS,S antigen is adjuvanted with GSK’s proprietary Adjuvant System 
AS01 (liposome formulation with MPL and QS21 immunostimulants). By way of its 
recombinant antigen, RTS,S/AS01E offers protection against malaria disease due to
P. falciparum and induces a good antibody response against infection with hepatitis B 
virus (HBV).
In studies completed to date, the RTS,S/AS candidate malaria vaccines consistently 
demonstrated efficacy with promising safety profile when administered to infants and 
young children in co-administrations with routine EPI vaccines.
Phase II evaluations of the RTS,S/AS vaccines have shown that both AS02 and AS01 
pediatric formulations induce strong immune response to the S-antigen in RTS,S which is 
adequate to offer protection against hepatitis B infection [Malaria-046 Report (GSK data 
on file), 2008]. The antibody response to hepatitis B antigen induced by RTS,S/AS 
vaccines when administered to children [Malaria-026 Report (GSK data on file), 2006; 
Malaria-040 Report (GSK data on file), 2009] compared favourably with that of a 
licensed hepatitis B vaccine (Engerix-B), with anti-HBs seroprotection level (SP) after a 
3-dose course of RTS,S/AS02 above 95%, which is in line with the World Health 
Organisation’s position on SP level to be reached after Hepatitis B vaccination [WHO,
2009]. In addition, compared with a licensed Hepatitis B vaccine, there is evidence of 
improved persistence of circulating antibodies following 3 doses of RTS,S/AS02 
[Malaria-026 Report (GSK data on file), 2006; Malaria-038 Report (GSK data on file), 
2008].
GSK Biologicals intends to seek an indication of prevention of hepatitis B for its 
RTS,S/AS01E vaccine considering that Hepatitis B immunization is a policy 
recommended by the World Health Organisation which is being implemented in EPI 
programmes. [WHO, 2008].
Following recent recommendation by the WHO, [WHO, 1999; WHO, 2007] it is 
expected that pneumococcal and rotavirus vaccinations will be widely implemented in 
EPI programmes in the near future. Therefore GSK Biologicals intends to explore their 
interactions when co-administered with RTS,S/AS01E vaccine within EPI schedule.
 
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Please refer to the current Investigator Brochure for a review of the pre-clinical and 
clinical studies, and the potential risks and benefits of the candidate vaccine 
RTS,S/AS01E.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
This study aims to provide key information required to support the indication of the 
RTS,S/AS01E candidate vaccine for primary immunization of infants against the hepatitis 
B virus.
It is therefore designed to:

Evaluate the immune response to the hepatitis B antigen in recipients of 
RTS,S/AS01E versus recipients of a licensed hepatitis B vaccine, including memory 
response and the quality of the immune response.

Evaluate the immune response to the antigens contained in a conjugate
pneumococcal vaccine and in a rotavirus vaccine when administered concomitantly 
with RTS,S/AS01E, within the existing EPI schedules in African countries.

Demonstrate consistency of the hepatitis B response induced by RTS,S/AS01E
candidate vaccine produced at the intended scale for commercial production of 
RTS,S bulk antigen.
1.2.2.
Rationale for the hepatitis B vaccination in Africa
Hepatitis B is an infection of the liver due to hepatitis B virus (HBV); it is an important 
public health problem across the developing world. World-wide approximately 350 
million people carry HBV and about 1 million chronic carriers die annually [Vryheid
2001]. Sub-Sahara Africa has approximately 50 million of HBV carriers, the second 
largest population after Asia [Burnett, 2005]. The likelihood of the infection becoming
chronic is dependent upon the age at infection: 90% if infected in infancy, 30% to 50% if 
infected between the ages of 1 to 4 years, and low in adulthood. For those that become 
chronically infected during childhood, the risk of death from HBV-related liver cancer or 
cirrhosis in adult life is approximately 25% [WHO, 2008].
This information emphasizes the importance of hepatitis B vaccination in infants of sub-
Saharan African countries.
1.2.2.1.
Evaluation of memory response to the HBs antigen
The persistence of the immune response to the HBs antigen of the candidate malaria 
vaccine will be tested at yearly intervals over a 4 years follow-up. To evaluate the 
memory response to HBs antigen, an additional dose of Engerix-B will be administered 4 
years post Dose 3 to all study subjects. HBs antibody titers will be measured one month 
post administration of this additional dose of hepatitis B vaccine.
 
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1.2.3.
Rationale for the evaluation of co-administration with a conjugate
pneumococcal vaccine
The WHO estimates that, annually, at least 1 million deaths worldwide are attributable to 
pneumococcal infections, recommending that pneumococcal vaccination of infants and 
children would reduce this burden [WHO, 1999]. GSK pneumococcal vaccine (Synflorix)
is expected to protect against pneumococcal disease, in particular pneumococcal strains 
(serotypes 1, 5 and 7F) that are known to be responsible for a significant proportion of
invasive pneumococcal disease (IPD) [Hausdorff, 2001].
Since spring 2009, GSK Biologicals' 10-valent pneumococcal polysaccharide and non-
typeable Haemophilus influenzae protein D conjugate (10Pn-PD-DiT) vaccine has been 
licensed in the European Union, Canada, Australia and several other countries worldwide 
and is marketed under the trademark of Synflorix. Synflorix is also prequalified by WHO.
It is presumed that in the near future pneumococcal conjugate vaccine will be widely 
implemented as EPI vaccines across sub-Saharan Africa.
1.2.4.
Rationale for the evaluation of co-administration with a rotavirus 
vaccine
The WHO recommends the inclusion of rotavirus vaccination into the national 
immunization programmes as rotavirus vaccines have shown protection against severe 
rotavirus disease and against rotavirus diarrhoea of any severity. In Malawi and South 
Africa, vaccine efficacy against severe rotavirus disease in infants was respectively of 
49% and 77% [Madhi, 2010]. However, due to the large burden of disease, efficacy of 
this level will translate into important public health benefits. The GSK Biologicals 
licensed rotavirus vaccine (Rotarix) provides significant broad protection against diverse 
circulating rotavirus strains. Rotarix received prequalification by WHO. It is presumed 
that in the near future a rotavirus vaccine would be widely implemented as EPI vaccines 
across sub-Saharan Africa [WHO, 2007].
2.
OBJECTIVES
2.1.
Primary objective: immunogenicity

To demonstrate in terms of antibody response to the HBs antigen, the non-inferiority 
of RTS,S/AS01E to a primary vaccination regimen of a licensed hepatitis B vaccine 
(Engerix-B) integrated into an EPI regimen.
Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 
95% confidence interval (CI) on the difference in percent seroprotection below 5% 
between recipients of licensed hepatitis B vaccine (Engerix-B) and recipients of 
RTS,S/AS01E vaccine. 
Refer to Section 10.1 for the definition of the primary endpoint.
 
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2.2.
Secondary objectives
Immunogenicity

To demonstrate the non-inferiority of antibody responses to the pneumococcal 
conjugate vaccine when co-administered with versus without RTS,S/AS01E as part 
of an EPI regimen.
Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 
95% confidence interval (CI) on the GMC ratios of 10 pneumococcal serotypes titers 
(measured with an ELISA test), is below a limit of 2 for the pneumococcal conjugate 
vaccine when co-administered with versus without RTS,S/AS01E.

To describe the antibody responses to the 10 pneumococcal serotypes (1, 4, 5, 6B, 
7F, 9V, 14, 18C, 19F and 23F), measured by ELISA and OPA, when the 
pneumococcal conjugate vaccine is co-administered with and without RTS,S/AS01E
as part of an EPI-regimen.

To describe the antibody response to the Protein D (PD) component of the 
pneumococcal conjugate vaccine when co-administered with versus without 
RTS,S/AS01E as part of an EPI regimen.

To demonstrate the non-inferiority of antibody response to the rotavirus vaccine 
when co-administered with versus without RTS,S/AS01E as part of an EPI regimen.
Criteria for non-inferiority: one month post Dose 2, upper limit (UL) of the 2-sided 
95% confidence interval (CI) on the geometric mean titers (GMT) ratios of rotavirus 
antibodies (IgA) titers is below 2 for the rotavirus vaccine when co-administered 
with versus without RTS,S/AS01E.

To describe the antibody response to the rotavirus antigen when co-administered 
with and without RTS,S/AS01E as part of an EPI regimen.

To describe the antibody response to the HBs antigen, induced by RTS,S/AS01E
when administered as a 3 doses schedule (0, 1, 2-month) integrated into an EPI 
regimen.

To describe the antibody response to the HBs RF1 epitope, induced by RTS,S/AS01E
when administered as a 3 doses schedule (0, 1, 2-month) integrated into an EPI 
regimen.

To describe the antibody response to the CS antigen when RTS,S/AS01E is co-
administered with a pneumococcal conjugate vaccine as part of an EPI regimen.

To describe the antibody response to the CS antigen when RTS,S/AS01E is co-
administered with a rotavirus vaccine as part of an EPI regimen.

To demonstrate the lot-to-lot consistency in terms of anti-HBs immunogenicity 
between three commercial lots of the RTS,S/AS01E candidate malaria vaccine.
Criteria for consistency: one month post Dose 3 of RTS,S/AS01E, the two-sided 95% 
confidence interval (CI) of the geometric mean titer (GMT) ratio between all pairs of 
lots are within [0.5, 2].
 
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
To demonstrate the non-inferiority of antibody response to the acellular B pertussis 
antigens of the DTPa/Hib vaccine when co-administered with RTS,S/AS01E as part 
of an EPI regimen.
Criteria for non-inferiority: one month post Dose 3, upper limit (UL) of the 2-sided 
95% confidence interval (CI) on the GMT ratios of anti-PT, anti-FHA, anti-PRN 
antibody titers, is below a limit of 2 for the DTPa/Hib vaccine when co-administered 
with versus without RTS,S/AS01E.

To describe the antibody response to acellular B pertussis antigens pre- and post-
vaccination when a DTPa/Hib vaccine is co-administered with RTS,S/AS01E as part 
of an EPI-regimen.
Immunogenicity follow-up

To describe the long-term antibody response to the HBs antigen induced by 
RTS,S/AS01E, compared to a primary vaccination regimen of a licensed hepatitis B 
vaccine when administered as a 3 doses schedule (0, 1, 2-month) integrated into an 
EPI regimen.

Evaluation of the antibody response to the HBs antigen induced by a booster dose of 
a licensed hepatitis B vaccine.

Evaluation of the antibody response to HBs RF1 like antigen induced by a booster 
dose of a licensed hepatitis B vaccine.

To describe the long-term antibody response to the CS antigen induced by 
RTS,S/AS01E, when administered as a 3 doses schedule (0, 1, 2-month) integrated 
into an EPI regimen.

Evaluation of the antibody response to the 10 pneumococcal serotypes (1, 4, 5, 6B, 
7F, 9V, 14, 18C, 19F and 23F) induced by a booster dose of a licensed 
pneumococcal conjugate vaccine when co-administered with and without 
RTS,S/AS01E.
Safety

Evaluation of the safety profile of the RTS,S/AS01E candidate malaria vaccine, when 
co-administered with a pneumococcal conjugate vaccine or a rotavirus vaccine 
integrated into an EPI regimen.
Refer to Section 10.2 for the definition of the secondary endpoints.
 
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3.
STUDY DESIGN OVERVIEW
Figure 1
Study design diagram
HERo[P]s
Vac 1
Engerix B
& Infanrix/Hib
& Polio Sabin
Vac 2
Synflorix
Vac 3
Engerix B
& Infanrix/Hib
& Polio Sabin
& Rotarix
Vac 4
Synflorix
Vac 5
Engerix B
& Infanrix/Hib
& Polio Sabin
& Rotarix
Vac 6
Synflorix
Primary Vaccination Epoch
Immuno FU 1
Epoch
Clinic 
visit 8
Week
12
BS
Clinic 
visit 2
Week
0
Clinic 
visit 3
Week
2
Clinic 
visit 4
Week
4
Clinic 
visit 5
Week
6
Clinic 
visit 6
Week
8
Clinic 
visit 7
Week
10
Clinic 
visit 11
Month
16
Clinic 
visit 13
Month
26
BS
Clinic 
visit 15
Month
50
BS
Clinic 
visit 14
Month
38
BS
Clinic 
visit 10
Month
14
BS
Primary Analysis
 Immuno analysis
HEP[Ro]s
Vac 1
Engerix B
& Infanrix/Hib
& Polio Sabin
& Synflorix
Vac 2
Engerix B
& Infanrix/Hib
& Polio Sabin
& Synflorix
Vac 4
Engerix B
& Infanrix/Hib
& Polio Sabin
& Synflorix
RE[RoP]s
Vac 1
RTS,S/AS01E
& Infanrix/Hib
& Polio Sabin
Vac 2
Synflorix
Vac 3
RTS,S/AS01E
& Infanrix/Hib
& Polio Sabin
Vac 4
Synflorix
& Rotarix
Vac 5
RTS,S/AS01E
& Infanrix/Hib
& Polio Sabin
Vac 6
Synflorix
& Rotarix
Booster 1
Infanrix/Hib
& Synflorix
Booster 2
Engerix B
RERo[P]s
Vac 1
RTS,S/AS01E
& Infanrix/Hib
& Polio Sabin
Vac 2
Synflorix
Vac 3
RTS,S/AS01E
& Infanrix/Hib
& Polio Sabin
& Rotarix
Vac 4
Synflorix
Vac 5
RTS,S/AS01E
& Infanrix/Hib
& Polio Sabin
& Rotarix
Vac 6
Synflorix
Vac 1
RTS,S/AS01E
& Infanrix/Hib
& Polio Sabin
& Synflorix
Vac 2
RTS,S/AS01E
& Infanrix/Hib
& Polio Sabin
& Synflorix
Vac 4
RTS,S/AS01E
& Infanrix/Hib
& Polio Sabin
& Synflorix
Vac = vaccination; SCR = Screening Epoch; FU = Follow-up; BS = blood sample
R = RTS,S/AS01E; E = Infanrix/Hib + Polio Sabin EPI vaccines; P = pneumococcal conjugate vaccine (Synflorix); 
Ro = Rotavirus vaccine (Rotarix); H = Hepatitis B vaccine (Engerix B);
R1 = RTS,S/AS01E lot 1; R2 = RTS,S/AS01E lot 2; R3 = RTS,S/AS01E lot 3
REP[Ro]s
Randomization
R1
R2
R3
R1
R3
R2
R1
R2
R3
 Safety Analysis
Vac 3
Rotarix
Vac 5
Rotarix
Vac 3
Rotarix
Vac 5
Rotarix
Clinic 
visit 9
Week
32
Vac
Measles
+ yellow fever
Clinic 
visit 12
Month
17
BS
Clinic 
visit 16
Month
51
BS
Clinic 
visit 1
Week
-2 to 0
BS
Final Analysis
Immuno FU 2
Epoch
Safety 
FU
Epoch
SCR
 
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
Experimental design: Phase III, multi-center, open, randomized, controlled trial 
with 11 study groups.

Study population: male and female infants, aged 8-12 weeks at the time of first 
vaccination, who are eligible based on inclusion and exclusion criteria.

Control: Engerix-B

Treatment allocation: Subjects will be randomized into 11 study groups in a 1:1:1 : 
1:1:1 : 1:1:1 :3:3 ratio [this means 5 treatment groups of which the 3 RTS,S/AS01E
groups will be randomized to receive 3 different lots].

Treatment groups and vaccination schedule:
The primary vaccination schedule for all treatment groups is presented in Table 3
and Table 4. In the RTS,S arms, 3 doses of RTS,S will be administered on a 0, 1, 2-
month schedule. All groups will receive the measles vaccine 6 months post Dose 3 of 
RTS,S/AS01E or Engerix-B. Yellow fever vaccine will be given according to local 
treatment regulations, at 6 months post Dose 3 of RTS,S/AS01E or Engerix-B. All 
groups will receive Synflorix and Infanrix/Hib booster vaccinations at approximately 
18 months of age (Visit 11), and an Engerix-B booster vaccination at 48 months after 
the third dose of Engerix-B in the primary vaccination schedule.

Blinding: open-label.
Table 1
Blinding of study epochs
Study Epochs
Blinding
Screening Epoch
open
Primary vaccination Epoch
open
Safety follow-up Epoch
open
Immunogenicity follow-up 1 Epoch
open
Immunogenicity follow-up 2 Epoch
open

Type of study: self-contained.

Data collection: Where technically possible, this study will use electronic case 
report form (eCRF) by remote data entry (RDE) in preference to conventional paper 
case report form (CRF).

Duration of the study: approximately 52 months per study participant, including a 
screening period and 49 months follow-up after the third vaccination of 
RTS,S/AS01E or Engerix-B.

