Efficacy, Safety and Immunogenicity Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Schedules With or With-out Fractional Doses, Early Dose 4 and Yearly Doses, in Children 5-17 Months of Age
Phase: PHASE2
Conditions: Malaria
Sponsor: GlaxoSmithKline

Protocol Amendment 3
Study ID:  204889
Official Title of Study: Efficacy, Safety and Immunogenicity Study of GSK 
Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Schedules With 
or With-out Fractional Doses, Early Dose 4 and Yearly Doses, in Children 
5-17 Months of Age
NCTID: NCT03276962
Date of Document: 14 November 2019

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4 -N O V -2 0 1 9
1
Cli ni c al St u d y Pr ot o c ol
S p o n s or:
Gl a x o S mit h Kli n e Bi ol o gi c al s
R u e d e l’I n stit ut 8 9, 1 3 3 0 Ri x e n s art,
B el gi u m
Pri m ar y st u d y 
v acc i ne/ pr o duct a n d 
n u m ber

Gla x o S mit h Kli ne ( G S K) Bi ol o gicals’ ca n di date 
Pl as m o di u m f alci p ar u m malaria vacci ne 
R T S, S/ A S 0 1 E ( S B 2 5 7 0 4 9).
Ot her s t u d y 
v acci ne/ pr o d uct

Ra bies vacci ne ( Ra bi p ur ™)
e Tr ac k st u d y n u m ber a n d 
a b bre vi ate d title
2 0 4 8 8 9 (M A L A RI A -0 9 4 )
E u dr a C T n u m ber
2 0 1 6 -0 0 0 2 9 0 -2 0
D ate of pr ot oc ol
Fi nal : 1 6 Fe br uar y  2 0 1 6
D ate of pr ot oc ol 
a me n d me nt
A me n d me nt 1 Fi nal: 1 3 Se pte m ber 2 0 1 6
A me n d me nt 2 Fi nal : 0 6 A pril 2 0 1 7
A me n d me nt 3 Fi n al : 1 4 N ove m ber 2 0 1 9
Title
Efficac y , safet y a n d i m m u n o ge nicit y st u d y of G S K 
Bi ol o gicals’ ca n di date malaria vacci ne ( S B 2 5 7 0 4 9) 
e val uati n g sc he d ules wit h or wit h o ut fracti o nal d oses, 
earl y D ose 4 a n d ye arl y d oses, i n c hil dre n 5 -1 7 m o nt hs 
of a ge.
Det aile d title
P hase II b ra n d o mize d, o pe n -la bel, c o ntr olle d, m ulti-
ce nter st u d y of t he efficac y, safet y a n d 
i m m u n o ge nicity of G S K Bi ol o gicals’ ca n di date 
malaria vacci ne R T S, S/ A S 0 1 E e val uati n g sc he d ules 
wit h or wit h o ut fracti o nal d oses, earl y D ose 4 a n d 
ye arl y d oses, i n c hil dre n 5 -1 7 m o nt hs of a ge li vi n g i n 
s u b-Sa hara n Africa.
C o or di n ati n g a ut h or
,
Pr oject Ma na ger S cie nce W riti n g, M alaria V acci nes
C o ntri b uti n g a ut h ors / 
Revie wers

, T C S, a n d 
, I C O N, St u d y  Data Ma na gers, 
c o ntract ors f or G S K Bi ol o gicals

, 
St u d y  Deli ver y Lea d s

, Vacci ne S u p pl y  C o or di nat or

, Bi ostatistics

 
 Safet y P h ysicia ns

, Cli nical La b orat or y  Scie nces Lea d
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
2
e Tr ac k st u d y n u m ber a n d 
a b bre vi ate d title
2 0 4 8 8 9 ( M A L A RI A - 0 9 4)
E u dr a C T n u m ber
2 0 1 6- 0 0 0 2 9 0- 2 0
D ate of pr ot oc ol
Fi nal: 1 6 Fe br uar y  2 0 1 6
D ate of pr ot oc ol 
a me n d me nt
A me n d me nt 1 Fi nal: 1 3 Se pte m ber 2 0 1 6
A me n d me nt 2 Fi nal : 0 6 A pril 2 0 1 7
A me n d me nt 3 Fi n al : 1 4 N ove m ber 2 0 1 9
Det aile d title
P hase II b ra n d o mize d, o pe n -la bel, c o ntr olle d, m ulti-
ce nter st u d y of t he efficac y, safet y a n d 
i m m u n o ge nicity of G S K Bi ol o gicals’ ca n di date 
malaria vacci ne R T S, S/ A S 0 1 E e val uati n g sc he d ules 
wit h or wit h o ut fracti o nal d oses, earl y D ose 4 a n d 
ye arl y d oses, i n c hil dre n 5 -1 7 m o nt hs of a ge li vi n g i n 
s u b-Sa hara n Africa.
C o ntri b uti n g a ut h ors / 
Revie wers (c o nti n ues)

, 
Cli nical L a b orat or y Scie nces St u d y Ma na gers

, Lea d 
Statisticia n s

 
Cli nical Researc h a n d De vel o p me nt Lea d s

, Se ni or 
L ocal Deli ver y  Lea ds

, Gl o bal Pate nt re prese ntati ve

, B usi ness a n d Decisi o n Life 
Scie nces, Pr oject Data Ma na ger s, c o ntract ors f or 
G S K Bi ol o gicals

, Pr oject 
Statisticia n s

, Cli nical Re g ulat or y 
Affairs re prese ntati ve

, St u dy Deli v er y Ma na ger

, Cli nical 
Researc h & De vel o p me nt, R & D Ce nter Bel gi u m
a n d 
, Cli nical & E pi de mi ol o g y  
Pr oject Lea d, D D W Vacci nes, Bel gi u m
G S K Bi ol o gic als’ Pr ot oc ol D S v 1 4. 1. 1
© 2 0 1 6 -2 0 1 9 G S K gr o u p of c o m p a nies or its lice ns or.
A me n de d 1 4 N ove m ber 2 0 1 9
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

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204889 (MALARIA-094)
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Protocol Amendment 3 Sponsor Signatory Approval
eTrack study number and 
abbreviated title
204889 (MALARIA-094)
EudraCT number
2016-000290-20
Date of protocol amendment
Amendment 3 Final: 14 November 2019
Detailed title
Phase IIb randomized, open-label, controlled, multi-
center study of the efficacy, safety and 
immunogenicity of GSK Biologicals’ candidate 
malaria vaccine RTS,S/AS01E evaluating schedules 
with or without fractional doses, early Dose 4 and 
yearly doses, in children 5-17 months of age living in 
sub-Saharan Africa.
Sponsor signatory
François Roman, Clinical & Epidemiology Project 
Lead, DDW Vaccines
Signature
Date

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204889 (MALARIA-094)
Protocol Amendment 3 Final
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Protocol Amendment 3 Rationale
Amendment number:
Amendment 3
Rationale/background for changes: 
Case definition of severe P. falciparum malaria: Per protocol, impaired consciousness 
was to be evaluated using the Glasgow coma score for children ≥ 2 years and using the 
Blantyre coma score for children < 2 years (Appendix C: Case definition of severe P. 
falciparum malaria). However, local practice is to use the Blantyre coma score for 
children. After discussion with the Independent Data Monitoring Committee (IDMC),
only the Blantyre coma score is to be used for assessment of impaired consciousness in 
all age groups in the study. 
Per protocol, filter paper blood spots were to be collected for use in the ancillary study, 
MALARIA-095, to look at vaccine efficacy against clinical and asymptomatic malaria 
infection using ultra-sensitive molecular amplification and sequencing methodology. 
However, the MALARIA-095 protocol will use samples only up to Month 32. The 
MALARIA-094 protocol has been amended to reflect filter paper sampling up until the 
Month 32 timepoint.
In the assessment of vaccine efficacy against all episodes of malaria (Section 11.7.2), 
an estimated seven days for drug clearance (half-life) following an episode meeting the 
case definition under evaluation was to be subtracted from the follow-up time. This has 
been changed to 14 days to be in line with actual clearance and also to allow for 
comparison with previous Phase III efficacy data in the same population (MALARIA-
055 data).
The anti-CS immunogenicity endpoint for the immunogenicity secondary objective 
‘Immune response to the CS antigen’ was inadvertently omitted between protocol 
amendment 1 and protocol amendment 2 and has been reinstated.
According to EU regulation, the definition of end of study (EoS) must be included in 
the clinical protocol, and the study report submitted in a predefined timeframe based on 
the EoS milestone. Per GSK policies, a summary of the study results have to be 
publicly disclosed, the reference milestone for which is based on the primary 
completion date. The definitions for the EoS and primary completion date have been 
clarified. Details for the disclosure of protocol information and study results have been 
updated (Section 12.5).
APPENDIX D Safety Laboratory Testing: CLS South Africa: the number of tests that 
can be performed by polymerase chain reaction (PCR) on cerebrospinal fluid (CSF) 
and serum samples has increased. The Appendix has been amended to show the 
breadth of analyses available.

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Protocol Amendment 3 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GSK Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccine and other study-related duties and 
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative (LAR).

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s).

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine, and more generally about his/her financial 
ties with the sponsor. GSK Biologicals will use and disclose the information solely 
for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study.

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.

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204889 (MALARIA-094)
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eTrack study number and 
abbreviated title
204889 (MALARIA-094)
EudraCT number
2016-000290-20
Date of protocol amendment
Amendment 3 Final: 14 November 2019
Detailed title
Phase IIb randomized, open-label, controlled, multi-
center study of the efficacy, safety and 
immunogenicity of GSK Biologicals’ candidate 
malaria vaccine RTS,S/AS01E evaluating schedules 
with or without fractional doses, early Dose 4 and 
yearly doses, in children 5-17 months of age living in 
sub-Saharan Africa.
Investigator name
Signature
Date

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204889 (MALARIA-094)
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 9.3.2.

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SYNOPSIS
Detailed Title
Phase IIb randomized, open-label, controlled, multi-center 
study of the efficacy, safety and immunogenicity of GSK 
Biologicals’ candidate malaria vaccine RTS,S/AS01E
evaluating schedules with or without fractional doses, early 
Dose 4 and yearly doses, in children 5-17 months of age living 
in sub-Saharan Africa.
Indication
Primary immunization against malaria disease caused by 
Plasmodium falciparum (P. falciparum) in children.
Rationale for the 
study and study 
design
Rationale for the study
GSK Biologicals and PATH are committed to develop a 
malaria vaccine for reduction of malaria disease burden in 
children and contribution to the malaria elimination goal. 
Characterization of an optimal dosing regimen and boosting 
schedules will be critical.
The results of the efficacy study MALARIA-055 PRI, 
including the long term follow-up data and efficacy of the 
fourth dose administered 18 months after the third dose, and the 
preliminary results of MALARIA-071 were reviewed by the 
European Medicines Agency (EMA) during the assessment of 
the initial Application of the RTS,S/AS01E candidate vaccine. 
The EMA asked the company to address the following points in 
ongoing or future studies:  1) the timing of the fourth dose and 
evaluation of the safety and efficacy of an early fourth dose;  2) 
the efficacy and safety of multiple yearly doses and whether the 
vaccine predisposes to some degree of hyporesponsiveness to 
sequential doses; and  3) the plans to further investigate the 
potential utility of a delayed and fractionated third dose 
schedule in the target age range.
The current study is designed to address these points in the 
pediatric population. It aims to:

Establish proof of concept (POC) for a fractional (Fx) dose 
schedule under conditions of natural exposure.

Establish the role of third dose spacing in a fractional dose 
schedule.

Describe the effect of an earlier full fourth dose at 
Month 14.

Describe the effect of multiple fractional or full yearly 
doses.

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Rationale for the study design
A recent controlled human malaria infection (CHMI) study
(MALARIA-071) demonstrated superior protection against 
malaria infection associated with the use of a fractional third 
dose in a 0, 1, 7-month schedule with a vaccine efficacy against 
infection of 86.7% (95% CI: 66.8; 94.6; p<0.0001) versus 
62.5% (95% CI: 29.4; 80.1; p=0.0009) in the standard 0, 1, 2-
month schedule. The incremental efficacy of the 0, 1, 7-month 
schedule over the 0, 1, 2-month schedule was 64.4% (95% 
CI: -7.9; 88.3; p=0.0741) [Regules, 2016]. The current study 
intends to establish POC for a fractional dose schedule under 
conditions of natural exposure. The study will be conducted in 
children 5-17 months old at first vaccination living in areas of 
mid to high malaria transmission, in line with the age group 
recommended by the World Health Organization (WHO)
[WHO, 2016]. Infants 6-12 weeks old will not be included in 
this POC study to avoid interference of co-administration with 
the standard Expanded Program on Immunization (EPI) 
vaccines.
Results from this study will be critical in informing future 
possibilities for the development of vaccine-based strategies 
which, in combination with other interventions, may contribute 
to the malaria elimination agenda.
The study proposed herein will include five study groups. One 
group (R012-20) will receive the standard schedule consisting 
of RTS,S/AS01E full dose given at Month 0, Month 1, Month 2 
and a fourth dose at Month 20. This corresponds to the schedule 
that received a positive scientific opinion from EMA. The four 
other groups will receive alternative schedules as follow:

Group R012-14-mD will receive RTS,S/AS01E full dose at 
Month 0, Month 1, Month 2, an early fourth dose at Month 
14 and yearly full doses at Month 26 and Month 38.

Group Fx012-14-mFxD will receive RTS,S/AS01E full 
dose at Month 0 and Month 1, RTS,S/AS01E fractional 
dose (1/5th dose) at Month 2 and yearly fractional doses at 
Month 14, Month 26, Month 38.

Group Fx017-mFxD will receive RTS,S/AS01E full dose at 
Month 0 and Month 1, RTS,S/AS01E delayed fractional 
third dose (1/5th dose) at Month 7 and yearly fractional 
doses at Month 20 and Month 32.

Control group: will receive three doses of rabies vaccine at 
Month 0, Month 1 and Month 2.

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Rationale for the inclusion of a control group
This study plans to evaluate malaria occurrence in subjects 
vaccinated with RTS,S/AS01E according to various schedules 
and in subjects vaccinated with a non-malaria comparator 
vaccine (rabies vaccine). While partial protection provided by 
RTS,S/AS01E in the age range of subjects which will be 
enrolled in this study has been demonstrated, the use of a non-
malaria comparator vaccine is deemed acceptable, in line with 
relevant published references about the use of placebo in 
vaccine trials [Rid, 2014; WHO, 2013].
It is deemed unacceptable to use a placebo control when study 
participants are exposed to unacceptable levels of risk from 
delaying administration of a safe and effective vaccine that is 
accessible through the public health system of the country in 
which the study is planned. However, the Nuffield Council on 
Bioethics guidelines state that the use of placebos may be 
acceptable if participants are not deprived of a treatment they 
would have otherwise received, but are provided at a minimum 
with the standard of care that is the best available in the 
country’s public health system. CIOMS (Council for 
International Organizations of Medical Sciences), ICH 
(International Committee on Harmonization) and UNAIDS 
(Joint United Nations Programme on HIV/AIDS) guidelines
stipulate that researchers must take steps to minimize any risks 
associated with the use of controls. The protocol should explain 
clearly the scientific justification for using a placebo-controlled 
design, and specifically address whether (1) the study question 
cannot be answered with an active-controlled study design; and 
(2) the risks of delaying an existing efficacious vaccine are 
adequately minimized or mitigated; and (3) the use of a placebo 
control is justified by the potential public health value of the 
research; and (4) the research is responsive to local health 
needs.
In accordance with these recommendations, the use of a non-
malaria comparator vaccine in this study is deemed acceptable 
as:
1.
Local availability. Local regulatory recommendation for 
RTS,S/AS01E use has not been granted. If granted, it is 
anticipated that availability in the local health system will 
take some time to deploy. It is therefore not the case that 
study subjects would be deprived from a locally available 
effective prevention tool.

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2.
Risk mitigation. Subjects will have access to the best 
locally available malaria prevention and treatment options. 
All screened subjects will be provided with an insecticide-
treated bednet (ITN), and malaria diagnosis and treatment
will be ensured. The investigator will make every effort to 
ensure that preventive measures as provided by the 
government are adhered to and under circumstances where 
this is not possible discussions with the sponsor need to 
take place. It is anticipated that subjects will benefit from 
participation in the study in terms of facilitated access to 
care and relatively intense health monitoring. Reduced 
levels of morbidity related to participation in a 
RTS,S/AS01E study has been documented [Hamel, 2014].
3.
Study design justification. Without a control group, the 
following scientific questions could not be answered with 
scientific integrity:

Comparison of malaria incidence between different 
time periods. 
Without a control group, the direct comparison of 
post-RTS,S/AS01E vaccination malaria incidence 
between two different study periods (example: 
assessment of post-Dose 3 protection in the 0, 1, 2-
month and 0, 1, 7-month schedules, evaluation of 
optimal timing of the fourth dose, waning of efficacy) 
would carry a risk of bias associated with seasonal 
variations in malaria incidence.

Evaluation of strain-specificity of protection. 
A genetic characterization of malaria infections is 
planned as an ancillary study (using samples collected 
in the present study) with the aim to determine 
whether vaccine efficacy varies according to the 
parasite strain. This requires comparison of parasite 
genetics in the vaccinated groups with the Control 
group.
4.
Public health need. RTS,S/AS01E has been shown to 
prevent malaria with a moderate level of efficacy [The 
RTS,S Clinical Trials Partnership, 2015]. The development 
of a malaria vaccine with higher efficacy remains an 
important public health need [Malaria Vaccine Technology 
Roadmap, 2013]. Finding the immunization schedule able 
to provide the highest protection is very relevant to local 
public health needs.
To be noted, the study subjects in the Control group will get the 
benefit of receiving a rabies vaccine as comparator vaccine, 

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204889 (MALARIA-094)
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also advocated as a valuable preventive health intervention by 
the WHO [WHO, 2007].
Rationale for the use of a rabies vaccine as a comparator 
vaccine
Subjects randomized to the Control group will receive three 
doses of a cell culture rabies vaccine on a 0, 1, 2-month 
schedule. In humans, rabies is almost invariably fatal once 
clinical signs occur. Bites by rabid domestic dogs cause 99% of 
human rabies deaths globally. More than 3.3 billion people live 
in regions where rabies is enzootic. Approximately 55 000 
people die from rabies each year, the vast majority of these 
deaths occurring in Asia and Africa [WHO, 2007]. Estimates of 
risks of infection with rabies in Africa are available from the 
WHO [WHO, 2015].
The efficacy of cell culture-derived rabies vaccines including 
human diploid cells vaccine (HDCV), purified Vero cell rabies
vaccine (PVRV), purified chick embryo cells vaccine 
(PCECV), purified hamster kidney cells vaccine (PHKCV) and 
purified duck embryo cells vaccine (PDEV) has been 
demonstrated [WHO, 2010]. In this study, a PCECV (Rabipur) 
will be used as comparator vaccine.
PCECV has been widely used for rabies pre-exposure 
prophylaxis in children. In total, PCECV has been administered 
to more than 1200 children in clinical studies, from toddlers to 
those in elementary school, demonstrating safety and 
immunogenicity. Various schedules of PCECV (2-doses and 3-
doses) and administration route (intramuscular and intradermal) 
were evaluated in children. Intramuscular administration 
resulted in 3- to 5-fold higher titers than intradermal 
administration [Malerczyk, 2013]. In studies using pre-
exposure prophylaxis in children, all children achieved 
adequate rabies virus neutralizing antibody (VNA) 
concentrations by Day 14, i.e., after receiving two doses of 
vaccine, even before the third dose of vaccine was received. 
Regardless of the route of administration (intramuscular or 
intradermal), VNA concentrations reached levels above 
0.5 IU/ml [Malerczyk, 2013]. The definition of a target 
antibody titer varies among laboratories and is influenced by 
the type of test conducted. WHO specifies a titer of 0.5 IU/ml 
[WHO, 2007].

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Objectives
Primary

Efficacy: Incremental efficacy of a schedule with a 
fractional third dose at Month 2 over the standard 
schedule
To demonstrate the superiority of a 3-dose schedule of 
GSK Biologicals’ malaria vaccine RTS,S/AS01E with a 
fractional third dose at Month 2 compared to a standard 
schedule of RTS,S/AS01E with three full doses in terms of 
vaccine efficacy against clinical malaria (primary case 
definition) over 12 months post-Dose 3.
Criterion:
The lower limit of the 95% CI of the incremental vaccine 
efficacy estimate is above 0.
Secondary

Efficacy

To assess the incremental vaccine efficacy against 
clinical malaria of a schedule with a fractional third 
dose at Month 2 versus a schedule with 3 full doses 
(primary and secondary case definitions) over 12 
months post-Dose 3.

To assess the incremental vaccine efficacy against 
clinical malaria, over 7 and 12 months post-Dose 3, of 
a schedule with a fractional third dose at Month 7 
versus a schedule with a fractional third dose at Month 
2.

To assess the incremental vaccine efficacy against 
clinical malaria, over 7 and 12 months post-Dose 3, of 
a schedule with a fractional third dose at Month 7 
versus a schedule with 3 full doses. 

To assess the incremental vaccine efficacy against 
clinical malaria, over 12 months post-Dose 4, post-
Dose 5 and post-Dose 6 of a schedule with a fractional 
third dose at Month 2 and yearly fractional doses 
versus a schedule with full doses at Month 0, Month 1, 
Month 2 and yearly full doses.

To assess the incremental vaccine efficacy against 
clinical malaria, over 12 months post-Dose 4, of a 
schedule with a fractional third dose at Month 7 versus 
a standard schedule with 4 full doses at 0,1,2,20 
months.

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
To assess the vaccine efficacy and impact of each 
RTS,S/AS01E schedule over the entire study period by 
measuring the efficacy against clinical malaria at 
Months 14, 20, 26, 32, 38 and 50.

To assess the prevalence of P. falciparum infections of 
each RTS,S/AS01E schedule at cross-sectional visits 
(monthly from Month 0-20 and every three months 
thereafter till study end).

To assess the vaccine efficacy against incident P. 
falciparum infections defined by positive blood slide 
over the entire study period.

Immunogenicity: Immune response to the CS and HBs 
antigens

To describe the antibody response to the anti-
circumsporozoite protein of P. falciparum (anti-CS) 
for each schedule. 

To describe the antibody response to the hepatitis B 
surface antigen (anti-HBs) for each schedule.

Safety and reactogenicity

To assess the safety of RTS,S/AS01E for each 
schedule in terms of serious adverse events (SAEs), 
unsolicited adverse events (AEs) and AEs of specific 
interest.

To assess the reactogenicity of RTS,S/AS01E in terms 
of solicited local and general AEs.

To assess the safety of RTS,S/AS01E in terms of 
biochemistry (alanine aminotransferase [ALT], 
creatinine) and hematology (hemoglobin, white blood 
cells [WBC], platelets) parameters.
Tertiary

Immunogenicity

To describe the anti-CS antibody response in terms of 
avidity.
Of note, blood samples taken in this study may also be used in 
ancillary studies. More details on ancillary studies are provided 
in the study design section of this protocol.

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Study design

Experimental design: Phase IIB, randomized, open-label, 
controlled, multi-centric study with five parallel groups.

Duration of the study: Approximately 50 months, with 
two interim analyses and option for conditional 
continuation (see next bullet point).

Epoch 001: Starting at Visit 1 (Screening) and ending 
at Visit 17 (Month 13). Note: the data up to Visit 18 
(Month 14) pertains to Epoch 001.

Epoch 002: Starting at Visit 18 (Month 14) and ending 
at Visit 26 (Month 23). Note: the data up to Visit 27
(Month 26) pertains to Epoch 002.

Epoch 003: Starting at Visit 27 (Month 26) and ending 
at Visit 32 (Month 35). Note: the data up to Visit 33
(Month 38) pertains to Epoch 003.

Epoch 004: Starting at Visit 33 (Month 38) and ending 
at Visit 38 (Month 50).

Primary completion date: Visit 18 (Month 14) or last visit 
of Epoch 001.
Refer to the GLOSSARY OF TERMS for the definition of 
primary completion date.

End of Study (EoS): Last testing results released of 
samples collected at Visit 38 (Month 50).
Refer to the GLOSSARY OF TERMS for the definition of 
EoS.
Amended 14 November 2019

Sequence of analyses and conditional continuation:

A first analysis will be performed on data collected up 
to Month 21 (Visit 25) to evaluate the primary 
objective and relevant secondary objectives.

A second analysis will be performed on data collected 
up to Month 33 (Visit 31) to evaluate relevant 
secondary objectives.

A final analysis will be performed at study end (Month 
50) on data collected up to Month 50. An integrated 
study report presenting all results until Month 50 will 
be produced.
After the interim analyses, the Independent Data Monitoring 
Committee (IDMC) will have the possibility to recommend the 
suspension of further vaccinations and termination of specific 
study group(s) upon consideration of the study results. In the 
event that the IDMC recommend the suspension of further 
vaccinations, the group(s) impacted will be followed up for 12 
months after their last study vaccination.

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
Study groups:
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Vaccination schedule
Number 
of 
subjects
Age 
(Min/Max)
Epochs
Epoch 
001
Epoch 
002
Epoch 
003
Epoch 
004
R012-20
RTS,S/AS01E full dose at 
Month 0, Month 1, Month 2 + 
a full dose at Month 20
300
5 months -
17 months
x
x
x
x
R012-14-mD
RTS,S/AS01E full dose at 
Month 0, Month 1, Month 2 + 
yearly full doses at Month 14, 
Month 26, Month 38
300
5 months -
17 months
x
x
x
x
Fx012-14-mFxD
RTS,S/AS01E full dose at 
Month 0, Month 1 
+ RTS,S/AS01E 1/5th dose at 
Month 2, Month 14, Month 26, 
Month 38
300
5 months -
17 months
x
x
x
x
Fx017-mFxD
RTS,S/AS01E full dose at 
Month 0, Month 1 
+ RTS,S/AS01E 1/5th dose at 
Month 7, Month 20, Month 32
300
5 months -
17 months
x
x
x
x
Control
Rabies vaccine at Month 0, 
Month 1, Month 2
300
5 months -
17 months
x
x
x
x
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name Vaccine/Product 
name
Injectable 
volume
Study groups
R012-20
R012-14-
mD
Fx012-14-
mFxD
Fx017-
mFxD
Control
RTS,S/AS01E
(Full dose)
RTS,S (25 µg)
0.5 ml
x
x
x
x
AS01E
x
x
x
x
RTS,S/AS01E
(1/5th dose)
RTS,S (25 µg)
0.1 ml
x
x
AS01E
x
x
Rabies vaccine
Rabipur
1.0 ml
x

Control: active control, (Active comparator: rabies 
vaccine).

Vaccination schedules: are provided in Synopsis Table 1.

Treatment allocation: randomized.

Blinding: open.

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
1 7
S y n o p si s T a bl e 3
Bli n di n g of st u d y  e p o c h s
St u d y e p o c h s
Bli n di n g
E p oc h 0 0 1
o p e n
E p oc h 0 0 2
o p e n
E p oc h 0 0 3
o p e n
E p oc h 0 0 4
o p e n

S a m pli n g sc he d ule:

Bl o o d sa m ples f or i m m u n o ge nicit y will be ta ke n i n all 
s u bjects at ti me p oi nts descri be d i n S yn o psis Ta ble 4. 
F or t he e val uati o n of a nti-C S a n d a nti - H Bs res p o nses, a 
s u bset of 5 0 s u bjects ( 2 5 s u bjects per site) i n eac h gr o u p 
(i m m u n o ge nicity s u bset) will be teste d at s pecifie d 
ti me p oi nts
 

I n a d diti o n t o t he bl o o d sa m ples liste d i n S y n o psis 
Ta ble 4, a s mall a m o u nt of bl o o d (f or bl o o d s mear a n d 
filter pa per) will be ta ke n e ver y  m o nt h fr o m Da y 0 u ntil 
M o nt h 2 0 , a n d t hereafter e ver y t hree m o nt hs u ntil 
M o nt h 5 0 f or bl o o d s me ar a n d u ntil M o nt h 3 2 f or filter 
p a per i n all s u bjects f or t he e val uati o n of P. f alci p ar u m
i nfecti o ns.
A me n de d 1 4 N ove m ber 2 0 1 9

Bl o o d sa m ples f or t he e val uati o n of bi oc he mistr y  a n d 
he mat ol o g y  para meters will be ta ke n i n a s u b-c o h ort 
c o nsisti n g of t he first 5 0 s u bjects ( 2 5 s u bjects per site) 
e nr olle d i n eac h gr o u p (react o ge nicit y s u b-c o h ort). 
Bi oc he mistr y  ( A L T, creati ni ne) a n d he mat ol o g y 
( he m o gl o bi n, W B C, platelets) para meters will be 
assesse d bef ore D ose 3, se ve n da y s p ost-D ose 3 a n d 3 0 
da y s p ost-D ose 3 (see S y n o psis Ta ble 4 ).
C CI

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Synopsis Table 4
Blood sampling timepoints
Visit 
1
Visit 
2
Visit 
4
Visit 
5
Visit 
6
Visit 
10
Visit 
11
Visit 
12
Visit 
18
Visit 
19
Visit 
24
Visit 
25
Visit 
27
Visit 
28
Visit 
30
Visit 
31
Visit 
33
Visit 
34
Visit 
38
Study group
Type of blood 
sampling
Scr
D0
M2
M2 + 
7d
M3
M7
M7 + 
7d
M8
M14
M15
M20
M21
M26
M27
M32
M33
M38
M39
M50
R012-20
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
R012-14-mD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
x
Fx012-14-mFxD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
x
Fx017-mFxD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
Control
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
* At screening, hemoglobin will be assessed in all subjects screened.
** Blood samples for hematology and biochemistry will be taken in a sub-cohort consisting of the first 50 subjects enrolled in each group.
§ Blood samples for immunogenicity will be taken in all subjects enrolled.
Scr: Screening
M: Month
D: Day

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
Efficacy surveillance:

Capture of malaria cases: malaria cases will be captured 
by passive case detection (PCD). Parents/LARs will be 
advised to present their child to the health center if the 
child is unwell. Care will be administered according to 
local recommendations. All children with fever and/or 
history of fever will have a blood sample taken for the 
evaluation of vaccine efficacy (blood slide throughout 
the study and filter paper for polymerase chain reaction 
[PCR] up until month 32). All anti-malaria treatments 
administered during the study should be recorded in the 
subject’s eCRF.
Amended 14 November 2019

Cross-sectional surveys: to evaluate the vaccine efficacy 
against incident and prevalent P. falciparum infections, 
monthly cross-sectional surveys will be performed from 
Day 0 until Month 20 to measure P. falciparum 
parasitemia. Thereafter until study end (Month 50) 
parasitemia will be measured every three months. Blood 
slides from cross-sectional surveys will not be read in 
real time.

The research team at each study center will provide all 
screened subjects with an ITN, and malaria diagnosis 
and treatment will be ensured.

Type of study: self-contained.

Ancillary studies:

The incidence of P. falciparum infection assessed by 
PCR and parasite genotyping will be evaluated in an 
ancillary study, with details provided in a separate 
protocol, using filter paper samples collected as 
described in the present protocol.

In addition, further characterization of the immune 
response and translational research for correlates of 
protection may be evaluated in ancillary studies, with 
details provided in a separate scope of work, using 
samples collected as described in the present protocol.

Data collection: Electronic case report form (eCRF).

Safety monitoring:

This study will be overseen by a formally constituted 
IDMC operating under a charter.

Each subject will be observed for at least 30 minutes 
after vaccination to evaluate and treat any acute AEs.

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
Cases of severe malaria and cerebral malaria will be 
reported as part of the safety surveillance until study end 
(Month 50) and clinical details of each case will be 
reported in a specific eCRF screen.

All SAEs will be reported until study end (Month 50).

Where possible autopsies will be performed. Verbal 
autopsy will be performed on all cases of mortality 
occurring outside hospital if autopsies cannot be 
performed.

All AEs and SAEs leading to withdrawal from further 
vaccination will be reported until study end (Month 50).

Meningitis and potential immune-mediated diseases 
(pIMDs) are AEs of specific interest to be reported until 
study end (Month 50). All seizures occurring within 30 
days post-vaccination are also AEs of specific interest. 
Clinical details according to the Brighton collaboration 
guidelines [Bonhoeffer, 2004] pertaining to seizures 
occurring within seven days of vaccination will be 
documented in a specific eCRF screen. All AEs of 
specific interest are to be reported as SAEs.

Reactogenicity data collection will be aimed at 
characterizing reactions to the fractional doses relative 
to full doses and reactions to a fourth dose and multiple 
yearly doses, full or fractional. Post-Dose 1 and post-
Dose 2 data will not be collected as these have already 
been largely characterized in previous studies including 
Phase III evaluation. Solicited local and general AEs 
will be collected in the first 50 subjects enrolled in each 
group (reactogenicity sub-cohort) during four days (day 
of vaccination and three subsequent days) after Dose 3 
of study vaccine (all groups including controls), after 
Dose 4 (R012-20, R012-14-mD, Fx012-14-mFxD and 
Fx017-mFxD), after Dose 5 (R012-14-mD, Fx012-14-
mFxD and Fx017-mFxD) and after Dose 6 (R012-14-
mD and Fx012-14-mFxD). Evidence from Phase III 
evaluation showed that the significant reactogenicity 
reactions to RTS,S/AS01E are concentrated in the first 
48 hours post-vaccination. On the day of vaccination the 
evaluation will be carried out by the study physician at 
the study center. On Days 1, 2 and 3 after vaccination, 
trained study personnel will visit the children to record 
solicited AEs on diary cards.

Unsolicited AEs will be collected during 30 days (day of 
vaccination and 29 subsequent days) after each dose of 
study vaccine. Unsolicited AEs will be captured through 

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passive surveillance at inpatient and outpatient facilities 
and during study visits.

Biochemistry (ALT, creatinine) and hematology 
(hemoglobin, WBC, platelets) parameters will be 
assessed in the first 50 subjects enrolled in each group 
(reactogenicity sub-cohort) before Dose 3, seven days 
post-Dose 3 and 30 days post-Dose 3.
Case definitions

Clinical malaria and P. falciparum infection
Synopsis Table 5
Case definitions of clinical malaria
Primary case 
definition
P. falciparum asexual parasitemia > 5000 parasites/μl
AND presence of fever (axillary temperature 37.5°C) at the time of presentation
AND occurring in a child who is unwell and brought for treatment to a healthcare facility
Secondary case 
definition
P. falciparum asexual parasitemia > 0
AND presence of fever (axillary temperature 37.5°C) at the time of presentation or history of 
fever within 24 hours of presentation
AND occurring in a child who is unwell and brought for treatment to a healthcare facility
Synopsis Table 6
Case definition of incident P. falciparum infection*
Case definition 1
A documented P. falciparum asexual parasite density > 0 detected by blood slide reading at a 
cross-sectional survey or as captured by the secondary case definition of clinical malaria (active 
detection of infection and passive case detection).
Synopsis Table 7
Case definition of prevalent P. falciparum infection
Case definition 1
A documented P. falciparum asexual parasite density > 0 detected by blood slide reading at a 
cross-sectional survey (active detection of infection [ADI]).
*Note, the incidence of P. falciparum infection defined by 
positive PCR and parasite genotyping will be evaluated in the 
context of an ancillary study, using samples collected as 
described in the present protocol.

Severe malaria and cerebral malaria

Cases of severe malaria and cerebral malaria will be 
reported as part of the safety surveillance. Case 
definitions adapted from the WHO case definitions of 
severe malaria and cerebral malaria will be used as 
reference for diagnosis.
Number of subjects
Approximately 1500 subjects (300 per group) will be enrolled in 
this study.

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Endpoints
Primary

Efficacy:

The occurrence of clinical malaria meeting the primary 
case definition from Month 2.5 up to Month 14.
Secondary

Efficacy:

The occurrence of clinical malaria meeting the primary 
and secondary case definitions from Day 0 up to 
Month 50. 

The occurrence of incident P. falciparum infections 
from Day 0 to Month 50.

The prevalence of P. falciparum infections defined by 
positive blood slide at each cross-sectional survey.

Immunogenicity: Immune response to the CS and HBs 
antigens (immunogenicity subset)

Anti-CS antibody concentrations and seropositivity 
measured before Dose 1, one month post-Dose 2 
(group Fx017-mFxD only), before and one month 
post-Dose 3, before and one month after Dose 4, before 
and one month after each yearly dose and at study end 
(Month 50).

Anti-HBs antibody concentrations and seropositivity 
measured before Dose 1, one month post-Dose 2 (group 
Fx017-mFxD only), before and one month post-Dose 3, 
before and one month after Dose 4, before and one 
month after each yearly dose and at study end 
(Month 50).
Amended 14 November 2019

Safety

The occurrence of SAEs (all, fatal and related) during 
the whole study period according to the MedDRA 
classification.

The occurrence of AEs and SAEs leading to withdrawal 
from further vaccination from Dose 1 (Day 0) up to 
Month 50, according to the MedDRA classification.

The occurrence of severe malaria cases and cerebral 
malaria cases during the whole study period.

The occurrence of pIMDs from Day 0 up to Month 50, 
according to the MedDRA classification.

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
The occurrence of meningitis from Day 0 up to Month 
50, according to the MedDRA classification.

The occurrence of seizures within 30 days (day of 
vaccination and 29 subsequent days) after each dose of 
study vaccine, according to the MedDRA classification.

The occurrence of generalized convulsive seizure within 
seven days (day of vaccination and six subsequent days) 
after each dose of study vaccine, according to the 
Brighton collaboration guidelines [Bonhoeffer, 2004].

The occurrence of unsolicited AEs within 30 days (day 
of vaccination and 29 subsequent days) after each dose 
of study vaccine, according to the MedDRA 
classification.

The concentration of biochemistry (ALT, creatinine) 
and hematology (hemoglobin, WBC, platelets) 
parameters in the first 50 subjects (25 subjects per site) 
enrolled in each group (reactogenicity sub-cohort) 
before Dose 3, seven days post-Dose 3 and 30 days 
post-Dose 3.

Reactogenicity (reactogenicity sub-cohort)

The occurrence of solicited local and general AEs in a 
the first 50 subjects enrolled in each group within four 
days (day of vaccination and three subsequent days) 
after Dose 3 of study vaccine (all groups including 
controls), after Dose 4 (groups R012-20, R012-14-mD, 
Fx012-14-mFxD and Fx017-mFxD), after Dose 5 
(groups R012-14-mD, Fx012-14-mFxD and Fx017-
mFxD) and after Dose 6 (groups R012-14-mD and 
Fx012-14-mFxD).
Tertiary

Immunogenicity

Anti-CS antibody avidity at specified timepoints.

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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................33
GLOSSARY OF TERMS ...............................................................................................37
TRADEMARKS .............................................................................................................42
1.
INTRODUCTION....................................................................................................43
1.1.
Background ................................................................................................43
1.2.
Rationale for the study................................................................................45
1.2.1.
Rationale for the study design......................................................45
1.2.2.
Rationale for the inclusion of a control group ...............................46
1.2.3.
Rationale for the use of a rabies vaccine as a comparator 
vaccine ........................................................................................48
1.2.3.1.
Rationale for the rabies vaccine schedule ..................48
1.2.4.
Cross-immunization against human catalase...............................49
1.3.
Benefit : Risk assessment...........................................................................49
1.3.1.
Risk assessment..........................................................................49
1.3.2.
Benefit assessment .....................................................................51
1.3.3.
Overall Benefit : Risk conclusion..................................................52
2.
OBJECTIVES.........................................................................................................52
2.1.
Primary objective ........................................................................................52
2.2.
Secondary objectives..................................................................................52
2.3.
Tertiary objectives.......................................................................................53
3.
STUDY DESIGN OVERVIEW ................................................................................54
4.
CASE DEFINITIONS..............................................................................................62
4.1.
Case definitions of clinical malaria ..............................................................62
4.2.
Case definitions of P. falciparum infection...................................................62
4.3.
Severe malaria and cerebral malaria ..........................................................62
5.
STUDY COHORT...................................................................................................62
5.1.
Number of subjects/centers ........................................................................62
5.2.
Inclusion criteria for enrolment....................................................................63
5.3.
Exclusion criteria for enrolment...................................................................64
6.
CONDUCT OF THE STUDY ..................................................................................65
6.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................65
6.2.
Subject identification and randomization of treatment .................................66
6.2.1.
Subject identification....................................................................66
6.2.2.
Randomization of treatment.........................................................66
6.2.2.1.
Randomization of supplies..........................................66
6.2.2.2.
Treatment allocation to the subject.............................67

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6.2.2.2.1.
Study group and treatment 
number allocation ...................................67
6.2.2.2.2.
Treatment number allocation for 
subsequent doses ..................................67
6.2.3.
Allocation of subjects to assay subsets........................................67
6.3.
Method of blinding ......................................................................................68
6.4.
General study aspects ................................................................................68
6.4.1.
Independent Data Monitoring Committee oversight .....................68
6.4.2.
Standard of care provided to the subjects during the study..........69
6.5.
Outline of study procedures ........................................................................70
6.6.
Detailed description of study procedures ....................................................83
6.6.1.
Informed consent.........................................................................83
6.6.2.
Check inclusion and exclusion criteria .........................................83
6.6.3.
Check the subject’s vaccination card ...........................................83
6.6.4.
Check screening laboratory results..............................................83
6.6.5.
Collect demographic data ............................................................83
6.6.6.
Check medical history..................................................................83
6.6.7.
Physical examination ...................................................................83
6.6.8.
Measure and record length and weight ........................................84
6.6.9.
Issue subject’s identification card.................................................84
6.6.10.
Check subject’s identification card ...............................................84
6.6.11.
Study group and treatment number allocation 
(randomization)............................................................................84
6.6.12.
Record if the subject belongs to the reactogenicity sub-
cohort ..........................................................................................84
6.6.13.
Check contraindications, warnings and precautions to 
vaccination...................................................................................84
6.6.14.
Record pre-vaccination body temperature ...................................84
6.6.15.
Study vaccines administration......................................................85
6.6.16.
Blood sampling for all subjects.....................................................85
6.6.17.
Blood sampling for the reactogenicity sub-cohort.........................86
6.6.18.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................86
6.6.19.
Recording of unsolicited AEs, SAEs and AEs of specific 
interest.........................................................................................86
6.6.20.
Recording of solicited AEs in the reactogenicity sub-cohort .........86
6.6.21.
Study conclusion..........................................................................87
6.7.
Biological sample handling and analysis.....................................................87
6.7.1.
Use of specified study materials ..................................................88
6.7.2.
Biological samples.......................................................................88
6.7.3.
Laboratory assays .......................................................................90
6.7.4.
Biological samples evaluation......................................................92
6.7.4.1.
Immunological read-outs ............................................92
6.7.4.2.
Parasitemia ................................................................94
6.7.4.3.
Hematology/Blood chemistry......................................95
6.7.5.
Immunological correlates of protection.........................................96
7.
STUDY VACCINES AND ADMINISTRATION ........................................................97
7.1.
Description of study vaccines......................................................................97
7.2.
Storage and handling of study vaccines......................................................97
7.3.
Dosage and administration of study vaccines .............................................98
7.3.1.
RTS,S/AS01E...............................................................................98

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7.3.2.
Rabies vaccine ............................................................................99
7.4.
Replacement of unusable vaccine doses....................................................99
7.5.
Contraindications to subsequent vaccination ............................................100
7.6.
Warnings and precautions ........................................................................100
7.7.
Concomitant medications/products and concomitant vaccinations............101
7.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations...........................................................101
7.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses......................102
7.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses .......................................................................102
8.
HEALTH ECONOMICS ........................................................................................102
9.
SAFETY...............................................................................................................103
9.1.
Safety definitions ......................................................................................103
9.1.1.
Definition of an adverse event....................................................103
9.1.2.
Definition of a serious adverse event .........................................104
9.1.3.
Solicited adverse events............................................................105
9.1.3.1.
Solicited local (injection-site) adverse events............105
9.1.3.2.
Solicited general adverse events..............................105
9.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ..........................................................................106
9.1.5.
Severe malaria and cerebral malaria .........................................106
9.1.6.
Adverse events of specific interest.............................................106
9.1.6.1.
Potential immune-mediated diseases .......................106
9.1.6.2.
Seizures within 30 days post-vaccination .................108
9.1.6.3.
Meningitis .................................................................108
9.2.
Detecting and recording adverse events and serious adverse events.......109
9.2.1.
Time period for detecting and recording adverse events 
and serious adverse events .......................................................109
9.2.2.
Post-study adverse events and serious adverse events.............112
9.2.3.
Evaluation of adverse events and serious adverse events.........112
9.2.3.1.
Active questioning to detect adverse events 
and serious adverse events......................................112
9.2.3.2.
Assessment of adverse events.................................112
9.2.3.2.1.
Assessment of intensity........................112
9.2.3.2.2.
Assessment of causality .......................114
9.2.3.3.
Assessment of outcomes..........................................115
9.2.3.4.
Toxicity grading scale for hematology and 
biochemistry parameters ..........................................116
9.2.3.5.
Medically attended visits...........................................116
9.2.3.6.
Verbal autopsy process ............................................116
9.3.
Reporting of serious adverse events and other events..............................116
9.3.1.
Prompt reporting of serious adverse events and other 
events to GSK Biologicals..........................................................116
9.3.2.
Contact information for reporting serious adverse events 
and adverse events of specific interest ......................................117
9.3.3.
Completion and transmission of serious adverse events 
reports to GSK Biologicals .........................................................117

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9.3.3.1.
Back-up system in case the electronic reporting 
system does not work...............................................118
9.3.4.
Reporting of adverse events of specific interest to GSK 
Biologicals .................................................................................118
9.3.5.
Updating of serious adverse events and adverse events of 
specific interest information after removal of write access 
to the subject’s eCRF.................................................................119
9.3.6.
Regulatory reporting requirements for serious adverse 
events........................................................................................119
9.4.
Follow-up of adverse events and serious adverse events .........................119
9.4.1.
Follow-up during the study.........................................................119
9.4.2.
Follow-up after the subject is discharged from the study............120
9.5.
Treatment of adverse events ....................................................................120
9.6.
Subject card..............................................................................................120
10. SUBJECT COMPLETION AND WITHDRAWAL...................................................121
10.1.
Subject completion ...................................................................................121
10.2.
Subject withdrawal....................................................................................121
10.2.1.
Subject withdrawal from the study..............................................121
10.2.2.
Subject withdrawal from investigational vaccines.......................122
10.3.
Screen and baseline failures.....................................................................122
11. STATISTICAL METHODS....................................................................................122
11.1.
Primary endpoint.......................................................................................122
11.2.
Secondary endpoints ................................................................................123
11.3.
Tertiary endpoints.....................................................................................124
11.4.
Determination of sample size....................................................................124
11.5.
Cohorts for analyses.................................................................................125
11.5.1.
Total vaccinated cohort..............................................................125
11.5.2.
ATP cohort for efficacy...............................................................125
11.5.3.
ATP cohort for immunogenicity..................................................125
11.6.
Derived and transformed data...................................................................125
11.7.
Analysis of efficacy ...................................................................................126
11.7.1.
Strategy of analysis and rationale ..............................................126
11.7.2.
Measures of incidence (P. falciparum infection and clinical 
malaria)......................................................................................127
11.7.3.
Measure of prevalence (P. falciparum infection) ........................128
11.7.4.
Measure of impact (clinical malaria)...........................................128
11.7.5.
Primary analysis of efficacy (primary objective)..........................128
11.7.6.
Secondary analyses of efficacy..................................................128
11.8.
Analysis of demographics .........................................................................133
11.9.
Analysis of immunogenicity.......................................................................133
11.10. Analysis of safety......................................................................................134
11.11. Interpretation of analyses..........................................................................135
11.12. Conduct of analyses .................................................................................135
11.12.1. Sequence of analyses................................................................135
11.12.2. Statistical considerations for interim analyses............................136
12. ADMINISTRATIVE MATTERS .............................................................................136
12.1.
Electronic case report form instructions ....................................................136
12.2.
Study monitoring by GSK Biologicals........................................................137
12.3.
Record retention .......................................................................................137

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12.4.
Quality assurance.....................................................................................138
12.5.
Posting of information on publicly available clinical trial registers and 
publication policy ......................................................................................138
12.6.
Provision of study results to investigators .................................................138
13. COUNTRY SPECIFIC REQUIREMENTS.............................................................139
14. REFERENCES.....................................................................................................140

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LIST OF TABLES
PAGE
Table 1
Risk assessment....................................................................................49
Table 2
Study groups and epochs foreseen in the study.....................................57
Table 3
Study groups and treatment foreseen in the study .................................57
Table 4
Blinding of study epochs ........................................................................57
Table 5
Blood sampling timepoints .....................................................................59
Table 6
Case definitions of clinical malaria..........................................................62
Table 7
Case definition of incident P. falciparum infection* .................................62
Table 8
Case definition of prevalent P. falciparum infection ................................62
Table 9
Sub-cohort .............................................................................................63
Table 10
Subset....................................................................................................63
Table 11
List of study procedures for clinic visits ..................................................70
Table 12
List of study procedures for field worker visits - Part 1 (Day 0 to 
Month 19)...............................................................................................78
Table 13
List of study procedures for field worker visits - Part 2 (Month 20 
to Month 50)...........................................................................................80
Table 14
Intervals between study visits.................................................................82
Table 15
Biological samples (whole blood) ...........................................................89
Table 16
Humoral immunity (antibody determination) ...........................................91
Table 17
Assessment of P. falciparum infection....................................................91
Table 18
Hematology and biochemistry ................................................................91
Table 19
Immunological read-outs........................................................................92
Table 20
Parasitemia (blood smear and blood for ancillary study) ........................94
Table 21
Hematology/Blood chemistry..................................................................96
Table 22
Study vaccines.......................................................................................97
Table 23
Dosage and administration.....................................................................99
Table 24
Solicited local adverse events ..............................................................105

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Table 25
Solicited general adverse events..........................................................105
Table 26
List of potential immune-mediated diseases.........................................107
Table 27
Reporting periods for collecting safety information ...............................110
Table 28
Intensity scales for solicited symptoms in infants/toddlers ....................113
Table 29
Toxicity grading scales for analysis of hematology and 
biochemistry parameters......................................................................116
Table 30
Timeframes for submitting serious adverse event and other 
events reports to GSK Biologicals ........................................................117
Table 31
GSK Biologicals’ laboratories ...............................................................144
Table 32
Outsourced laboratories.......................................................................144
Table 33
Case definition of severe P. falciparum malaria....................................145
Table 34
Case definition of cerebral P. falciparum malaria..................................145

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LIST OF FIGURES
PAGE
Figure 1
Study design: clinic visits........................................................................54
Figure 2
Study design: visits for assessment of parasite prevalence....................55

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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .....................................................................143
APPENDIX B CLINICAL LABORATORIES ................................................................144
APPENDIX C CASE DEFINITIONS OF SEVERE MALARIA AND CEREBRAL 
MALARIA .............................................................................................145
APPENDIX D SAFETY LABORATORY TESTING: CLS SOUTH AFRICA..................146
APPENDIX E AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................149

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LIST OF ABBREVIATIONS
012M:
Group of subjects enrolled in study MALARIA-071, who 
were randomized to receive three full doses of RTS,S/AS01B
at Month 0, Month 1 and Month 2.
Ab:
Antibody
ADI:
Active detection of infection
AE:
Adverse event
AI:
Avidity index
AIDS:
Acquired immune deficiency syndrome
ALT:
Alanine aminotransferase
Anti-CS:
Antibody to the Plasmodium falciparum circumsporozoite 
(CS) repeat domain
Anti-HBs:
Antibody to the hepatitis B surface antigen
AS01E:
GSK’s proprietary Adjuvant System containing MPL, QS-
21 and liposome (25 µg MPL and 25 µg QS-21)
ATP:
According-to-protocol
CEVAC:
Center for Vaccinology, Ghent University, Belgium
CHMI:
Controlled human malaria infection
CI:
Confidence interval
CIOMS:
Council for International Organizations of Medical Sciences
CLIA:
Chemiluminescence enzyme immunoassay
CLS:
Clinical laboratory sciences
CS:
Circumsporozoite protein of Plasmodium falciparum
CSF:
Cerebrospinal fluid
DSUR:
Development safety update report
DTPHepB:
Diphtheria, tetanus, pertussis, hepatitis B vaccine
eCRF:
Electronic case report form

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ELISA:
Enzyme-linked immunosorbent assay
EMA:
European Medicines Agency
EoS:
End of study
EPI:
Expanded Program on Immunization
eTDF:
Electronic temperature excursion decision form
EU/ml:
ELISA unit per milliliter
FDA:
Food and Drug Administration, United States of America
Fx:
Fractional
Fx017M:
Group of subjects enrolled in study MALARIA-071, who 
were randomized to receive two full doses of RTS,S/AS01B
at Month 0 and Month 1 and a third fractional dose (1/5th
dose) at Month 7.
g/dl:
Gram per deciliter
GCP:
Good Clinical Practice
GMC:
Geometric mean concentration
GSK:
GlaxoSmithKline
HDCV:
Human diploid cells vaccine
HIV:
Human immunodeficiency virus
ICF:
Informed consent form
ICH:
International Committee on Harmonization
IDMC:
Independent Data Monitoring Committee
IEC:
Independent Ethics Committee
IgG:
Immunoglobulin G
IM:
Intramuscular
IMP:
Investigational medicinal product
IRB:
Institutional Review Board
ITN:
Insecticide-treated bednet

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IU/ml:
International unit per milliliter
KEMRI/USAMRU-K, 
WRP:
Kenya Medical Research Institute / US Army Medical
Research Unit Kenya, Walter Reed Project
LAR:
Legally acceptable representative
MATEX:
MATerial EXcellence
MedDRA:
Medical dictionary for regulatory activities
mEq/l: 
Milliequivalents per liter
mg/dl:
Milligram per deciliter
mIU/ml:
Milli-international unit per milliliter
mmol/l:
Millimole per liter
MPL:
3-O-desacyl-4’-monophosphoryl lipid A (produced by GSK)
PBS:
Phosphate buffered saline
PCD:
Passive case detection
PCECV:
Purified chick embryo cells vaccine
PCR:
Polymerase chain reaction
PDEV:
Purified duck embryo cells vaccine
P. falciparum:
Plasmodium falciparum
PHKCV:
Purified hamster kidney cells vaccine
pIMD:
Potential immune-mediated disease
POC:
Proof of concept
PT:
Preferred term
PVRV:
Purified Vero cell rabies vaccine
Pyr:
Person year at risk
QS-21:
Quillaja saponaria Molina, fraction 21 (Licensed by GSK 
from Antigenics Inc., a wholly owned subsidiary of Agenus 
Inc., a Delaware, USA corporation)
RDT:
Rapid diagnostic test

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RTS,S:
Particulate antigen, containing both RTS and S (hepatitis B 
surface antigen) proteins
RTS,S/AS01E:
GSK Biologicals’ candidate Plasmodium falciparum malaria 
vaccine adjuvanted with GSK Biologicals’ proprietary 
Adjuvant System AS01E
SAE:
Serious adverse event
SAS:
Statistical Analysis System
SBIR:
Randomization System on Internet
SCR:
Screening
SD:
Standard deviation
SDV:
Source document verification
SmPC:
Summary of product characteristics
SPM:
Study procedures manual
TVC:
Total vaccinated cohort
UNAIDS:
Joint United Nations Programme on HIV/AIDS
USA:
United States of America
Vacc:
Vaccination
VNA:
Virus neutralizing antibody
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 adverse event (AE) can therefore be any unfavorable
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse.
Active detection of 
infection:
Detection of a malaria infection by the regular
examination of each subject for malaria parasitemia i.e.
regardless of whether the subject had signs or symptoms
of infection.
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
open-label study, no blind is used. Both the investigator 
and the subject know the identity of the treatment
assigned.
Child in care:
A child who has been placed under the control or 
protection of an agency, organization, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian.
Comparator vaccine:
In this study, the comparator vaccine is a non-malaria
vaccine (rabies vaccine) administered to subjects
randomized in the Control group.