Epochs:

Screening Epoch
starting Visit 1 and ending before Visit 2 (Day 0)

Primary vaccination Epoch
starting Visit 2 (Day 0) and ending at Visit 8 (Week 12)
 
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
Safety follow-up Epoch
starting after Visit 8 (Week 12) and ending at Visit 9 (Month 18)

Immunogenicity follow-up 1 Epoch
starting after Visit 9 (Month 8) and ending at Visit 13 (Month 26)

Immunogenicity follow-up 2 Epoch
starting after Visit 13 (Month 26) and ending at Visit 16 (Month 51)
Table 2
Study groups and epochs foreseen in the study
Study Group
Number 
of 
subjects
Age 
(Min/Max)
Epochs
Screening 
Epoch
Primary 
vaccinati
on Epoch
Safety 
follow-up 
Epoch
Immunog
enicity 
follow-up 
1 Epoch
Immunog
enicity 
follow-up 
2 Epoch
REP[Ro]s lot 1
47
8-12 weeks
x 
x 
x 
x 
x 
REP[Ro]s lot 2
47
8-12 weeks
x 
x 
x 
x 
x 
REP[Ro]s lot 3
47
8-12 weeks
x 
x 
x 
x 
x 
RERo[P]s lot 1
47
8-12 weeks
x 
x 
x 
x 
x 
RERo[P]s lot 2
47
8-12 weeks
x 
x 
x 
x 
x 
RERo[P]s lot 3
47
8-12 weeks
x 
x 
x 
x 
x
RE[RoP]s lot 1
47
8-12 weeks
x 
x 
x 
x 
x 
RE[RoP]s lot 2
47
8-12 weeks
x 
x 
x 
x 
x 
RE[RoP]s lot 3
47
8-12 weeks
x 
x 
x 
x 
x 
HEP[Ro]s
141
8-12 weeks
x 
x 
x 
x 
x 
HERo[P]s
141
8-12 weeks
x 
x 
x 
x 
x 
Table 3
Treatment groups
Treatment 
Group
Study Group
Primary vaccination schedule
Number of 
subjects
REP[Ro]s
REP[Ro]s lot 1
RTS,S/AS01Ea + CoAd (Infanrix/Hiba + Polio Sabina + 
Synflorixa) + Rotarixb staggered
141 
(47+47+47)
REP[Ro]s lot 2
REP[Ro]s lot 3
RERo[P]s
RERo[P]s lot 1
RTS,S/AS01Ea + CoAd (Infanrix /Hiba + Polio Sabina + 
Rotarixc) + Synflorixd staggered
141
(47+47+47)
RERo[P]s lot 2
RERo[P]s lot 3
RE[RoP]s
RE[RoP]s lot 1
RTS,S/AS01Ea + CoAd (Infanrix /Hiba + Polio Sabina) + 
staggered (Synflorixd + Rotarixb)
141
(47+47+47)
RE[RoP]s lot 2
RE[RoP]s lot 3
HEP[Ro]s
HEP[Ro]s
Engerix-Ba+ CoAd (Infanrix /Hiba + Polio Sabina + Synflorixa) 
+ Rotarixb staggered
141
HERo[P]s
HERo[P]s
Engerix-Ba + CoAd (Infanrix /Hiba + Polio Sabina + Rotarixc) 
+ Synflorixd staggered
141
a. Administration at Visit 2, Visit 4 and Visit 6
b. Administration at Visit 5 and Visit 7
c. Administration at Visit 4 and Visit 6 
d. Administration at Visit 3, Visit 5 and Visit 7
 
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Table 4
Treatment groups (primary vaccination)
Vaccine 
name
REP[Ro]s
RERo[P]s
RE[RoP]s
HEP[Ro]s HERo[P]s
REP[Ro]s
lot 1
REP[Ro]s
lot 2
REP[Ro]s
lot 3
RERo[P]s
lot 1
RERo[P]s
lot 2
RERo[P]s
lot 3
RE[RoP]s
lot 1
RE[RoP]s
lot 2
RE[RoP]s
lot 3
HEP[Ro]s HERo[P]s
RTS,S/AS01E
x
x
x
x
x
x
x
x
x
Infanrix/Hib
x
x
x
x
x
x
x
x
x
x
x
Polio Sabin 
x
x
x
x
x
x
x
x
x
x
x
Synflorix 
x
x
x
x
x
x
x
x
x
x
x
Rotarix
x
x
x
x
x
x
x
x
x
x
x
Engerix-B 
x
x
Screening of pregnant women

Pregnant women will be identified at antenatal clinics or in the community and will 
be informed about the study. If interested in participating they will be asked to sign a 
consent form for screening for hepatitis B or HIV infection.

Infants born to mothers who are HBsAg positive and are therefore at high risk of 
vertical transmission of hepatitis B infection will be excluded from this trial. These 
infants will be offered a licensed hepatitis B vaccine in a schedule beginning at birth. 
Women who are tested positive for HBsAg with symptoms will be referred to an 
appropriate health care center.

Infants born to mothers who are HIV positive will be excluded from this trial. 
Voluntary counselling and testing (VTC), highly active anti retroviral therapy 
(HAART) and prevention of mother-to-child transmission (PMCT) are available at 
the study center according to national policies.

The site study team will ensure that insecticide treated bednet use is optimized in the 
study population.
Screening of infants

Mothers who were screened negative for HBsAg and HIV and who agree to let their 
child participate in the study will be invited for the screening visit (Visit 1).

Prior to any other study procedures, the parents will be asked to sign/thumb-print a 
consent form to allow their child to participate in the trial.
Surveillance for safety

Each subject will be observed for at least 60 minutes after vaccination to evaluate 
and treat any acute adverse events (AEs).

There will be a 7-day follow-up period (day of vaccination and 6 subsequent days) 
after each dose of RTS,S/AS01E or Engerix-B co-administered with EPI vaccines for 
recording of solicited AEs (+ any unsolicited AEs). On day of vaccination (day 0) 
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 personnels will visit the children to 
record solicited AEs and any unsolicited AEs.
 
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
There will be a 30-day follow-up period (day of vaccination and 29 subsequent days) 
after each dose of RTS,S/AS01E or Engerix-B co-administered with EPI vaccines for 
reporting unsolicited adverse events.

All SAEs will be reported until 8 months post Dose 1 of RTS,S/AS01E or Engerix-B.

This study will be overseen by a formally constituted IDMC operating under a 
charter.
Blood sampling

Groups RERo[P]s, RE[RoP]s and HERo[P]s will have a total of 7 blood samples 
taken: at Visit 1 (screening) and Visit 8, 10, 13, 14, 15, 16 (post Dose 3 of 
RTS,S/AS01E or Engerix-B).

Groups REP[Ro]s and HEP[Ro]s will have a total of 8 blood samples taken: at Visit 1 
(screening) and Visit 8, 10, 12, 13, 14, 15, 16 (post Dose 3 of RTS,S/AS01E or 
Engerix-B).

Blood for safety evaluation will be collected at screening (Visit 1) to ensure healthy 
children are recruited.
Surveillance for immunogenicity

Immune responses to the HBs antigen will be assessed at screening (Visit 1), at 
Visit 8 (one month post Dose 3 of RTS,S/AS01E or Engerix-B), at Visit 10 
(Month 14), at Visit 13 (Month 26), at Visit 14 (Month 38), at Visit 15 (Month 50) 
and at Visit 16 (Month 51).

Immune responses to the CS antigen will be assessed at screening (Visit 1), at Visit 8 
(one month post Dose 3 of RTS,S/AS01E or Engerix-B), at Visit 10 (Month 14), at 
Visit 13 (Month 26), at Visit 14 (Month 38) and at Visit 15 (Month 50).

Immune response to the 10 pneumococcal serotypes will be assessed at one month 
post Dose 3 of pneumococcal conjugate vaccine with RTS,S/AS01E co-
administration (Visit 8) and one month post booster dose of pneumococcal conjugate 
vaccine (Visit 12).

Immune response to rotavirus antigen will be assessed at one month post Dose 2 of 
rotavirus vaccine with RTS,S/AS01E co-administration (Visit 8).
Statistical analysis

The primary analysis will be performed on data collected up to Visit 8 (1 month post 
Dose 3 of RTS,S/AS01E or Engerix-B) and will include primary and secondary 
immunogenicity and safety endpoints. Results will be reported in a final study report.

A safety analysis will be performed on data (SAEs) collected until 8 months post 
Dose 1 of RTS,S/AS01E or Engerix-B (Visit 9) and will be reported in an annex 
report.
 
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
An immunogenicity analysis based on data collected until Visit 13 (Month 26) will
include anti-CS and anti-HBs antibody responses and will be reported in an annex 
report.

The final analysis will be performed on further safety and immunogenicity data 
collected up to the last study visit (Visit 16), 51 months following the administration 
of the first dose of study vaccine. Results will be presented in an annex report.
4.
STUDY COHORT
4.1.
Number of subjects/centres
A total of 705 subjects will be enrolled (141 per group), in order to have at least 600 
evaluable subjects (approximately120 per group).
Refer to Section 10.3 for a detailed description of the criteria used in the estimation of 
sample size.
4.2.
Overview of the recruitment plan
This study is intended to be conducted in multiple centers in sub-Saharan Africa. Details 
of the geography, demographics, healthcare provision and relevant site-specific 
information for each center are provided in the study center specific document.
Enrolment will be terminated when approximately 705 children have been recruited.
4.3.
Inclusion criteria for enrolment
All subjects must satisfy ALL the following criteria at study entry:

A male or female infant aged between 8 and 12 weeks inclusive at the time of first 
vaccination.

Signed or thumb-printed informed consent obtained from the parent(s)/LAR(s) of the 
child. Where parent(s)/LAR(s) are illiterate, the consent form will be countersigned 
by an independent witness.

Subjects who the investigator believes that their parent(s)/LAR(s) can and will 
comply with the requirements of the protocol (e.g. return for follow-up visits).

Healthy subjects as established by medical history and clinical examination before 
entering into the study.

Born to a mother who is HBsAg negative.

Born to a mother who is HIV negative.

Born after a normal gestation period of 36 to 42 weeks inclusive.
 
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4.4.
Exclusion criteria for enrolment
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care. Please refer to the GLOSSARY OF TERMS for the definition of child 
in care.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 37.5°C on oral, axillary or tympanic setting, or
38.0°C on rectal setting.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.

Serious acute or chronic illness determined by clinical or physical examination and 
laboratory screening tests including, but not limited to: 

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing 
required).

A family history of congenital or hereditary immunodeficiency.

Major congenital defects.

History of any neurologic disorders or seizures.

Moderate malnutrition at screening defined as weight for age Z-score less
than -2.

Laboratory screening tests out of range, specifically:

ALT above acceptable limit (i.e. > 60 IU/L).

Creatinine above acceptable limit (i.e. > 60 µmol/L).

Hemoglobin below acceptable limit (i.e. < 8.0 g/dL).

Platelet count below acceptable limit (i.e. < 100 x 103/µL).

Total white cell count below acceptable limit (i.e. < 4.0 x 103/µL).
Note that screening laboratory tests must be performed within 14 days of Dose 1.

Previous vaccination with diphtheria, tetanus, pertussis (whole-cell or acellular), 
Haemophilus influenzae type b, Streptococcus pneumoniae, hepatitis B vaccine or 
rotavirus vaccines.

Planned administration/administration of a licensed vaccine (i.e. a vaccine that is 
approved by one of the following authorities: FDA or EU member state or WHO 
[with respect to prequalification]) not foreseen by the study protocol within 7 days of 
the first dose of study vaccine.

Use of a drug or vaccine that is not approved for that indication (by one of the 
following authorities: FDA or EU member state or WHO [with respect to 
 
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prequalification]) other than the study vaccines within 30 days preceding the first 
dose of study vaccine, or planned use during the study period.

Administration of immunoglobulins and/or any blood products in the period between 
birth and Dose 1 and within the three months preceding planned vaccine 
administration during the study period.

Chronic administration (defined as more than 14 days in total) of immuno-
suppressants or other immune-modifying drugs in the period between birth and 
Dose 1. For corticosteroids, this will mean prednisone ≥0.5 mg/kg/day, or 
equivalent. Inhaled and topical steroids are allowed.

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 product (pharmaceutical product or device).

Same sex twin (to avoid misidentification). 

Maternal death. 

History of allergic reactions (significant IgE-mediated events) or anaphylaxis to 
previous immunizations. 

History of allergic disease or reactions likely to be exacerbated by any component of 
the vaccine. 

Any other findings that the investigator feels would increase the risk of having an 
adverse outcome from participation in the trial. 

Any other findings that the investigator feels would result in data collected being 
incomplete or of poor quality. 

Previous participation in any other malaria vaccine trial.
A list of criteria that may eliminate subjects from ATP analyses can be found in Sections 
6.7.1, 6.8 and 10.4.
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 (International Conference on 
Harmonisation) 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 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
pediatric population (ICH E11) and all other applicable ethical guidelines.
 
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GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject’s parent(s)/LAR(s) informed consent.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written informed consent must be obtained from each subject’s 
parent(s)/LAR(s) prior to participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the Sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
5.2.
Subject identification and randomisation of treatment
The target will be to enrol approximately 705 eligible subjects. Subjects will be 
randomized to 11 study groups with age and study centre used as a minimization factor. 
The allocation ratio will be 1:1:1 : 1:1:1 : 1:1:1 :3:3. This means 5 treatment groups of 
which the 3 RTS,S/AS01E groups will be randomized to receive 3 different lots.
5.2.1.
Subject identification
Subject numbers will be assigned sequentially to subjects consenting to participate in the 
study, according to the range of subject numbers allocated to each study center.
 
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5.2.2.
Randomisation of treatment
5.2.2.1.
Randomisation of supplies
The randomization will be performed at GSK Biologicals, Rixensart, using MATEX, a 
program developed for use in SAS® (Cary, NC, USA) by GSK Biologicals.
5.2.2.2.
Treatment allocation to the subject
The treatment allocation at the investigator site will be performed using a central 
randomisation system on internet (SBIR). The vaccine numbers will be allocated by 
component. The randomisation algorithm will use a minimisation procedure accounting 
for centre.
When SBIR is not available, please refer to the SBIR user guide or the SPM for specific 
instructions.
After having checked the eligibility of the subject and obtaining the ICF form, the site 
staff in charge of the vaccination will access SBIR. Upon providing the subject 
identification number, the randomisation system will use the minimisation algorithm to 
determine the treatment group and the vaccine number to be used for the subject. Each 
vaccine number must be recorded in the CRF/eCRF on the Vaccine Administration 
form/screen.
5.3.
Method of blinding
The study is open-label.
5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM provides the 
investigator and the site personnel with administrative and detailed technical information 
that does not impact the safety of the subjects.
5.4.1.
Safety Monitoring Plan
The ethical and safety aspects of the conduct of this trial are overseen by an independent 
data monitoring committee (IDMC) operating under a charter assisted by a local safety 
monitor (LSM).
5.4.1.1.
Independent data monitoring committee (IDMC)
The role of the IDMC includes the review of the implementation and progress of the 
study. It provides initial, regular and closing advice on safety-related issues to GSK 
Biologicals. Its advice is based on the interpretation of study data with reference to the 
study protocol.
 
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The IDMC will review the Protocol, Report and Analysis Plan (RAP). The IDMC will 
review all safety data available for the RTS,S/AS01E pediatric development plan. 
Meetings may be face to face or via teleconference. Meetings must be documented and 
minutes made available to the sponsors. The IDMC may, if deemed necessary, convene a 
meeting with, or request further information from the Principal Investigators, the Medical 
Monitor/LSMs and GSK Biologicals’ or MVI’s designated project representatives at any 
stage of the study.
The IDMC may recommend to the Sponsor to suspend the enrolment to the trial and/or 
vaccination based on their review of safety data arising in this trial or other relevant trials 
of the same product.
5.4.1.2.
Data Reviewed by the IDMC
The IDMC will review the following safety data:

All SAEs.
In addition, The IDMC 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).
5.4.1.3.
Local Safety Monitor (LSM)
The overall role of the LSM (experienced clinicians based in-country) will be to support 
the clinical investigators and to act as a link between the investigators and the IDMC.
The LSM’s role will include:

Acting as the study volunteer’s advocate.

Promptly communicating relevant safety information to the IDMC.

Providing advice to the investigators on whether a set of clinical circumstances in a 
study warrants formal notification to the IDMC.

Liaising closely with the chair of the IDMC throughout the course of the trial.
5.4.1.4.
Data Reviewed by the LSM
The relevant LSM will be informed by the investigator on an ‘as received’ basis of:

All SAEs.

All withdrawals of study subjects by the Principal Investigators (PIs) or the 
parent(s)/LAR(s) of a subject due to AEs within 2 weeks of vaccination.
 
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5.4.1.5.
Process if the trial is suspended
If the Principal Investigator or LSM suspends the trial at their site, they must immediately 
notify the IDMC, and GSK Biologicals (the study sponsor) via the contacts for safety 
reporting (refer to Section 8.3).
If the trial is suspended, the IDMC will review all available information and make a 
recommendation to the study sponsor (GSK Biologicals) whether to restart the trial or to 
stop the trial permanently.
It is the responsibility of the sponsor (GSK Biologicals) to make the decision whether or 
not the trial should be stopped permanently.
5.4.1.6.
Safety Review Team (SRT)
A safety review team (SRT) at GSK Biologicals comprising a clinical safety physician, 
medical monitor and a statistician will review, on an ongoing basis, SAEs occurring 
during the trial. They will review all safety reports.
5.5.
Outline of study procedures
The list of study procedures to be conducted is detailed in Table 5.
 