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Compound:
A cluster of buildings in an enclosure, such as the houses
of an extended family. The enclosure may be a wall, a
fence, a hedge or some other structure, or it may be
formed by the buildings themselves, when they are built
around an open area or joined together.
Control group:
A concurrent control group is one chosen from the same
population as the test group and treated in a defined way
as part of the same trial that studies the test treatment, and
over the same period of time. The test and control groups
should be similar with regard to all baselines and on
treatment variables that could influence outcome, except
for the study treatment [ICH E10, 2000].
In this study the Control group will receive a non-malaria
comparator vaccine (rabies vaccine).
Electronic case report 
form:
Auditable electronic record designed to capture
information required by the clinical trial protocol to be
reported to the sponsor on each trial subject.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
End of Study (EoS):
(Synonym of End of 
Trial)
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV).
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of 
the last testing/reading released of the Human 
Biologicals Samples or imaging data, related to primary 
and secondary endpoints. EoS must be achieved no 
later than 8 months after LSLV.
Epoch:
An epoch is a self-contained set of consecutive 
timepoints or a single timepoint from a single protocol. 
Self-contained means that data collected for all subjects 
at all timepoints within that epoch allows to draw a 
complete conclusion to define or precise the targeted 
label of the product. Typical examples of epochs are 
primary vaccinations, boosters, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety.
eTrack:
GSK’s tracking tool for clinical trials.

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Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Sections 7.7.2 and 11.5 for details on criteria for 
evaluability).
Immunological correlate 
of protection:
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent.
Investigational vaccine:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorization when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
Legally acceptable 
representative:
(The terms legal 
representative or legally 
authorized 
representative are used 
in some settings.)
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial.
Potential immune-
mediated disease:
Potential immune-mediated diseases (pIMDs) are a subset 
of AEs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune etiology.
Passive case detection:
Detection of malaria disease by self-presentation to health 
facility in the study area. If there is a history of fever 
within 24 hours or axillary temperature is 37.5°C at 
presentation then a blood slide is taken and examined for 
parasitemia.
Primary completion 
date:
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated.
Protocol amendment:
The International Conference on Harmonization (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 

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scope of the investigation, study design, or scientific 
integrity of the study.
Protocol administrative 
change:
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.
Randomization:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Self-contained study:
Study with objectives not linked to the data of another 
study.
Site monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
Serious adverse event:
A serious adverse event (SAE) is any untoward medical
occurrence that:
a.
results in death;
b.
is life-threatening;
c.
requires hospitalization or prolongation of existing
hospitalization;
d.
results in disability/incapacity.
Medical or scientific judgment should be exercised in
deciding whether reporting is appropriate in other
situations, such as important medical events that may not
be immediately life-threatening or result in death or
hospitalization but may jeopardize the subject or may
require medical or surgical intervention to prevent one of
the other outcomes listed in the above definition. These
should also be considered serious. Examples of such
events are invasive or malignant cancers, intensive
treatment in an emergency room or at home for allergic
bronchospasm or blood dyscrasias or convulsions that do
not result in hospitalization.
In this study, the AEs of specific interest (i.e. pIMDs, 
meningitis and seizure within 30 post-vaccination) will be 
reported as SAEs.
Solicited adverse event:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period.

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Sub-cohort:
A group of subjects for whom specific study procedures 
are planned as compared to other subjects.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine or as a control.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Subset:
A group of subjects who have the same biological 
samples taken at the same timepoint, but the assay to be 
performed on that biological sample will be different.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomization or treatment allocation.
Treatment number:
A number identifying a treatment to a subject, according 
to the study randomization or treatment allocation.
Unsolicited adverse 
event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
Amended 14 November 2019

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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 will be written without the superscript symbol ™ or ® and in italics.
Trademark of the GlaxoSmithKline group 
of companies
Generic description
Rabipur™
Purified chick embryo cell culture rabies 
vaccine
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1.
INTRODUCTION
1.1.
Background
GlaxoSmithKline (GSK) Biologicals in partnership with PATH is developing a first 
generation P. falciparum malaria vaccine for routine immunization of infants and 
children living in malaria-endemic areas with the objective of reducing the risk of malaria 
and severe malaria during the first years of life.
GSK Biologicals has developed a candidate pre-erythrocytic Plasmodium falciparum
(P. falciparum) malaria vaccine, RTS,S/AS01E, which consists of sequences of the 
circumsporozoite (CS) protein of P. falciparum and hepatitis B surface antigen 
adjuvanted with the Adjuvant System AS01E, containing two immune enhancers MPL 
(3’-O-desacyl-4’-monophosphoryl-lipid A) and QS-21 (Quillaja saponaria Molina, 
fraction 21), in a liposome suspension.
A large Phase III study (MALARIA-055 PRI), conducted in infants and children at 11 
study sites in seven countries across sub-Saharan Africa, showed the potential for the 
current pediatric formulation of the candidate vaccine to play a role in future malaria 
control strategies. The efficacy of this pediatric formulation, RTS,S/AS01E, (25 µg of 
RTS,S antigen with AS01E containing 25 g MPL, 25 g QS-21 and liposomes) against 
all episodes of clinical malaria, when delivered according to a 0, 1, 2-month schedule, in 
children aged 5-17 months was estimated to be 55.1% (95% confidence interval [CI]: 
50.5; 59.3) over 12 months post-Dose 3 [The RTS,S Clinical Trials Partnership, 2011].
Long-term follow-up efficacy data showed a decline in efficacy against clinical and 
severe malaria over time in both children and infants who did not receive a booster dose 
(referred to as the fourth dose in this protocol) of the RTS,S/AS01E vaccine [The RTS,S 
Clinical Trials Partnership, 2015]. The administration of a RTS,S/AS01E fourth dose 
enhanced protection against malaria in infants and children. Efficacy against all episodes 
of clinical malaria over 48 months post-Dose 1 was estimated to be 28.3% (95% CI: 23.3; 
32.9) in children aged 5-17 months at first dose who did not receive a fourth dose and 
36.3% (95% CI: 31.8; 40.5) in children who were administered a fourth dose (intention-
to-treat cohort).
While Phase III evaluation of the RTS,S/AS01E candidate malaria vaccine was ongoing, 
GSK Biologicals, in collaboration with PATH, continued to investigate ways to further 
improve vaccine efficacy levels. Higher vaccine efficacy levels may lead to improved 
malaria control and contribute to the malaria elimination goal set as a long term target by 
the global health community [Malaria Vaccine Technology Roadmap, 2013].
In a previous controlled human malaria infection (CHMI) study (WRMAL-003) 
evaluating, in malaria-naïve adults, vaccine formulations based on the RTS,S antigen, one 
study group showed high levels of vaccine efficacy against sporozoite challenge, with six 
out of seven subjects protected [Stoute, 1997]. Subjects in this study group had received 
an adjuvanted formulation of RTS,S antigen, referred to as RTS,S/AS02. The 
immunization schedule under evaluation was a 0, 1, 7-month schedule. After having 
observed high general reactogenicity in two subjects after the second immunization, and 

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in view of limited experience of adjuvant safety at the time, there was a decision to 
reduce the third immunization dose to a fifth of the standard 0.5 ml dose.
Later in the RTS,S clinical development program, immunization schedules with three 
subsequent identical doses given one month apart were used. In a further Phase II study, 
MALARIA-050, the spacing of the third (full) dose at Month 7 (i.e. a 0, 1, 7-month 
schedule) showed no increased benefit over the 0, 1, 2-month schedule [Asante, 2011]. In
view of the supportive safety, immunogenicity and efficacy data, as well as 
considerations related to vaccine implementation in sub-Saharan Africa, the 0, 1, 2-month 
schedule was selected for further vaccine development.
The 0, 1, 7-month schedule, with a fractional dose delivered as the third immunization 
(Fx017M group), has been further investigated recently in a CHMI study in malaria-naïve 
adults (MALARIA-071). The biological hypothesis was that the delayed fractional dose 
has allowed a better qualitative immune maturation in the germinal center, with antigen 
selection of the B cells harboring surface immunoglobulin with highest antigen affinity. 
Preliminary analyses showed high efficacy in the Fx017M group compared to standard 
doses given at 0, 1, 2-months (012M group): 4/30 subjects in the Fx017M group 
developed parasitemia (vaccine efficacy: 86.7% [95% CI: 66.8; 94.6]); 6/16 subjects in 
the 012M group developed parasitemia (vaccine efficacy: 62.5% [95% CI: 29.4; 80.1]); 
all 12 control subjects (no vaccine) developed parasitemia confirming the validity of the 
malaria challenge. MALARIA-071 was not powered to detect superiority of the Fx017M 
group over the 012M group, but the study did show some evidence of a difference in 
vaccine efficacy comparing the two groups (increase in proportion of protected subjects = 
64.4% [95% CI: -7.9; 88.3], p=0.0741, Fisher’s exact; difference in time to parasitemia 
p=0.0455, logrank). In the follow-up phase of the study, subjects who were protected in 
the initial challenge were randomized to receive a fractional fourth dose or no fourth 
dose, before being exposed to a second sporozoite challenge approximately six months 
after the initial challenge. Amongst subjects initially in the Fx017M group, three out of 
seven subjects who did not receive a boost were protected in this second challenge, while 
nine out of 10 subjects who were initially protected and received a fractional fourth dose 
were protected. The results from the study follow-up phase and the second challenge 
suggest that there is waning immunity with the fractional schedule too but that the 
protection can be extended with an additional fractional dose. These results from the 
MALARIA-071 challenge study may indicate a simple way to improve the efficacy of the 
RTS,S/AS01E candidate vaccine and requires further assessment in the pediatric 
population, under conditions of natural exposure. Preliminary immunological analyses of 
serum samples from subjects participating in MALARIA-071 suggest that the fractional 
delayed dose does lead to the production of antibodies with higher antigen avidity as 
compared to a classical immunization regimen with three full doses.
Please refer to the current Investigator Brochure for information regarding the pre-clinical 
and clinical studies of RTS,S/AS01E.

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1.2.
Rationale for the study
GSK Biologicals and PATH are committed to develop a malaria vaccine for reduction of 
malaria disease burden in children and contribution to the malaria elimination goal. 
Characterization of an optimal dosing regimen and boosting schedules will be critical.
The results of the efficacy study MALARIA-055 PRI, including the long term follow-up 
data and efficacy of the fourth dose administered 18 months after the third dose, and the 
preliminary results of MALARIA-071 were reviewed by the European Medicines 
Agency (EMA) during the assessment of the initial Application of the RTS,S/AS01E
candidate vaccine. The EMA asked the company to address the following points in 
ongoing or future studies:  1) the timing of the fourth dose and evaluation of the safety 
and efficacy of an early fourth dose;  2) the efficacy and safety of multiple yearly doses 
and whether the vaccine predisposes to some degree of hyporesponsiveness to sequential 
doses; and  3) the plans to further investigate the potential utility of a delayed and 
fractionated third dose schedule in the target age range.
The current study is designed to address these points in the pediatric population. It aims 
to:

Establish proof-of-concept (POC) for a fractional (Fx) dose schedule under 
conditions of natural exposure.

Establish the role of third dose spacing in a fractional dose schedule.

Describe the effect of an earlier full fourth dose at Month 14.

Describe the effect of multiple fractional or full yearly doses.
1.2.1.
Rationale for the study design
A recent CHMI study (MALARIA-071) demonstrated superior protection against 
malaria infection associated with the use of a fractional third dose in a 0, 1, 7-month 
schedule with a vaccine efficacy against infection of 86.7% (95% CI: 66.8; 94.6; 
p<0.0001) versus 62.5% (95% CI: 29.4; 80.1; p=0.0009) in the standard 0, 1, 2-month 
schedule. The incremental efficacy of the 0, 1, 7-month schedule over the 0, 1, 2-month
schedule was 64.4% (95% CI: -7.9; 88.3; p=0.0741) [Regules, 2016]. The current study 
intends to establish POC for a fractional dose schedule under conditions of natural 
exposure. The study will be conducted in children 5-17 months old at first vaccination 
living in areas of mid to high malaria transmission, in line with the age group 
recommended by the World Health Organization (WHO) [WHO, 2016]. Infants 6-12 
weeks old will not be included in this POC study to avoid interference of co-
administration with the standard Expanded Program on Immunization (EPI) vaccines.
Results from this study will be critical in informing future possibilities for the 
development of vaccine-based strategies which, in combination with other interventions, 
may contribute to the malaria elimination agenda.

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The study proposed herein will include five study groups. One group (R012-20) will 
receive the standard schedule consisting of RTS,S/AS01E full dose given at Month 0, 
Month 1, Month 2 and a fourth dose at Month 20. This corresponds to the schedule that 
received a positive scientific opinion from EMA. The four other groups will receive 
alternative schedules as follow:

Group R012-14-mD will receive RTS,S/AS01E full dose at Month 0, Month 1, 
Month 2, an early fourth dose at Month 14 and yearly full doses at Month 26 and 
Month 38.

Group Fx012-14-mFxD will receive RTS,S/AS01E full dose at Month 0 and Month 
1, RTS,S/AS01E fractional dose (1/5th dose) at Month 2 and yearly fractional doses at 
Month 14, Month 26, Month 38.

Group Fx017-mFxD will receive RTS,S/AS01E full dose at Month 0 and Month 1, 
RTS,S/AS01E delayed fractional third dose (1/5th dose) at Month 7 and yearly 
fractional doses at Month 20 and Month 32.

Control group: will receive three doses of rabies vaccine at Month 0, Month 1 and 
Month 2.
1.2.2.
Rationale for the inclusion of a control group
This study plans to evaluate malaria occurrence in subjects vaccinated with RTS,S/AS01E
according to various schedules and in subjects vaccinated with a non-malaria comparator 
vaccine (rabies vaccine). While partial protection provided by RTS,S/AS01E in the age 
range of subjects which will be enrolled in this study has been demonstrated, the use of a 
non-malaria comparator vaccine is deemed acceptable, in line with relevant published 
references about the use of placebo in vaccine trials [Rid, 2014; WHO, 2013].
It is deemed unacceptable to use a placebo control when study participants are exposed to 
unacceptable levels of risk from delaying administration of a safe and effective vaccine 
that is accessible through the public health system of the country in which the study is 
planned. However, the Nuffield Council on Bioethics guidelines state that the use of 
placebos may be acceptable if participants are not deprived of a treatment they would 
have otherwise received, but are provided at a minimum with the standard of care that is 
the best available in the country’s public health system. CIOMS (Council for 
International Organizations of Medical Sciences), ICH (International Committee on 
Harmonization) and UNAIDS (Joint United Nations Programme on HIV/AIDS)
guidelines stipulate that researchers must take steps to minimize any risks associated with 
the use of controls. The protocol should explain clearly the scientific justification for 
using a placebo-controlled design, and specifically address whether (1) the study question 
cannot be answered with an active-controlled study design; and (2) the risks of delaying 
an existing efficacious vaccine are adequately minimized or mitigated; and (3) the use of 
a placebo control is justified by the potential public health value of the research; and (4) 
the research is responsive to local health needs.

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In accordance with these recommendations, the use of a non-malaria comparator vaccine 
in this study is deemed acceptable as:
1.
Local availability. Local regulatory recommendation for RTS,S/AS01E use has not 
been granted. If granted, it is anticipated that availability in the local health system 
will take some time to deploy. It is therefore not the case that study subjects would 
be deprived from a locally available effective prevention tool.
2.
Risk mitigation. Subjects will have access to the best locally available malaria 
prevention and treatment options. All screened subjects will be provided with an 
insecticide-treated bednet (ITN), and malaria diagnosis and treatment will be 
ensured. The investigator will make every effort to ensure that preventive measures 
as provided by the government are adhered to and under circumstances where this is 
not possible discussions with the sponsor need to take place. It is anticipated that 
subjects will benefit from participation in the study in terms of facilitated access to 
care and relatively intense health monitoring. Reduced levels of morbidity related to 
participation in a RTS,S/AS01E study has been documented [Hamel, 2014].
3.
Study design justification. Without a control group, the following scientific 
questions could not be answered with scientific integrity:

Comparison of malaria incidence between different time periods. 
Without a control group, the direct comparison of post-RTS,S/AS01E
vaccination malaria incidence between two different study periods (example: 
assessment of post-Dose 3 protection in the 0, 1, 2-month and 0, 1, 7-month 
schedules, evaluation of optimal timing of the fourth dose, waning of efficacy) 
would carry a risk of bias associated with seasonal variations in malaria 
incidence.

Evaluation of strain-specificity of protection. 
A genetic characterization of malaria infections is planned as an ancillary study 
(using samples collected in the present study) with the aim to determine whether 
vaccine efficacy varies according to the parasite strain. This requires comparison 
of parasite genetics in the vaccinated groups with the Control group.
4.
Public health need. RTS,S/AS01E has been shown to prevent malaria with a 
moderate level of efficacy [The RTS,S Clinical Trials Partnership, 2015]. The
development of a malaria vaccine with higher efficacy remains an important public 
health need [Malaria Vaccine Technology Roadmap, 2013]. Finding the
immunization schedule able to provide the highest protection is very relevant to 
local public health needs.
To be noted, the study subjects in the Control group will get the benefit of receiving a 
rabies vaccine as comparator vaccine, also advocated as a valuable preventive health 
intervention by the WHO [WHO, 2007].

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1.2.3.
Rationale for the use of a rabies vaccine as a comparator vaccine
Subjects randomized to the Control group will receive three doses of a cell culture rabies 
vaccine on a 0, 1, 2-month schedule. In humans, rabies is almost invariably fatal once 
clinical signs occur. Bites by rabid domestic dogs cause 99% of human rabies deaths 
globally. More than 3.3 billion people live in regions where rabies is enzootic. 
Approximately 55 000 people die from rabies each year, the vast majority of these deaths 
occurring in Asia and Africa [WHO, 2007]. Estimates of risks of infection with rabies in
Africa are available from the WHO [WHO, 2015].
The efficacy of cell culture-derived rabies vaccines including human diploid cells vaccine 
(HDCV), purified Vero cell rabies vaccine (PVRV), purified chick embryo cells vaccine 
(PCECV), purified hamster kidney cells vaccine (PHKCV) and purified duck embryo 
cells vaccine (PDEV) has been demonstrated [WHO, 2010]. In this study, a PCECV
(Rabipur) will be used as comparator vaccine.
PCECV has been widely used for rabies pre-exposure prophylaxis in children. In total, 
PCECV has been administered to more than 1200 children in clinical studies, from 
toddlers to those in elementary school, demonstrating safety and immunogenicity. 
Various schedules of PCECV (2-doses and 3-doses) and administration route 
(intramuscular and intradermal) were evaluated in children. Intramuscular administration 
resulted in 3- to 5-fold higher titers than intradermal administration [Malerczyk, 2013]. In 
studies using pre-exposure prophylaxis in children, all children achieved adequate rabies 
virus neutralizing antibody (VNA) concentrations by Day 14, i.e., after receiving two 
doses of vaccine, even before the third dose of vaccine was received. Regardless of the 
route of administration (intramuscular or intradermal), VNA concentrations reached 
levels above 0.5 IU/ml [Malerczyk, 2013]. The definition of a target antibody titer varies 
among laboratories and is influenced by the type of test conducted. WHO specifies a titer 
of 0.5 IU/ml [WHO, 2007].
1.2.3.1.
Rationale for the rabies vaccine schedule
In this study, the rabies vaccine will be administered according to a 0, 1, 2-month 
schedule which is different from the schedule recommended by the manufacturer of the 
rabies vaccine (i.e. days 0, 7, 21 or 28) [Rabipur SmPC, 2010]. The vaccine may 
therefore not provide the full protection under the 0, 1, 2-month schedule as if it was 
administered according to the recommended schedule. Parent(s)/Legally acceptable 
representative(s) (LAR[s]) will be instructed to bring their child promptly for treatment if 
the child is bitten by an animal.
Rabipur has been used as a comparator vaccine in several earlier studies in the GSK 
malaria vaccine program including a schedule as the one that will be used in this study.
Over the entire follow-up period of each study (up to 24 months of follow-up), no case of 
rabies was reported in subjects from the control group who had received Rabipur
according to a 0, 1, 2-month schedule [Laurens, 2013;Ogutu, 2009; Owusu-Agyei, 2009; 
Polhemus, 2009; Thera, 2008; Thera, 2010; Thera, 2011].

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1.2.4.
Cross-immunization against human catalase
Yeast cytosolic catalase is present in small quantity in RTS,S/AS01E vaccine lots. The 
significance of the presence of yeast cytosolic catalase was investigated in the 
uncontrolled study MALARIA-061 where three lots of RTS,S/AS01E formulated from 
commercial scale (1600L) RTS,S purified bulk and one lot of RTS,S/AS01E formulated 
from pilot scale (20L) RTS,S purified bulk were administered to children 5-17 months of 
age at first dose. Amongst the 300 children tested, one child was positive one month post-
Dose 3, indicating that he has some antibodies cross-reacting with human catalase. This 
child was negative pre-vaccination. This child reported two adverse events (AE) not 
related to vaccination within 30 days post-vaccination (upper respiratory tract infection 
and respiratory tract infection); no AE related to vaccination and no SAE was reported 
during the six months follow-up period post-vaccination.
Anti-human catalase antibodies have not been evaluated in control recipients in malaria 
clinical studies and the background rate of anti-catalase positivity is not known. Based on 
the fact that only one child was highly positive amongst the three groups of children 
vaccinated with an RTS,S/AS01E lot formulated from a 1600L scale RTS,S purified bulk, 
it seems unlikely that the observed response is related to the yeast catalase contained in 
RTS,S/AS01E. However, it cannot be ruled out that the seroconversion of this subject was 
induced by the RTS,S/AS01E vaccination. Cross-immunization against human catalase 
will be further investigated in a planned randomized controlled study.
1.3.
Benefit : Risk assessment
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of RTS,S/AS01E.
Please refer to the Prescribing Information for information regarding the summary 
potential risks and benefits of the rabies vaccine (Rabipur).
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
1.3.1.
Risk assessment
Table 1
Risk assessment
Important potential/identified risk
Data/rationale for risk
Mitigation strategy
Investigational study vaccine (RTS,S/AS01E)
Important identified risk: Febrile 
convulsion
The increased risk of febrile 
convulsion within seven days 
post-vaccination has been 
identified.
Past seizures constitute an exclusion 
criterion (see Section 5.3), and 
children will not be vaccinated if they 
have concurrent fever. Parent(s)/
LAR(s) will be informed of this risk 
and instructed how to manage high 
fever post-vaccination. Seizure is an 
AE of specific interest and will be 

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Important potential/identified risk
Data/rationale for risk
Mitigation strategy
captured through the electronic 
Expedited Adverse Events Report 
(see Section 9.1.6). Clinical details 
according to the Brighton 
collaboration guidelines [Bonhoeffer, 
2004] of each seizure occurring within 
seven days post- vaccination will be 
captured in a specific eCRF screen.
Important potential risk: Meningitis
In the large Phase III study, 
MALARIA-055 PRI, an imbalance 
of meningitis cases of any etiology 
(i.e. including cases with 
confirmed etiology and cases with 
no etiology found), with no cluster 
in time-to-onset, has been 
observed in children 5-17 months 
of age at first dose.
Parent(s)/LAR(s) will be instructed on 
the need to attend the clinic if their 
child is unwell. A high level of medical 
supervision is in place to detect and 
treat meningitis if it occurs. Meningitis 
is an AE of specific interest (see 
Section 9.1.6). Clinical details of each 
case will be captured through the 
electronic Expedited Adverse Events 
Report and in a specific eCRF screen.
Important potential risk: Delayed 
increased incidence of severe 
malaria in relation with delayed 
acquisition of blood-stage 
immunity
In the large phase III study 
MALARIA-055 PRI, an increased 
incidence of severe malaria 
relative to the control group has 
been observed, starting around 
two years after RTS,S/AS01E
primary vaccination course, in 
children 5-17 months of age at 
first dose that did not receive a 
RTS,S/AS01E fourth dose. This 
higher risk of severe malaria 
might result from a delay in the 
acquisition of blood-stage 
immunity associated with a 
decreased exposure in children 
vaccinated with RTS,S/AS01E
relative to controls.
All studies with long term follow-up 
showed that the overall benefit stays 
in favor of the vaccine despite 
delayed acquisition of blood-stage 
immunity. The receipt of a fourth dose 
increased that benefit. The study 
MALARIA-055 PRI showed no 
evidence of a delayed increased 
incidence in severe malaria in children 
who received a fourth dose, up to two 
years post-fourth dose. In the present 
study all RTS,S/AS01E groups will 
receive at least one additional dose 
(fourth dose).
Severe malaria cases will be reported 
as serious adverse events (SAEs). 
The occurrence of severe malaria 
cases will be described.
Important potential risk: 
Hypersensitivity (including 
anaphylaxis)
As with other vaccines, 
hypersensitivity and anaphylaxis 
to one or several components of 
the vaccine can rarely occur.
One case of erythema multiforme 
and two cases of bronchospasm 
within 30 days following 
RTS,S/AS01E vaccination were 
reported as hypersensitivity 
reactions in past studies.
No case of anaphylaxis has been 
reported following RTS,S/AS01E
vaccination to date.
Subjects will be observed closely for 
at least 30 minutes following 
administration of the vaccine with 
appropriate medical treatment readily 
available in case of anaphylaxis.
History of anaphylaxis post-
vaccination and history of any 
reaction or hypersensitivity likely to be 
exacerbated by any component of the 
vaccine are exclusion criteria in this 
study (see Section 5.3).
Previous anaphylactic reaction to a 
vaccine is a contraindication to further 
experimental vaccinations in this 
study (see Section 7.5).

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Important potential/identified risk
Data/rationale for risk
Mitigation strategy
Important potential risk: potential 
immune-mediated disease (pIMD)
pIMD is a theoretical concern with 
adjuvanted vaccines as no 
evidence of autoimmune disease 
caused by RTS,S/AS01E has 
been observed.
Parent(s)/LAR(s) will be informed of 
this theoretical risk and the need to 
attend the clinic if their child is unwell. 
pIMD diagnostic capacity will be 
reinforced. pIMD is an AE of specific 
interest (see Section 9.1.6). The 
occurrence of pIMD cases will be 
described.
Study procedures
Pain when taking blood samples
When taking the blood samples, 
the subject may feel faint; or 
experience mild pain, bruising, 
irritation or redness.
Parent(s)/LAR(s) will be advised to 
call the study doctor immediately if 
their child has any side effects that 
they perceive as serious.
Other (comparator rabies vaccine)
Hypersensitivity and anaphylaxis 
following rabies vaccination
Hypersensitivity and anaphylaxis 
to one or several components of 
the vaccine can rarely occur.
The subjects will be observed closely 
for at least 30 minutes following 
administration of the vaccine with 
appropriate medical treatment readily 
available in case of anaphylaxis.
History of anaphylaxis post-
vaccination and history of any 
reaction or hypersensitivity likely to be 
exacerbated by any component of the 
vaccine are exclusion criteria in this 
study (see Section 5.3).
Previous anaphylactic reaction to a 
vaccine is a contraindication to further 
experimental vaccinations in this 
study (see Section 7.5).
Auto-immune disorders following 
rabies vaccination
There have been individual 
reports of nervous system 
disorders (such as paresthesia, 
paresis or Guillain-Barré-
Syndrome) following rabies 
vaccination but a causal 
relationship has not been 
established.
Parent(s)/LAR(s) will be informed of 
this risk and the need to attend the 
clinic if their child is unwell. pIMD 
diagnostic capacity will be reinforced. 
pIMD is an AE of specific interest (see 
Section 9.1.6). The occurrence of 
pIMD cases will be described.
1.3.2.
Benefit assessment
The results of previous clinical studies showed a significant efficacy of RTS,S/AS01E
against malaria disease caused by P. falciparum. In children aged 5-17 months, the 
vaccine efficacy against all episodes of clinical malaria was estimated to be 55.1% (95% 
CI: 50.5; 59.3) over 12 months post-Dose 3, and over four years of follow-up (48 months 
post-Dose 1, intention-to-treat population) the efficacy against all episodes of clinical 
malaria was 28.3% (95% CI: 23.3; 32.9) in children who did not receive a fourth dose 
and 36.3% (95% CI: 31.8; 40.5) in children who were administered a fourth dose 18 
months after the third dose [The RTS,S Clinical Trials Partnership, 2011; The RTS,S 
Clinical Trials Partnership, 2015].

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Children randomized to the rabies Control group will not receive RTS,S/AS01E
vaccination, but may benefit from study participation due to the implementation of best 
available standards of care according to national recommendations within the study and 
strengthened access to care. In addition individuals vaccinated with rabies vaccine in the 
study may benefit from a reduced risk of contracting rabies.
1.3.3.
Overall Benefit : Risk conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential or identified risks in association with RTS,S/AS01E (SB257049) or 
with the rabies vaccine are justified by the potential benefits (prevention / treatment) that 
may be afforded to subjects receiving RTS,S/AS01E (reduced risk of clinical and severe 
disease due to P. falciparum) and to subjects receiving the rabies vaccine in the Control 
group (reduced risk of contracting rabies).
2.
OBJECTIVES
2.1.
Primary objective

Efficacy: Incremental efficacy of a schedule with a fractional third dose at 
Month 2 over the standard schedule

To demonstrate the superiority of a 3-dose schedule of GSK Biologicals’ 
malaria vaccine RTS,S/AS01E with a fractional third dose at Month 2 compared 
to a standard schedule of RTS,S/AS01E with three full doses in terms of vaccine 
efficacy against clinical malaria (primary case definition) over 12 months post-
Dose 3.
Criterion:
The lower limit of the 95% CI of the incremental vaccine efficacy estimate is 
above 0.
Refer to Section 11.1 for the definition of the primary endpoint.
2.2.
Secondary objectives

Efficacy

To assess the incremental vaccine efficacy against clinical malaria of a schedule 
with a fractional third dose at Month 2 versus a schedule with 3 full doses 
(primary and secondary case definitions) over 12 months post-Dose 3.

To assess the incremental vaccine efficacy against clinical malaria, over 7 and 
12 months post-Dose 3, of a schedule with a fractional third dose at Month 7 
versus a schedule with a fractional third dose at Month 2.

To assess the incremental vaccine efficacy against clinical malaria, over 7 and 
12 months post-Dose 3, of a schedule with a fractional third dose at Month 7 
versus a schedule with 3 full doses.

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
To assess the incremental vaccine efficacy against clinical malaria, over 12 
months post-Dose 4, post-Dose 5 and post-Dose 6 of a schedule with a fractional 
third dose at Month 2 and yearly fractional doses versus a schedule with full 
doses at Month 0, Month 1, Month 2 and yearly full doses.

To assess the incremental vaccine efficacy against clinical malaria, over 12 
months post-Dose 4, of a schedule with a fractional third dose at Month 7 versus 
a standard schedule with 4 full doses at 0,1,2,20 months.

To assess the vaccine efficacy and impact of each RTS,S/AS01E schedule over 
the entire study period by measuring the efficacy against clinical malaria at 
Months 14, 20, 26, 32, 38 and 50.

To assess the prevalence of P. falciparum infections of each RTS,S/AS01E
schedule at cross-sectional visits (monthly from Month 0-20 and every three 
months thereafter till study end).

To assess the vaccine efficacy against incident P. falciparum infections defined 
by positive blood slide over the entire study period.

Immunogenicity: Immune response to the CS and HBs antigens

To describe the antibody response to the anti-circumsporozoite protein of 
P. falciparum (anti-CS) for each schedule.

To describe the antibody response to the hepatitis B surface antigen (anti-HBs) 
for each schedule.

Safety and reactogenicity

To assess the safety of RTS,S/AS01E for each schedule in terms of serious 
adverse events (SAEs), unsolicited adverse events (AEs) and AEs of specific 
interest.

To assess the reactogenicity of RTS,S/AS01E in terms of solicited local and 
general AEs.

To assess the safety of RTS,S/AS01E in terms of biochemistry (alanine 
aminotransferase [ALT], creatinine) and hematology (hemoglobin, white blood 
cells [WBC], platelets) parameters.
Refer to Section 11.2 for the definition of the secondary endpoints.
2.3.
Tertiary objectives

Immunogenicity

To describe the anti-CS antibody response in terms of avidity.
Of note, blood samples taken in this study may also be used in ancillary studies. More 
details on ancillary studies are provided in the study design section (Section 3) of this 
protocol.
Refer to Section 11.3 for the definition of the tertiary endpoints.

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3.
STUDY DESIGN OVERVIEW
Figure 1
Study design: clinic visits

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In addition to the clinic visits presented in the figure above, parasite prevalence will be assessed at the following visits (these will be 
fieldworker visits or clinic visits depending on the timepoint and the group):
Figure 2
Study design: visits for assessment of parasite prevalence
Visits for parasite prevalence
Year 1
Visit 2
Day 0
Visit 3
Month 1
Visit 4
Month 2
Visit 6
Month 3
Visit 7
Month 4
Visit 8
Month 5
Visit 9
Month 6
Visit 10
Month 7
Visit 12
Month 8
Visit 13
Month 9
Visit 14
Month 10
Visit 15
Month 11
Visit 16
Month 12
Year 2
Visit 17
Month 13
Visit 18
Month 14
Visit 19
Month 15
Visit 20
Month 16
Visit 21
Month 17
Visit 22
Month 18
Visit 23
Month 19
Visit 24
Month 20
Visit 26
Month 23
Year 3
Visit 27
Month 26
Visit 29
Month 29
Visit 30
Month 32
Visit 32
Month 35
Year 4
Visit 33
Month 38
Visit 35
Month 41
Visit 36
Month 44
Visit 37
Month 47
Year 5
Visit 38
Month 50

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Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 6.5), are essential and required for 
study conduct.

Experimental design: Phase IIB, randomized, open-label, controlled, multi-centric
study with five parallel groups.

Duration of the study: Approximately 50 months, with two interim analyses and 
option for conditional continuation (see next bullet point).

Epoch 001: Starting at Visit 1 (Screening) and ending at Visit 17 (Month 13). 
Note: the data up to Visit 18 (Month 14) pertains to Epoch 001.

Epoch 002: Starting at Visit 18 (Month 14) and ending at Visit 26 (Month 23). 
Note: the data up to Visit 27 (Month 26) pertains to Epoch 002.

Epoch 003: Starting at Visit 27 (Month 26) and ending at Visit 32 (Month 35). 
Note: the data up to Visit 33 (Month 38) pertains to Epoch 003.

Epoch 004: Starting at Visit 33 (Month 38) and ending at Visit 38 (Month 50).

Primary completion date: Visit 18 (Month 14) or last visit of Epoch 001.
Refer to the GLOSSARY OF TERMS for the definition of primary completion 
date.

End of Study (EoS): Last testing results released of samples collected at Visit 38
(Month 50).
Refer to the GLOSSARY OF TERMS for the definition of EoS.
Amended 14 November 2019

Sequence of analyses and conditional continuation:

A first analysis will be performed on data collected up to Month 21 (Visit 25) to 
evaluate the primary objective and relevant secondary objectives.

A second analysis will be performed on data collected up to Month 33 (Visit 31) 
to evaluate relevant secondary objectives.

A final analysis will be performed at study end (Month 50) on data collected up 
to Month 50. An integrated study report presenting all results until Month 50 
will be produced.
After the interim analyses, the Independent Data Monitoring Committee (IDMC)
will have the possibility to recommend the suspension of further vaccinations and 
termination of specific study group(s) upon consideration of the study results. In the 
event that the IDMC recommend the suspension of further vaccinations, the group(s) 
impacted will be followed up for 12 months after their last study vaccination.

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
Study groups:
Table 2
Study groups and epochs foreseen in the study
Study groups
Vaccination schedule
Number 
of 
subjects
Age 
(Min/Max)
Epochs
Epoch 
001
Epoch 
002
Epoch 
003
Epoch 
004
R012-20
RTS,S/AS01E full dose at 
Month 0, Month 1, Month 2 + 
a full dose at Month 20
300
5 months -
17 months
x
x
x
x
R012-14-mD
RTS,S/AS01E full dose at 
Month 0, Month 1, Month 2 + 
yearly full doses at Month 14, 
Month 26, Month 38
300
5 months -
17 months
x
x
x
x
Fx012-14-mFxD
RTS,S/AS01E full dose at 
Month 0, Month 1 
+ RTS,S/AS01E 1/5th dose at 
Month 2, Month 14, Month 26, 
Month 38
300
5 months -
17 months
x
x
x
x
Fx017-mFxD
RTS,S/AS01E full dose at 
Month 0, Month 1 
+ RTS,S/AS01E 1/5th dose at 
Month 7, Month 20, Month 32
300
5 months -
17 months
x
x
x
x
Control
Rabies vaccine at Month 0, 
Month 1, Month 2
300
5 months -
17 months
x
x
x
x
Table 3
Study groups and treatment foreseen in the study
Treatment name Vaccine/Product 
name
Injectable 
volume
Study groups
R012-20
R012-14-
mD
Fx012-14-
mFxD
Fx017-
mFxD
Control
RTS,S/AS01E
(Full dose)
RTS,S (25 µg)
0.5 ml
x
x
X
x
AS01E
x
x
X
x
RTS,S/AS01E
(1/5th dose)
RTS,S (25 µg)
0.1 ml
X
x
AS01E
X
x
Rabies vaccine
Rabipur
1.0 ml
x

Control: active control, (Active comparator: rabies vaccine).

Vaccination schedules: are provided in Table 2.

Treatment allocation: randomized. Refer to Section 6.2 for a detailed description of 
the randomization method.

Blinding: open.
Table 4
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
open
Epoch 002
open
Epoch 003
open
Epoch 004
open

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
5 8

S a m pli n g sc he d ule:

Bl o o d sa m ples f or i m m u n o ge nicit y  will be ta ke n i n all s u bjects at ti me p oi nts 
descri be d i n Ta ble 5 . F or t he e val uati o n of a nti-C S a n d a nti -H Bs res p o nses, a 
s u bset of 5 0 s u bjects ( 2 5 s u bjects per site) i n eac h gr o u p (i m m u n o ge nicit y
s u bset, see Secti o n 5 ) will be teste d at s pecifie d ti me p oi nts (see Ta ble 5 a n d 
Secti o n 6. 7. 4. 1 ). 
 
.

I n a d diti o n t o t he bl o o d sa m ples liste d i n Ta ble 5 , a s mall a m o u nt of bl o o d (f or 
bl o o d s mear a n d filter pa per) will be ta ke n e ver y  m o nt h fr o m Da y 0 u ntil M o nt h 
2 0 , a n d t hereafter e ver y t hree m o nt hs u ntil M o nt h 5 0 f or bl o o d s me ar a n d u ntil 
M o nt h 3 2 f or filter p a per i n all s u bjects f or t he e val uati o n of P. f alci p ar u m
i nfecti o ns (see Secti o n 6. 7. 4. 2 ).
A me n de d 1 4 N ove m ber 2 0 1 9

Bl o o d sa m ples f or t he e val uati o n of bi oc he mistr y  a n d he mat ol o g y para meters 
will be ta ke n i n a s u b -c o h ort c o nsisti n g of t he first 5 0 s u bjects ( 2 5 s u bjects per 
site) e nr olle d i n eac h gr o u p (react o ge nicit y s u b -c o h ort, see Secti o n 5 ).
Bi oc he mistr y  ( A L T, creati ni ne) a n d he mat ol o g y ( he m o gl o bi n, W B C, platelets) 
para meters will be assesse d bef ore D ose 3, se ve n da y s p ost-D ose 3 a n d 3 0 da y s 
p ost -D ose 3 (see Ta ble 5 a n d Secti o n 6. 7. 4. 3 ).
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Table 5
Blood sampling timepoints
Visit 
1
Visit 
2
Visit 
4
Visit 
5
Visit 
6
Visit 
10
Visit 
11
Visit 
12
Visit 
18
Visit 
19
Visit 
24
Visit 
25
Visit 
27
Visit 
28
Visit 
30
Visit 
31
Visit 
33
Visit 
34
Visit 
38
Study group
Type of blood 
sampling
Scr
D0
M2
M2 + 
7d
M3
M7
M7 + 
7d
M8
M14
M15
M20
M21
M26
M27
M32
M33
M38
M39
M50
R012-20
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
R012-14-mD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
x
Fx012-14-mFxD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
x
Fx017-mFxD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
Control
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
* At screening, hemoglobin will be assessed in all subjects screened.
** Blood samples for hematology and biochemistry will be taken in a sub-cohort consisting of the first 50 subjects enrolled in each group.
§ Blood samples for immunogenicity will be taken in all subjects enrolled.
Scr: Screening
M: Month
D: Day

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
Efficacy surveillance:

Capture of malaria cases: malaria cases will be captured by passive case 
detection (PCD). Parents/LARs will be advised to present their child to the 
health center if the child is unwell. Care will be administered according to local 
recommendations. All children with fever and/or history of fever will have a 
blood sample taken for the evaluation of vaccine efficacy (blood slide 
throughout the study and filter paper for polymerase chain reaction [PCR] up 
until month 32). All anti-malaria treatments administered during the study 
should be recorded in the subject’s eCRF (see Section 7.7.1).
Amended 14 November 2019

Cross-sectional surveys: to evaluate the vaccine efficacy against incident and 
prevalent P. falciparum infections, monthly cross-sectional surveys will be 
performed from Day 0 until Month 20 to measure P. falciparum parasitemia. 
Thereafter until study end (Month 50) parasitemia will be measured every three 
months. Blood slides from cross-sectional surveys will not be read in real time.

The research team at each study center will provide all screened subjects with an 
ITN, and malaria diagnosis and treatment will be ensured.

Type of study: self-contained.

Ancillary studies:

The incidence of P. falciparum infection assessed by PCR and parasite 
genotyping will be evaluated in an ancillary study, with details provided in a 
separate protocol, using filter paper samples collected as described in the present 
protocol (see Table 20).

In addition, further characterization of the immune response and translational 
research for correlates of protection may be evaluated in ancillary studies, with 
details provided in a separate scope of work, using samples collected as 
described in the present protocol (See Section 6.6.16 and Table 15).

Data collection: eCRF.

Safety monitoring:

This study will be overseen by a formally constituted IDMC operating under a 
charter.

Each subject will be observed for at least 30 minutes after vaccination to 
evaluate and treat any acute AEs.

Cases of severe malaria and cerebral malaria will be reported as part of the 
safety surveillance until study end (Month 50) and clinical details of each case 
will be reported in a specific eCRF screen.

All SAEs will be reported until study end (Month 50).

Where possible autopsies will be performed. Verbal autopsy will be performed 
on all cases of mortality occurring outside hospital if autopsies cannot be 
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
All AEs and SAEs leading to withdrawal from further vaccination will be 
reported until study end (Month 50).

Meningitis and pIMDs are AEs of specific interest to be reported until study end 
(Month 50). All seizures occurring within 30 days post-vaccination are also AEs 
of specific interest. Clinical details according to the Brighton collaboration 
guidelines [Bonhoeffer, 2004] pertaining to seizures occurring within seven days
of vaccination will be documented in a specific eCRF screen. All AEs of 
specific interest are to be reported as SAEs (see Section 9.1.6).

Reactogenicity data collection will be aimed at characterizing reactions to the 
fractional doses relative to full doses and reactions to a fourth dose and multiple 
yearly doses, full or fractional. Post-Dose 1 and post-Dose 2 data will not be 
collected as these have already been largely characterized in previous studies 
including Phase III evaluation. Solicited local and general AEs will be collected 
in the first 50 subjects enrolled in each group (reactogenicity sub-cohort) during 
four days (day of vaccination and three subsequent days) after Dose 3 of study 
vaccine (all groups including controls), after Dose 4 (R012-20, R012-14-mD, 
Fx012-14-mFxD and Fx017-mFxD), after Dose 5 (R012-14-mD, Fx012-14-
mFxD and Fx017-mFxD) and after Dose 6 (R012-14-mD and Fx012-14-mFxD). 
Evidence from Phase III evaluation showed that the significant reactogenicity 
reactions to RTS,S/AS01E are concentrated in the first 48 hours post-
vaccination. On the day of vaccination the evaluation will be carried out by the 
study physician at the study center. On Days 1, 2 and 3 after vaccination, trained 
study personnel will visit the children to record solicited AEs on diary cards.

Unsolicited AEs will be collected during 30 days (day of vaccination and 29 
subsequent days) after each dose of study vaccine. Unsolicited AEs will be 
captured through passive surveillance at inpatient and outpatient facilities and 
during study visits.

Biochemistry (ALT, creatinine) and hematology (hemoglobin, WBC, platelets) 
parameters will be assessed in the first 50 subjects enrolled in each group 
(reactogenicity sub-cohort) before Dose 3, seven days post-Dose 3 and 30 days 
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4.
CASE DEFINITIONS
4.1.
Case definitions of clinical malaria
Table 6
Case definitions of clinical malaria
Primary case 
definition
P. falciparum asexual parasitemia > 5000 parasites/μl
AND presence of fever (axillary temperature 37.5°C) at the time of presentation
AND occurring in a child who is unwell and brought for treatment to a healthcare facility
Secondary case 
definition
P. falciparum asexual parasitemia > 0
AND presence of fever (axillary temperature 37.5°C) at the time of presentation or history of 
fever within 24 hours of presentation
AND occurring in a child who is unwell and brought for treatment to a healthcare facility
4.2.
Case definitions of P. falciparum infection
Table 7
Case definition of incident P. falciparum infection*
Case definition 1
A documented P. falciparum asexual parasite density > 0 detected by blood slide reading at a 
cross-sectional survey or as captured by the secondary case definition of clinical malaria (active 
detection of infection and passive case detection).
Table 8
Case definition of prevalent P. falciparum infection
Case definition 1
A documented P. falciparum asexual parasite density > 0 detected by blood slide reading at a 
cross-sectional survey (active detection of infection [ADI]).
*Note, the incidence of P. falciparum infection defined by positive PCR and parasite 
genotyping will be evaluated in the context of an ancillary study, using samples collected 
as described in the present protocol (see Section 6.7.4.2).
4.3.
Severe malaria and cerebral malaria
Cases of severe malaria and cerebral malaria will be reported as part of the safety 
surveillance (see Section 9.1.5). Case definitions adapted from the WHO case definitions
of severe malaria and cerebral malaria will be used as reference for diagnosis. Refer to 
APPENDIX C for the case definitions.
5.
STUDY COHORT
5.1.
Number of subjects/centers
Approximately 1500 subjects (300 per group) will be enrolled in this study. Refer to 
Section 11.4 for a detailed description of the criteria used in the estimation of sample 
size.

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
6 3
I n t his st u dy t he bi oc he mistr y a n d he mat ol o g y para meters a n d t he react o ge nicit y will be 
e val uate d i n a s u b -c o h ort of s u bjects. T he a nti -C S a n d a nti -H Bs i m m u ne res p o nses will 
be teste d i n a s u bset; see t he gl ossar y  of ter ms f or t he defi niti o ns of s u bset a n d s u b-
c o h ort.
T a bl e 9
S u b -c o h ort
S u b -c o h ort n a m e
D e s cri pti o n
E sti m at e d n u m b er of s u bj e ct s
R e act o g e nicity*
S olicit e d l oc al a n d g e n er al A Es will b e c oll ect e d i n a 
s u b-c o h ort c o nsisti n g of t h e first 5 0 s u bj ects 
e nr oll e d i n e ac h gr o u p. H e m at ol o gy a n d 
bi oc h e mistry p ar a m et ers will b e m e as ur e d i n t h e 
s a m e s u b-c o h ort.
2 5 0 ( 5 0 s u bj ects p er gr o u p, 2 5 
s u bj ects p er sit e)
* S u bj ects b el o n gi n g t o t his s u b-c o h ort will h av e s p ecific st u dy pr oc e d ur es p erf or m e d f or t h e ass ess m e nt of 
r e act o g e nicity, h e m at ol o gy a n d bi oc h e mistry p ar a m et ers (r ef er t o T a bl e 1 1 , T a bl e 1 2 a n d T a bl e 1 3 ). 
T a bl e 1 0
S u b s et
S u b s et n a m e
D e s cri pti o n
E sti m at e d n u m b er of s u bj e ct s
I m m u n o g e nicity*
A nti -C S a n d a nti -H Bs i m m u n e r es p o ns es will b e 
t est e d i n a s u bs et c orr es p o n di n g t o t h e first 5 0 
s u bj ects e nr oll e d i n e ac h gr o u p.
2 5 0 (5 0 s u bj ects p er gr o u p , 2 5 
s u bj ects p er sit e)
*I n t his st u dy, all s u bj ects e nr oll e d will h av e bl o o d s a m pl es t ak e n f or ass ess m e nt of i m m u n o g e nicity . N ot all s a m pl es 
will b e us e d f or t esti n g: a nti -C S a n d a nti -H Bs i m m u n e r es p o ns es will b e t est e d i n a s u bs et (i. e. t h e i m m u n o g e nicity 
s u bs et w hic h i ncl u d es t h e s a m e s u bj ects as i n t h e r e act o g e nicity s u b -c o h ort) 
 
5. 2.
I n cl u si o n crit eri a f or e nr ol m e nt
De viati o ns fr o m i ncl usi o n criteria are n ot all o we d beca use t he y  ca n p ote ntiall y je o par dize 
t he scie ntific i nte grity of t he st u d y, re g ulat or y acce pta bilit y or s u bjec t safet y. T heref ore, 
a d here nce t o t he criteria as s pecifie d i n t he pr ot oc ol is esse ntial.
All s u bjects m ust satisf y  A L L t he f oll o wi n g criteria at st u d y e ntr y:

S u bjects’ pare nt(s)/ L A R(s) w h o, i n t he o pi ni o n of t he i n vesti gat or, ca n a n d will 
c o m pl y wit h t he re q uire me nts of t he pr ot oc ol (e. g. ret ur n f or f oll o w-u p visits).