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Table 5
List of study procedures
Epoch
SCR
Primary vaccination
Sft 
FU
Immunogenicity
FU1
Immunogenicity 
FU2
STUDY MONTH
0
1
2
3
8
14
16
17
26
38
50
51
STUDY WEEK
0
2
4
6
8
10
12
32
STUDY DAY
-14 - 0
0
1-6
14
28
29-34
42
56
57-62
70
Visit
1
2
a-f
3
4
g-l
5
6
m-r
7
8
9
10
11
12
13
14
15
16
Informed consent 
● 
Assign subject number
● 
Demographic data 
●
Medical history 
●
O
Check inclusion/exclusion criteria
●
O
Complete physical examination 
●
O
O
O 
O 
O
O 
O
O
O
O
O
Measure/record length (less than 2 years of age) or 
height (equal or above 2 years of age)
●
● 
● 
Measure/record weight 
O
●
O 
O
O 
●
●
Body temperature 
●
O
● 
● 
O 
● 
● 
O 
● 
O
O
● 
O
O
O
● 
Check contraindications to vaccination 
● 
● 
● 
● 
● 
● 
●
● 
● 
Check warnings and precautions 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Randomisation 
O
Recording of vaccine number
● 
● 
● 
● 
● 
● 
● 
● 
Administer Infanrix/Hib vaccine (all groups)
● 
● 
●
Administer Polio Sabin vaccine (all groups) 
●
● 
● 
Administer RTS,S/AS01E vaccine to groups 
REP[Ro]s, RERo[P]s and RE[RoP]s
● 
● 
● 
Administer Engerix-B vaccine to groups HEP[Ro]s 
and HERo[P]s
● 
● 
● 
Administer Synflorix vaccine to groups REP[Ro]s and 
HEP[Ro]s
● 
● 
● 
Administer Synflorix vaccine to groups RERo[P]s, 
RE[RoP]s and HERo[P]s
● 
● 
● 
Administer Rotarix vaccine to groups RERo[P]s and 
HERo[P]s
● 
● 
Administer Rotarix vaccine to groups REP[Ro]s, 
RE[RoP]s and HEP[Ro]s
● 
● 
Administer measles and yellow fever vaccine (all 
groups) 
● 
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Epoch
SCR
Primary vaccination
Sft 
FU
Immunogenicity
FU1
Immunogenicity 
FU2
STUDY MONTH
0
1
2
3
8
14
16
17
26
38
50
51
STUDY WEEK
0
2
4
6
8
10
12
32
STUDY DAY
-14 - 0
0
1-6
14
28
29-34
42
56
57-62
70
Visit
1
2
a-f
3
4
g-l
5
6
m-r
7
8
9
10
11
12
13
14
15
16
Administer Infanrix/Hib vaccine and Synflorix booster 
(all groups)
●
Administer Engerix-B booster (all groups) 
●
Record any concomitant medication/vaccination 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●
●
● 
● 
● 
Record any intercurrent medical conditions** 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●
●
● 
● 
● 
Recording of solicited symptoms *** 
●a
●a
●a
●a
●a
●a
Recording of unsolicited symptoms
●b
●b
●b   ●b
●b
●b
●b
●b
●b
●b
Reporting of serious adverse events
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Reporting of SAEs related to study participation or 
any fatal SAE and immune mediated disorders 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●
● 
● 
●
●
● 
● 
● 
Blood sampling for hemoglobin, WBC, platelets, ALT 
and Creatinine (all groups)
● 
Blood sampling for HBs antibody determination (all 
groups) 
● 
● 
● 
●
● 
● 
● 
Blood sampling for HBs RF1-like antibody 
determination (all groups) 
● 
● 
Blood sampling for CS antibody determination (all 
groups) 
● 
● 
● 
●
● 
● 
Blood sampling for pneumococcal serotype antibody 
determination (ELISA + OPA + PD) (REP[Ro]s and 
HEP[Ro]s)
● 
● 
Blood sampling for Rotavirus IgA antibody 
determination (RERo[P]s and HERo[P]s) 
● 
Blood sampling for acellular B Pertussis (BPT) 
antibody determination (all groups)
●
● 
PRIMARY ANALYSIS 
● 
SAFETY ANALYSIS 
●
IMMUNOGENICITY ANALYSIS
●
FINAL ANALYSIS 
●
STUDY CONCLUSION
● 
● 
●
●
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● is used to indicate a study procedure that requires documentation in the individual CRF/eCRF; ○ is used to indicate a study procedure that does not require documentation in the 
individual CRF/eCRF
SCR = Screening; Sft FU = Safety Follow-up; FU = follow-up
** Refer to section 6.8.
*** Local symptoms will be recorded separately for each injection site (i.e. for RTS,S/AS01E, Engerix-B, Infanrix/Hib and Synflorix); general symptoms will be recorded for all vaccines
a  Study personnel will visit the infants on days 1, 2, 3, 4, 5 and day 6 after each vaccination of RTS,S/AS01E or Engerix-B.
b  Unsolicited symptoms will be recorded for 30 days (day of vaccination and 29 subsequent days) after the first, second and third doses of RTS,S/AS01E or Engerix-B.
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It is the investigator’s responsibility to ensure that the intervals between visits/contacts 
are strictly followed. These intervals determine each subject’s evaluability in the 
according to protocol analyses. The intervals are tabulated in Table 6.
Table 6
Intervals between study visits
Interval
Optimal length of interval1
Minimum - maximum interval 
allowed2
Clinic Visit 1 (Screening)Clinic Visit 2
-
-140 days
Clinic Visit 2Clinic Visit 3
14 days
721 days
Clinic Visit 2Clinic Visit 4
28 days
2842 days
Clinic Visit 4Clinic Visit 5
14 days
721 days
Clinic Visit 4Clinic Visit 6
28 days
2842 days
Clinic Visit 6Clinic Visit 7
14 days
721 days
Clinic Visit 6Clinic Visit 8
28 days
2842 days
Clinic Visit 2Clinic Visit 9
8 months
79 months
Clinic Visit 2Clinic Visit 10
14 months
1315 months
Clinic Visit 2Clinic Visit 11
16 months
1517 months
Clinic Visit 2Clinic Visit 12
17 months
1618 months
Clinic Visit 2 Clinic Visit 13
26 months
2627 months
Clinic Visit 2Clinic Visit 14
38 months
3839 months
Clinic Visit 2Clinic Visit 15
50 months
5051 months
Clinic Visit 15Clinic Visit 16
28 days
2142 days
1 Whenever possible the investigator should arrange study visits within this interval
2 Subjects will not be eligible for inclusion in the ATP-cohort for analysis if they make the study visit outside this interval
5.6.
Detailed description of study procedures
5.6.1.
Procedures prior to study participation
5.6.1.1.
Informed consent of pregnant women
Pregnant women will be identified at antenatal clinics or in the community and will be 
informed about the study. If interested in participating they will be asked to sign a 
consent form for screening for hepatitis B or HIV infection.
Mothers who were screened negative for HBsAg and HIV and who agree to let their child 
participate in the study will be invited for the screening visit (Visit 1).
5.6.1.2.
Informed consent of infants
Before performing any other study procedure, the signed/thumb-printed informed consent 
of the subject’s parent(s)/LAR(s) needs to be obtained. When the parent(s)/LAR(s) of the 
child are illiterate, the ICF will also be signed and dated by a literate impartial witness. 
Refer to Section 5.1 for the requirements on how to obtain informed consent, as 
appropriate.
 
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The parent(s)/LAR(s) of children who have been consented for the study and found to be 
ineligible will receive a full explanation by a study clinician at a private meeting. Any 
clinically relevant finding will be treated appropriately by a physician.
5.6.2.
Procedures prior to the first vaccination
5.6.2.1.
Assign subject number
Subject number to be assigned at the screening visit.
5.6.2.2.
Collect demographic data
Record demographic data such as age and gender in the subject’s CRF/eCRF.
5.6.2.3.
Medical history
Perform a history-directed medical examination and record any pre-existing conditions or 
signs and/or symptoms present in the subject prior to the start of the study in the 
CRF/eCRF. Treatment of any abnormality observed during this examination has to be 
performed according to local medical practice outside this study or by referral to an 
appropriate health care provider.
5.6.2.4.
Check inclusion and exclusion criteria
Check all applicable inclusion and exclusion criteria as described in Sections 4.3 and 
4.4 before enrolment.
5.6.2.5.
Physical examination
Discuss with the parent(s)/LAR(s) about the current health of their child and then perform 
a physical examination of the child. Collected information needs to be recorded in the 
CRF/eCRF.
5.6.2.6.
Blood sampling for safety or immune response assessments
As specified in the List of Study Procedures in Section 5.5 (Table 5), blood samples are 
to be taken at specific study visits. After centrifugation, serum samples must be kept at –
20°C until shipment. Volumes of blood to be taken are given in Table 7.
Refer to the Module on Biospecimen Management in the SPM for general handling of 
blood samples.
5.6.3.
Procedures during the primary vaccination epoch
Note that some of the procedures to be performed during the primary epoch are also 
performed at screening/prior to the first vaccination and are described in Section 5.6.2.
 
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5.6.3.1.
Check and record concomitant medication/vaccination and intercurrent 
medical conditions
Concomitant medication/vaccination must be recorded in the CRF/eCRF as described in 
Section 6.7. Refer also to Section 6.7 for details on the medication/vaccination forbidden 
and/or allowed during the study.
At each study visit subsequent to the first vaccination visit, it must be verified if the 
subject has experienced or is experiencing any intercurrent medical condition listed 
in Section 6.8. If it is the case, the condition(s) must be recorded in the CRF/eCRF.
5.6.3.2.
Check contraindications, warnings and precautions to vaccination
Contraindications, warnings and precautions to vaccination are to be checked at the 
beginning of each vaccination visit. Refer to Section 6.5 and 6.6.
5.6.3.3.
Assess pre-vaccination body temperature
The body temperature of all subjects needs to be measured prior to any study vaccine 
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 on axillary 
setting, or 38.0°C on rectal setting] on the day of vaccination, the vaccination visit will 
be rescheduled within the interval for this visit (see Table 6).
5.6.3.4.
Randomization
At the first vaccination visit, randomization will occur as explained in Section 5.2.
5.6.3.5.
Vaccine number assignment
At each vaccination visit, the subject will be assigned a vaccine number defining the 
treatment he/she will be receiving. The vaccine number must be recorded in the
CRF/eCRF at each vaccination visit.
5.6.3.6.
Vaccination
After completing the prerequisite procedures prior to vaccination, study vaccines will be 
administered (refer to Section 6.3 for detailed description of the vaccine administration 
procedure). If the investigator or delegate determines that the subject’s health on the day 
of vaccination temporarily precludes vaccination, the visit will be rescheduled within the 
interval for this visit.
The vaccinees will be observed closely for at least 60 minutes, with appropriate medical 
treatment readily available in case of anaphylaxis following the administration of 
vaccines.
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.
 
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5.6.3.7.
Recording of non-serious AEs and SAEs
Refer to Section 8.2 for procedures for the Investigator to record AEs and SAEs that are 
related to study participation or GSK concomitant medication/vaccination and to Section 
8.3 for guidelines on how to report these AEs/SAEs 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.
SAEs will be detected through the in-patient and out-patient services in the study area 
through close cooperation between study personnels performing the home visits and the 
medical staff at government facilities.
Solicited AEs will be collected for 7 days (day 0 to 6) following the administration of 
each dose of RTS,S/AS01E or Engerix-B co-administered with EPI vaccines. Study 
personnels will visit each child after primary vaccination with RTS,S/AS01E or Engerix-
B and record any local and general solicited AEs and unsolicited AEs.
Unsolicited AEs will be collected for 30 days (day 0 to 29) following the administration 
of each dose of RTS,S/AS01E or Engerix-B co-administered with EPI vaccines.
SAEs will be collected until 8 months after Dose 1 of RTS,S/AS01E or Engerix-B. The 
capture of SAEs will be facilitated by means of clinic visits. During the planned visits, 
the subject’s parent(s)/LAR(s) will be asked retrospectively if any medical event that 
might be an SAE occurred since the last visit and this information will be recorded. 
Unreported SAEs detected in this way will be investigated and reported by the PI or 
delegate on the corresponding SAE screen/SAE form. In the case of a death which has 
occurred at home, supplementary information will be obtained using the verbal autopsy 
technique. The verbal autopsy will be conducted according to previously published 
methods and detailed in the SOPs on file with the investigators [Smith, 1991].
If any child is reported to be unwell at the time of a home visit, the study personnel will 
advise the parent(s)/LAR(s) to seek care at the vaccination center. In the event that a 
child is seriously ill, the study personnel will inform the PI or designate, and transport 
will be arranged, as applicable, to the referral hospital, if judged appropriate by the 
responsible clinician.
5.6.3.8.
Conclusion of the primary epoch
A primary analysis will be performed on safety and immunogenicity data collected up to 
one month following the administration of the third dose of study vaccine (Clinic Visit 8). 
At the end of the primary vaccination epoch, the investigator is to fill in the study 
conclusion page of the CRF/eCRF.
 
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5.6.4.
Procedures during follow-up epochs
Note that some of the procedures to be performed during the follow-up epochs are also 
performed during the screening epoch and during the primary vaccination epoch and are 
described in Sections 5.6.2 and 5.6.3.
5.6.4.1.
Study conclusions
A safety analysis will be performed on data (SAEs) collected up to 8 months post Dose 1
of RTS,S/AS01E or Engerix-B (Visit 9). At the end of the Safety follow-up epoch, the 
investigator is to fill in the study conclusion page of the CRF/eCRF.
An immunogenicity analysis based on data collected until Visit 13 (Month 26) will 
include anti-CS and anti-HBs antibody responses. At the end of the Immunogenicity 
follow-up 1 epoch, the investigator is to fill in the study conclusion page of the 
CRF/eCRF.
A final analysis will be performed on further safety and immunogenicity data collected 
up to the last study visit (Visit 16), 51 months following the administration of the first 
dose of study vaccine. At the end of the immunology follow-up 2 epoch, the investigator 
is to fill in the study conclusion page of the CRF/eCRF.
5.7.
Biological sample handling and analysis
Please refer to the SPM for details of biospecimen management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subjects but will 
be coded with the identification number for the subject (subject number).
Collected samples may be used in other assays, for test improvement or test development 
of analytical methods related to the study vaccines and its constituents or the disease 
under study for a more reliable measurement of the vaccine response. Under these 
circumstances, additional testing on the samples may be performed by GSK Biologicals 
outside the scope of this protocol.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s).
Any human pharmacogenetic testing will require specific consent from the individual 
subject’s parent(s)/LAR(s) and the ethics committee approval.
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).
 
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If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed.
Collected samples will be stored for up to 15 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 MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 10.4 for the definition of 
study cohorts to be evaluated). The investigator must ensure that his/her personnel and 
the laboratory(ies) under his/her supervision comply with this requirement. However, 
when GSK Biologicals does not provide material for collecting and storing clinical 
samples, appropriate materials from the investigator’s site are to be used. Refer to the 
Module on Clinical Trial Supplies in the SPM.
5.7.2.
Biological samples
Details of the quantity of blood to be taken at each timepoint during the study are 
provided in Table 7.
Table 7
Biological samples
Time point
Subjects
Sample type
Quantity
Unit
Screening Clinic Visit 1
(Day -14 to 0)
All
Blood  
3.0
ml
Clinic Visit 8 (Month 3)
REP[Ro]s
Blood  
4.8
ml
RERo[P]s
Blood  
2.1
ml
RE[RoP]s
Blood  
1.6
ml
HEP[Ro]s
Blood  
4.8
ml
HERo[P]s
Blood  
2.1
ml
Clinic Visit 10 (Month 14)
All
Blood  
0.6
ml
Clinic Visit 12 (Month 17)
REP[Ro]s
Blood  
3.2
ml
HEP[Ro]s
Blood  
3.2
ml
Clinic Visit 13 (Month 26)
All
Blood  
0.6
ml
Clinic Visit 14 (Month 38)
All
Blood  
0.6
ml
Clinic Visit 15 (Month 50)
All
Blood  
0.6
ml
Clinic Visit 16 (Month 51)
All
Blood  
1.0
ml
 
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5.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study.
Serological assays for the determination of antibodies against CS, HBs, HBs RF1, 10 
pneumococcal vaccine serotypes, protein D, 3 pertussis antigens and rotavirus will be 
performed by ELISA at a GSK Biologicals’ laboratory or in a validated laboratory 
designated by GSK Biologicals using standardised and validated procedures (refer to 
Table 8).
Determination of opsonophagocytic activity against the 10 pneumococcal vaccine 
serotypes will be conducted at GSK Biologicals’ laboratory according to standard 
methodologies as detailed in the laboratory SOP’s (see APPENDIX A).
Table 8
Humoral immunity (antibody determination)
System
Component
Method
Unit
Cut-
off
Laboratory
0492.001  Plasmodium 
falciparum.Circumsporozoite 
Protein.R32LR Ab.IgG  
Enzyme Linked Immuno 
Sorbent Assay
enzyme linked 
immunosorbent assay 
unit per milliliter 
0.5
Leroux-Roels 
Laboratory, 
CEVAC, Ghent, 
Belgium
0177.004  Hepatitis B Virus.Surface Ab
Enzyme Linked Immuno 
Sorbent Assay
milli-international unit 
per milliliter 
10  GSK Bio*, 
Rixensart
0494.001 Hepatitis B Virus.RF1 Ab
Enzyme Linked Immuno 
Sorbent Assay
enzyme linked 
immunosorbent assay 
unit per milliliter
33
Leroux-Roels
Laboratory, 
CEVAC, Ghent, 
Belgium
0497.001 Rotavirus Ab.IgA
Enzyme Linked Immuno 
Sorbent Assay
unit per milliliter
20
GSK Bio*, 
Rixensart
0486.001  Bordetella pertussis.Pertussis 
Toxin Ab.IgG  
Enzyme Linked Immuno 
Sorbent Assay  †
renzyme linked 
immunosorbent assay 
unit per milliliter
5  
GSK Bio*, 
Rixensart
0137.001  Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG  
Enzyme Linked Immuno 
Sorbent Assay  †
enzyme linked 
immunosorbent assay 
unit per milliliter
5  
GSK Bio*, 
Rixensart
0470.001  Bordetella pertussis.Pertactin 
Ab.IgG  
Enzyme Linked Immuno 
Sorbent Assay  †
enzyme linked 
immunosorbent assay 
unit per milliliter
5  
GSK Bio*, 
Rixensart
0393.001 (Non Typeable) Haemophilus 
influenzae. Protein D Ab. IgG
Enzyme Linked Immuno 
Sorbent Assay
enzyme linked 
immunosorbent assay 
unit per milliliter
100 GSK Bio*, 
Rixensart
0405.002  Streptococcus 
pneumoniae.Polysaccharide 
01 Ab.IgG  
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
0427.002 Streptococcus 
pneumoniae.Polysaccharide 
04 Ab.IgG
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
0430.002 Streptococcus 
pneumoniae.Polysaccharide 
05 Ab.IgG
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
0434.002 Streptococcus 
pneumoniae.Polysaccharide 
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
 