Si g ne d or t h u m b -pri nte d a n d wit nesse d i nf or me d c o nse nt o btai ne d fr o m t he 
pare nt(s)/ L A R(s) of t he s u bject pri or t o perf or ma nce of a n y st u d y s pecific pr oce d ure. 
W here pare nt(s)/ L A R(s) are illit erate, t he c o nse nt f or m will be c o u ntersi g ne d b y  a n 
i n de pe n de nt wit ness.

A male or fe male bet wee n, a n d i ncl u di n g, fi ve a n d 1 7 m o nt hs of a ge at t he ti me of 
t he first vacci nati o n.

Healt h y s u bjects as esta blis he d b y  me dical hist or y a n d cli nical e xa mi nati o n bef ore 
e nteri n g i nt o t he st u d y.

Pre vi o usl y  recei ve d t hree d oc u me nte d d oses of di p ht heria, teta n us, pert ussis, 
he patitis B vacci ne ( D T P He p B), a n d at least t hree d oses of oral p oli o vacci ne.
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5.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care.
Please refer to the glossary of terms for the definition of child in care.

Use of a drug or vaccine that is not approved for that indication (by one of the 
following regulatory authorities: Food and Drug Administration [FDA; USA] or 
European Union member state or WHO [with respect to prequalification]) other than 
the study vaccines during the period starting 30 days before the first dose of study 
vaccines (Day -29 to Day 0), or planned use during the study period.

Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to the first vaccine dose. For corticosteroids, this will mean prednisone 
( 0.5 mg/kg/day (for pediatric subjects) or equivalent. Inhaled and topical steroids are 
allowed.

Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting seven days before each dose and ending seven days 
after each dose of vaccine administration.

Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device).

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

Family history of congenital or hereditary immunodeficiency.

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines.

History of anaphylaxis post-vaccination.

History of any, or documented, serious adverse reaction to rabies vaccination.

Contraindication to rabies vaccination (Rabipur is contraindicated in subjects with an
history of a severe hypersensitivity to any of the ingredients in the vaccine. Note that the 
vaccine contains polygeline and residues of chicken proteins, and may contain traces of 
neomycin, chlortetracycline and amphotericin B) (Refer to the [Rabipur SmPC, 2010]).

Major congenital defects.

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
Serious chronic illness.

Children with a past history of a neurological disorder or atypical febrile seizure (a 
febrile seizure is atypical if it meets one of the following criteria: not associated with 
fever; lasts > 5 minutes; focal (not generalized); followed by transient or persistent 
neurological abnormality; occurs in a child < 6 months of age).

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature ≥ 37.5°C/99.5°F for oral, axillary or tympanic 
route, or ≥ 38.0°C/100.4°F for rectal route.

Subjects with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may, be enrolled at the discretion of the investigator.

Administration of immunoglobulins and/or any blood products during the period 
starting three months before the first dose of study vaccine or planned administration 
during the study period.

Moderate or severe malnutrition at screening defined as weight for age or weight for 
height Z-score < -2.

Hemoglobin concentration < 8 g/dl at screening.

Same sex twins (to avoid misidentification).

Maternal death.

Prior receipt of an investigational malaria vaccine.
6.
CONDUCT OF THE STUDY
6.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the ICH Guideline for GCP, all 
applicable subject privacy requirements and the guiding principles of the Declaration of 
Helsinki. 
The study has been designed and will be conducted in accordance with the ICH 
Harmonized Tripartite Guideline for clinical investigation of medicinal products in the 
pediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favorable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favorable opinion/approval of study protocol and any subsequent amendments.

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
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 or witnessed/ thumb-printed 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.
6.2.
Subject identification and randomization of treatment
6.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study center.
Subject identification cards with the subject number will be provided to each subject’s 
parents/LAR(s).
6.2.2.
Randomization of treatment
6.2.2.1.
Randomization of supplies
The randomization of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centers /warehouse(s).
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centers in this multi-center study and to thus reduce the overall 
study recruitment period, an over-randomization of supplies will be prepared.

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
6 7
6. 2. 2. 2.
Tr e at m e nt all o c ati o n t o t h e s u bj e ct
T he tre at me n t n u m bers will be all oc ate d b y d ose.
6. 2. 2. 2. 1.
St u d y gr o u p a n d tr e at m e nt n u m b er all o c ati o n
T he tar get will be t o e nr oll a p pr o xi matel y 1 5 0 0 eli gi ble s u bjects w h o will be ra n d o ml y 
assi g ne d t o fi ve st u d y gr o u ps i n a ( 1: 1: 1: 1: 1) rati o (a p pr o xi matel y 3 0 0 s u bjects i n eac h 
gr o u p).
All ocati o n of t he s u bject t o a st u d y  gr o u p at t he i n vesti gat or site will be perf or me d usi n g 
a ran d o mizati o n s yste m o n i nter net ( S BI R). T he ra n d o mizati o n al g orit h m will use a 
mi ni mizati o n pr oce d ure acc o u nti n g f or ce nter.
After o btai ni n g t he si g ne d ( or t h u m b-pri nte d a n d wit nesse d) a n d date d I C F fr o m t he 
s u bject’s pare nt(s)/ L A R(s) a n d ha vi n g c hec ke d t he eli gi bilit y of t he s u bject, t he site staff 
i n c har ge of t he vacci ne a d mi nistrati o n will access S BIR. U p o n pr o vi di n g t he s u bject 
i de ntificati o n n u m ber, t he ra n d o mizati o n s yste m will deter mi ne t he st u d y gr o u p a n d will 
pr o vi de t he treat me nt n u m ber t o be use d f or t he first d ose.
T he n u m ber of eac h a d mi nistere d treat me nt m ust be rec or de d i n t he e C R F o n t he v acci ne 
ad mi nistrati o n scree n.
W he n S BI R is n ot a vaila ble, please refer t o t he S BI R user g ui de or t he st u d y pr oce d ures 
m a n ual ( S P M) f or s pecific i nstr ucti o ns.
6. 2. 2. 2. 2.
Tr e at m e nt n u m b er all o c ati o n f or s u b s e q u e nt d o s e s
F or eac h d ose s u bse q ue nt t o t he first d ose, t he st u d y staff i n c har ge of t he vacci ne
a d mi nistrati o n will access S BIR, pr o vi de t he s u bject i de ntificati o n n u m ber, a n d t he 
s yste m will pr o vi de a treat me nt n u m ber c o nsiste nt wit h t he all ocate d st u d y gr o u p.
T he n u m ber of eac h a d mi nistere d treat m e nt m ust be rec or de d i n t he e C R F o n t he v acci ne 
ad mi nistrati o n scree n.
6. 2. 3.
Al l o c ati o n of s u bj e ct s t o a s s a y s u b s et s
Bl o o d sa m ples f or i m m u n o ge nicit y  will be ta ke n i n all s u bjects at ti me p oi nts descri be d i n 
Ta ble 5 . N ot all sa m ples will be use d f or testi n g:

A nti -C S a n d a nti - H Bs i m m u ne res p o nses will be teste d i n a s u bset w hic h i ncl u des
t he sa me s u bjects as i n t he react o ge nicity s u b -c o h ort (t he first 5 0 s u bjects e nr olle d i n 
eac h gr o u p ).
C CI

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6.3.
Method of blinding
Due to the different vaccination schedules between the various study groups the study 
will be open-label.
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.
6.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects.
6.4.1.
Independent Data Monitoring Committee oversight
This study will be overseen by formally constituted IDMC operating under a charter. 
Overall, the role of the IDMC includes the review and protection of data integrity and 
rights and safety of study subjects throughout the study period. It will provide initial, 
regular, and closing advice to GSK Biologicals on medical, ethical, scientific and safety-
related issues. Its advice will be based on the interpretation of study data with reference 
to the study protocol.
The IDMC will review the study protocol and the statistical analysis plan. Meetings will 
be documented and the minutes of open sessions of the IDMC meetings will be made 
available to the sponsor. The IDMC may, if deemed necessary, convene a meeting with, 
or request further information from the principal investigators and GSK Biologicals’ 
designated project representatives at any stage of the study.
The IDMC may recommend to the sponsor to suspend the enrollment to the study and/or 
vaccination based on their ongoing review of safety data.
The IDMC will receive the following safety data:

Periodic safety reports (such as the annual development safety update reports 
[DSUR]).
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).

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6.4.2.
Standard of care provided to the subjects during the study
During the study, subjects will receive standard medical care according to national 
guidelines.
Subjects should continue with their routine EPI immunizations as applicable to their age 
whilst participating in the study. 
Clinical malaria episodes are detected by PCD and treatment will be guided by rapid 
diagnostic test (RDT)/clinical evaluation at the discretion of the investigator. Blood slides 
will also be collected, however, these will not be read in real time but sent to a central 
laboratory (see Table 17) where all blood samples will be read according to a 
standardized method. Case definitions of clinical malaria will be based on final parasite 
density obtained from this process.
Malaria infections will be detected through active detection of infections through cross-
sectional blood sampling. Blood slides obtained will not be read in real time and will 
follow the same process as described above. As a result, non-febrile parasite positive 
children with no symptoms will not be treated for malaria at the time of cross-sectional 
visits.

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6.5.
Outline of study procedures
Table 11
List of study procedures for clinic visits
Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
27c
Visit 
28c
Visit 
30f
Visit 
31f
Visit 
33c
Visit 
34c
Visit 
38
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Control group
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
Measure and record length and weight
●
Issue subject's identification card
O
Check subject's identification card
O
O
O
O
O
O
Randomization
●
Distribute ITN
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
Treatment number allocation
O
O
O
Administer study vaccine
●
●
●
Recording of administered treatment number
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.5 ml)
●
●
●
●
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
27c
Visit 
28c
Visit 
30f
Visit 
31f
Visit 
33c
Visit 
34c
Visit 
38
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n,o
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
Study Conclusion
●
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
Group R012-20
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
O
Measure and record length and weight
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
27c
Visit 
28c
Visit 
30f
Visit 
31f
Visit 
33c
Visit 
34c
Visit 
38
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Issue subject's identification card
O
Check subject's identification card
O
O
O
O
O
O
O
Randomization
●
Distribute ITN
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
●
Treatment number allocation
O
O
O
O
Administer study vaccine
●
●
●
●
Recording of administered treatment number
●
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.5 ml)
●
●
●
●
●
●
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n, o
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p
●
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
●
Study Conclusion
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
27c
Visit 
28c
Visit 
30f
Visit 
31f
Visit 
33c
Visit 
34c
Visit 
38
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
●j
Groups R012-14-mD and Fx012-14-mFxD
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
O
O
O
O
O
Measure and record length and weight
●
Issue subject's identification card
O
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
Randomization
●
Distribute ITN
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
●
●
●
Treatment number allocation
O
O
O
O
O
O
Administer study vaccine
●
●
●
●
●
●
Recording of administered treatment number
●
●
●
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.5 ml)
●
●
●
●
●
●
●
●
●
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
27c
Visit 
28c
Visit 
30f
Visit 
31f
Visit 
33c
Visit 
34c
Visit 
38
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n, 0
●
●
●
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
●k
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p
●
●
●
●
●
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
●
●
●
●
●
Study Conclusion
●
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
●j
●j
●j
Group Fx017-mFxD
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
O
O
O
O
Measure and record length and weight
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
27c
Visit 
28c
Visit 
30f
Visit 
31f
Visit 
33c
Visit 
34c
Visit 
38
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Issue subject's identification card
O
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
Randomization
●
Distribute ITN
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
●
●
Treatment number allocation
O
O
O
O
O
Administer study vaccine
●
●
●
●
●
Recording of administered treatment number
●
●
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.5 ml)
●
●
●
●
●
●
●
●
●
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n, o
●
●
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p
●
●
●
●
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
●
●
●
●
Study Conclusion
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
27c
Visit 
28c
Visit 
30f
Visit 
31f
Visit 
33c
Visit 
34c
Visit 
38
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
●j
●j
Note: The double-line border following Month 21 (Visit 25) and Month 33 (Visit 31) indicates the two interim analyses which will be performed on all data collected up to respectively 
Month 21 and up to Month 33 (i.e. data that are as clean as possible, except clinical malaria fully cleaned up to Month 14). The final analysis will be performed on fully cleaned data 
collected up to study end (Month 50).
D: Day, M: Month.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
a. Clinic visit 5 (Month 2 + 7 days) and clinic visit 6 (Month 3) are only for groups R012-20, R012-14-mD, Fx012-14-mFxD and Control. The group FX017-mFXD has a field worker 
visit at Month 3 for assessment of parasitemia.
b. Clinic visit 10 (Month 7), clinic visit 11 (Month 7 + 7 days) and clinic visit 12 (Month 8) are only for group Fx017-mFxD. The other groups have field worker visits at Month 7 and 
Month 8 respectively for assessment of parasitemia.
c. Clinic visit 18 (Month 14), clinic visit 19 (Month 15), clinic visit 27 (Month 26), clinic visit 28 (Month 27), clinic visit 33 (Month 38) and clinic visit 34 (Month 39) are only for groups 
R012-14-mD and Fx012-14-mFxD. The other groups have field worker visits at Month 14, Month 15, Month 26 and Month 38 respectively for assessment of parasitemia. 
d. Clinic visit 24 (Month 20) is only for groups R012-20, Fx017-mFxD and Control. The other groups have a field worker visit at Month 20 for assessment of parasitemia.
e. Clinic visit 25 (Month 21) is only for groups R012-20 and Fx017-mFxD.
f.
Clinic visit 30 (Month 32) and clinic visit 31 (Month 33) are only for group Fx017-mFxD. The other groups have a field worker visit at Month 32 for assessment of parasitemia.
g. The screening laboratory results (hemoglobin) must be checked during the screening activities and before randomization.
h. There is no specific section in the eCRF to record the contraindications, warnings and precautions. The absolute contraindications to further administration of study vaccines have 
to be recorded in the AE or SAE section of the eCRF.
i.
At screening, hemoglobin will be assessed in all subjects screened.
j.
Solicited local and general AEs will be collected in the first 50 subjects enrolled in each group (reactogenicity sub-cohort) during four days (day of vaccination and three subsequent 
days) after vaccination as indicated in the table above. On the day of vaccination the evaluation will be carried out by the study physician at the study center. On Days 1, 2 and 3 
after vaccination, trained study personnel will visit the children to record solicited AEs on diary cards.
k. Unsolicited AEs will be collected during 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine. Unsolicited AEs will be captured through passive 
surveillance at inpatient and outpatient facilities and during study visits.

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l.
AEs of specific interest include all seizures occurring within 30 days post-vaccination, meningitis and pIMDs (see Section 9.1.6). pIMDs will be reported via the electronic Expedited
Adverse Events Report. Meningitis and seizures will be reported via the electronic Expedited Adverse Events Report and in addition clinical details of each case will be reported in 
a specific eCRF screen.
m. If a subject is considered momentarily ineligible on the day of the screening visit (i.e. failing to meet one or more eligibility criteria) procedures for screening can be repeated one
further time, within the time window allowed for screening (see Table 14). No more than one repeat is allowed.
n. Blood for parasitemia (0.5 ml) includes the blood for the slide reading (to Month 50) and for the filter paper (to Month 32). The parasitemia assessment by blood slide reading will 
include blood-stage parasites and gametocytes counts.
o. In addition to the scheduled clinic visits, malaria cases will be captured by PCD throughout the study. All sick children presenting with fever and/or history of fever will have a blood 
sample taken for the evaluation of vaccine efficacy (for blood slide to Month 50 and filter paper for PCR to Month 32).
p. Case of severe malaria or cerebral malaria will be reported via the electronic Expedited Adverse Events Report (refer to Section 9.3.1) and in addition clinical details of each case
will be reported in a specific eCRF screen.
Amended 14 November 2019

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Table 12
List of study procedures for field worker visits - Part 1 (Day 0 to Month 19)
Epochs
Epoch 001
Epoch 002
Type of contact: Field worker visits
Visit 
a*
Visit 
b*
Visit 
c*
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 
10
Visit 
d*
Visit 
e*
Visit 
f*
Visit 
12
Visit 
13
Visit 
14
Visit 
15
Visit 
16
Visit 
17
Visit 
18
Visit 
g*
Visit 
h*
Visit 
i*
Visit 
19
Visit 
20
Visit 
21
Visit 
22
Visit 
23
Timepoints
M2 
+ 1d
M2 
+ 2d
M2 
+ 3d
M3 M4
M5 M6 M7 M7 
+ 1d
M7 
+ 2d
M7 
+ 3d
M8 M9 M10 M11 M12 M13 M14 M14 
+ 1d
M14 
+ 2d
M14 
+ 3d
M15 M16 M17 M18 M19
Control group
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●
Group R012-20
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●
Groups R012-14-mD and Fx012-14-mFxD
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●
●
●
●
Group Fx017-mFxD
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●

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M: Month, d: day.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
*
Visits a-u are restricted to the subjects in the reactogenicity sub-cohort; these visits are for the recording of solicited local and general AEs in the three days following each 
vaccination.
†
Blood for parasitemia (0.5 ml) includes the blood for the slide reading and for the filter paper. The parasitemia assessment by blood slide reading will include blood-stage parasites 
and gametocytes counts.
§
In addition to the scheduled clinic visits, malaria cases will be captured by PCD throughout the study. All sick children presenting with fever and/or history of fever will have a blood 
sample taken for the evaluation of vaccine efficacy (for blood slide and filter paper for PCR).

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Table 13
List of study procedures for field worker visits - Part 2 (Month 20 to Month 50)
Epochs
Epoch 002
Epoch 003
Epoch 004
Type of contact: Field worker visits
Visit 
24
Visit 
j*
Visit 
k*
Visit 
l*
Visit 
25
Visit 
26
Visit 
27
Visit 
m*
Visit 
n*
Visit 
o*
Visit 
28
Visit 
29
Visit 
30
Visit 
p*
Visit 
q*
Visit 
r*
Visit 
32
Visit 
33
Visit 
s*
Visit 
t*
Visit 
u*
Visit 
35
Visit 
36
Visit 
37
Timepoints
M20 M20 
+ 1d
M20 
+ 2d
M20 
+ 3d
M21 M23 M26 M26 
+ 1d
M26 
+ 2d
M26 
+ 3d
M27 M29 M32 M32+ 
1d
M32 
+ 2d
M32 
+ 3d
M35 M38 M38 
+ 1d
M38 
+ 2d
M38 
+ 3d
M41 M44 M47
Control group
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort only: 
Record solicited local and general AEs
(Days 0-3)
Group R012-20
Check subject's identification card
O 
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
● 
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●
Groups R012-14-mD and Fx012-14-
mFxD
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●
●
●
●
Group Fx017-mFxD
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●

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Epochs
Epoch 002
Epoch 003
Epoch 004
Type of contact: Field worker visits
Visit 
24
Visit 
j*
Visit 
k*
Visit 
l*
Visit 
25
Visit 
26
Visit 
27
Visit 
m*
Visit 
n*
Visit 
o*
Visit 
28
Visit 
29
Visit 
30
Visit 
p*
Visit 
q*
Visit 
r*
Visit 
32
Visit 
33
Visit 
s*
Visit 
t*
Visit 
u*
Visit 
35
Visit 
36
Visit 
37
Timepoints
M20 M20 
+ 1d
M20 
+ 2d
M20 
+ 3d
M21 M23 M26 M26 
+ 1d
M26 
+ 2d
M26 
+ 3d
M27 M29 M32 M32+ 
1d
M32 
+ 2d
M32 
+ 3d
M35 M38 M38 
+ 1d
M38 
+ 2d
M38 
+ 3d
M41 M44 M47
For the reactogenicity sub-cohort only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●
●
●
●
M: Month, d: day.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
*
Visits a-u are restricted to the subjects in the reactogenicity sub-cohort; these visits are for the recording of solicited local and general AEs in the three days following each 
vaccination.
†
Blood for parasitemia (0.5 ml) includes the blood for the slide reading (to Month 50) and for the filter paper (to Month 32). The parasitemia assessment by blood slide reading will 
include blood-stage parasites and gametocytes counts.
§
In addition to the scheduled clinic visits, malaria cases will be captured by PCD throughout the study. All sick children presenting with fever and/or history of fever will have a blood 
sample taken for the evaluation of vaccine efficacy (for blood slide to Month 50 and filter paper for PCR to Month 32).
In addition to the field worker visits detailed in Table 12 and Table 13, field workers may visits the subjects ahead of the planned visit to ensure presence during the next visit an
d maintain subject compliance.
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Table 14
Intervals between study visits
Interval
Optimal length of 
interval 1
Allowed interval2
Visit 1Visit 2 (Vacc)
0 to 28 days
0 - 28 days
Visit 2Visit 3 (Vacc)
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 3Visit 4 (Vacc)
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 4Visit 5
7 days
Minimum 6 days - Maximum 8 days
Visit 4Visit 6
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 6Visit 7
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 7Visit 8
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 8Visit 9
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 3Visit 10 (Vacc)
6 months
Minimum 161 days (23 weeks) - Maximum 203 days (29 weeks)
Visit 10Visit 11
7 days
Minimum 6 days - Maximum 8 days
Visit 10Visit 12
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 12Visit 13
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 13Visit 14
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 14Visit 15
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 15Visit 16
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 16Visit 17
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 4Visit 18 (Vacc)
12 months
Minimum 336 days (48 weeks) - Maximum 392 days (56 weeks)
Visit 18Visit 19
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 19Visit 20
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 20Visit 21
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 21Visit 22
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 22Visit 23
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 4Visit 24 (Vacc)*
18 months
Minimum 518 days (74 weeks) - Maximum 574 days (82 weeks)
Visit 10Visit 24 (Vacc)**
13 months
Minimum 364 days (52 weeks) - Maximum420 days (60 weeks)
Visit 24Visit 25
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 24 Visit 26
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 18Visit 27 (Vacc)
12 months
Minimum 336 days (48 weeks) - Maximum 392 days (56 weeks)
Visit 27Visit 28
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 27Visit 29
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 24Visit 30 (Vacc)
12 months
Minimum 336 days (48 weeks) - Maximum 392 days (56 weeks)
Visit 30Visit 31
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 30Visit 32
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 27Visit 33 (Vacc)
12 months
Minimum 336 days (48 weeks) - Maximum 392 days (56 weeks)
Visit 33Visit 34
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 33Visit 35
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 35Visit 36
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 36Visit 37
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 37Visit 38
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
1. Whenever possible the investigator should arrange study visits within this interval.
2. Subjects will not be eligible for inclusion in the according-to-protocol (ATP) cohorts if they make the study visit 
outside this interval: to be included in the ATP cohort for efficacy, subjects should receive all vaccinations within the 
protocol specified intervals; to be included in the ATP cohort for immunogenicity, subjects should receive all 
vaccinations within the protocol specified intervals and perform all blood samplings for immunogenicity within the 
protocol specified intervals.
* Interval between Visit 4 and Visit 24 is for groups Control and R012-20.
** Interval between Visit 10 and Visit 24 is for group Fx017-mFxD.
Vacc: vaccination in at least one group.

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6.6.
Detailed description of study procedures
6.6.1.
Informed consent
The signed/witnessed/thumb-printed informed consent of the subject’s parent(s)/LAR(s)
must be obtained before study participation. Refer to Section 6.1 for the requirements on
how to obtain informed consent.
6.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 5.2 and 5.3 before 
enrolment.
If a subject is considered momentarily ineligible on the day of the screening visit (i.e.
failing to meet one or more eligibility criteria) procedures for screening can be repeated 
one further time, within the time window allowed for screening (see Table 14). No more 
than one repeat is allowed.
6.6.3.
Check the subject’s vaccination card
Check the subjects’ vaccination card to assess if the subject meets the related inclusion 
criterion described in Section 5.2.
6.6.4.
Check screening laboratory results
Check the result of the hemoglobin level to assess if the subject meets the related 
exclusion criterion described in Section 5.3.
6.6.5.
Collect demographic data
Record demographic data such as date of birth and gender in the subject’s eCRF.
6.6.6.
Check medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF.
6.6.7.
Physical examination
Perform a physical examination of the subject, including assessment of body temperature, 
heart rate and respiratory rate. Collected information needs to be recorded in the eCRF at 
Visit 1 (Screening).
Physical examination at each study visit subsequent to the first visit will be performed 
only if the subject indicates during questioning that there might be some underlying 
pathology(ies) or if deemed necessary by the investigator or delegate.

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Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
6.6.8.
Measure and record length and weight
Perform anthropometric measurements of the subject (length and weight) at Visit 1 
(Screening). Collected information needs to be recorded in the eCRF.
The methodologies used for length and weight measurements have been adapted from 
Cogill [Cogill, 2003] and are based on guidelines of the United Nations [United Nations, 
1986]. These procedures are fully described in the SPM.
6.6.9.
Issue subject’s identification card
At Visit 2, take a picture of the subject and his/her parent(s)/LAR(s) to make an 
identification card with subject’s picture and number. Give this identification card to the 
subject’s parent(s)/LAR(s).
6.6.10.
Check subject’s identification card
At each subsequent clinic visits AND field worker visits, check the subject’s 
identification card.
6.6.11.
Study group and treatment number allocation (randomization)
Study group and treatment number allocation will be performed as described in Section 
6.2.2. The number of each administered treatment must be recorded in the eCRF.
6.6.12.
Record if the subject belongs to the reactogenicity sub-cohort
The reactogenicity sub-cohort will consist of the first 50 subjects enrolled in each group
(see Section 5). Record in the eCRF if the subject belongs to the reactogenicity sub-
cohort.
6.6.13.
Check contraindications, warnings and precautions to 
vaccination
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 7.5 and 7.6 for more details.
6.6.14.
Record pre-vaccination body temperature
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be 
measured prior to any study vaccines administration. The preferred route for recording 
temperature in this study will be axillary. If the subject has fever (fever is defined as 
temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 38.0°C/100.4°F for 

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rectal route) on the day of vaccination, the vaccination visit will be rescheduled within 
the allowed interval for this visit (see Table 14).
6.6.15.
Study vaccines administration
After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly in the left deltoid (refer to Section 7.3 for 
detailed description of the vaccines administration procedure). If the investigator or 
delegate determines that the subject’s health on the day of administration temporarily 
precludes vaccine administration, the visit will be rescheduled within the allowed interval 
for this visit (refer to Table 14).
The subjects will be observed closely for at least 30 minutes following the administration 
of the vaccine, with appropriate medical treatment readily available in case of 
anaphylaxis.
Vaccination will take place at the vaccination center. All vaccinations will be given by a 
qualified person: a nurse or a doctor. A staff member experienced in the resuscitation of 
children will be available at all vaccination sessions.
6.6.16.
Blood sampling for all subjects
Blood samples will be taken during certain study visits as specified in Table 11, Table 12
and Table 13.
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.

Blood sampling for assessment of immunogenicity
A volume of approximately 2.5 ml of whole blood should be drawn from all subjects 
at each pre-defined timepoint. Out of this, a volume of approximately 1.5 ml of 
whole blood will provide 600 l of serum (300 l of serum for anti-CS enzyme-
linked immunosorbent assay [ELISA] + anti-CS avidity and 250 l of serum for anti-
HBs) and serum from a volume of approximately 1.0 ml of whole blood will be 
stored to support potential ancillary studies for the further characterization of the 
immune response and translational research for correlates of protection.
After centrifugation, serum samples should be kept at -20°C/ -4°F or below until 
shipment. Refer to the SPM for more details on sample storage conditions.

Blood sampling for assessment of hemoglobin at screening
A volume of approximately 0.5 ml of whole blood should be drawn from all subjects
screened at Visit 1 (Screening) to measure hemoglobin concentration.

Blood sampling for assessment of parasitemia
A volume of approximately 0.5 ml of whole blood should be drawn from all subjects 
at each pre-defined timepoint for the assessment of P. falciparum parasitemia (until 
Month 50 for blood slide and until Month 32 for filter paper).

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In addition to the scheduled clinic visits, malaria cases will be captured by PCD 
throughout the study. All sick children presenting with fever and/or history of fever 
will have a blood sample taken for the evaluation of vaccine efficacy (until Month 
50 for blood slide and until Month 32 for filter paper).
Amended 14 November 2019
6.6.17.
Blood sampling for the reactogenicity sub-cohort
Blood samples for the assessment of hematology and biochemistry parameters will be 
taken in subjects belonging to the reactogenicity sub-cohort (i.e. the first 50 subjects 
enrolled in each group) during certain study visits as specified in Table 11.

Blood sampling for assessment of safety
A volume of approximately 1.0 ml of whole blood should be drawn at each pre-
defined timepoint for the assessment of hematology (hemoglobin, WBC, platelets) 
biochemistry (ALT, creatinine) parameters.
6.6.18.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 7.7.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 7.8.
6.6.19.
Recording of unsolicited AEs, SAEs and AEs of specific interest
Refer to Section 9.2 for procedures for the investigator to record AEs, SAEs and AEs of 
specific interest. Refer to Section 9.3 for guidelines and how to report SAE and AEs of 
specific interest reports to GSK Biologicals.
The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subjects manifest any signs or symptoms they perceive as serious.
Unsolicited AEs will be collected during 30 days (day of vaccination and 29 subsequent 
days) after each dose of study vaccine. Unsolicited AEs will be captured through passive 
surveillance at inpatient and outpatient facilities and during study visits.
Where possible autopsies will be performed. Verbal autopsy will be performed on all 
cases of mortality occurring outside hospital if it is not possible to perform the autopsies
(Refer to Section 9.2.3.6).
6.6.20.
Recording of solicited AEs in the reactogenicity sub-cohort
Solicited local and general AEs will be collected in the first 50 subjects enrolled in each 
group (reactogenicity sub-cohort) during four days (day of vaccination and three 
subsequent days) after Dose 3 of study vaccine (all groups including controls), after Dose 

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4 (R012-20, R012-14-mD, Fx012-14-mFxD and Fx017-mFxD), after Dose 5 (R012-14-
mD, Fx012-14-mFxD and Fx017-mFxD) and after Dose 6 (R012-14-mD and Fx012-14-
mFxD). On the day of vaccination the evaluation will be carried out by the study 
physician at the study center. On Days 1, 2 and 3 after vaccination, trained study 
personnel will visit the children to record solicited AEs on diary cards.
6.6.21.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness

complete the Study Conclusion screen in the eCRF.
6.7.
Biological sample handling and analysis
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be asked to give a specific consent
to allow GSK or a contracted partner to use the samples for future research. Future 
research will be subject to the laws and regulations in the respective countries and 
will only be performed once an independent Ethics Committee or Review Board has 
approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s).
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
If additional testing is performed, the marker priority ranking given in Section 6.7.4 may 
be changed.

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Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
6.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 11.5 for the definition of 
cohorts to be analyzed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when 
GSK Biologicals does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM.
6.7.2.
Biological samples
Sample type to be collected in the study: whole blood.

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Table 15
Biological samples (whole blood)
Timepoint
Assessment
Total volume of blood per visit (ml)
R012-20
R012-14-mD
Fx012-14-
mFxD
Fx017-mFxD
Control
Visit 1 (Screening)
Safety 
(hemoglobin)†
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 2 (Day 0)
Immunogenicity 2.5 ml
2.5 ml
2.5 ml
2.5 ml l
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0 ml
3.0 ml
3.0 ml
3.0 ml
3.0 ml
Visit 3 (Month 1)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 4 (Month 2)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Immunogenicity 2.5 ml
2.5 ml
2.5 ml
2.5 ml
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
4.0 or 3.0 ml** 4.0 or 3.0 ml** 4.0 or 3.0 ml** 3.0 ml
4.0 or 3.0 ml**
Visit 5 (Month 2 + 
7d)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Visit 6 (Month 3)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Immunogenicity 2.5 ml
2.5 ml
2.5 ml
-
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
4.0 or 3.0 ml** 4.0 or 3.0 ml** 4.0 or 3.0 ml** 0.5 ml
4.0 or 3.0 ml**
Visit 7 (Month 4)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 8 (Month 5)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 9 (Month 6)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 10 (Month 7)
Safety*
-
-
-
1.0 ml*
-
Immunogenicity -
-
-
2.5 ml
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
4.0 or 3.0 ml**
0.5 ml
Visit 11 (Month 7 + 
7d)
Safety*
-
-
-
1.0 ml*
-
Visit 12 (Month 8)
Safety*
-
-
-
1.0 ml*
-
Immunogenicity -
-
-
2.5 ml
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
4.0 or 3.0 ml**
0.5 ml
Visit 13 (Month 9)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 14 (Month 10)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 15 (Month 11)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 16 (Month 12)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 17 (Month 13)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 18 (Month 14)
Immunogenicity -
2.5 ml
2.5 ml
-
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 19 (Month 15)
Immunogenicity -
2.5 ml
2.5 ml
-
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 20 (Month 16)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 21 (Month 17)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 22 (Month 18)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 23 (Month 19)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 24 (Month 20)
Immunogenicity 2.5 ml
-
-
2.5 ml
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0 ml
0.5 ml
0.5 ml
3.0 ml
3.0 ml
Visit 25 (Month 21)
Immunogenicity 2.5 ml
-
-
2.5 ml
-
Visit 26 (Month 23)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml

CONFIDENTIAL
204889 (MALARIA-094)
Protocol Amendment 3 Final
14-NOV-2019
90
Timepoint
Assessment
Total volume of blood per visit (ml)
R012-20
R012-14-mD
Fx012-14-
mFxD
Fx017-mFxD
Control
Visit 27 (Month 26)
Immunogenicity -
2.5 ml
2.5 ml
-
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 28 (Month 27)
Immunogenicity -
2.5 ml
2.5 ml
-
-
Visit 29 (Month 29)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 30 (Month 32)
Immunogenicity -
-
-
2.5 ml
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
3.0 ml
0.5 ml
Visit 31 (Month 33)
Immunogenicity -
-
-
2.5 ml
-
Visit 32 (Month 35)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 33 (Month 38)
Immunogenicity -
2.5 ml
2.5 ml
-
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 34 (Month 39)
Immunogenicity -
2.5 ml
2.5 ml
-
-
Visit 35 (Month 41)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 36 (Month 44)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 37 (Month 47)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 38 (Month 50)
Immunogenicity 2.5 ml
2.5 ml
2.5 ml
2.5 ml
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0 ml
3.0 ml
3.0 ml
3.0 ml
3.0 ml
† At screening, hemoglobin will be assessed in all subjects screened.
* Blood samples for hematology and biochemistry will be taken only in subjects belonging to the reactogenicity sub-
cohort.
** The total volume of blood to be taken depends if the subject belongs to the reactogenicity sub-cohort or not.
d: day.
‡ Blood for parasitemia (0.5 ml) includes the blood for the slide reading (to Month 50) and for the filter paper (to 
Month 32).
Amended 14 November 2019
6.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis.
Serological assays for the determination of anti-CS antibodies will be performed by 
ELISA at a laboratory designated by GSK Biologicals using standardized and validated 
procedures (refer to Table 16).
Serological assays for the determination of anti-CS antibody avidity will be performed by 
ELISA at a laboratory designated by GSK Biologicals using standardized procedures 
(refer to Table 16).
Serological assays for the determination of anti-HBs antibodies will be performed by 
chemiluminescence enzyme immunoassay (CLIA) at a GSK Biologicals laboratory using 
standardized and validated procedures (refer to Table 16).

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
9 1
T a bl e 1 6
H u m or al i m m u nit y  (a nti b o d y  d et er mi n ati o n)
S y st e m*
C o m p o n e nt
M et h o d
Kit / 
M a n uf a ct ur er
U nit
C ut -off
L a b or at or y
S E R U M 
Pl as m o di u m 
f alci p ar u m. Circ u ms p or oz oit e 
Pr ot ei n. R 3 2 L R A b.I g G
E LI S A
i n h o us e
E U/ ml
0 . 5
C E V A C
S E R U M 
H e p atitis B Vir us. S urf ac e A b
C LI A
A D VI A C e nt a ur 
a nti -H Bs 2 
( Si e m e ns 
H e alt hc ar e)
mI U/ ml
6. 2
G S K 
Bi ol o gic als**
S E R U M
Pl as m o di u m 
f alci p ar u m. Circ u ms p or oz oi d e 
Pr ot ei n. R 3 2 L R A b.I g G Avi dity
E LI S A
i n h o us e
%
N ot 
a p plic a bl e
C E V A C
.
** G S K Bi ol o gic als l a b or at ory r ef ers t o t h e Cli nic al L a b or at ory Sci e nc es ( C L S) i n Rix e ns art, B el gi u m; W avr e, B el gi u m.
A b: a nti b o dy
C E V A C: C e nt er f or V acci n ol o gy, G h e nt, B el gi u m
C LI A: c h e m il u mi n esc e nc e e nzy m e i m m u n o ass ay
E LI S A: E nzy m e -li nk e d i m m u n os or b e nt ass ay
E U/ ml: E LI S A u nit p er millilit er
I g G: I m m u n o gl o b uli n G
mI U/ ml: milli -i nt er n ati o n al u nit p er millilit er
T a bl e 1 7
A s s e s s m e nt of P. f al ci p ar u m i nf e cti o n
S y st e m
C o m p o n e nt
M et h o d
U nit
L a b or at or y
W h ol e Bl o o d*
Pl as m o di u m f alci p ar u m 
p ar asit es **
N ot a p plic a bl e***
N ot a p plic a bl e
K E M RI/ U S A M R U -K, 
W R P, M al ari a 
Di a g n ostics C e nt er, 
Kis u m u §
K E M RI/ U S A M R U -K, W R P: K e ny a M e dic al R es e arc h I nstit ut e / U S Ar my M e dic al R es e arc h U nit K e ny a, W alt er R e e d 
Pr oj ect.
* T h e i nci d e nc e of P. f alci p ar u m i nf ecti o n ass ess e d by P C R a n d p ar asit e g e n oty pi n g will b e ev al u at e d i n a n a ncill ary 
st u dy, usi n g s a m pl es c oll ect e d as d escri b e d i n t h e pr es e nt pr ot oc ol ( s e e T a bl e 2 0 ).
** P. f alci p ar u m p ar asit e c o u nt i ncl u d es bl o o d -st a g e p ar asit es a n d g a m et ocyt es c o u nts.
*** M et h o d us e d will b e bl o o d sli d e micr osc o p e r e a di n g.
§ A n d/ or ot h er G S K d esi g n at e d l a b or at ory.
T a bl e 1 8
H e m at ol o g y  a n d bi o c h e mi str y
S y st e m
C o m p o n e nt
M et h o d
S c al e
L a b or at or y
W h ol e bl o o d
H e m o gl o bi n
N ot a p plic a bl e
Q u a ntit ativ e
St u dy sit e*
L e uk ocyt es ( W hit e Bl o o d C ells)
Pl at el ets
S er u m
Al a ni n e A mi n otr a nsf er as e
N ot a p plic a bl e
Q u a ntit ativ e
St u dy sit e*
Cr e ati ni n e
* A n d/ or ot h er G S K-d esi g n at e d l a b or at ory
T he G S K Bi ol o gicals’ cli nical la b orat ories ha ve esta blis he d a q ualit y  sys te m s u p p orte d 
b y  pr oce d ures. T he acti vities of G S K Bi ol o gicals’ cli nical la b orat ories are a u dite d 
re g ularly f or q ualit y assess me nt b y  a n i nter nal (s p o ns or-de pe n de nt) b ut la b orat or y -
i n de pe n de nt q ualit y d e part me nt.
C CI

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
9 2
6. 7. 4.
Bi ol o gi c al s a m pl e s e v al u ati o n
6. 7. 4. 1.
I m m u n ol o gi c al r e a d-o ut s
I n t his st u dy, all s u bjects e nr olle d will ha ve bl o o d sa m ples ta ke n f or assess me nt of 
i m m u n o ge nicity. N ot all sa m ples will be use d f or testi n g: A nti -C S a n d a nti -H Bs i m m u ne 
res p o nses will be teste d i n a s u bset c orres p o n di n g t o t he fir st 5 0 s u bjects e nr olle d i n eac h 
gr o u p (i.e. t he i m m u n o ge nicit y  s u bset w hic h i ncl u de t he sa me s u bjects as i n t he 
react o ge nicit y s u b-c o h ort; see Secti o n 5 )
T a bl e 1 9
I m m u n ol o gi c al r e a d-o ut s
Bl o o d s a m pli n g ti m e p oi nt
St u d y gr o u p s
S u b s et n a m e
N o. 
s u bj e ct s
C o m p o n e nt
C o m p o n e nt s 
pri orit y r a n k 
T y p e of c o nt a ct 
a n d ti m e p oi nt
S a m pli n g 
ti m e p oi nt
Visit 2 ( D ay 0)
Pr e -V acc
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti - C S
1
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -C S avi dity
2
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -H Bs
3
Visit 4 ( M o nt h 2)
P ost -D os e 2 
( Fx 0 1 7-m Fx D) 
/ Pr e-D os e 3 
( ot h er gr o u ps)
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -C S
1
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -C S avi dity
2
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -H Bs
3
Visit 6 ( M o nt h 3)
P ost -D os e 3
R 0 1 2 -2 0
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
C o ntr ol
I m m u n o g e nicity
2 0 0
A nti -C S
1
R 0 1 2 -2 0
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
C o ntr ol
I m m u n o g e nicity
2 0 0
A nti -C S avi dity
2
R 0 1 2 -2 0
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
C o ntr ol
I m m u n o g e nicity
2 0 0
A nti -H Bs
3
Visit 1 0
Pr e -D os e 3
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -C S
1
( M o nt h 7)
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -C S avi dity
2
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -H Bs
3
Visit 1 2
P ost -D os e 3
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -C S
1
( M o nt h 8)
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -C S avi dity
2
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -H Bs
3
Visit 1 8
( M o nt h 1 4)
Pr e -D os e 4
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S
1
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S avi dity
2
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -H Bs
3
C CI

CONFIDENTIAL
204889 (MALARIA-094)
Protocol Amendment 3 Final
14-NOV-2019
93
Blood sampling timepoint
Study groups
Subset name
No. 
subjects
Component
Components 
priority rank 
Type of contact 
and timepoint
Sampling 
timepoint
Visit 19
(Month 15)
Post-Dose 4
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS
1
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS avidity
2
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-HBs
3
Visit 24
(Month 20)
Pre-Dose 4
R012-20
Fx017-mFxD
Control
Immunogenicity
150
Anti-CS
1
R012-20
Fx017-mFxD
Control
Immunogenicity
150
Anti-CS avidity
2
R012-20
Fx017-mFxD
Control
Immunogenicity
150
Anti-HBs
3
Visit 25
(Month 21)
Post-Dose 4
R012-20
Fx017-mFxD
Immunogenicity
100
Anti-CS
1
R012-20
Fx017-mFxD
Immunogenicity
100
Anti-CS avidity
2
R012-20
Fx017-mFxD
Immunogenicity
100
Anti-HBs
3
Visit 27
(Month 26)
Pre-Dose 5
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS
1
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS avidity
2
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-HBs
3
Visit 28
(Month 27)
Post-Dose 5
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS
1
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS avidity
2
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-HBs
3
Visit 30
Pre-Dose 5
Fx017-mFxD
Immunogenicity
50
Anti-CS
1
(Month 32)
Fx017-mFxD
Immunogenicity
50
Anti-CS avidity
2
Fx017-mFxD
Immunogenicity
50
Anti-HBs
3
Visit 31
Post-Dose 5
Fx017-mFxD
Immunogenicity
50
Anti-CS
1
(Month 33)
Fx017-mFxD
Immunogenicity
50
Anti-CS avidity
2
Fx017-mFxD
Immunogenicity
50
Anti-HBs
3
Visit 33
(Month 38)
Pre-Dose 6
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS
1
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS avidity
2
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-HBs
3
Visit 34
(Month 39)
Post-Dose 6
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS
1
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS avidity
2
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-HBs
3

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
9 4
Bl o o d s a m pli n g ti m e p oi nt
St u d y gr o u p s
S u b s et n a m e
N o. 
s u bj e ct s
C o m p o n e nt
C o m p o n e nt s 
pri orit y r a n k 
T y p e of c o nt a ct 
a n d ti m e p oi nt
S a m pli n g 
ti m e p oi nt
Visit 3 8
St u dy e n d
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -C S
1
( M o nt h 5 0)
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -C S avi dity
2
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -H Bs
3
 
I n case of i ns ufficie nt bl o o d sa m ple v ol u me t o perf or m assa ys f or all a nti b o dies, t he 
sa m ples will be a nalyz e d acc or di n g t o pri orit y ra n ki n g pr o vi de d i n Ta ble 1 9 .
6. 7. 4. 2.
P ar a sit e mi a
T a bl e 2 0 
P ar a sit e mi a ( bl o o d s m e ar a n d bl o o d f or a n cill ar y st u d y )
Bl o o d s a m pli n g ti m e p oi nt
St u d y gr o u p s
N o. s u bj e ct s
C o m p o n e nt
C o m p o n e nt s 
pri orit y r a n k 
Visit 2 ( D ay 0)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 3 ( M o nt h 1)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 4 ( M o nt h 2)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 6 ( M o nt h 3)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 7 ( M o nt h 4)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 8 ( M o nt h 5)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 9 ( M o nt h 6)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 1 0 ( M o nt h 7)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 1 2 ( M o nt h 8)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 1 3 ( M o nt h 9)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 1 4 ( M o nt h 1 0)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 1 5 ( M o nt h 1 1)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 1 6 ( M o nt h 1 2)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 1 7 ( M o nt h 1 3)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 1 8 ( M o nt h 1 4)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 1 9 ( M o nt h 1 5)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 2 0 ( M o nt h 1 6)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
Visit 2 1 ( M o nt h 1 7)
All gr o u ps
1 5 0 0
Bl o o d s m e ar 
+ bl o o d f or a ncill ary st u dy*
1
C CI

CONFIDENTIAL
204889 (MALARIA-094)
Protocol Amendment 3 Final
14-NOV-2019
95
Blood sampling timepoint
Study groups
No. subjects
Component
Components 
priority rank 
Visit 22 (Month 18)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 23 (Month 19)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 24 (Month 20)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 26 (Month 23)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 27 (Month 26)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 29 (Month 29)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 30 (Month 32)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 32 (Month 35)
All groups
1500
Blood smear 
1
Visit 33 (Month 38)
All groups
1500
Blood smear 
1
Visit 35 (Month 41)
All groups
1500
Blood smear 
1
Visit 36 (Month 44)
All groups
1500
Blood smear 
1
Visit 37 (Month 47)
All groups
1500
Blood smear 
1
Visit 38 (Month 50)
All groups
1500
Blood smear 
1
* The incidence of P. falciparum infection assessed by PCR and parasite genotyping will be evaluated in an ancillary 
study, using samples collected until Month 32 as described in the present protocol. The blood for the ancillary study 
will be collected on filter paper.
Amended 14 November 2019
6.7.4.3.
Hematology/Blood chemistry
At screening, hemoglobin will be assessed in all subjects screened. Other hematology and 
biochemistry parameters will be measured in the first 50 subjects enrolled in each group 
(reactogenicity sub-cohort).

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Table 21
Hematology/Blood chemistry
Blood sampling timepoint
Study groups
Sub-cohort 
name
No. 
subjects
Component
Components 
priority rank 
Type of 
contact and 
timepoint
Sampling 
timepoint
Visit 1
(Day -28 to 0)
Screening
All groups
Not applicable
All 
screened 
subjects
Hemoglobin
Not 
applicable
Visit 4
Before
R012-20
Reactogenicity
200
Hemoglobin
Not 
(Month 2)
Dose 3
R012-14-mD 
White blood cells
applicable
Fx012-14-mFxD
Platelets
Control
Alanine aminotransferase
Creatinine
Visit 5
(Month 2 + 7d)
7 days post-
Dose 3
R012-20 
Reactogenicity
200
Hemoglobin
Not 
R012-14-mD 
White blood cells
applicable
Fx012-14-mFxD
Platelets
Control
Alanine aminotransferase
Creatinine
Visit 6
30 days 
post-Dose 3
R012-20 
Reactogenicity
200
Hemoglobin
Not 
(Month 3)
R012-14-mD 
White blood cells
applicable
Fx012-14-mFxD
Platelets
Control
Alanine aminotransferase
Creatinine
Visit 10
Before 
Fx017-mFxD
Reactogenicity
50
Hemoglobin
Not 
(Month 7)
Dose 3
White blood cells
applicable
Platelets
Alanine aminotransferase
Creatinine
Visit 11
(Month 7 + 7d)
7 days post-
Dose 3
Fx017-mFxD
Reactogenicity
50
Hemoglobin
Not 
White blood cells
applicable
Platelets
Alanine aminotransferase
Creatinine
Visit 12
30 days 
post-Dose 3
Fx017-mFxD
Reactogenicity
50
Hemoglobin
Not 
(Month 8)
White blood cells
applicable
Platelets
Alanine aminotransferase
Creatinine
6.7.5.
Immunological correlates of protection
No correlate of protection has been demonstrated so far for the CS antigen.
For the hepatitis B surface antigen, the conventional correlate of protection is anti-HBs 
antibody concentrations above 10 mIU/ml [European Consensus Group on Hepatitis B 
Immunity, 2000].
All subjects enrolled in the study should have received three doses of a hepatitis B-
containing vaccine (DTPHepB) prior to enrollment (refer to inclusion criteria in Section 
5.2).
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects/subjects’ parent(s)/LAR(s).

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For the subjects identified as non-responders, it remains the responsibility of the 
investigator in charge of the subject’s clinical management to determine the medical need 
for re-vaccination and to re-vaccinate the subjects as per local/regional practices.
7.
STUDY VACCINES AND ADMINISTRATION
7.1.
Description of study vaccines
The candidate RTS,S/AS01E vaccine has been developed and manufactured by GSK 
Biologicals. The quality control standards and requirements for the 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 (SmPC).
Table 22
Study vaccines
Treatment 
name
Vaccine/product 
name
Formulation
Presentation
Volume to 
be 
administered
Number 
of doses
RTS,S/AS01E
(Full dose)
RTS,S
RTS,S=25µg
Lyophilized pellet in a 
two-dose glass vial
0.5 ml
2 to 6*
AS01E
MPL=25µg; 
QS21=25µg; 
Liposomes
Liquid solution in a two-
dose glass vial
RTS,S/AS01E
(1/5th dose)
RTS,S
RTS,S=25µg
Lyophilized pellet in a 
two-dose glass vial
0.1 ml
3 to 4**
AS01E
MPL=25µg; 
QS21=25µg; 
Liposomes
Liquid solution in a two-
dose glass vial
Rabies vaccine
Rabipur
Rabies 
virus=2.5IU
Powder and solvent for 
solution for injection. 
After dissolution of the 
white lyophilisate
(powder), a clear 
colorless solution is 
obtained.
1.0 ml
3
* RTS,S/AS01E full dose (0.5 ml): Group R012-20 will receive four doses, group R012-14-mD will receive six doses, 
group Fx012-14-mFxD and group Fx017-mFxD will receive two doses.
** RTS,S/AS01E 1/5th dose (0.1 ml): Group Fx012-14-mFxD will receive four doses and group Fx017-mFxD will receive 
three doses.
7.2.
Storage and handling of study vaccines
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines.

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Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor.
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion.
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines.
7.3.
Dosage and administration of study vaccines
7.3.1.
RTS,S/AS01E
In this study, the commercial presentation of RTS,S/AS01E will be used, i.e. a two-dose 
glass vial of lyophilized RTS,S antigen (50 µg) to be reconstituted with a two-dose glass 
vial of AS01E Adjuvant System (1.0 ml). The final product for administration will be 
prepared by reconstitution of the lyophilized antigen with the liquid adjuvant. From the 
reconstituted vaccine vial, 0.5 ml will be withdrawn to administer the RTS,S/AS01E full 
doses or 0.1 ml will be withdrawn to administered the RTS,S/AS01E fractional doses 
(1/5th dose). All vials of vaccine provided in this study are intended for single use only.
Disinfect the top of the vaccine vial (pellet) and adjuvant vial with alcohol swabs and let 
dry. Withdraw the content of the adjuvant vial in a syringe and inject the adjuvant into the 
vial of lyophilized antigen. The pellet is then dissolved by gently shaking the vial. Wait 
for one minute to ensure the complete dissolution of the vial content before withdrawing 
one full dose of RTS,S/AS01E (0.5 ml) or a fractional dose of RTS,S/AS01E (0.1 ml). For 
the full dose of RTS,S/AS01E, 0.5 ml should be administered using a fresh 25 gauge 
needle with a length of one inch (25 mm). For the fractional dose of RTS,S/AS01E, 
0.1 ml should be administered using a 1 ml syringe and fresh 25 gauge needle with a 
length of one inch (25 mm). The reconstituted vaccine should be administered by slow 
intramuscular injection into the left deltoid. The vaccine should be injected within four 
hours of reconstitution (storage at +2°C to +8°C). Refer to the SPM for full details of 
how to fill the syringe and inject the fractional dose.