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System
Component
Method
Unit
Cut-
off
Laboratory
06B Ab.IgG
0437.002 Streptococcus 
pneumoniae.Polysaccharide 
07F Ab.IgG
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
0442.002 Streptococcus 
pneumoniae.Polysaccharide 
09V Ab.IgG
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
0411.002 Streptococcus 
pneumoniae.Polysaccharide 
14 Ab.IgG
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
0414.002 Streptococcus 
pneumoniae.Polysaccharide 
18C Ab.IgG
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
0418.002 Streptococcus 
pneumoniae.Polysaccharide 
19F Ab.IgG
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
0421.002 Streptococcus 
pneumoniae.Polysaccharide 
23F Ab.IgG
Enzyme Linked Immuno 
Sorbent Assay
µg/ml
0.05 GSK Bio*, 
Rixensart
0449.001 Streptococcus pneumoniae 
Serotype 01/37 Brugmann 
Hospital Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
0457.001 Streptococcus pneumoniae 
Serotype 04/2656 Brugmann 
Hospital Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
0458.001 Streptococcus pneumoniae 
Serotype 05 Ambrose- Statens 
Serum Institut Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
0460.001 Streptococcus pneumoniae 
Serotype 06B/DS2212/94 
Centers for Disease Control 
Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
0461.001 Streptococcus pneumoniae 
Serotype 07F/46 Brugmann 
Hospital Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
0463.001 Streptococcus pneumoniae 
Serotype 09V/112 161/95 
Statens Serum Institut Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
0450.001 Streptococcus pneumoniae 
Serotype 14/58 Brugmann 
Hospital Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
0451.001 Streptococcus pneumoniae 
Serotype 18C/4593/40 Statens 
Serum Institut Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
0453.001 Streptococcus pneumoniae 
Serotype 19F/2737 Brugmann 
Hospital Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
0454.001 Streptococcus pneumoniae 
Serotype 23F Mac-Statens 
Serum Institut Ab
Opsonophagocytose
1/dilution
8
GSK Bio*, 
Rixensart
*GSK Biologicals’ (Rixensart, Belgium) central laboratory, or in a validated laboratory designated by GSK Biologicals
† or a multiplex assay
 
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Table 9
Hematology, Serum Chemistry
System
Component
Scale
0692.001
Hemoglobin
Quantitative
0747.001
Leukocytes (White Blood Cells)
Quantitative
0713.001
Platelets
Quantitative
0628.001
Alanine Aminotransferase
Quantitative
0658.001
Creatinine
Quantitative
Collected samples will be used for purposes related to the quality assurance of data 
generated within the scope of this protocol, such as for maintenance of assays described 
in this protocol and comparison between analytical methods and/or laboratories.
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
Summary of blood sampling time points, immunological read-outs 
and volumes to be collected for infants in treatment group REP[Ro]s
Blood sampling time point
Component
No. 
subjects
Laboratory
Priority 
Rank
Volume 
of whole 
blood 
required
Timing
Time point
Visit 
No.
Pre Dose 1
screening 
visit
1
Safety analysis
Hemoglobin and total WBC
141
on-site
1
2 ml
Platelets
141
on-site
ALT and Creatinine
141
on-site
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
2
0.4 ml
Anti-CS antibodies
141
GSK Bio*
3
0.2 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
4
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
Month 3
8
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
4
0.2 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
Pneumococcal vaccine 
serotypes 1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F, 23F (ELISA)
141
GSK Bio*
3
1.5 ml
Pneumococcal vaccine 
serotypes 1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F and 23F (OPA)
141
GSK Bio*
7
1.5 ml
Protein D antibodies
141
GSK Bio*
5
0.2 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
6
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(1 year)
Month 14
10
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
1 month post 
Booster 1
Month 17
12 
Investigational analysis
Pneumococcal vaccine 
serotypes 1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F, 23F (ELISA)
141
GSK Bio*
1
1.5 ml
Pneumococcal vaccine 
serotypes 1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F and 23F (OPA)
141
GSK Bio*
2
1.5 ml
Protein D antibodies
141
GSK Bio*
3
0.2 ml
Eight months post 
Booster 1
Month 26
13
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(3 years)
Month 38
14
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(4 years)
Month 50
15
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
One month post 
Booster 2
Month 51
16
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
* or validated laboratory designated by GSK Biologicals
 
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Table 11
Summary of blood sampling time points, immunological read-outs 
and volumes to be collected for infants in treatment group RERo[P]s
Blood sampling time point
Component
No. 
subjects
Laboratory
Priority 
Rank
Volume 
of whole 
blood 
required
Timing
Time point
Visit 
No.
Pre Dose 1
Screening
1
Safety analysis
Hemoglobin and total WBC
141
on-site
1
2 ml
Platelets
141
on-site
ALT and Creatinine
141
on-site
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
2
0.4 ml
Anti-CS antibodies
141
GSK Bio*
3
0.2 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
4
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
Month 3
8
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
4
0.2 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
Rotavirus IgA
141
GSK Bio*
3
0.5 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
5
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(1 year)
Month 14
10
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Eight months post 
Booster 1
Month 26
13
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(3 years)
Month 38
14
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(4 years)
Month 50
15
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
One month post 
Booster 2
Month 51
16
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
* or validated laboratory designated by GSK Biologicals
 
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Table 12
Summary of blood sampling time points, immunological read-outs 
and volumes to be collected for infants in treatment group RE[RoP]s
Blood sampling time point
Component
No. 
subjects
Laboratory
Priority 
Rank
Volume 
of whole 
blood 
required
Timing
Time point
Visit 
No.
Pre Dose 1
Screening
1
Safety analysis
Hemoglobin and total WBC
141
on-site
1
2 ml
Platelets
141
on-site
ALT and Creatinine
141
on-site
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
2
0.4 ml
Anti-CS antibodies
141
GSK Bio*
3
0.2 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
4
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
Month 3
8
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
3
0.2 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
4
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(1 year)
Month 14
10
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Eight months post 
Booster 1
Month 26
13
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(3 years)
Month 38
14
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(4 years)
Month 50
15
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
One month post 
Booster 2
Month 51
16
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
* or validated laboratory designated by GSK Biologicals
 
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Table 13
Summary of blood sampling time points, immunological read-outs 
and volumes to be collected for infants in treatment group HEP[Ro]s
Blood sampling time point
Component
No. 
subjects
Laboratory
Priority 
Rank
Volume 
of whole 
blood 
required
Timing
Time point
Visit 
No.
Pre Dose 1
Screening
1
Safety analysis
Hemoglobin and total WBC
141
on-site
1
2 ml
Platelets
141
on-site
ALT and Creatinine
141
on-site
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
2
0.4 ml
Anti-CS antibodies
141
GSK Bio*
3
0.2 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
4
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
Month 3
8
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
4
0.2 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
Pneumococcal vaccine 
serotypes 1, 4, 5, 6B, 7F, 9V,
14, 18C, 19F, 23F (ELISA)
141
GSK Bio*
3
1.5 ml
Pneumococcal vaccine 
serotypes 1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F, 23F (OPA)
141
GSK Bio*
7
1.5 ml
Protein D antibodies
141
GSK Bio*
5
0.2 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
6
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(1 year)
Month 14
10
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
1 month post 
Booster 1
Month 17
12  
Investigational analysis
Pneumococcal vaccine 
serotypes 1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F, 23F (ELISA)
141
GSK Bio*
1
1.5 ml
Pneumococcal vaccine 
serotypes 1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F and 23F (OPA)
141
GSK Bio*
2
1.5 ml
Protein D antibodies
141
GSK Bio*
3
0.2 ml
Eight months post 
Booster 1
Month 26
13
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(3 years)
Month 38
14
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(4 years)
Month 50
15
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
One month post 
Booster 2
Month 51
16
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
* or validated laboratory designated by GSK Biologicals
 
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Table 14
Summary of blood sampling time points, immunological read-outs 
and volumes to be collected for infants in treatment group HERo[P]s
Blood sampling time point
Component
No. 
subjects
Laboratory
Priority 
Rank
Volume 
of whole 
blood 
required
Timing
Time point
Visit 
No.
Pre Dose 1
Screening
1
Safety analysis
Hemoglobin and total WBC
141
on-site
1
2 ml
Platelets
141
on-site
ALT and Creatinine
141
on-site
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
2
0.4 ml
Anti-CS antibodies
141
GSK Bio*
3
0.2 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
4
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
Month 3
8
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
4
0.2 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
Rotavirus IgA
141
GSK Bio*
3
0.5 ml
anti-acellular B-pertussis 
antibodies (Anti-PT, anti-FHA 
and anti-PRN)
141
GSK Bio*
5
0.4 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(1 year)
Month 14
10
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Eight months post 
Booster 1
Month 26
13
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(3 years)
Month 38
14
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
Post Dose 3 of 
RTS,S/AS01E or 
Engerix-B
(4 years)
Month 50
15
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-CS antibodies
141
GSK Bio*
2
0.2 ml
One month post 
Booster 2
Month 51
16
Investigational analysis
Anti-HBs antibodies
141
GSK Bio*
1
0.4 ml
Anti-HBs RF1 like antibodies
141
GSK Bio*
2
0.6 ml
* or validated laboratory designated by GSK Biologicals
Additional testing on the immune response to the vaccine antigens may be done if 
specific validated assays become available in the GSK Biological laboratory or in a 
validated laboratory designated by GSK Biological’s, or if they are deemed necessary 
based on the results of this study, other studies or medical advancements or for 
development of new assays regarding the diseases or vaccines under evaluation.
5.7.5.
Immunological correlates of protection
No correlate of protection has been demonstrated so far for the CS antigen or for the 
rotavirus IgA.
 
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For the HBsAg, the conventional correlate of protection is anti-HBs antibody titers above 
10 mIU/ml [European Consensus Group on Hepatitis B Immunity, 2000].
At the time this protocol was prepared, a pneumococcal correlate of protection had not 
been clearly established.
For pertussis antigens, clinical protection has recently been shown to be correlated with 
the presence of antibodies against pertactin, pertussis toxin and fimbrial agglutinogens 2 
and 3. However, no definite serological correlates, i.e., threshold antibody concentrations, 
of protection have been established to date. Subjects presenting with the following 
antibody responses after vaccination will be offered an additional dose of an approved 
vaccine:

anti-PT antibody concentration < 5 El.U/ml,

anti-FHA antibody concentration < 5 El.U/ml,

anti-PRN antibody concentration < 5 El.U/ml.
6.
STUDY VACCINES AND ADMINISTRATION
6.1.
Description of study vaccines
The Quality Control Standards and Requirements for each candidate vaccine are 
described in separate Quality Assurance documents (e.g. release protocols, certificate of 
analysis) and the required approvals have been obtained.
The vaccines are labelled and packed according to applicable regulatory requirements.
Commercial vaccines are assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics.
 
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Table 15
Study vaccines
Vaccine
Formulation
Presentation
Volume
Number of 
doses
RTS,S/AS01E
RTS,S antigen: 31.25 g of RTS,S with 15.75 mg of sucrose as 
cryoprotectant per 3 ml monodose vial.
AS01E adjuvant: 25 g of MPL and 25 g QS21 (a triterpene glycoside 
purified from the bark of Quillaja saponaria) with liposomes.
RTS,S antigen: Lyophilized pellet in a glass vial. The pellet is 
reconstituted with adjuvant in liquid form and 0.5 ml of 
reconstituted vaccine contains 25µg RTS,S.
AS01E adjuvant: liquid solution in a monodose glass vial.
The reconstituted RTS,S/AS01E vaccine is an opalescent liquid.
0.5 ml
3
Engerix-B
The pediatric dosage vial contains 10 g of purified major hepatitis B 
surface antigen adsorbed onto 0.25 mg of Al+++ as aluminium hydroxide.
The content, upon storage, may present a fine white deposit with 
a clear colourless supernatant. Once shaken, the vaccine is 
slightly opaque.
0.5 ml
3 + 1 booster
Infanrix/Hib
After reconstitution, 1 dose (0.5 ml) contains: diphtheria toxoid, tetanus 
toxoid, pertussis antigens (pertussis toxoid, Filamentous Haemagglutinin, 
Pertactin), Haemophilus influenzae type b polysaccharide and conjugated 
to tetanus toxoid. The diphtheria toxoid, tetanus toxoid and acellular 
pertussis vaccine components are adsorbed on aluminium salts. The final 
vaccine is formulated in saline.
The excipients of Infanrix/Hib comprise lactose, aluminium hydroxide, 
sodium chloride and water for injections.
The liquid DTPa component is presented as a turbid white 
suspension in a pre-filled syringe.
The Hib component is supplied as a white freeze-dried pellet in 
monodose vials to be reconstituted before use with the liquid 
DTPa component supplied in the pre-filled syringe.
0.5 ml
3 + 1 booster
Polio Sabin 
Polio Sabin (OPV MRC5) is a stabilized suspension of types 1, 2 and 3 live 
attenuated polioviruses (Sabin strains): Type 1 (strain LSc, 2ab), Type 2 
(strain P 712 ch, 2ab), Type 3 (strain Leon 12a, 1b). The viruses are 
propagated in human diploid cells.
The excipients of Polio Sabin (oral) comprise magnesium chloride, L-
arginine, polysorbate 80, neomycin sulphate (residual), polymyxin B 
sulphate (residual) and purified water.
Polio Sabin is a stabilized suspension in a glass vial. For the 
multidose container (WHO formulation), one immunizing dose of 
0.1 ml is contained in 2 drops.
0.1 ml 
(2 drops)
3
Synflorix
Synflorix is a liquid 10-valent conjugate vaccine with protein D and 
diphtheria and tetanus toxoids as protein carriers.
The excipients of Synflorix comprise sodium chloride and water.
It is presented as a turbid white suspension in a pre-filled syringe. 0.5 ml
3 + 1 booster
Rotarix
Rotarix contains not less than 106.0 CCID50 (Cell Culture Infectious Dose 
50%) of live attenuated human rotavirus RIX4414 strain. 
The excipients of Rotarix (oral) comprise sucrose, dextran, sorbitol, amino 
acids, Dulbecco’s Modified Eagle Medium (DMEM), calcium carbonate, 
xanthan and sterile water.
It is presented as powder in a glass container and an oral 
applicator containing the diluent.
1.5 1.0 ml 2
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6.1.1.
Vaccines given according to local policy
6.1.1.1.
Measles
A measles vaccine, either licensed by the FDA or by the EMA and/or prequalified by 
WHO, will be used to vaccinate the infants. The vaccine that will be used will be sourced
locally.
6.1.1.2.
Yellow fever
Yellow fever vaccine will be given according to local treatment regulations. The vaccine 
that will be used will be sourced locally.
6.2.
Storage and handling of study vaccines
The study vaccines to be administered to the subjects must be stored in a safe and locked 
place with no access by unauthorised personnel.
The study vaccines must be stored at the defined temperature range (i.e. +2 to +8°C). 
Please refer to the Module on Clinical Trial Supplies in the SPM for more details on 
storage of the study vaccines. The storage temperature of the vaccines will be monitored 
daily with temperature monitoring device(s) (at the minimum calibrated) and will be 
recorded as specified in the SPM.
The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact.
Any temperature deviation outside the range 0 to +8C must be reported to the sponsor as 
soon as detected. Following an exposure to a temperature deviation, vaccines will not be 
used until approval has been given by the Sponsor.
In case of temperature deviation between 0 and +2C, the impacted study vaccines can 
still be administered, but the site must take adequate actions to go back to the defined 
range +2 to +8°C and avoid re-occurrence of such a temperature deviation.
Please refer to the Module on Clinical Trial Supplies in the SPM for details and 
instructions on the Temperature deviation process, packaging and accountability of the 
study vaccines.
 