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7.3.2.
Rabies vaccine
Disinfect the top of the vaccine vial (pellet) with alcohol swabs and let dry. Inject the 
entire content of the diluent ampoule into the vaccine vial. The lyophilized vaccine pellet 
is dissolved by gently shaking the vial. Wait for one minute to ensure the complete 
dissolution of the vial content before withdrawing a sufficient volume to provide a 1.0 ml 
dose. The original needle should then be replaced with a fresh needle for intramuscular 
injection. The reconstituted vaccine should be administered by slow intramuscular 
injection, using a fresh 25 gauge needle with a length of one inch (25 mm), into the left 
deltoid directly after reconstitution. The vaccine should be stored at +2°C to +8°C.
Table 23
Dosage and administration
Type of contact 
and timepoint
Volume to be 
administered
Study group
Treatment name
Route 1
Site
Side
Visit 2 (Day 0)
0.5 ml
R012-20
R012-14-mD
Fx012-14-mFxD
Fx017-mFxD
RTS,S/AS01E (Full dose)
IM
Deltoid
Left
1.0 ml
Control
Rabies vaccine
IM
Deltoid
Left
Visit 3 (Month 1)
0.5 ml
R012-20
R012-14-mD
Fx012-14-mFxD
Fx017-mFxD
RTS,S/AS01E (Full dose)
IM
Deltoid
Left
1.0 ml
Control
Rabies vaccine
IM
Deltoid
Left
Visit 4 (Month 2)
0.5 ml
R012-20
R012-14-mD
RTS,S/AS01E (Full dose)
IM
Deltoid
Left
0.1 ml
Fx012-14-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
1.0 ml
Control
Rabies vaccine
IM
Deltoid
Left
Visit 10 (Month 7)
0.1 ml
Fx017-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 18 (Month 14)
0.5 ml
R012-14-mD
RTS,S/AS01E (Full dose)
IM
Deltoid
Left
0.1 ml
Fx012-14-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 24 (Month 20)
0.5 ml
R012-20
RTS,S/AS01E (Full dose)
IM
Deltoid
Left
0.1 ml
Fx017-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 27 (Month 26)
0.5 ml
R012-14-mD
RTS,S/AS01E (Full dose)
IM
Deltoid
Left
0.1 ml
Fx012-14-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 30 (Month 32)
0.1 ml
Fx017-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 33 (Month 38)
0.5 ml
R012-14-mD
RTS,S/AS01E (Full dose)
IM
Deltoid
Left
0.1 ml
Fx012-14-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
1 Intramuscular (IM)
The subjects will be observed closely for at least 30 minutes following the administration 
of the vaccines, with appropriate medical treatment readily available in case of 
anaphylaxis.
7.4.
Replacement of unusable vaccine doses
In addition to the vaccine doses provided for the planned number of subjects (including
over-randomization when applicable), at least 10% additional vaccine doses will be 
supplied to replace those that are unusable.

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7.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of
RTS,S/AS01E or the rabies vaccine. If any of these events occur during the study, the 
subject must not receive additional doses of vaccines but may continue other study 
procedures at the discretion of the investigator (see Section 9.4).

Anaphylaxis following the administration of vaccine(s).

Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe.

RTS,S/AS01E malaria vaccine should not be administered to subjects with known 
hypersensitivity to any component of the vaccine or to a previous dose of 
RTS,S/AS01 E malaria vaccine or hepatitis B vaccines. Any subject who shows signs 
of hypersensitivity to the vaccine should not be given further doses.

Rabipur is contraindicated in subjects with an history of a severe hypersensitivity to any 
of the ingredients in the vaccine. Note that the vaccine contains polygeline and residues 
of chicken proteins, and may contain traces of neomycin, chlortetracycline and 
amphotericin B) (Refer to the [Rabipur SmPC, 2010]).

Occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the 
opinion of the investigator, expose the subject to unacceptable risk from subsequent 
vaccination. In such cases, the investigator should use his/her clinical judgement 
prior to administering the next dose of the vaccine(s)/product(s). Refer to Section 
9.1.6.1 for the definition of pIMDs.
The following events constitute contraindications to administration of RTS,S/AS01E or 
the rabies vaccine 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 6.5), or the subject may be withdrawn at the 
discretion of the investigator (see Section 9.4).

Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 37.5°C/99.5°F for oral, axillary or tympanic 
route, or 38.0°C/100.4°F for rectal route. The preferred route for recording 
temperature in this study will be axillary.

Subjects with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever can be administered all vaccines.

Administration of vaccine not foreseen by the study protocol within seven days of 
any dose of study vaccine.
7.6.
Warnings and precautions
Refer to the approved product label/package insert for the marketed rabies vaccine 
(Rabipur) used in the study.

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7.7.
Concomitant medications/products and concomitant 
vaccinations
At each clinic visit, the investigator should question the subject’s parent(s)/LAR(s) about 
any medications/products taken and vaccinations received by the subject.
7.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF.

Anti-inflammatory, analgesics, anti-pyretic, and systemic antibiotics administered 
during the period starting seven days following each dose of study vaccines (Day 0
to Day 6).

Any concomitant vaccination administered in the period starting seven days before 
the first dose of study vaccines and ending at the last study visit (Day -7 to Month 
50).

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 
38.0°C/100.4°F for rectal route].

Any concomitant medications/products/vaccines listed in Section 7.7.2.

Anti-malaria medication administered at any time during the study (Day 0 to 
Month 50).

Any concomitant medications/products/vaccines relevant to a SAE/pIMD to be 
reported as per protocol or administered at any time during the study period for the 
treatment of a SAE/pIMD. In addition, concomitant medications relevant to SAEs 
and pIMD need to be recorded on the Expedited Adverse Events Report.

In this study, medications administered for the treatment of any solicited local or 
general AE should be recorded for subjects belonging to the reactogenicity sub-
cohort and during the time period for collection of solicited AEs. Medications 
administered for the treatment of unsolicited AEs should be recorded for all subjects 
during the time period for collection of unsolicited AEs (see Section 9.2.1 and Table 
27), except for anti-malaria treatments that must be collected for all subjects during 
the entire study period.

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7.7.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analysis. See Section 11.5 for cohorts to be analyzed.

Use of a drug or vaccine that is not approved for that indication (by one of the 
following regulatory authorities: FDA or European Union member state or WHO 
[with respect to prequalification]) other than the study vaccines during the study 
period.

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days in total) during the study period. For corticosteroids, this will 
mean prednisone ≥ 0.5 mg/kg/day (for pediatric subjects), or equivalent. Inhaled and 
topical steroids are allowed.

A vaccine not foreseen by the study protocol administered during the period starting 
seven days before each dose and ending seven days after each dose of vaccine*.
* In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organized by the public health authorities, outside the routine 
immunization program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its SmPC or Prescribing 
Information and according to the local governmental recommendations and provided 
a written approval of the Sponsor is obtained.

Immunoglobulins and/or any blood products administered during the study period.
7.8.
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses
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. If it is the 
case, the condition(s) must be recorded in the eCRF.
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 (i.e. 
confirmed HIV/AIDS) or are confirmed to have an alteration of their initial immune 
status.
8.
HEALTH ECONOMICS
Not applicable.

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9.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAE as provided in 
this protocol.
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subject manifest any signs or symptoms they perceive as serious.
9.1.
Safety definitions
9.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.
Examples of an AE include:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after investigational vaccines 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 vaccines or a concurrent medication (overdose per se should not be 
reported as an AE/SAE).

Signs, symptoms temporally associated with vaccines administration.

Significant failure of expected pharmacological or biological action.

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 9.1.3. All other
AEs will be recorded as UNSOLICITED AEs.

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Examples of an AE DO NOT include:

Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF.
9.1.2.
Definition of a serious adverse event
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalization or prolongation of existing hospitalization,
Note: In general, hospitalization signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalization are also considered AEs. If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity.
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza like illness, and accidental trauma (e.g. sprained ankle) 
which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.

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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 hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization.
In this study, the AEs of specific interest (i.e. pIMDs, meningitis and seizure within 30 
post-vaccination) will be reported as SAEs.
All cases of severe malaria and cerebral malaria will be reported as SAEs and clinical 
details of each case will be reported in a specific eCRF screen (refer to Section 9.1.5).
9.1.3.
Solicited adverse events
9.1.3.1.
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 24
Solicited local adverse events
All age groups
Pain at injection site
Redness* at injection site
Swelling at injection site
* In case the principal investigator or designate is unable 
to determine the extent of redness on darkly pigmented 
skin, it will be reported as uninterpretable in the eCRF
9.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 25
Solicited general adverse events
Infant/Toddler/Child (< 6 years)
Drowsiness
Fever
Irritability/Fussiness
Loss of appetite
Note: Temperature will be recorded daily. Should additional temperature measurements 
be performed at other times of day, the highest temperature will be recorded in the eCRF.

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9.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
hematology, urinalysis) or other abnormal assessments (e.g. failure to thrive) that are 
judged by the investigator to be clinically significant will be recorded as AE or SAE if 
they meet the definition of an AE or SAE (refer to Sections 9.1.1 and 9.1.2). Clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen following the start of the study will also be reported as 
AEs or SAEs.
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.
9.1.5.
Severe malaria and cerebral malaria
All cases of severe malaria and cerebral malaria will be reported as SAEs as part of the 
safety surveillance until study end (Month 50) and clinical details of each case will be 
reported in a specific eCRF screen. Case definitions adapted from the WHO case 
definitions of severe malaria and cerebral malaria will be used as reference for diagnosis. 
Refer to APPENDIX C for the case definitions.
9.1.6.
Adverse events of specific interest
AEs of specific interest for safety monitoring include all seizures occurring within 30 
days post-vaccination, meningitis and pIMDs.
9.1.6.1.
Potential immune-mediated diseases
pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory 
and/or neurologic disorders of interest which may or may not have an autoimmune 
etiology. AEs that need to be recorded and reported as pIMDs include those listed in 
Table 26.
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.
To support the diagnosis of pIMDs, access to reference laboratories will be initiated so 
that serum samples or histopathologic specimens could be sent to perform analyses which 
would not be available locally.

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Table 26
List of potential immune-mediated diseases
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve disorders, 
including paralyses/paresis 
(e.g. Bell’s palsy) 

Optic neuritis

Multiple sclerosis

Transverse myelitis

Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other variants

Acute disseminated 
encephalomyelitis, including 
site specific variants: e.g. non-
infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis

Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome 

Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy 
and polyneuropathies 
associated with monoclonal 
gammopathy).

Narcolepsy

Systemic lupus 
erythematosus and 
associated conditions

Systemic scleroderma
(Systemic sclerosis), 
including diffuse systemic 
form and CREST syndrome
Idiopathic inflammatory 
myopathies, including 
dermatomyositis 

Polymyositis 

Antisynthetase syndrome

Rheumatoid arthritis, and 
associated conditions 
including juvenile chronic 
arthritis and Still’s disease

Polymyalgia rheumatica

Spondyloarthritis, including 
ankylosing spondylitis, 
reactive arthritis (Reiter's 
Syndrome) and 
undifferentiated 
spondyloarthritis 

Psoriatic arthropathy

Relapsing polychondritis

Mixed connective tissue 
disorder

Psoriasis

Vitiligo

Erythema nodosum

Autoimmune bullous skin 
diseases (including pemphigus, 
pemphigoid and dermatitis 
herpetiformis)

Alopecia areata

Lichen planus

Sweet’s syndrome

Localized Scleroderma 
(Morphoea)
Vasculitides
Blood disorders
Others

Large vessels vasculitis 
including: giant cell arteritis 
such as Takayasu's arteritis 
and temporal arteritis. 

Medium sized and/or small 
vessels vasculitis including: 
polyarteritis nodosa, 
Kawasaki's disease, 
microscopic polyangiitis, 
Wegener's granulomatosis, 
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis), Buerger’s disease 
(thromboangiitis obliterans), 
necrotizing vasculitis and anti-
neutrophil cytoplasmic antibody 
(ANCA) positive vasculitis (type 
unspecified), Henoch-
Schonlein purpura, Behcet's 
syndrome, leukocytoclastic 
vasculitis.

Autoimmune hemolytic 
anemia

Autoimmune 
thrombocytopenia

Antiphospholipid syndrome

Pernicious anemia

Autoimmune aplastic 
anaemia

Autoimmune neutropenia 

Autoimmune pancytopenia

Autoimmune 
glomerulonephritis (including 
IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis)

Ocular autoimmune diseases 
(including autoimmune uveitis 
and autoimmune retinopathy)

Autoimmune 
myocarditis/cardiomyopathy
Sarcoidosis

Stevens-Johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary fibrosis

Goodpasture syndrome

Raynaud’s phenomenon

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Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune hepatitis

Primary biliary 
cirrhosis

Primary sclerosing 
cholangitis

Autoimmune 
cholangitis

Inflammatory Bowel disease, 
including Crohn’s disease, ulcerative 
colitis, microscopic colitis, ulcerative 
proctitis 

Celiac disease

Autoimmune pancreatitis

Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis)

Grave's or Basedow’s disease

Diabetes mellitus type I

Addison’s disease

Polyglandular autoimmune 
syndrome

Autoimmune hypophysitis
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the 
final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely.
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start. Tests for further evaluation of 
pIMDs may be conducted at Clinical Laboratory Sciences (CLS) South Africa if there is 
an indication for the test (see APPENDIX D for details of tests available at CLS South 
Africa).
9.1.6.2.
Seizures within 30 days post-vaccination
All seizures occurring within 30 days post-vaccination will be reported as SAEs in the 
eCRF. Clinical details according to the Brighton collaboration guidelines [Bonhoeffer, 
2004] pertaining to seizures occurring within seven days of vaccination will be 
documented in a specific eCRF screen.
9.1.6.3.
Meningitis
For further evaluation of the safety signal of meningitis, all cases of meningitis occurring 
during the study will be reported as a SAE and additional clinical details of each case will 
be reported in a specific eCRF screen.
Investigators will be instructed to report cases according to the following case definitions:

Clinically suspected meningitis: A child with sudden onset of fever and one of the 
following signs: neck stiffness, altered consciousness not due to an alternative more 
probable cause, or other meningeal sign such as bulging fontanelle in children less 
than one year of age.

Confirmed meningitis: A child with clinically suspected meningitis with 
confirmatory evidence of meningitis from cerebrospinal fluid (CSF) examination.

Etiology-confirmed meningitis: A child with confirmed meningitis and evidence 
from CSF examination of a specific causative agent.

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The recommended method for evaluation of meningitis will be through CSF analysis.
Lumbar puncture should be performed by qualified medical personnel in subjects when 
there is an indication for testing. The initial CSF testing to aid in the diagnosis of 
meningitis including, and not limited to, microscopy and gram staining, differential white 
cell and red blood cell count, CSF biochemistry, antigen/agglutination tests and culture, 
amongst others, is to be carried out by the site. For every suspected meningitis case, a 
CSF sample will be collected and from this approximately 500 µl will be sent to CLS 
South Africa for CSF polymerase chain reaction (PCR) testing for selected common 
aetiological pathogens of meningitis (see APPENDIX D for details of additional tests 
available at CLS South Africa for the evaluation of meningitis).
9.2.
Detecting and recording adverse events and serious 
adverse events
9.2.1.
Time period for detecting and recording adverse events and
serious adverse events
All AEs starting within 30 days following administration of each dose of study vaccines
(Day 0 to Day 29) must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine (Day 0) and will end at the last study visit (Month 50) for each subject. See 
Section 9.3 for instructions on reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine (Day 0) until study end (Month 50).
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study.
The time period for collecting and recording of AEs of specific interest will begin at the 
first receipt of study vaccine (Day 0) and will end at the last study visit (Month 50) See 
section 9.3 for instructions on reporting of AEs of specific interest.
Solicited local and general AEs will be collected in the first 50 subjects enrolled in each 
group (reactogenicity sub-cohort) during four days (day of vaccination and three 
subsequent days) after Dose 3 of study vaccine (all groups including controls), after 
Dose 4 (R012-20, R012-14-mD, Fx012-14-mFxD and Fx017-mFxD), after Dose 5 
(R012-14-mD, Fx012-14-mFxD and Fx017-mFxD) and after Dose 6 (R012-14-mD and 
Fx012-14-mFxD). On the day of vaccination the evaluation will be carried out by the 
study physician at the study center. On Days 1, 2 and 3 after vaccination, trained study 
personnel will visit the children to record solicited AEs on diary cards.
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 27.

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Table 27
Reporting periods for collecting safety information
Study visits
1
2
3
4
10
18
24
27
30
33
38
Event
Scr* Vac 
1
Vac 
2
Vac 
3
Vac 
4
Vac 
5
Vac 
6
Vac 
7
Vac 
8
Vac 
9
Study 
end
Study timepoint:
D -28 
to -1
D0
D0 + 
3d
D0 + 
29d
M1 M1 + 
3d
M1 + 
29d
M2 M2 + 
3d
M2 + 
29d
M7 M7 + 
3d
M7 + 
29d
M14 M14 
+ 3d
M14 
+ 
29d
M20 M20 
+ 3d
M20 
+ 
29d
M26 M26 
+ 3d
M26 
+ 
29d
M32 M32 
+ 3d
M32 
+ 
29d
M38 M38 
+ 3d
M38 
+ 
29d
M50
For ALL groups
AEs/SAEs leading to 
withdrawal from 
further vaccination
SAEs related to 
study participation or 
concurrent GSK 
medication/vaccine
SAEs (All, fatal, 
related to the 
investigational 
vaccine)
AEs of specific 
interest**
Group R012-20 
Solicited local and 
general AEs***
Unsolicited AEs
Group R012-14-mD and Fx012-14-mFxD 
Solicited local and 
general AEs***

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Study visits
1
2
3
4
10
18
24
27
30
33
38
Event
Scr* Vac 
1
Vac 
2
Vac 
3
Vac 
4
Vac 
5
Vac 
6
Vac 
7
Vac 
8
Vac 
9
Study 
end
Study timepoint:
D -28 
to -1
D0
D0 + 
3d
D0 + 
29d
M1 M1 + 
3d
M1 + 
29d
M2 M2 + 
3d
M2 + 
29d
M7 M7 + 
3d
M7 + 
29d
M14 M14 
+ 3d
M14 
+ 
29d
M20 M20 
+ 3d
M20 
+ 
29d
M26 M26 
+ 3d
M26 
+ 
29d
M32 M32 
+ 3d
M32 
+ 
29d
M38 M38 
+ 3d
M38 
+ 
29d
M50
Unsolicited AEs
Group Fx017-mFxD
Solicited local and 
general AEs***
Unsolicited AEs
Control group
Solicited local and 
general AEs***
Unsolicited AEs
* i.e. consent obtained.
** AEs of specific interest include seizures occurring within 30 days post-vaccination, meningitis and pIMDs.
*** Solicited local and general AEs will be collected in the first 50 subjects enrolled in each group (reactogenicity sub-cohort).
Scr: Screening; Vac: Vaccination; D: Day; M: Month; 3d: 3 days; 29d: 29 days.

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9.2.2.
Post-study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 27. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccines, the investigator will promptly 
notify the Study Contact for Reporting SAEs.
9.2.3.
Evaluation of adverse events and serious adverse events
9.2.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject’s parent(s)/LAR(s) should be asked 
a non-leading question such as:
‘Has your child acted differently or felt different in any way since receiving the vaccines 
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 in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by 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.
9.2.3.2.
Assessment of adverse events
9.2.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:

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Table 28
Intensity scales for solicited symptoms in infants/toddlers
Infant/Toddler (15–24 months)
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/°F
Irritability/Fussiness
0
Behavior 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
Behavior 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 extent of redness on darkly pigmented skin, 
it will be reported as uninterpretable in the eCRF.
** Fever is defined as temperature 37.5°C / 99.5°F for oral, axillary or tympanic route, or 38.0°C / 100.4°F for 
rectal route. The preferred route for recording temperature in this study will be axillary.
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 (the 
preferred route for recording temperature in this study will be axillary):
0
:
< 37.5°C
1
:
37.5 – 38.0°C
2
:
> 38.0 – 39.0°C
3
:
> 39.0°C
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.

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The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities (in a young 
child, such an AE would, for example, prevent attendance at a 
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 used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 9.1.2.
9.2.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between investigational vaccines 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational vaccine(s) will be considered and 
investigated. The investigator will also consult the investigator brochure and/or 
prescribing information for marketed products to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of general AEs to the individual vaccine administered. 
The investigator should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccines.

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All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine?
YES
:
There is a reasonable possibility that the vaccine contributed to the AE.
NO
:
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine. There are other, more likely causes 
and administration of the study vaccine is not suspected to have 
contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 9.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccines, if applicable.

Erroneous administration.

Other cause (specify).
9.2.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).

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9.2.3.4.
Toxicity grading scale for hematology and biochemistry parameters
Table 29
Toxicity grading scales for analysis of hematology and biochemistry 
parameters
Test
Acceptable 
limit/Normal range
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
≥ 8.0 g/dl
7.9 to 6.0 g/dl
5.9 to 5.0 g/dl
< 5.0 g/dl
< 5.0 g/dl and 
clinical signs of 
heart failure
WBC
≥ 4.0 x103/μl
< 17 x103/μl
2.5 to 4.0 x 103/μl
1.5 to 2.4 x 103/μl
1.0 to 1.4 x 103/μl
< 1.0 x 103/μl
Platelets
≥ 100 x103/μl
50 to 99 x 103/μl
25 to 49 x 103/μl
< 25 x 103/μl
< 25 x 103/μl and 
clinical signs of 
bleeding
ALT
≤ 60 IU/L
1.1 to 2.5 x ULN
2.6 to 5.0 x ULN
5.1 to 10.0 x ULN
> 10.0 x ULN
Creatinine
≤ 60 μmol/L
(or 0.6 mg/dl)
1.1 to 1.5 x ULN
1.6 to 3.0 x ULN
3.1 to 6.0 x ULN
> 6.0 x ULN or 
requires dialysis
ALT = alanine aminotransferase; ULN = upper limit of the normal range; WBC = white blood cells
Grading scale adapted from: [NIAID, 2004] Division of AIDS table for grading the severity of adult and pediatric 
adverse events, December 2004.
9.2.3.5.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the in the 
eCRF.
9.2.3.6.
Verbal autopsy process
Where possible autopsies will be performed. Verbal autopsies will be carried out on all 
children who die outside a health facility to ascribe the cause of death if it is not possible 
to perform the autopsies. The questionnaire used will be based on the INDEPTH standard 
and adapted to be locally appropriate [WHO, 2007].
9.3.
Reporting of serious adverse events and other events
9.3.1.
Prompt reporting of serious adverse events and other events to 
GSK Biologicals
SAEs that occur in the time period defined in Section 9.2 will be reported promptly to 
GSK within the timeframes described in Table 30, once the investigator determines that 
the event meets the protocol definition of a SAE. In addition, clinical details of each case 
of severe malaria and cerebral malaria will be reported in a specific eCRF screen.

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AEs of specific interest (i.e. seizures occurring within 30 days post-vaccination, pIMDs 
and meningitis) that occur in the time period defined in Section 9.2 will be reported 
promptly to GSK within the timeframes described in Table 30, once the investigator 
determines that the event meets the protocol definition of an AE of specific interest.
Table 30
Timeframes for submitting serious adverse event and other events 
reports to GSK Biologicals
Type of event
Initial reports
Follow-up of relevant information on a 
previous report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours*‡
Electronic Expedited 
Adverse Events Report§
24 hours*
Electronic Expedited Adverse 
Events Report§
AEs of specific 
interest**
24 hours*‡
Electronic Expedited 
Adverse Events Report***
24 hours*
Electronic Expedited Adverse 
Events Report***
‡ The investigator will be required to confirm review of the SAE/AE of specific interest causality by ticking the ‘reviewed’ 
box in the electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/AE of specific 
interest.
* Timeframe allowed after receipt or awareness of the information.
** AEs of specific interest include seizures occurring within 30 days post-vaccination, pIMDs and meningitis.
*** pIMDs will be reported via the electronic Expedited Adverse Events Report. Meningitis and seizures will be reported 
via the electronic Expedited Adverse Events Report and in addition clinical details of each case will be reported in a 
specific eCRF screen.
§ Case of severe malaria or cerebral malaria will be reported via the electronic Expedited Adverse Events Report (refer 
to Section 9.3.1) and in addition clinical details of each case will be reported in a specific eCRF screen.
9.3.2.
Contact information for reporting serious adverse events and 
adverse events of specific interest
Study Contact for Reporting SAEs, and AEs of specific interest
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs and AEs of specific interest
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US & Canada sites:
Fax: +32 2 656 51 16 or +32 2 656 80 09
Email address: Rix.CT-safety-vac@gsk.com
9.3.3.
Completion and transmission of serious adverse events reports 
to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.

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The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
9.3.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.
9.3.4.
Reporting of adverse events of specific interest to GSK 
Biologicals
Once an AE of specific interest (i.e. seizures occurring within 30 days post-vaccination, 
pIMD or meningitis) is diagnosed (serious or non-serious) in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS after he/she becomes aware of the 
diagnosis. The report allows to specify that the event is a pIMD and whether it is serious 
or non-serious. For pIMDs, the report will always be completed as thoroughly as possible 
with all available details of the event, in accordance with the pIMD standard 
questionnaire provided. Even if the investigator does not have all information regarding 
an AE of specific interest, the report should still be completed within 24 hours. Once 
additional relevant information is received, the report should be updated WITHIN 24 
HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report.
The investigator will be required to confirm the review of the causality of an AE of 
specific interest by ticking the ‘reviewed’ box in the electronic Expedited Adverse Events 
Report within 72 hours of submission of the AE of specific interest.
Refer to Section 9.3.3.1 for back-up system in case the electronic reporting system does 
not work.

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9.3.5.
Updating of serious adverse events and adverse events of 
specific interest information after removal of write access to the 
subject’s eCRF
When additional SAE and AEs of specific interest information is received after removal 
of the write access to the subject’s eCRF, new or updated information should be recorded 
on the appropriate paper report, with all changes signed and dated by the investigator. 
The updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance
department within the designated reporting time frames specified in Table 30.
9.3.6.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 9.3.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
In addition, the investigators will report SAEs to their IRB/IEC in accordance with the
IRB/IEC requirements.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccines and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation.
9.4.
Follow-up of adverse events and serious adverse events
9.4.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 30).
All SAEs and AEs of specific interest (i.e. seizures occurring within 30 days post-
vaccination, pIMDs and meningitis) (serious or non-serious) documented at a previous 
visit/contact and designated as not recovered/not resolved or recovering/resolving will be 
reviewed at subsequent visits/contacts until the end of the study.
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.