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6.3.
Dosage and administration of study vaccines
Table 16
Dosage and administration
Type of contact and 
timepoint
Vaccine
Treatment Groups
Route 1
Site 2
Side 3
visit 2 (Day 0)
RTS,S/AS01E  
REP[Ro]s, RERo[P]s, RE[RoP]s
IM  
Ant T  
L  
Engerix-B
HEP[Ro]s, HERo[P]s
IM
Ant T
L
Infanrix/Hib
all groups
IM
D
R
Polio Sabin
all groups
O  
-
-
Synflorix  
REP[Ro]s, HEP[Ro]s
IM
Ant T
R
visit 3 (Day 14)
Synflorix  
RERo[P]s, RE[RoP]s, HERo[P]s
IM
Ant T
R
visit 4 (Day 28)
RTS,S/AS01E  
REP[Ro]s, RERo[P]s, RE[RoP]s
IM  
Ant T  
L  
Engerix-B
HEP[Ro]s, HERo[P]s
IM
Ant T
L
Infanrix/Hib
all groups
IM
D
R
Polio Sabin
all groups
O  
-
-
Synflorix  
REP[Ro]s, HEP[Ro]s
IM
Ant T
R
Rotarix
RERo[P]s, HERo[P]s
O
-
-
visit 5 (Day 42)
Synflorix  
RERo[P]s, RE[RoP]s, HERo[P]s
IM
Ant T
R
Rotarix
REP[Ro]s, RE[RoP]s, HEP[Ro]s
O
-
-
visit 6 (Day 56)
RTS,S/AS01E
REP[Ro]s, RERo[P]s, RE[RoP]s
IM  
Ant T  
L  
Engerix-B
HEP[Ro]s, HERo[P]s
IM
Ant T
L
Infanrix/Hib
all groups
IM
D
R
Polio Sabin
all groups
O  
-
-
Synflorix  
REP[Ro]s, HEP[Ro]s
IM
Ant T
R
Rotarix
RERo[P]s, HERo[P]s
O
-
-
visit 7 (Day 70)
Synflorix  
RERo[P]s, RE[RoP]s, HERo[P]s
IM
Ant T
R
Rotarix
REP[Ro]s, RE[RoP]s, HEP[Ro]s
O
-
-
visit 9  (Month 8)
Measles
all groups
IM
D
-
Yellow fever
all groups
IM
D
-
visit 11 (Month16)
Infanrix/Hib
all groups
IM
D
R
Synflorix  
all groups
IM
Ant T
R
visit 15  (Month 50)
Engerix-B
all groups
IM
Ant T
L
1Oral (O)/ Intramuscular (IM) 
2Deltoid (D); Ant T = Anterolateral thigh
3Left (L)/ Right (R)
The vaccinees will be observed closely for at least 60 minutes following the 
administration of all vaccines used in the study, with appropriate medical treatment 
readily available in case of an anaphylactic reaction.
6.3.1.
RTS,S/AS01E (0.5 ml dose)
RTS,S/AS01E will be supplied such that the reconstituted vaccine volume will provide a 
0.5 ml pediatric dose. One 0.5 ml dose will be withdrawn from each vial and used.
 
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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 1 
minute to ensure complete dissolution of vial contents before withdrawing the content of 
the vial (0.5 ml). The reconstituted vaccine should be administered by slow IM injection, 
using a fresh 25G needle with length of 1 inch (25 mm): for children 8 to 12 weeks of age 
at enrolment inject into the left antero lateral thigh for primary course. Vaccine should be 
injected within 4 hours of reconstitution (storage at +2°C to +8°C).
6.3.2.
Engerix-B (0.5 ml dose)
Disinfect the top of the vaccine vial with alcohol swabs and shake gently while letting the 
alcohol dry. Then withdraw the contents of the vial into a syringe for injection using a 
fresh syringe and needle. Remove and discard the needle using appropriate safety 
precautions. Use a fresh needle for injection. The vaccine should be administered soon 
afterwards intramuscularly in the left antero-lateral thigh, using a 25G needle with length 
of 1 inch (25 mm) (storage at 2°C to 8°C). Children of both groups should be injected in 
the left antero-lateral thigh with Engerix-B as booster.
6.3.3.
Polio Sabin
The OPV vaccine will be administered orally. For the multidose container (WHO 
formulation), one immunizing dose of 0.1 ml is contained in 2 drops.
After opening, multidose containers should be kept in a refrigerator and used within eight 
hours.
6.3.4.
Infanrix/Hib (0.5 ml dose)
One dose of the GSK Biologicals’ Infanrix™ vaccine will be used to reconstitute one 
dose of the Hib vaccine as follows: The Hib vial should be taken out of the refrigerator 5 
minutes before reconstitution. The liquid Infanrix vaccine should always be shaken 
before use. Cleanse the rubber stopper of the Hib conjugate vaccine with a suitable 
germicide and inject the entire volume of the Infanrix pre-filled syringe into the vial of 
lyophilized Hib. The vial must be shaken well until the lyophilized Hib vaccine pellet has 
completely dissolved. After reconstitution, withdraw the reconstituted vaccine (0.5 ml). 
Remove and discard the needle used for reconstitution and replace it with a new needle to 
administer the vaccine. The vaccine must be used immediately after reconstitution. When 
reconstituted with Hib, the liquid Infanrix may appear as a slightly more cloudy 
suspension than the liquid components alone. In the event of other variations being 
observed, the vaccine should be discarded.
In order to ensure proper intramuscular injection of the study vaccines, a needle of at 
least 1 inch (2.54 cm) length, 25 gauge will be used. The vaccine will be administered as 
an intramuscular injection into the left right deltoid.
 
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6.3.5.
Rotarix (1.5 1.0 ml dose)
To prepare the vaccine for administration, the entire content of one pre-filled oral 
applicator containing the liquid for reconstitution should be transferred into the vial of the 
lyophilized product (vaccine) by using the transfer adaptor. The vial should be shaken 
well to resuspend the vaccine. The entire volume of the resuspended product should be 
withdrawn into the same oral applicator, the transfer adaptor should be discarded and the 
resuspended product should then be administered smoothly as a single oral dose.
6.3.6.
Synflorix (0.5 ml dose)
The syringe containing the liquid pneumococcal vaccine (10Pn-PD-DiT conjugate 
vaccine or Synflorix) must be shaken before use to obtain a homogeneous whitish 
suspension. One dose of 0.5 ml of the vaccine will be injected intramuscularly into the 
right anterolateral thigh. The vaccine should be administered by slow IM injection.
6.3.7.
Measles
The measles vaccine will be used according to manufacturer instructions and the 
Summary of Product Characteristics. The vaccine will be administered as an 
intramuscular injection into the deltoid.
6.3.8.
Yellow fever
The yellow fever vaccine will be used according to manufacturer instructions and the 
Summary of Product Characteristics. The vaccine will be administered as an 
intramuscular injection into the deltoid.
6.4.
Replacement of unusable vaccine doses
Additional vaccine doses will be provided to replace those that are unusable (see the 
Module on Clinical Trial Supplies in the SPM for details).
In addition to the vaccine doses provided for the planned number of subjects, at least 5%
additional doses will be supplied to replace those that are unusable. 
6.5.
Contraindications to subsequent vaccination
6.5.1.
Absolute contraindications to further 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 vaccine but may continue other study procedures at the discretion of 
the investigator (see Section 8.3.4).

Acute allergic reaction, significant IgE-mediated event or anaphylactic shock
following the administration vaccines.
 
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
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including human immunodeficiency virus (HIV) infection.

Failure to thrive.

Any other findings that the investigator feels would increase the risk of having an 
adverse outcome from participation in the trial.
6.5.2.
Indications for deferral of vaccination
The following events constitute contraindications to administration of study vaccines at 
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 
protocol (see Section 5.5), or withdrawn at the discretion of the investigator (see Section 
8.3.4).

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 37.5°C on oral, axillary or tympanic setting, or 
38.0°C on rectal setting.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.

A lesion that would prevent intramuscular injection

Administration of a vaccine not foreseen by the study protocol within 7 days of any 
dose of RTS,S/AS01E or Engerix-B vaccine.
6.6.
Warnings and precautions
Refer to the approved product label/package insert or in the Summary of Product 
Characteristics.
6.7.
Concomitant medication/vaccination
At each study visit/contact, the investigator should question the subject’s 
parent(s)/LAR(s) about any medication taken and vaccination received by the subject.
All concomitant medication/vaccination, with the exception of vitamins and/or dietary 
supplements, are to be recorded in the CRF/eCRF. This also applies to concomitant 
medication administered prophylactically in anticipation of reaction to the vaccination 
and any medication intended to treat an AE.
A prophylactic medication is a 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).
 
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Similarly, concomitant medication administered for the treatment of a SAE, at any time, 
must be recorded on the SAE Report / SAE screens in the eCRF, as applicable. Refer to 
Section 8.1.2 for the definition of an SAE.
6.7.1.
Medications/products that may lead to the elimination of a 
subject from ATP analyses
The following criteria should be checked at each visit subsequent to the first vaccination. 
If any become applicable during the study, it will not require withdrawal of the subject 
from the study but may determine a subject’s evaluability in the according-to-protocol 
(ATP) analysis. See Section 10.4 for definition of study cohorts to be evaluated.

Use of a drug or vaccine that is not approved for that indication (by one of the 
following authorities: FDA or EU member state or WHO [with respect to 
prequalification]) other than the study vaccines during the study period.

Chronic administration (defined as more than 14 days) of immunosuppressants or 
other immune-modifying drugs during the study period. For corticosteroids, this will 
mean prednisone ≥ 0.5 mg/kg/day, or equivalent. Inhaled and topical steroids are 
allowed.

Administration of a licensed vaccine (i.e. a vaccine that is approved by one of the 
following authorities: FDA or EU member state or WHO [with respect to 
prequalification]) not foreseen by the study protocol within 7 days of any dose of 
RTS,S/AS01E or Engerix-B.

Administration of immunoglobulins and/or any blood products during the study 
period. 
A detailed, comprehensive list of reasons for elimination from ATP analyses will be 
established at the time of data cleaning.
6.7.2.
Time window for recording concomitant medication/vaccination
in the CRF/eCRF
All antipyretics, analgesics, anti-inflammatories and systemic antibiotics administered in 
the 7-day period (day of vaccination and 6 subsequent days) following each vaccine dose 
(i.e. time period for assessment of reactogenicity) will be recorded. The indication for 
administration (‘prophylaxis’ or ‘treatment’) will be recorded (Table 17).
Any licensed vaccine (i.e. a vaccine that is approved by one of the following authorities: 
FDA or EU member state or WHO [with respect to prequalification]) not foreseen in the 
study protocol administered in the period beginning 30 days preceding each dose of study 
vaccine and ending 30 days after each dose of study vaccine is to be recorded in the 
eCRF.
Any investigational medication or vaccine (i.e. drug or vaccine that is not approved for 
that indication by one of the following authorities: FDA or EU member state or WHO 
[with respect to prequalification]) administered throughout the study (i.e. from Day 0 
through Month 51) must be recorded in the eCRF.
 
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Any immunosuppressants or other immune-modifying drugs, any immunoglobulins 
and/or any blood products administered throughout the study (i.e. from Day 0 through 
Month 51) must be recorded in the eCRF.
Table 17
Time window for recording concomitant medication/vaccination
Time period
Medication/vaccine
Recording period
Primary epoch
Investigational drug or vaccine, immunosuppressants 
and other immune-modifying drugs, immunoglobulins 
and blood products
Throughout
Antipyretics, analgesics, anti-inflammatories, systemic 
antibiotics
Day of vaccination and 6 
subsequent days
Concomitant vaccination (Licensed vaccine not foreseen in 
the study protocol)
30 days before and 30 days after 
each dose of study vaccine
Follow-up
epochs
Investigational drug or vaccine, immunosuppressants 
and other immune-modifying drugs, immunoglobulins 
and blood products 
Throughout
6.8.
Intercurrent medical conditions that may lead to elimination
from an ATP cohort
Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response or are 
confirmed to have an immunodeficiency condition. 
7.
HEALTH ECONOMICS
Not applicable.
8.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The investigator or site staff is/are responsible during the study for the detection and 
documentation of events meeting the criteria and definition of an AE or SAE as 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 unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
 
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the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.
Examples of an AE include:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after investigational product 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 product or a concurrent medication (overdose per se should not be 
reported as an AE/SAE).

Signs, symptoms temporally associated with vaccine administration.
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.

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. 

For therapeutic studies, the disease/disorder being studied, or expected progression, 
signs, or symptoms of the disease/disorder being studied, unless more severe than 
expected for the subject’s condition.
AEs may include 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).
NB AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All 
other AEs will be recorded as UNSOLICITED AEs.
Example of events to be recorded in the medical history section of the CRF/eCRF:

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
start of the study (i.e. prior to the first study vaccination).
 
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8.1.2.
Definition of a serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that:
a.
Results in death.
b.
Is life-threatening.
NB: 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 hospitalisation or prolongation of existing hospitalisation.
NB: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or out-patient setting. Complications that 
occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known/diagnosed 
prior to informed consent signature) that did not worsen from baseline is NOT
considered an AE.
d.
Results in disability/incapacity.
NB: 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, diarrhoea, 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.
e.
Adverse event of specific interest
NB: AEs of specific interest include all seizures occurring within a 30-day period 
of vaccination and immune-mediated disorders. Key information pertaining to 
seizures occurring within 7 days of vaccination will be documented in the 
CRF/eCRF [refer to Bonhoeffer, 2004]. AEs of specific interest to be reported as 
SAEs also include specific auto-immune diseases and other immune mediated 
disorders as listed in section 8.2.2.5.
Medical or scientific judgement 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 hospitalisation but may jeopardise 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.
 
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8.1.3.
Solicited adverse events
The following local (injection-site) AEs will be considered as solicited:
Table 18
Solicited local adverse events
Pain at injection site
Redness* at injection site
Swelling at injection site
* In case the principal investigator or designate is unable 
to determine the extend of redness on darkly pigmented 
skin, it will be reported as uninterpretable in the eCRF and 
Diary Card.
The following general AEs will be considered as solicited:
Table 19
Solicited general adverse events
Drowsiness
Fever
Irritability/Fussiness
Loss of appetite
NB Temperature will be recorded daily. Should additional temperature measurements be 
performed, the highest temperature will be recorded in the CRF/eCRF.
Each infant will be observed for at least 60 minutes after vaccination to evaluate and treat 
any acute adverse events.
After each dose of RTS,S/AS01E or Engerix-B co-administered with EPI vaccines, 
trained study personnels will visit the children to detect adverse events (AEs) occurring 
after vaccination for one week (days 1, 2, 3, 4, 5 and day 6 after each vaccination). 
Thermometers will be provided by the study personnels performing the home visit to 
record axillary temperature and any local (at the injection site) or general adverse events.
8.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
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 AEs or SAEs if they meet the definition of an AE, as defined in Section 
8.1.1 or of a SAE, as defined in Section 8.1.2. Clinically significant abnormal laboratory 
findings or other abnormal assessments that are detected during the study or are present at 
baseline and significantly worsen following the start of the study will be reported as AEs 
or SAEs.
 
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The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
8.2.
Detecting and recording adverse events and serious 
adverse events
8.2.1.
Time period for detecting and recording adverse events, serious 
All AEs starting within 30 days following administration of each dose of RTS,S/AS01E
or Engerix-B co-administered with EPI vaccines must be recorded onto/into the AE
form/screen in the subject’s CRF/eCRF, irrespective of intensity or whether or not they 
are considered vaccination-related.
The standard time period for collecting and recording SAEs will begin at the first receipt 
of study vaccine and will end 8 months following administration of the first dose of 
RTS,S/AS01E or Engerix-B for each subject. See Section 8.3 for instructions on reporting 
and recording SAEs.
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (e.g. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine or any fatal SAE will be collected and 
recorded from the time the subject consents to participate in the study until she/he is 
discharged.
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 20.
Table 20
Reporting periods for adverse events and serious adverse events
Visits
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Study day 
-14 to 0
0
1-6
14
28
29-34
42
56
57-62
70
Reporting of new 
onset/worsening of 
AE of specific interest 
Reporting of solicited 
local and general AEs
Reporting of 
unsolicited AEs
Reporting of SAEs
Reporting of SAEs 
related to study 
participation or any 
fatal SAE
 
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A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 20. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study, and 
he/she considers the event reasonably related to the investigational product, the 
investigator will promptly notify the Study Contact for Reporting SAEs.
8.2.2.
Evaluation of adverse events and serious adverse events
8.2.2.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of detecting soliciting 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 CRF/eCRF or SAE Report Form/screens as applicable. It is not 
acceptable for the investigator to send photocopies of the subject’s medical records to 
GSK Biologicals instead of the appropriate completed AE/SAE pages/SAE screens in the 
CRF/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.
8.2.2.2.
Assessment of adverse events
8.2.2.2.1.
Assessment of intensity
Intensity of the following AEs will be assessed as described:
 
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Table 21
Intensity scales for solicited symptoms in infants/toddlers and 
children less than 6 years of age
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Minor reaction to touch
2
Moderate: Cries/protests on touch
3
Severe: Cries when limb is moved/spontaneously painful
Redness* at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fever**
Record temperature in °C
Irritability/Fussiness
0
Behaviour as usual
1
Mild: Crying more than usual/no effect on normal activity
2
Moderate: Crying more than usual/interferes with normal activity
3
Severe: Crying that cannot be comforted/prevents normal 
activity
Drowsiness
0
Behaviour as usual
1
Mild: Drowsiness easily tolerated
2
Moderate: Drowsiness that interferes with normal activity
3
Severe: Drowsiness that prevents normal activity
Loss of appetite
0
Appetite as usual
1
Mild: Eating less than usual/no effect on normal activity
2
Moderate: Eating less than usual/interferes with normal activity
3
Severe: Not eating at all
* In case the principal investigator or designate is unable to determine the extend of redness on darkly pigmented skin, 
it will be reported as uninterpretable in the eCRF and Diary Card.
** Fever is defined as: rectal temperature 38°C /axillary temperature 37.5°C /oral temperature 37.5°C /tympanic 
temperature on oral setting 37.5°C, tympanic temperature on rectal setting 38°C. The preferred route for recording 
temperature in this study will be axillary.
The maximum intensity of local injection site redness/swelling 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:
0
:
< 37.5°C
1
:
37.5 – 38.0°C
2
:
> 38 – 39.0°C
3
:
> 39.0°C
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all other AEs, i.e. unsolicited symptoms, including SAEs reported during the 
study. The assessment will be based on the investigator’s clinical judgement.
 
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The intensity of each AE and SAE recorded in the CRF/eCRF or SAE Report 
Form/screens, as applicable, 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 center and 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 utilised 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.
8.2.2.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between investigational product 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, based on natural history of the 
underlying diseases, concomitant therapy, other risk factors and the temporal relationship 
of the event to the investigational product will be considered and investigated. The 
investigator will also consult the Investigator Brochure or Product Information for 
marketed products in the determination of 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 SAE to GSK Biologicals. The investigator may change his/her
opinion of causality in light of follow-up information, amending the SAE information 
accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of general AEs to the individual vaccines administered. 
The investigator should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccines.
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 
product?
 
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NO
:
The AE is not causally related to administration of the study 
vaccine(s). There are other, more likely causes and administration 
of the study vaccine(s) is not suspected to have contributed to the 
AE.
YES
:
There is a reasonable possibility that the vaccine(s) contributed to 
the AE.
Non-serious and serious AEs will be evaluated as two distinct events. If an event meets 
criteria to be determined ‘serious’ (see Section 8.1.2 for definition of serious adverse 
event), additional examinations/tests will be performed by the investigator in order to 
determine ALL possible contributing factors applicable to 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).
8.2.2.3.
Assessment of outcomes
Outcome of any non-serious AE occurring within 30 days following administration of 
each dose of RTS,S/AS01E or Engerix-B co-administered with EPI vaccines (i.e. 
unsolicited AE) or any SAE reported during the entire study will be assessed as:

Recovered/resolved.

Not recovered/not resolved.

Recovering/resolving.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
8.2.2.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalisation, an emergency room visit or a visit to or from medical personnel (medical 
doctor) for any reason and this information will be recorded in the CRF/eCRF.
 
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8.2.2.5.
AEs of specific interest
Adverse events of specific interest for safety monitoring include seizures within 30 days 
of vaccination and immune-mediated disorders (IMDs), rashes and mucocutaneous 
lesions. Support for specific laboratory testing of IMDs and histopathology will be made 
available by the sponsor.
Seizures within 30 days of vaccination
All seizures occurring within a 30-day period of vaccination will be reported as SAEs and 
medical documentation of the events will be reported in appropriate targeted follow-up 
forms included in the CRF/eCRF. Key information pertaining to seizures occurring 
within 7 days of vaccination will be documented in the CRF/eCRF [refer to Bonhoeffer, 
2004].
Immune-mediated disorders (IMDs)
Occurrence of IMDs such as those listed below will be reported for all subjects over the 
entire study period. Medical documentation of the events will be reported in appropriate 
targeted follow-up forms included in the CRF/eCRF. The specific interest in the detailed 
description of occurrence of IMDs results from the theoretical concern that vaccination 
may interfere with immunological self-tolerance. These IMDs will be reported as SAEs 
in the CRF/eCRF.

Neuroinflammatory disorders: Optic neuritis, multiple sclerosis, demyelinating 
disease, transverse myelitis, Guillain-Barré syndrome, myasthenia gravis, 
encephalitis, neuritis, Bell’s palsy.

Musculoskeletal disorders: Systemic lupus erythematosus, cutaneous lupus, 
Sjogren’s syndrome, scleroderma, dermatomyositis, polymyositis, rheumatoid 
arthritis, juvenile arthritis, polymyalgia rheumatica, reactive arthritis, psoriatic 
arthropathy, ankylosing spondylitis, undifferentiated spondyloarthropathy.

Gastrointestinal disorders: Crohn’s disease, ulcerative colitis, ulcerative proctitis, 
celiac disease.

Metabolic diseases: Autoimmune thyroiditis, Grave's or Basedow’s disease, 
Hashimoto thyroiditis, Diabetes Mellitus Type 1, Addison’s disease.

Skin disorders: Psoriasis, vitiligo, Raynaud’s phenomenon, erythema nodosum, 
autoimmune bullous skin diseases.

Others: Auto-immune hemolytic anemia, idiopathic thrombocytopenic purpura, 
antiphospholipid syndrome, vasculitis, pernicious anemia, autoimmune hepatitis, 
primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune 
glomerulonephritis, autoimmune uveitis, autoimmune myocarditis, sarcoidosis, 
Stevens-Johnson syndrome.
 
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8.2.2.6.
Rashes and mucocutaneous lesions
Occurrence of rashes and mucocutaneous lesions that occur within 30 days of vaccination 
will be reported as AEs/SAEs. Medical documentation of the events will be reported in 
the CRF/eCRF. Rashes and mucocutaneous lesions that meet the criteria for an SAE are 
reported in all subjects throughout the study period as usual.
8.3.
Reporting and follow-up of adverse events and serious 
adverse events
8.3.1.
Prompt reporting of serious adverse events and other events to 
GSK Biologicals
SAEs will be reported promptly to GSK as described in Table 22 once the investigator 
determines that the event meets the protocol definition of an SAE.
Table 22
Time frames for submitting SAEs and other events reports to GSK 
Biologicals
Initial Reports
Follow-up Information on a Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours*
SAE report/SAE screen
24 hours*
SAE report/SAE screen
* Time frame allowed after receipt or awareness of the information.
In case the electronic reporting system is temporarily unavailable, a back-up system is in 
place. Please refer to Section 8.3.3 for a detailed description
Study Contact for Reporting SAEs
Please see the Sponsor Information Sheet for contact details of who to contact in the 
event of an SAE.
Back-up Study Contact for Reporting SAEs
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: 
 or
24/24 hour and 7/7 day availability
Back-up e-mail if fax is not working: 
8.3.2.
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.
 
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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 product and unexpected. The 
purpose of the report is to fulfil specific regulatory and Good Clinical Practice (GCP) 
requirements, regarding the product under investigation.
8.3.3.
Completion and transmission of SAEs reports to GSK Biologicals
8.3.3.1.
Studies using the paper CRF
Once an investigator becomes aware that an SAE has occurred in a study subject, she/he 
will report the information to GSK within 24 hours. The SAE Report Form will always 
be completed as thoroughly as possible with all available details of the event, signed by 
the investigator (or designee), and forwarded to GSK within the designated time frames. 
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying GSK of the event and completing the 
form. The form will be updated when additional relevant information is received and 
forwarded to GSK WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report.
Facsimile (Fax) transmission of the SAE Report Form is the preferred method to transmit 
this information to the Study Contact for Reporting SAEs. In rare circumstances and in 
the absence of facsimile equipment, notification by telephone is acceptable, with a copy 
of the SAE Report Form sent by overnight mail. Initial notification via the telephone does 
not replace the need for the investigator to complete and sign the SAE Report Form 
within 24 hours.
In the event of a death determined by the investigator to be related to vaccination, 
sending of the fax must be accompanied by telephone call to the Study Contact for 
Reporting SAEs.
8.3.3.2.
Studies using RDE
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator will complete and submit the information in the SAE screens in eCRF within 
24 hours. The SAE screens in eCRF will always be completed as thoroughly as possible 
with all available details of the event and will be submitted by the investigator. If the 
investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying GSK of the event and completing the 
SAE screens in eCRF. The SAE screens in eCRF should be updated when additional
relevant information is received WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report.
 
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Back-up system in case the electronic SAE reporting system does not work
If the SAE reporting system has been down for 24 hours, the investigator or his/her 
delegate should fax an SAE report form directly to the GSK Central Safety department 
(please refer to Section 8.3.1) within 24 hours. The maximum timeline for reporting 
SAEs to central safety is therefore 48 hours.
NB. 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 delegate 
must update the SAE screens in the eCRF within 24 hours.
The final valid information for regulatory reporting will be the information reported 
through the electronic system.
When additional information is received on a SAE after freezing of the subject’s eCRF, 
new or updated information is to be recorded on the paper SAE Report Form, with all 
changes signed and dated by the investigator. The updated SAE Report Form should be 
sent to GSK Biologicals WITHIN 24 HOURS of receipt of the follow-up information.
In rare circumstances, if the electronic system for reporting SAEs does not work and in 
the absence of facsimile equipment, notification by telephone is acceptable, with a copy 
of the SAE Report Form sent by email or by mail. Initial notification via the telephone 
does not replace the need for the investigator to complete and submit SAE screens in the 
eCRF (or complete and sign the SAE Report Form if the back-up system needs to be 
used).
In the event of a death determined by the investigator to be related to vaccination, 
completion of SAE screens in the eCRF/sending of the fax (if the electronic SAE 
reporting system does not work or after freezing of the subject’s eCRF) must be 
accompanied by telephone call to the Study Contact for Reporting SAEs.
8.3.4.
Follow-up of adverse events and serious adverse events
After the initial AE/SAE report, the investigator is required to proactively follow-up each 
subject and provide further information to GSK Biologicals on the subject’s condition.
All SAEs 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.
Investigators will follow-up subjects:
 
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
With SAEs or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up.

Or, in the case of other non-serious AEs, until they complete the study or they are 
lost to follow-up.
Clinically significant laboratory abnormalities will be followed up until they have 
returned to normal, or a satisfactory explanation has been provided. Additional 
information (including but not limited to laboratory results) relative to the subsequent 
course of such abnormalities noted for any subject must be made available to the Site 
Monitor.
GSK Biologicals may request that the investigator perform or arrange for 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 recognised follow-up period, 
GSK Biologicals will be provided with a copy of any available post-mortem findings, 
including histopathology.
Support for specific laboratory testing of IMDs and histopathology will be made 
available by the sponsor.
8.4.
Treatment of adverse events
Treatment of any adverse event is at the sole discretion of the investigator and according 
to current good medical practice. Any medication administered for the treatment of an 
AE should be recorded in the subject’s CRF/eCRF. Refer to Section 6.7.
8.5.
Unblinding
Not applicable.
8.6.
Emergency unblinding
This study will be open-label, i.e. both the investigator and the subject’s parent(s)/LAR(s) 
will be aware of the vaccine being administered to the subjects. Therefore, the 
information given hereunder is limited to the unblinding of SAEs to any third parties (e.g. 
any doctor other than the study investigator), in accordance with GSK Biologicals’ 
standard operating procedures.
The investigator, or other physician managing the subject, should contact GSK 
Biologicals’ Central Safety Physician to discuss the need for emergency unblinding. 
Alternatively the investigator may contact the local contact who will in turn contact the 
GSK Central Safety Physician.
The investigator, or person designated by the investigator, should contact GSK 
Biologicals’ Central Safety physician directly or via the local safety contact (see below 
 
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and Study Contact for Emergency Code Break in the Sponsor Information page) to 
discuss the need for emergency unblinding.
An investigator should request unblinding of the subject’s treatment code only in the case 
of a medical emergency, or in the event of a serious medical condition, when knowledge 
of the investigational study vaccine(s)/product(s) is essential for the clinical management 
or welfare of the subject.
The GSK Biologicals’ Central Safety Office will be allowed to access the individual 
randomisation code. The code will be broken by the GSK Biologicals’ Central Safety 
physician (see below and Study Contact for Emergency Code Break in Sponsor 
Information) only in the case of medical events that the investigator/physician in charge 
of the subject feels cannot be treated without knowing the identity of the study 
vaccine(s)/product(s).
GSK Biologicals Central Safety Physician 
(Study Contact for Emergency Code Break)
Phones for 7/7 day availability:
(GSK Biologicals Central Safety Physician on-call)
Back-up phone contact (all countries):
8.7.
Subject card
Study subjects’ parent(s)/LAR(s) must be provided with the address and telephone 
number of the main contact for information about the trial.
Investigator/delegate should therefore provide a “subject card” to each subject’s 
parent(s)/LAR(s). The aim of this card is to inform any physician having to deal with a 
subject in an emergency situation that the subject is in a clinical trial and that he/she can 
contact the trial investigator for more relevant information.
Subjects’ parent(s)/LAR(s) must be instructed to keep these 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.
 
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9.2.
Subject withdrawal
Subjects who are withdrawn because of SAEs/AEs must be clearly distinguished from 
subjects who are withdrawn for other reasons. Investigators will follow subjects who are 
withdrawn as result of a SAE/AE until resolution of the event (see Section 8.3).
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 to contact those subjects who do not return for
scheduled visits or follow-up.
Information relative to the withdrawal will be documented in the CRF/eCRF. The 
investigator will document whether the decision to withdraw a subject from the study was 
made by the subject’s parent(s) or LAR(s), or by the investigator, as well as which of the 
following possible reasons was responsible for withdrawal:

SAE

Non-serious AE

Protocol violation (specify)

Consent withdrawal, not due to an adverse event

Moved from the study area

Lost to follow-up

Death

Other (specify).
9.2.2.
Subject withdrawal from investigational vaccine
A ‘withdrawal’ from the investigational vaccine refers 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 vaccine may 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.
 
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Information relative to premature discontinuation of the investigational vaccine will be 
documented on the Vaccine Administration page/screen of the CRF/eCRF. The 
investigator will document whether the decision to discontinue further 
vaccination/treatment was made the subject’s parent(s) or LAR(s), by or the investigator, 
as well as which of the following possible reasons was responsible for withdrawal:

SAE

Non-serious AE

Other (specify).
10.
DATA EVALUATION: CRITERIA FOR EVALUATION OF 
OBJECTIVES
10.1.
Primary endpoint: immunogenicity

Non-inferiority of the immune response to the hepatitis B antigen induced by 
RTS,S/AS01E vaccine versus a licensed hepatitis B vaccine.

Anti-HBs antibody titers one month post Dose 3 of RTS,S/AS01E or Engerix-B.
10.2.
Secondary endpoints
Immunogenicity

Non-inferiority of the immune response to the 10 pneumococcal serotype antigens 
when pneumococcal conjugate vaccine is given as part of an EPI regimen with and 
without RTS,S/AS01E co-administration.

Anti-pneumococcal serotypes (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) 
antibody concentrations one month post Dose 3 of pneumococcal conjugate 
vaccine.

Immune response to the 10 pneumococcal serotype antigens of the pneumococcal 
conjugate vaccine, when given as part of an EPI regimen with and without 
RTS,S/AS01E co-administration.

Anti-pneumococcal serotypes (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) 
antibody concentrations one month post Dose 3 of pneumococcal conjugate 
vaccine.

Opsonophagocytic titers to each of the 10 pneumococcal serotypes one month 
post Dose 3 of pneumococcal conjugate vaccine.

Immune response against the protein D (PD) component of the pneumococcal 
antigen.

Anti-PD antibody titers one month post Dose 3 of pneumococcal conjugate 
vaccine.

Non-inferiority of the immune response to the rotavirus antigen when the rotavirus 
vaccine is given as part of an EPI regimen with and without RTS,S/AS01E co-
administration.
 
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
Anti-rotavirus antibody (IgA) titers one month post Dose 2 of rotavirus vaccine.

Immune response to the rotavirus antigen of the rotavirus vaccine, when given as 
part of an EPI regimen with and without RTS,S/AS01E co-administration.

Anti rotavirus antibody (IgA) titers one month post Dose 2 of rotavirus vaccine.

Immune response to hepatitis B antigen of the investigational vaccine RTS,S/AS01E
or a licensed hepatitis B vaccine.

Anti-HBs antibody titers one month post Dose 3 of RTS,S/AS01E or Engerix-B.

Anti-HBs RF1 like antibody titers one month post Dose 3 of RTS,S/AS01E or 
Engerix-B.

Immune response to the CS antigen of the investigational vaccine RTS,S/AS01E
when given as part of an EPI regimen with and without pneumococcal conjugate 
vaccine co-administration.

Anti-CS antibody titers one month post Dose 3 of RTS,S/AS01E.

Immune response to the CS antigen of the investigational vaccine RTS,S/AS01E
when given as part of an EPI regimen with and without rotavirus co-administration.

Anti-CS antibody titers one month post Dose 3 of RTS,S/AS01E.

Lot-to lot consistency for immunogenicity of three lots of the investigational vaccine 
RTS,S/AS01E.

Anti-HBs antibody titers one month post Dose 3 of RTS,S/AS01E.

Non-inferiority of the immune response to the acellular B pertussis antigens of the 
DTPa/Hib vaccine when given with and without RTS,S/AS01E co-administration.

Anti-acellular B pertussis (BPT) antibody titers (anti-PT, anti-FHA, anti-PRN) 
at screening and one month post Dose 3 of the DTPa/Hib vaccine.

Immune response to the acellular B pertussis antigens of the DTPa/Hib vaccine (anti-
PT, anti-FHA, anti-PRN) when given with RTS,S/AS01E.

Anti-acellular B-Pertussis (BPT) antibody titers (anti-PT, anti-FHA, anti-PRN) 
at screening and one month post Dose 3 of the DTPa/Hib vaccine.
Immunogenicity follow-up

Immune response (on a long-term) to the hepatitis B antigen after a primary course 
of investigational vaccine RTS,S/AS01E or a licensed hepatitis B vaccine.

Anti-HBs antibody titers assessed at 12, 24, 36 and 48 months post Dose 3 of 
RTS,S/AS01E or Engerix-B.

Immune response to a booster dose of a licensed hepatitis B vaccine.

Anti-HBs antibody titers one month post booster dose of Engerix-B.
 
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
Anti-HBs RF1 like antibody titers one month post booster dose of Engerix-B.

Immune response (on a long-term) to the CS-antigen after a primary course of the 
investigational vaccine RTS,S/AS01E.

Anti-CS antibody titers assessed 12, 24, 36 and 48 months post Dose 3 of 
RTS,S/AS01E.

Immune response to a booster dose of pneumococcal conjugate vaccine when 
primary vaccination is given as part of an EPI regimen with and without 
RTS,S/AS01E co-administration.

Anti- pneumococcal serotypes (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) 
antibody concentrations one month post booster dose of pneumococcal 
conjugate vaccine.

Opsonophagocytic titers to each of the 10 pneumococcal serotypes one month 
post booster dose of pneumococcal conjugate vaccine.

Anti-protein D antibody titers one month post booster dose of pneumococcal 
conjugate vaccine.
Safety

For each of the 5 vaccination regimens corresponding to the 5 treatment groups 
(REP[Ro]s, RERo[P]s, RE[RoP]s, HEP[Ro]s and HERo[P]s), to describe the 
occurrence of solicited general and local adverse events (AEs) over a 7-day follow-
up period (day of vaccination and 6 subsequent days) after the first, second and third 
doses of RTS,S/AS01E or a licensed hepatitis B vaccine.

For each of the 5 vaccination regimens corresponding to the 5 treatment groups 
(REP[Ro]s, RERo[P]s, RE[RoP]s, HEP[Ro]s and HERo[P]s), to describe the 
occurrence of unsolicited AEs over a 30-day follow-up period (day of vaccination 
and 29 subsequent days) after the first, second and third doses of RTS,S/AS01E or a 
licensed hepatitis B vaccine.

To describe the occurence of serious adverse events (SAEs).

SAEs from the time of first vaccination until 3 month post Dose 1 (Visit 8) of 
RTS,S/AS01E or a licensed hepatitis B vaccine.

SAEs from the time of first vaccination until 8 month post Dose 1 (Visit 9) of 
RTS,S/AS01E or a licensed hepatitis B vaccine.

Fatal SAEs from study start until study end.

Immune mediated disorders (IMDs) from study start until study end.
10.3.
Estimated sample size
A total of 705 subjects (141 per treatment group) are planned to be enrolled in order to 
have at least 600 evaluable subjects (approximately 120 subjects in each treatment 
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For the primary endpoint, defined as non-inferiority of the anti-HBs seroprotection rate, 
the study has 92% power to detect an upper limit of the 95% CI on the difference in 
seroprotection rates (HEP[Ro]s + HERo[P]s groups minus REP[Ro]s + RERo[Po]s + 
RE[RoP]s groups) below 5%, with a sample size of 120 evaluable subjects per treatment 
group (standardized asymptotic 95%; 1-sided alpha 0.025) under the assumption of post 
vaccination anti-HBs seroprotection rates above 97%. In order to account for drop-out 
and non-evaluable subjects 141 subjects per treatment group will be enrolled.
For each secondary non-inferiority endpoint, the power for each individual test to 
demonstrate the following is presented in Table 23:

non-inferiority of REP[Ro]s versus HEP[Ro]s in terms of anti PCV response to 
each of the pneumococcal 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F;

non-inferiority of RERo[P]s versus HERo[P]s in terms of anti-rotavirus;
Table 23
Power for secondary non-inferiority endpoints
Endpoint
Reference value
(Log SD)
Limit of non-
inferiority
Power
Synflorix [10PN-PD-DIT-001, GSK data on file 2007; Vesikari 2009]
Anti-4
0.36
2-fold
99%
Anti-6B
0.7
2-fold
91%
Anti-9V
0.4
2-fold
99%
Anti-14
0.39
2-fold
99%
Anti-18C
0.46
2-fold
99%
Anti-19F
0.54
2-fold
99%
Anti-23F
0.43
2-fold
99%
Anti-1
0.36
2-fold
99%
Anti-5
0.35
2-fold
99%
Anti-7F
0.35
2-fold
99%
Rotarix [ROTA-037, GSK data on file 2009; Madhi 2010]*
Anti-RV
0.8
2-fold
83%
Non-inferiority test, alpha (1 sided) = 0.025, N= in each group, power under the alternative of equal 
proportions/means in both groups, PASS 2005, equivalence of proportions/means
* This study was conducted at multiple sites in South Africa and Malawi.
For the secondary anti-HBs lot-to-lot consistency endpoint, the trial has 80% power to 
demonstrate equivalence in terms of anti-HBs response for each GMT ratio between any 
2 lots with a log standard deviation not exceeding 0.8 and an equivalence limit of [0.5, 2].
10.4.
Study cohorts to be evaluated
10.4.1.
Total vaccinated cohort (TVC)
The TVC will include all vaccinated subjects for whom data are available. Thus, the total 
analysis of safety will include all subjects with at least one vaccine administration 
documented and the total analysis of immunogenicity will include vaccinated subjects for 
 
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whom data concerning immunogenicity endpoint measures are available. The TVC
analysis will be performed per treatment actually administered.
10.4.2.
According-To-Protocol (ATP) cohort for analysis of safety
The ATP cohort for analysis of safety will include all vaccinated and eligible subjects

Who have received at least one dose of study vaccine according to their random 
assignment.

For whom administration site of study vaccine is known.

Who have not received a vaccine not specified or forbidden in the protocol.
10.4.3.
According-to-protocol (ATP) cohort for analysis of 
immunogenicity
The ATP cohort for analysis of immunogenicity will include all evaluable subjects (i.e. 
those meeting all eligibility criteria, complying with the procedures defined in the 
protocol, with no elimination criteria during the study) for whom data concerning 
immunogenicity endpoint measures are available. The maximum intervals between study 
visits allowed for inclusion in the ATP analysis are described in Table 6.
10.5.
Derived and transformed data
Immunogenicity

A subject seropositive for anti-CS antibody is a subject whose antibody titer is 
greater than or equal to the cut-off value (anti-CS 0.5 EU/ml).

A subject seropositive for anti- RF1 antibody is a subject whose antibody titer is 
greater than or equal to the cut-off value (anti-CS 33 EU/ml).

Seroprotection rate for Rotavirus IgA is defined as the percentage of subjects with 
antibody titers greater than or equal to an established cut-off (anti-rotavirus IgA 
20 U/ml).

Seroprotection rate for HBsAg is defined as the percentage of subjects with antibody 
titers greater than or equal to an established cut-off (anti-HBs 10 mIU/ml).

A subject seropositive for 10 pneumococcal vaccine serotypes (1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F and 23F) is a subject whose antibody titer is greater than or equal to the 
cut-off value (pneumococcal serotype specific total IgG 0.05 g/ml).

A subject seropositive for 10 pneumococcal vaccine serotypes (1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F and 23F) is a subject where the opsonic titer able to sustain 50 % 
killing of live pneumococci under the assay conditions is greater than or equal to the 
cut-off value (opsonic dilution 8).

A subject seropositive for pneumococcal conjugate vaccine is defines as a subject 
whose anti-PD antibody concentrations 100 EU/ml.
 
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
A subject seropositive for anti-PT, anti-FHA and anti-PRN is defined as a subject 
whose antibody concentration 5 EL.U/mL. Vaccine response to anti-PT, anti-FHA 
and anti-PRN is defined as seroconversion in initially seronegative subjects (prior to 
vaccination) or a concentration post vaccination at least equal to the concentration 
prior to vaccination in initially seropositive subjects.

The Geometric Mean Titers/Concentrations (GMTs/GMCs) calculations are 
performed by taking the anti-log of the mean of the log titer/concentration 
transformations. Antibody titers/concentrations below the cut-off of the assay will be 
given an arbitrary value of half the cut-off for the purpose of GMT/GMC calculation.

For a given subject and a given immunogenicity measurement, missing or non-
evaluable measurements will not be replaced. Therefore, an analysis will exclude 
subjects with missing or non-evaluable measurements.
Reactogenicity and Safety

Handling of missing data: subjects who missed reporting symptoms 
(solicited/unsolicited or concomitant medications) will be treated as subjects without 
symptoms (solicited/unsolicited or concomitant medications, respectively). In case of 
significant non-compliance of study procedures for reporting symptoms, the analysis 
plan will be reassessed to ensure more accurate reporting of study data by further 
analysis.

For the analysis of solicited symptoms, missing or non-evaluable measurements will 
not be replaced. Therefore the analysis of the solicited symptoms based on the total 
vaccinated cohort will include only subjects/doses with documented safety data (i.e. 
symptom screen/sheet completed).
10.6.
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.
10.6.1.
Sequence of analyses

The primary analysis will be performed on data collected up to Visit 8 (1 month post 
Dose 3 of RTS,S/AS01E or Engerix-B) and will include primary and secondary 
immunogenicity and safety endpoints. Results will be reported in a final study report.

A safety analysis will be performed on data (SAEs) collected until 8 months post 
Dose 1 of RTS,S/AS01E or Engerix-B (Visit 9) and will be reported in an annex 
report.

An immunogenicity analysis based on data collected until Visit 13 (Month 26) will 
include anti-CS and anti-HBs antibody responses and will be reported in an annex 
report.

The final analysis will be performed on further safety and immunogenicity data 
collected up to the last study visit (Visit 16), 51 months following the administration 
of the first dose of study vaccine. Results will be presented in an annex report.
 
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10.6.2.
Statistical considerations for interim analyses
No interim analysis is planned before the primary analysis.
10.7.
Statistical methods
10.7.1.
Analysis of demographics/baseline characteristics
Demographic characteristics (age and gender) will be tabulated by group.
10.7.2.
Analysis of immunogenicity
The primary analysis will be based on the ATP cohort for analysis of immunogenicity. A 
second analysis based on the TVC will be performed to complement the ATP analysis.
10.7.2.1.
Statistical analysis for primary endpoint
For the primary endpoint, defined as non-inferiority of the anti-HBs seroprotection rate, 
the difference in percent SP between Engerix-B vaccine recipients minus RTS,S/AS01E
vaccine recipients (HEP[Ro]s + HERo[P]s groups minus REP[Ro]s + RERo[Po]s + 
RE[RoP]s groups), assessed one month post Dose 3 of RTS,S/AS01E or Engerix-B will be 
calculated as well as the 95% CI (standardized asymptotic) around this difference. If the 
upper limit of the two-sided 95% CI is below 5%, non-inferiority will have been 
demonstrated in terms of anti-HBs responses.
10.7.2.2.
Statistical analyses for secondary endpoints
10.7.2.2.1. Analysis of immunogenicity
The primary analysis will be based on the ATP cohort for analysis of immunogenicity. A 
second analysis based on the TVC will be performed to complement the ATP analysis.
Antibodies against Pneumococcal conjugate vaccine (PCV)
The percentage of subjects with seropositive levels of anti-PCV with 95% CI will be 
determined at each blood sampling time point for the groups REP[Ro]s and HEP[Ro]s: 
that is the proportion of subjects with anti-PCV -1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 
23F - antibody titers as determined by GSK assay greater than or equal to 0.2 g/ml, 
which correlates with the standard ELISA value of 0.35 g/ml. Antibody titers will be 
summarized by GMC with 95% CI at all time points at which serological samples are 
taken. Antibody titers after the third dose will also be investigated using reverse 
cumulative curves. The same analysis will be repeated on data resulting from a 
quantitative opsonophagocytic assay (95% CIs for the OPA GMT ratios).
The 95% CI of the GMC ratio (HEP[Ro]s over REP[Ro]s) will be calculated for each of 
the 10 serotypes (ELISA) one month post Dose 3 of pneumococcal conjugate vaccine. If 
the upper limit of this CI is below 2, non-inferiority will be concluded.
 
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Antibodies against Rotavirus Vaccine (RV)
The percentage of subjects with seropositive levels of anti-RV (proportion of subjects 
with anti-RV antibody titers as determined by ELISA greater than or equal to 20 U/ml) 
with 95% CI will be determined at each blood sampling time point for the groups 
RERo[P]s and HERo[P]s. Antibody titers will be summarized by GMT with 95% CI at all 
time points at which serological samples are taken. Antibody titers after the third dose 
will also be investigated using reverse cumulative curves (RCC).
The 95% CI of the GMT ratio (HERo[P]s over RERo[P]s) will be calculated one month 
post Dose 2 of rotavirus vaccine. If the upper limit of this CI is below 2, non-inferiority 
will be concluded.
Antibodies against HB
The seroprotective level for anti-HBs is 10 mIU/ml. The percentage of subjects with 
protective levels of anti-HBs (10 mIU/ml) with 95% confidence interval (95% CI) will 
be determined at each blood sampling time point (all groups). Antibody titers will be 
summarized by GMT with 95% CI at all time points at which serological samples are 
taken. Antibody titers after the third dose will also be investigated using RCC.
The 95% CI of the GMT ratio (Lot1/Lot2, Lot2/Lot3 and Lot1/Lot3 within the pooled 
REP[Ro]s, RERo[P]s and RE[RoP]s groups) will be calculated one month post Dose 3 of 
RTS,S/AS01E or Engerix-B. If the CIs are within [0.5, 2], consistency will be concluded.
Antibodies against RF1
The percentage of subjects with seropositive levels of anti-RF1 (proportion of subjects 
with anti-RF1 antibody titers greater than or equal to 33 EU/ml ) with 95% CI will be 
determined at each blood sampling time point (all groups). Antibody titers will be 
summarized by GMT with 95% CI at all time points at which serological samples are 
taken. Antibody titers after the third dose will also be investigated using RCC.
Antibodies against CS
The percentage of subjects with seropositive levels of anti-CS (proportion of subjects 
with anti-CS antibody titers greater than or equal to 0.5 EU/ml ) with 95% CI will be 
determined at each blood sampling time point (all groups). Antibody titers will be 
summarized by GMT with 95% CI at all time points at which serological samples are 
taken. Antibody titers after the third dose will also be investigated using RCC.
Antibodies against PT, FHA and PRN
The percentage of subjects with seropositive levels of anti-PT, anti-FHA and anti-PRN 
(proportion of subjects with antibody titers greater than or equal to 5 EU/ml) with 95% 
CI will be determined at each blood sampling time point (all groups). Antibody titers will 
be summarized by GMT with 95% CI at all time points at which serological samples are 
taken. Vaccine response to anti-PT, anti-FHA and anti-PRN following vaccination will 
 
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be tabulated with 95%CIs. Antibody titers after the third dose will also be investigated 
using RCC.
The 95% CI of the GMT ratio (HEP[Ro]s + HERo[P]s groups over REP[Ro]s + 
RERo[Po]s + RE[RoP]s groups) will be calculated one month post Dose 3 of DTPa/Hib 
vaccine. If the upper limit of this CI is below 2, non-inferiority will be concluded.
10.7.2.2.2. Analysis of safety
Safety will be analyzed on the TVC.
The proportion of subjects with an SAE, classified by the MedDRA preferred term level, 
reported from study start until Month 8 (8 months post Dose 1 of RTS,S/AS01E or 
Engerix-B) will be tabulated with exact 95% CI.
Withdrawal due to SAE/AEs will be described in detail.
The proportion 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-up period (7 days) 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 over the entire vaccination course, with exact 95% CI. 
The percentage of subjects reporting each individual solicited local and general AE 
during the solicited follow-up period (7 days) will be tabulated with exact 95% CI. The 
percentage of doses followed by each individual solicited local and general AE will be 
tabulated, overall and by vaccination course, with exact 95% CI. 
For all solicited symptoms, the same tabulation will be performed for Grade 3 AEs and 
for AEs with relationship to vaccination.
The proportion of subjects with at least one report of unsolicited AE classified by the 
Medical Dictionary for Regulatory Activities (MedDRA), whenever available, and 
reported up to 30 days after vaccination will be tabulated with exact 95% CI. The same 
tabulation will be performed for Grade 3 unsolicited AEs and for unsolicited AEs with a 
relationship to vaccination.
11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled.
 
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11.1.
Case Report Form/Remote Data Entry instructions
Case Report Form Instructions
CRFs (and subject diary cards, if applicable), will be supplied by GSK Biologicals for 
recording all data.
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed CRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent in-house CRF review may 
necessitate clarification or correction of data or omissions or inconsistencies with 
documentation and approval by the investigator or appropriately qualified designee. In all 
cases the investigator remains accountable for the study data collected.
Any questions or comments related to the CRF should be directed to the assigned Site 
Monitor.
The investigator will keep a paper copy of each CRF and any data query forms of the 
final version of the data generated at the investigational site.
Remote Data Entry instructions
Remote Data Entry (RDE), a validated computer application, will be used as the method 
for data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties.
11.2.
Monitoring by GSK Biologicals
Monitoring visits by a GSK Site Monitor are for the purpose of confirming that GSK 
Biologicals’ sponsored studies are being conducted in accordance with the ethical 
principles that have their origins in the Declaration of Helsinki and that are consistent 
 
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with Good Clinical practice (GCP) and the applicable regulatory requirement(s) 
(verifying continuing compliance with the protocol, amendment(s), reviewing the 
investigational product accountability records, verifying that the site staff and facilities 
continue to be adequate to conduct the study).
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a CRF/ RDE review and a Source 
Document Verification (SDV). By SDV we mean verifying CRF/ RDE entries by 
comparing them with the source data that will be made available by the investigator for 
this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the CRF/ RDE. This document should be completed and signed by the site 
monitor and investigator and should be filed in the monitor’s and investigator’s study file. 
Any data item for which the CRF/ RDE will serve as the source must be identified, 
agreed and documented in the source documentation agreement form.
For RDE, the monitor will mark completed and approved screens at each visit.
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements. When reviewing data collection procedures, the discussion will also 
include identification, agreement and documentation of data items for which the 
CRF/eCRF entries will serve as the source document.
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 and any 
amendments, 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.
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.
 
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11.3.
Archiving of data at study sites
Following closure of the study, the investigator must maintain all site study records in a 
safe and secure location. The records must be maintained to allow easy and timely 
retrieval, when needed (e.g. audit or inspection), and, whenever feasible, to allow any 
subsequent review of data 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 for studies with an eCRF); however, caution needs 
to be exercised before such action is taken. The investigator must assure 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 there is an acceptable back-up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the Sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by ICH GCP, any institutional 
requirements or applicable laws or regulations, or GSK standards/procedures; otherwise, 
the minimum retention period will default to 15 years. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to, the following: archival at an off-site facility, 
transfer of ownership of the records in the event the investigator leaves the site. 
11.4.
Audits
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.
11.5.
Posting of information on Clinicaltrials.gov
Study information from this protocol will be posted on clinicaltrials.gov before enrolment 
of subjects begins.
 
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11.6.
Ownership, confidentiality and publication
11.6.1.
Ownership
All information provided by GSK and all data and information generated by the site as 
part of the study (other than a subject’s medical records) are the sole property of GSK.
All rights, title, and interests in any inventions, know-how or other intellectual or 
industrial property rights which are conceived or reduced to practice by site staff during 
the course of or as a result of the study are the sole property of GSK, and are hereby 
assigned to GSK.
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between GSK and the study site, that 
contract’s ownership provisions shall apply rather than this statement.
11.6.2.
Confidentiality
Documented evidence that a potential investigator is aware and agrees to the confidential 
nature of the information related to the study must be obtained by means of a 
confidentiality agreement.
All information provided by GSK and all data and information generated by the site as 
part of the study (other than a subject’s medical records) will be kept confidential by the 
investigator and other site staff. This information and data will not be used by the 
investigator or other site personnel for any purpose other than conducting the study. 
These restrictions do not apply to: (i) information which becomes publicly available 
through no fault of the investigator or site staff; (ii) information which it is necessary to 
disclose in confidence to an IEC or IRB solely for the evaluation of the study; (iii) 
information which it is necessary to disclose in order to provide appropriate medical care 
to a study subject; or (iv) study results which may be published as described in the next 
paragraph. If a written contract for the conduct of the study which includes 
confidentiality provisions inconsistent with this statement is executed, that contract’s 
confidentiality provisions shall apply rather than this statement.
11.6.3.
Publication
For multicentre studies, the first publication or disclosure of study results shall be a 
complete, joint multicentre publication or disclosure coordinated by GSK. Thereafter, 
any secondary publications will reference the original publication(s).
Prior to submitting for publication, presentation, use for instructional purposes, or 
otherwise disclosing the study results generated by the site (collectively, a ‘Publication’), 
the investigator shall provide GSK with a copy of the proposed Publication and allow 
GSK a period to review the proposed Publication (at least twenty-one working days, or at 
least fifteen working days for abstracts/posters/presentations). Proposed Publications 
shall not include either GSK confidential information other than the study results or 
personal data on any subject, such as name or initials.
 
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At GSK’s request, the submission or other disclosure of a proposed Publication will be 
delayed a sufficient time to allow GSK to seek patent or similar protection of any 
inventions, know-how or other intellectual or industrial property rights disclosed in the 
proposed Publication.
If a written contract for the conduct of the study, which includes publication provisions 
inconsistent with this statement is executed, that contract’s publication provisions shall 
apply rather than this statement.
11.6.4.
Provision of study results to investigators, posting to the clinical 
trials registers and publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical 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.
The results summary will be posted to the GSK Clinical Study Register at the time of the 
first regulatory approval or within 12 months of any decision to terminate development. 
In addition, a manuscript will be submitted to a peer-reviewed journal for publication 
within 12 months of the first approval or within 12 months of any decision to terminate 
development. When manuscript publication in a peer-reviewed journal is not feasible, 
further study information will be posted to the GSK Clinical Study Register to 
supplement the results summary.
12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
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13.
REFERENCES
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attenuated human rotavirus 89-12 vaccine. Vaccine. 1998; 16:381-387.
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vaccine 89-12 in infants: a randomised placebo-controlled trial. Lancet. 1999;354:287-
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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.
Burnett RJ, François G, Kew MC et al. Hepatitis B virus and human immunodeficiency 
virus co-infection in sub-Saharan Africa: a call for further investigation. Liver Int. 2005; 
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Camargo ME, et al. Immunoenzymatic assay of anti-diphtheric toxin antibodies in human 
serum. J. Clin Microbiol. 1984; 20(4):772-4.
Concepcion NF, Frasch CE. Pneumococcal type 22f polysaccharide absorption improves 
the specificity of a pneumococcal-polysaccharide enzyme-linked immunosorbent assay. 
Clin Diagn Lab Immunol. 2001; 8(2):266-272.
European Consensus Group on Hepatitis B Immunity. Are booster immunisations needed 
for lifelong hepatitis B immunity? Lancet. 2000; 355(9203):561-565.
Granström M, Thoren M, Sato Y et al. Acellular Pertussis Vaccine in Adults: Adverse 
Reactions and Immune Response. Eur J Clin Microbiol. 1987; 6 (1):18-21.
GSK data on file: A double-blind randomised controlled Phase IIb study to evaluate the 
safety, immunogenicity and efficacy of GlaxoSmithKline Biologicals’ candidate malaria 
vaccine RTS,S/AS02A, administered IM according to a 0, 1 and 2 month vaccination 
schedule in toddlers and children aged 1 to 4 years in a malaria-endemic region of 
Mozambique. Report 257049 (Malaria-026) 12-April-2006. Data on File at 
GlaxoSmithKline Biologicals.
GSK data on file: A Phase I/IIb randomized, double-blind, controlled study of the safety, 
immunogenicity and proof-of-concept of RTS,S/AS02D, a candidate malaria vaccine in 
infants living in a malaria-endemic region. Report 103967 (Malaria-038) 16-February-
2009. Data on File at GlaxoSmithKline Biologicals.
GSK data on file: A Phase IIb randomized, double-blind, controlled study of the safety, 
immunogenicity and proof-of-concept of RTS,S/AS02D, a candidate malaria vaccine, 
when incorporated into an Expanded Program on Immunization (EPI) regimen that 
includes DTPw/Hib in infants living in a malaria-endemic region. Report 104298
(Malaria-040) 30-March-2009. Data on File at GlaxoSmithKline Biologicals.
 
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GSK data on file: A Phase II randomized, double-blind bridging study of the safety and 
immunogenicity of GlaxoSmithKline Biologicals’ candidate Plasmodium falciparum
malaria vaccine RTS,S/AS01E (0.5 mL dose) to RTS,S/AS02D (0.5 mL dose) 
administered IM according to a 0, 1, 2-month vaccination schedule in children aged 18 
months to 4 years living in Gabon. Report 105874 (Malaria-046) 10-December-2008. 
Data on File at GlaxoSmithKline Biologicals.
GSK data on file: A Phase II randomized, controlled, partially-blind study of the safety 
and immunogenicity of GlaxoSmithKline Biologicals’ candidate Plasmodium falciparum
vaccines RTS,S/AS02D and RTS,S/AS01E, when administered IM according to one of 
three dose schedules in children aged 5 to 17 months living in Ghana. Report 106367 
(Malaria-047) 23 March 2009. Data on File at GlaxoSmithKline Biologicals.
GSK data on file:. A phase III randomised, controlled study to assess in a double blind 
manner the lot-to-lot consistency of three consecutive production lots of 
GlaxoSmithKline (GSK) Biologicals’ 10-valent pneumococcal conjugate vaccine and to 
evaluate the non-inferiority to Prevenar in a single blind design, when administered as a 
3-dose primary immunization course before 6 months of age. Report 105553 (10PN-PD-
DIT-001) 13-June-2007. Data on File at GlaxoSmithKline Biologicals.
GSK data on file: A phase III, double-blind, randomised, placebo-controlled, multi-centre 
study to assess the efficacy, safety and immunogenicity of two or three doses of 
GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus (HRV) 
vaccine given concomitantly with routine Expanded Program of Immunisation (EPI) 
vaccinations in healthy infants. Report 102248 (Rota-037) 16-March-2009. Data on File 
at GlaxoSmithKline Biologicals.
Hausdorff WP, Siber G, Paradiso PR. Geographical differences in invasive pneumococcal 
disease rates and serotype frequency in young children. Lancet. 2001; 357:950-2.
Henckaerts I, Goldblatt D, Ashton L et al. Critical Differences between Pneumococcal 
Polysaccharide Enzyme-Linked Immunosorbent Assays with and without 22F Inhibition 
at Low Antibody Concentrations in Pediatric Sera. Clinical Vaccine Immunology. 2006; 
13:356-360.
Henckaerts I, Durant N, De Grave D et al. Validation of a routine opsonophagocytosis 
assay to predict invasive pneumococcal disease efficacy of conjugate vaccine in children. 
Vaccine. 2007; 25(13):2518-2527.
Karpinsky KF, Hayward S, Tryphonas H. Statistical considerations in the quantitation of 
serum immunoglobulin levels using the enzyme-linked immunosorbent assay (ELISA). J 
Immunol Methods. 1987; 103:189-94.
Madhi SA, Cunliffe NA, Steele D et al. Effect of human rotavirus vaccine on severe 
diarrhea in African infants. N Engl J Med. 2010; 362(4):289-298.
Melville-Smith ME, Seagroatt VA, Watkins JT. A comparison of enzyme-linked 
immunosorbent assay (ELISA) with the toxin neutralization test in mice as a method for 
the estimation of tetanus antitoxin in human sera. J Biol Stand. 1983; 11:137-44.
 
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Quataert SA, Kirch CS, Wiedl LJ et al. Assignment of weight-based antibody units to a 
human antipneumococcal standard reference serum, lot 89-S. Clin Diagn Lab Immunol. 
1995; 2(5):590-597.
Romero-Steiner S, Libutti D, Pais LB et al. Standardization of an opsonophagocytic 
assay for the measurement of functional antibody activity against Streptococcus 
pneumoniae using differentiated HL-60 cells. Clin Diagn Lab Immunol. 1997; 4(4):415-
422.
Sato Y, Sato H, Izumiya K et al. Role of antibody to filamentous hemagglutinin and to 
leukocytosis promoting factor-hemagglutinin in immunity to pertussis. In: Robbins J B, 
Hill J C, Sardoff J C ed. Seminars in Infectious Disease: Bacterial Vaccines. New-York: 
Thierne-Stratton, Inc. 1982; 380-85.
Smith PG, Morrow RH. Methods for Field Trials of Interventions against Tropical 
Diseases: A Toolbox. Oxford University Press. 1991; 152-155;168-175.
Vesikari T, Wysocki J, Chevallier B et al. Immunogenicity of the 10-valent 
pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-
CV) compared to the licensed 7vCRM vaccine. Pediatr Infect Dis J. 2009 (4 Suppl):S66-
S76
Vryheid RE, Kane MA, Muller N, Schatz GC, Bezabeh S. Infant and Adolescent 
Hepatitis B Immunization up to 1999: A Global Overview. Vaccine. 2001;19: 1026-1037.
WHO position paper on pneumococcal vaccines. Weekly epidemiological record No 74, 
1999, 177-183]
WHO position paper on Rotavirus vaccines. Weekly epidemiological record No. 32, 2007, 
82, 285-296.
WHO position paper on hepatitis B vaccines. Weekly epidemiological record No. 40, 
2009; 84:405-420.
WHO Hepatitis B Fact Sheet WHO/204. 2008. 
http://www.who.int/mediacentre/factsheets/fs204/en/index.html. Accessed 15 April 2010.
 
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APPENDIX A
LABORATORY ASSAYS
As serum represents approximately 50% of whole blood.
After blood centrifugation and serum separation, samples will be stored at -20°C until 
collection by the Sponsor. The aliquots of serum will be sent to GSK Biologicals for the 
tests described in the following paragraphs.
Antibody levels against CS
Antibody levels against CS will be measured at CEVAC (or a validated laboratory 
designated by GSK Biologicals) by standard ELISA methodology using plate adsorbed 
R32LR antigen with a standard reference antibody as a control according to SOPs from 
the laboratory. Results will be reported in EU/ml.
Antibody levels against HBsAg
Antibody responses against hepatitis B virus surface antigen (HBsAg) will be quantified 
at CEVAC using an in-house validated sandwich ELISA. Results are expressed in 
mIU/ml, and the cut-off for seroprotection is 10 mIU/ml.
Antibody levels against HB RF1-like antibodies
RF1-like antibodies will be measured at CEVAC using an in-house developed 
competitive ELISA with plate adsorbed HBs antigen. Dilutions of the test samples and 
the reference serum are mixed with a fixed amount of RF1 monoclonal antibody (mAb). 
The amount of antibody competing with RF1 mAb for binding to HBsAg is quantified by 
comparison with the reference serum according to SOPs from the laboratory. The results 
are expressed in ELISA Units per milliliter (EU/ml).
Measurement of rotavirus IgA Antibodies by ELISA
This assay allows the detection of rotavirus IgA in human serum and was initially 
designed by R. Ward [Bernstein 1998; Bernstein 1999]. It will be used for measuring the 
immune response after vaccination and/or infection. Samples will be analyzed at GSK 
Biologicals, Rixensart, Belgium (or a validated laboratory designated by GSK 
Biologicals). IgA antibody responses against rotavirus antigen will be quantified using an 
in-house validated sandwich ELISA. Results are expressed in U/ml, and the cut-off for 
seroprotection is 20 U/ml.
Pneumococcal ELISA test
Pneumococcal serotype specific total IgG antibodies (antibodies to 1, 4, 5, 6B, 7F, 9V, 
14, 18C, 19F and 23F) will each be measured by 22F-inhibition ELISA [Concepcion
2001; Henckaerts 2006]. The antibody concentration will be determined by logistic log 
comparison of the ELISA curves with a standard reference serum 89-SF available from 
the US Food and Drug Administration (FDA) for which concentration of IgG and IgM to 
the 10 serotypes are known in µg/ml [Quataert 1995]. The cut-off of the assay is 
0.05 g/ml.
 
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Pneumococcal opsonophagocytic activity
S. pneumoniae opsonophagocytic activity will be measured by a killing-assay using a HL 
60 cell line [Romero-Steiner 1997; Henckaerts 2007]. The results will be presented as the 
dilution of serum (opsonic titer) able to sustain 50 % killing of live pneumococci under 
the assay conditions. The cut-off of the assay is an opsonic dilution of 8.
Pneumococcal protein D
Anti-PD antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific PD antibodies will be determined, using a  
reference serum. The cut-off of the assay is 100 EU/ml.
Antibody levels against acellular B pertussis antigens (anti-PT, anti-FHA, 
anti-PRN)
Specific antibodies against diphtheria toxoid will be measured by ELISA techniques or 
multiplex techniques (Luminex technology). The cut-off of the test is 0.1 IU/ml. 
[Camargo, 1984]. Pre-booster samples with anti-diphtheria concentrations <0.1 IU/ml 
will be measured by the Vero-cell neutralisation test for which the cut-off is 0.016 IU/ml. 
Antibody concentrations greater than or equal to this value are considered as protective 
[Camargo, 1984].
Specific antibodies against tetanus toxoid will be measured by ELISA techniques 
[Melville-Smith, 1983] or multiplex techniques (Luminex technology). The cut-off of the 
test is 0.1 IU/ml.
IgG antibodies against the pertussis antigens (pertussis toxoid [PT], filamentous 
haemagglutinin [FHA] and pertactin [PRN]) will be measured by ELISA techniques or 
multiplex techniques (Luminex technology). The cut-off of the tests is 5 El.U/ml 
[Karpinsky, 1987; Granström, 1987; Sato, 1982].
 
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APPENDIX B
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Administrative change 1
eTrack study number and 
Abbreviated Title:
1136818 (MALARIA-063)
Administrative change number:
Administrative change 1
Administrative change date:
22 November 2011
Co-ordinating author:
 Project Manager Scientific 
Writer Malaria Vaccines
Rationale/background for changes:
Some typographical errors were corrected for clarity:

In Synopsis table 1 and in Table 3 : the footnote of Rotarix in the RE[RoP]s group 
was corrected (should be footnote b and not c)
RE[RoP]s
RE[RoP]s lot 1
RTS,S/AS01Ea + CoAd (Infanrix /Hiba + Polio Sabina) + 
staggered (Synflorixd + Rotarixb)
141
(47+47+47)
RE[RoP]s lot 2
RE[RoP]s lot 3

The volume of the reconsitued Rotarix is 1.0 ml. It was errouneously recorded as 
1.5 ml in table 15 and in the heading of section 6.3.5. and has been corrected.
Vaccine
Formulation
Presentation
Volume
Number 
of doses
Rotarix
Rotarix contains not less than 106.0 CCID50 
(Cell Culture Infectious Dose 50%) of live 
attenuated human rotavirus RIX4414 strain. 
The excipients of Rotarix (oral) comprise 
sucrose, dextran, sorbitol, amino acids, 
Dulbecco’s Modified Eagle Medium (DMEM), 
calcium carbonate, xanthan and sterile water.
It is presented as powder 
in a glass container and 
an oral applicator 
containing the diluent.
1.5 1.0 ml
2
6.3.5 Rotarix (1.5 1.0 ml dose)

Infanrix is administered in the right deltoid as described in Table 16. In section 
6.3.4. this was mistakenly mentioned in the left deltoid and has been corrected.
6.3.4. Infanrix/Hib (0.5 ml dose)
In order to ensure proper intramuscular injection of the study vaccines, a needle of at 
least 1 inch (2.54 cm) length, 25 gauge will be used. The vaccine will be administered 
as an intramuscular injection into the left right deltoid.
Corrected text has been indicated in bold italics, deletions are indicated by 
strikethrough.
 
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