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9.4.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs, AEs of specific interest (serious or non-serious), or subjects withdrawn 
from the study as a result of an AE, until the event has resolved, subsided, stabilized, 
disappeared, or until the event is otherwise explained, or the subject is lost to follow-
up.
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper/ electronic 
Expedited Adverse Events Report as applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognized follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
9.5.
Treatment of adverse events
Treatment of any AE 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 eCRF (refer to Section 7.7).
In this study, medications administered for the treatment of any solicited local or general 
AE should be recorded for subjects belonging to the reactogenicity sub-cohort and during 
the time period for collection of solicited AEs. Medications administered for the 
treatment of unsolicited AEs should be recorded for all subjects during the time period 
for collection of unsolicited AEs (see Section 9.2.1 and Table 27), except for anti-malaria 
treatments that must be collected for all subjects during the entire study period (see 
Section 7.7.1).
Cases of suspected malaria will be tested with a rapid diagnostic test (RDT) or blood 
slide and managed on the basis of their result. These tests are separate to samples taken 
for determination of efficacy against P. falciparum infection by blood slide reading and 
filter paper for PCR (see Section 6.7.3).
9.6.
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 clinical study.
The investigator (or designate) must therefore provide a “subject card” to each subject’s 
parent(s)/LAR(s). In an emergency situation this card serves to inform the responsible 
attending physician that the subject is in a clinical study and that relevant information 
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Subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times.
10.
SUBJECT COMPLETION AND WITHDRAWAL
10.1.
Subject completion
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study.
10.2.
Subject withdrawal
Withdrawals will not be replaced.
10.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol.
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up.
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).

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*In case a subject is withdrawn from the study because the subject’s parent(s)/LAR(s)
has withdrawn consent, the investigator will document the reason for withdrawal of 
consent, if specified by the subject’s parent(s)/LAR(s), in the eCRF.
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 9.4.2).
10.2.2.
Subject withdrawal from investigational vaccines
A ‘withdrawal’ from the investigational vaccines 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 vaccines 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.
Information relative to premature discontinuation of the investigational vaccines will be 
documented on the vaccine administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination/treatment was made by 
the subject’s parent(s)/LAR(s) or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Other (specify).
10.3.
Screen and baseline failures
Screening failures are defined as subjects who are withdrawn from the study after giving 
informed consent, but who do not meet the inclusion and exclusion criteria. Reason for 
screening failure will be collected.
11.
STATISTICAL METHODS
11.1.
Primary endpoint

Efficacy:

The occurrence of clinical malaria meeting the primary case definition from 
Month 2.5 up to Month 14.

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11.2.
Secondary endpoints

Efficacy:

The occurrence of clinical malaria meeting the primary and secondary case 
definitions from Day 0 up to Month 50.

The occurrence of incident P. falciparum infections from Day 0 to Month 50.

The prevalence of P. falciparum infections defined by positive blood slide at 
each cross-sectional survey.

Immunogenicity: Immune response to the CS and HBs antigens
(immunogenicity subset)

Anti-CS antibody concentrations and seropositivity measured before Dose 1, 
one month post-Dose 2 (group Fx017-mFxD only), before and one month 
post-Dose 3, before and one month after Dose 4, before and one month after 
each yearly dose and at study end (Month 50).

Anti-HBs antibody concentrations and seropositivity measured before Dose 1, 
one month post-Dose 2 (group Fx017-mFxD only), before and one month post-
Dose 3, before and one month after Dose 4, before and one month after each 
yearly dose and at study end (Month 50).
Amended 14 November 2019

Safety

The occurrence of SAEs (all, fatal and related) during the whole study period
according to the MedDRA classification. 

The occurrence of AEs and SAEs leading to withdrawal from further 
vaccination from Dose 1 (Day 0) up to Month 50, according to the MedDRA 
classification.

The occurrence of severe malaria cases and cerebral malaria cases during the 
whole study period.

The occurrence of pIMDs from Day 0 up to Month 50, according to the 
MedDRA classification.

The occurrence of meningitis from Day 0 up to Month 50, according to the 
MedDRA classification.

The occurrence of seizures within 30 days (day of vaccination and 29 
subsequent days) after each dose of study vaccine, according to the MedDRA 
classification.

The occurrence of generalized convulsive seizure within seven days (day of 
vaccination and six subsequent days) after each dose of study vaccine, according 
to the Brighton collaboration guidelines [Bonhoeffer, 2004].

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
The occurrence of unsolicited AEs within 30 days (day of vaccination and 29 
subsequent days) after each dose of study vaccine, according to the MedDRA 
classification.

The concentration of biochemistry (ALT, creatinine) and hematology 
(hemoglobin, WBC, platelets) parameters in the first 50 subjects (25 subjects per 
site) enrolled in each group (reactogenicity sub-cohort) before Dose 3, seven 
days post-Dose 3 and 30 days post-Dose 3.

Reactogenicity (reactogenicity sub-cohort)

The occurrence of solicited local and general AEs in a the first 50 subjects 
enrolled in each group within four days (day of vaccination and three subsequent 
days) after Dose 3 of study vaccine (all groups including controls), after Dose 4 
(groups R012-20, R012-14-mD, Fx012-14-mFxD and Fx017-mFxD), after Dose 
5 (groups R012-14-mD, Fx012-14-mFxD and Fx017-mFxD) and after Dose 6 
(groups R012-14-mD and Fx012-14-mFxD).
11.3.
Tertiary endpoints

Immunogenicity

Anti-CS antibody avidity at specified timepoints.
11.4.
Determination of sample size
For the primary endpoint, demonstrating incremental vaccine efficacy against clinical
malaria of a fractional dose schedule over the standard schedule, the study has at least 
90% power to show a significant incremental vaccine efficacy (lower limit of 95% CI 
above 0), assuming 250 evaluable subjects per group and an incidence of at least 0.5 
episodes/person year at risk (pyr) in the Control group, 0.29 episodes/pyr in the standard 
schedule groups and 0.16 episodes/pyr in the fractional dose schedule. This corresponds 
to an incremental efficacy (1-Hazard Rate) of 50% of the fractional dose schedule over 
the standard schedule. The primary endpoint compares the R012-20+R012-14-mD groups 
versus the Fx012-14-mFxD group (2:1). For secondary endpoints evaluating efficacy 
against P. falciparum infections, it is anticipated that incidence of infection in the study 
will be higher than incidence of clinical malaria resulting in adequate power.
In this study the reactogenicity (solicited local and general AEs) and the biochemistry 
and hematology parameters will be evaluated in a sub-cohort consisting of the first 50 
subjects enrolled in each group (total 250 subjects). The anti-CS and anti-HBs immune 
responses will be tested in a subset consisting of the first 50 subjects enrolled in each 
group (total 250 subjects); see the glossary of terms for the definitions of subset and sub-
cohort. 
Assuming a post-vaccination anti-CS GMC of approximately 50 IU/ml for the fractional 
dose schedules and a log SD of 0.5 the precision obtained by 95%CIs of the GMC with a 
sample size of 50 subjects per group is (36.3-68.8).

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11.5.
Cohorts for analyses
11.5.1.
Total vaccinated cohort
The total vaccinated cohort (TVC) will include all subjects who received at least one dose 
of study vaccine. The TVC analysis will be performed per treatment actually 
administered.
11.5.2.
ATP cohort for efficacy
The ATP cohort for efficacy will include all subjects included in the TVC who fulfilled 
eligibility criteria and who received all vaccinations according to protocol procedures 
within the protocol specified intervals that contribute to the time at risk in the follow-up 
period starting 14 days post-Dose 3. Subjects who have not received Dose 4 of study 
vaccine or subsequent yearly doses (Dose 5 and Dose 6) according to protocol will be 
censored at the last contact date recorded and will contribute to the ATP analysis up to 
censoring.
Of note, subjects with a prevalent P. falciparum infection at the beginning of the follow-
up period will not be included in the ATP analysis of vaccine efficacy against first or 
only incident P. falciparum infection. Sensitivity analyses by left censoring (i.e. start of 
follow up defined as first negative ADI visit for all children) will be performed.
11.5.3.
ATP cohort for immunogenicity
The ATP population for immunogenicity will include all subjects included in the TVC 
who received all vaccinations according to protocol procedures within the protocol 
specified intervals, performed blood samplings for immunogenicity according to protocol 
intervals, met all eligibility criteria, did not use any medication or blood products 
forbidden by the protocol and did not have any reported underlying medical condition 
influencing immune responses.
11.6.
Derived and transformed data

Immunogenicity

A subject seropositive for anti-CS antibody will be a subject whose antibody 
concentration will be greater than or equal to the cut-off value (anti-CS 0.5 
EU/ml).

Seroprotection rate for anti-HBs antibody is defined as the percentage of 
subjects with antibody concentration greater than or equal to an established cut-
off (anti-HBs 10 mIU/ml).

The geometric mean concentration (GMC) calculations will be performed by 
taking the anti-log of the mean of the log transformations (base 10). Antibody 
concentrations below the cut-off of the assay will be given an arbitrary value of 
half the cut-off for the purpose of GMC calculation. 

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
Handling of missing data: 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 symptom, missing or non-evaluable measurements 
will not be replaced. Therefore the analysis of the solicited symptoms based on 
the TVC will include only subjects/doses with documented safety data (i.e. 
symptom screen/sheet completed).
11.7.
Analysis of efficacy
The effect of the vaccine will be characterized using different complementary standard 
methodologies.
11.7.1.
Strategy of analysis and rationale
The strategy of analysis for the present study has been developed considering the 
following points:

Prevalent infections are only captured by ADI during the cross-sectional surveys 
performed at pre-defined timepoints throughout the study. Incident infections are 
captured via both ADI at cross-sectional surveys and via passive detection upon 
spontaneous presentation at health centers (see Section 4.2 for case definitions of 
P. falciparum infections). Episodes of clinical malaria will be treated when 
diagnosed. Samples collected at cross-sectional visits in asymptomatic children will 
not be processed in real time and will not lead to systematic treatment.

Vaccine efficacy against prevalent P. falciparum infections at the successive cross-
sectional surveys is an important measure as it is not influenced by care seeking 
behavior and possibly less influenced by blood-stage immunity. Reducing the 
prevalence of blood-stage infections at successive timepoints will be a good indicator 
of the potential to reduce transmission as it is directly associated with the potential to 
infect mosquitoes.

Vaccine efficacy against first or only episode of incident P. falciparum infection or 
against first or only episode of clinical malaria minimizes the bias related to 
differential acquisition of blood-stage immunity in the vaccine and Control groups, 
and is assumed to be the best way to assess the biological effect of the third dose 
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
Vaccine efficacy against all episodes of incident P. falciparum infection or clinical 
malaria is more relevant to public health but over longer time periods. There is a 
possibility of bias related to the fact that it will compare a Control group with 
frequent exposure and an intervention group with reduced exposure and a different 
build-up of blood-stage immunity over time, possibly influencing health seeking 
behaviors (hence the importance of also evaluating vaccine efficacy against 
prevalent infection and first or only episode).

Considering the measures of incidence:

For group comparisons with identical calendar time follow-up periods, the 
incidence rates will be directly compared. The incremental vaccine efficacy 
estimate is defined as 1-Incidence Rate Ratio in each group.

When different calendar time follow-up periods are compared, in order to 
account for seasonal variations in exposure, the incidences of the Control group 
over the relevant time frame will be taken into account. When comparing the 
0, 1, 2-month schedules against the 0, 1, 7-month schedule, the incremental 
efficacy will be defined as 1 minus the rate ratio of the relative reductions of 
each group versus the Control group, during the corresponding time frames.

The estimation of the number of cases of clinical malaria averted will inform on how 
the vaccine efficacy translates into impact, in a way that is dependent on exposure 
and hence transmission intensity.
11.7.2.
Measures of incidence (P. falciparum infection and clinical 
malaria)

First or only episode
Vaccine efficacy against first or only episode of incident P. falciparum infection or 
clinical malaria will be analyzed by Cox regression stratified by study site. The 95% CI 
and p-values of the vaccine efficacy estimates (1- Hazard Ratio) will be calculated from 
this model. Cumulative incidence graphs will be produced.

All episodes
Vaccine efficacy against all episodes of incident P. falciparum infection or clinical 
malaria will be analyzed by negative binomial regression allowing for interdependence 
between episodes within the same subject (non-linear mixed model with overdispersion 
parameter estimated from the random effect). The 95% CI and p-values of the vaccine 
efficacy estimates (1- Incidence Rate Ratio) will be calculated from this model. In case 
models do not converge or showed poor fit, alternative negative binomial models without 
random effects will be applied. Fourteen days following an episode meeting the case 
definition under evaluation will be subtracted from the follow-up time. The distribution 
of the total number of events per subject will be tabulated by group.
Amended 14 November 2019

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11.7.3.
Measure of prevalence (P. falciparum infection)
The prevalence of P. falciparum infection will be evaluated on the cross-sectional ADI 
samples only. At each pre-defined timepoint, the prevalence of P. falciparum infection 
will be calculated by group as well as between groups by relative risks together with 95% 
CIs. Graphical presentations of the prevalence over time will be produced.
11.7.4.
Measure of impact (clinical malaria)
The vaccine impact will be estimated by the number of cases of clinical malaria averted 
over the relevant time frame per 1000 subjects vaccinated. The number of cases averted 
will be calculated as the difference of the estimated cases between the Control group and 
the vaccine group. Estimated cases in each group will be calculated as the area under the 
curve of the incidence of clinical malaria over time and expressed as cumulative cases 
averted per 1000 subjects followed-up during the relevant period.
11.7.5.
Primary analysis of efficacy (primary objective)
A) Clinical malaria:
Analysis performed at Month 21:

Incremental efficacy of Fx012-14-mFxD versus (R012-20 + R012-14-mD) over 
M2.5-M14 (first or only episode, ATP).
11.7.6.
Secondary analyses of efficacy
A) Clinical malaria:
Early follow-up time periods (up to Month 14): Vaccine efficacy against first or only 
episode as well as all episodes of clinical malaria will be assessed both in the ATP and 
TVC cohorts.
Longer follow-up time periods (longer than Month 14): Vaccine efficacy against all 
episodes of clinical malaria will be assessed on the TVC. The analysis of vaccine impact 
will also be performed on the TVC.
Analysis performed at Month 21:

Incremental efficacy of Fx012-14-mFxD versus (R012-20 + R012-14-mD) over 
M2.5-M14 (all episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus (R012-20 + R012-14-mD) over 
D0-M14 (first or only and all episode, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over M2.5-M9 (first 
or only and all episodes, ATP).

Vaccine efficacy of Fx017-mFxD versus Control group over M7.5-M14 (first or
only and all episodes, ATP).

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
Vaccine efficacy of R012-20 + R012-14-mD versus Control group over M2.5-
M9 (first or only and all episodes, ATP).

Vaccine efficacy of Fx012-14-mFxD versus Control group over M2.5-M14 (first 
or only and all episodes, ATP).

Vaccine efficacy of Fx017-mFxD versus Control group over M7.5-M19 (first or 
only and all episodes, ATP).

Vaccine efficacy of R012-20 + R012-14-mD versus Control group over M2.5-
M14 (first or only and all episodes, ATP).

Incremental efficacy taking into account incidence in controls: Fx017-
mFxD/Control group over M7.5-M14 versus Fx012-14-mFxD/Control group 
over M2.5-M9 (first or only and all episodes, ATP).

Incremental efficacy taking into account incidence in controls: Fx017-
mFxD/Control group over M7.5-M14 versus groups (R012-20 + R012-14-
mD)/Control group over M2.5-M9 (first or only and all episodes, ATP).

Incremental efficacy taking into account incidence in controls: Fx017-
mFxD/Control group over M7.5-M19 versus Fx012-14-mFxD/Control group 
over M2.5-M14 (first or only and all episodes, ATP).

Incremental efficacy taking into account incidence in controls: Fx017-
mFxD/Control group over M7.5-M19 versus groups R012-20 + R012-14-mD 
/Control group over M2.5-M14 (first or only and all episodes, ATP).

Vaccine efficacy of R012-20 + R012-14-mD versus Control group over D0-M14 
(first or only and all episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M14 (first 
or only and all episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M14 (first or 
only and all episodes, TVC).

Vaccine efficacy and impact of R012-20 versus Control group over D0-M20 (all 
episodes, TVC).

Vaccine efficacy and impact of R012-14-mD versus Control group over 
D0-M20 (all episodes, TVC).

Vaccine efficacy and impact of Fx012-14-mFxD versus Control group over 
D0-M20 (all episodes, TVC).

Vaccine efficacy and impact of Fx017-mFxD versus Control group over 
D0-M20 (all episodes, TVC).
Analysis performed at Month 33:

Vaccine efficacy and impact of R012-20 versus Control group over D0-M26 (all 
episodes, TVC).

Vaccine efficacy and impact of R012-14-mD versus Control group over 
D0-M26 (all episodes, TVC).

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
Vaccine efficacy and impact of Fx012-14-mFxD versus Control group over 
D0-M26 (all episodes, TVC).

Vaccine efficacy and impact of Fx017-mFxD versus Control group over 
D0-M26 (all episodes, TVC).

Incremental efficacy of Fx017-mFxD versus R012-20 over M20-M32 (all 
episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M14-M26 
(all episodes, ATP).
Analysis performed at Month 50:

Vaccine efficacy and impact of R012-20 versus Control group over D0-M38 (all 
episodes, TVC).

Vaccine efficacy and impact of R012-20 versus Control group over D0-M50 (all 
episodes, TVC).

Vaccine efficacy and impact of R012-14-mD versus Control group over 
D0-M38 (all episodes, TVC).

Vaccine efficacy and impact of R012-14-mD versus Control group over 
D0-M50 (all episodes, TVC).

Vaccine efficacy and impact of Fx012-14-mFxD versus Control group over 
D0-M38 (all episodes, TVC).

Vaccine efficacy and impact of Fx012-14-mFxD versus Control group over 
D0-M50 (all episodes, TVC).

Vaccine efficacy and impact of Fx017-mFxD versus Control group over 
D0-M38 (all episodes, TVC).

Vaccine efficacy and impact of Fx017-mFxD versus Control group over 
D0-M50 (all episodes, TVC).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M26-M38 
(all episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M38-M50 
(all episodes, ATP).
B) Incident P. falciparum infections
Early follow-up time periods (up to Month 14): Vaccine efficacy against first or only 
episode as well as all episodes of incident P. falciparum infection will be assessed both in 
the ATP and TVC cohorts.
Longer follow-up time periods (longer than Month 14): Vaccine efficacy against all 
episodes of incident P. falciparum infection will be assessed on the TVC.

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Analysis performed at Month 21:

Incremental efficacy of Fx012-14-mFxD versus (R012-20 + R012-14-mD) over 
M2.5-M14 (first or only and all episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus (R012-20 + R012-14-mD) over 
D0-M14 (first or only and all episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over M2.5-M9 (first 
or only and all episodes, ATP).

Vaccine efficacy of Fx017-mFxD versus Control group over M7.5-M14 (first or 
only and all episodes, ATP).

Vaccine efficacy of R012-20 + R012-14-mD versus Control group over M2.5-
M9 (first or only and all episodes, ATP).

Vaccine efficacy of Fx012-14-mFxD versus Control group over M2.5-M14 (first 
or only and all episodes, ATP).

Vaccine efficacy of Fx017-mFxD versus Control group over M7.5-M19 (first or 
only and all episodes, ATP).

Vaccine efficacy of R012-20 + R012-14-mD versus Control group over M2.5-
M14 (first or only and all episodes, ATP).

Incremental efficacy taking into account incidence in controls: Fx017-
mFxD/Control group over M7.5-M14 versus Fx012-14-mFxD/Control group 
over M2.5-M9 (first or only and all episodes, ATP).

Incremental efficacy taking into account incidence in controls: Fx017-
mFxD/Control group over M7.5-M14 versus groups (R012-20 + R012-14-
mD)/Control group over M2.5-M9 (first or only and all episodes, ATP).

Incremental efficacy taking into account incidence in controls: Fx017-
mFxD/Control group over M7.5-M19 versus Fx012-14-mFxD/Control group 
over M2.5-M14 (first or only and all episodes, ATP).

Incremental efficacy taking into account incidence in controls: Fx017-
mFxD/Control group over M7.5-M19 versus groups R012-20 + R012-14-mD 
/Control group over M2.5-M14 (first or only and all episodes, ATP).

Vaccine efficacy of R012-20 + R012-14-mD versus Control group over D0-M14 
(first or only and all episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M14 (first 
or only and all episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M14 (first or 
only and all episodes, TVC).

Vaccine efficacy of R012-20 versus Control group over D0-M20 (all episodes, 
TVC).

Vaccine efficacy of R012-14-mD versus Control group over D0-M20 (all 
episodes, TVC).

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
Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M20 (all 
episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M20 (all 
episodes, TVC).
Analysis performed at Month 33:

Vaccine efficacy of R012-20 versus Control group over D0-M26 (all episodes, 
TVC).

Vaccine efficacy of R012-14-mD versus Control group over D0-M26 (all 
episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M26 (all 
episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M26 (all 
episodes, TVC).

Incremental efficacy of Fx017-mFxD versus R012-20 over M20-M32 (all 
episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M14-M26 
(all episodes, ATP).
Analysis performed at Month 50:

Vaccine efficacy of R012-20 versus Control group over D0-M38 (all episodes, 
TVC).

Vaccine efficacy of R012-20 versus Control group over D0-M50 (all episodes, 
TVC).

Vaccine efficacy of R012-14-mD versus Control group over D0-M38 (all 
episodes, TVC).

Vaccine efficacy of R012-14-mD versus Control group over D0-M50 (all 
episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M38 (all 
episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M50 (all 
episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M38 (all 
episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M50 (all 
episodes, TVC).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M26-M38 
(all episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M38-M50 
(all episodes, ATP).

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C) Prevalent P. falciparum infections
Prevalent P. falciparum infections will be assessed in the TVC.
Analysis performed at Month 21:

Prevalent P. falciparum infections at each cross-sectional survey at Month 14 
(TVC).

Prevalent P. falciparum infections at each cross-sectional survey at Month 20 
(TVC).
Analysis performed at Month 33:

Prevalent P. falciparum infections at each cross-sectional survey at Month 26 
(TVC).
Analysis performed at Month 50:

Prevalent P. falciparum infections at each cross-sectional survey at Month 38 
(TVC).

Prevalent P. falciparum infections at each cross-sectional survey at Month 50 
(TVC).
11.8.
Analysis of demographics
A study flow diagram (consort) will be generated to present the number of subjects 
screened, randomized, receiving doses and included in the ATP analyses.
Demographic characteristics (age and gender) and the baseline hemoglobin level will be 
tabulated per study group overall, and by site, for each cohort (TVC, ATP cohort for 
immunogenicity and ATP cohort for efficacy).
The mean age at first vaccination (in months) (plus range and standard deviation [SD]) of 
the vaccinated subjects as a whole, and per group, will be calculated.
11.9.
Analysis of immunogenicity
The primary analysis will be based on the ATP cohort for immunogenicity; however, 
analyses on the TVC will also be performed.
In the immunogenicity subset (first 50 subjects enrolled in each group), the percentage of 
subjects with seropositive levels of anti-CS (proportion of subjects with anti-CS antibody 
concentrations greater than or equal to 0.5 EU/ml) with 95% CI will be determined at 
specified blood sampling timepoints in each group (see Section 6.7.4.1). Anti-CS 
antibody concentrations will be summarized by GMCs with 95% CI. Anti-CS antibody 
concentrations after the third dose and each subsequent dose of study vaccine will also be
investigated using reverse cumulative curves.

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
1 3 4
T he ser o pr otecti ve le vel f or a nti -H Bs is 1 0 mI U/ ml. I n t he i m m u n o ge nicit y  s u bset, t he 
perce nta ge of s u bjects wit h pr otecti ve le vels of a nti- H Bs ( 1 0 mI U/ ml) wit h 9 5 % CI  will 
be deter mi ne d at s pecifie d bl o o d sa m pli n g ti me p oi nts i n eac h gr o u p (see Secti o n 6. 7. 4. 1 ).
A nti -H Bs a nti b o d y c o nce ntrati o ns will be s u m marize d b y G MC s wit h 9 5 % CI. A nti-H Bs 
a nti b o d y c o nce ntrati o ns after t he t hir d d ose a n d eac h s u bse q ue nt d ose of st u d y  vacci ne 
will als o be i n vesti gate d usi n g re verse c u m ulati ve c ur ves.
F or t he a nal ys is of t he tertiar y o bjecti ve, a vi dit y/ affi nit y i n de x a n d a vi dit y mat urati o n 
will be s u m marize d b y  mea n, S D, me dia n a n d q uartile. 
 
1 1. 1 0.
A n al y si s of s af et y
T he pri mar y  a nalys is will be base d o n t he T V C.
A m o n g t he react o ge nicit y  s u b-c o h ort (first 5 0 s u bjects e nr olle d i n eac h gr o u p) t he 
perce nta ge of s u bjects wit h at least o ne l ocal A E (s olicite d a n d u ns olicite d), wit h at least 
o ne ge neral A E (s olicite d a n d u ns olicite d) a n d wit h a n y  A E d uri n g t he solicite d f oll o w -
u p peri o d (i.e. f o ur da y s p ost-D ose 3, D ose 4, D ose 5 a n d D ose 6) will be ta b ulate d wit h 
e xact 9 5 % CI after eac h vacci ne d ose a n d o verall. T he perce nta ge of d oses f oll o we d b y at 
least o ne l ocal A E (s olicite d a n d u ns olicite d), by at least o n e ge neral A E (s olicite d a n d 
u ns olicite d) a n d b y a n y A E will be ta b ulate d f or t he w h ole s olicite d f oll o w -u p peri o d (i.e. 
f o ur da ys p ost-D ose 3, D ose 4, D ose 5 a n d D ose 6), wit h e xact 9 5 % CI . Si milar ta bles 
will be ge nerate d f or Gra de 3 A Es a n d A Es c o nsi dere d as ca usall y relate d t o vacci nati o n.
A m o n g t he react o ge nicit y  s u b- c o h ort (first 5 0 s u bjects e nr olle d i n eac h gr o u p), t he 
perce nta ge of s u bjects re p orti n g eac h i n di vi d ual s olicite d l ocal a n d ge neral A E d uri n g t he 
s olicite d f oll o w-u p peri o d (i.e. f o ur da y s p ost - D ose 3, D ose 4, D ose 5 a n d D ose 6) will be 
ta b ulate d wit h e xact 9 5 % CI. T he perce nta ge of d oses f oll o we d b y eac h i n di vi d ual 
s olicite d l ocal a n d ge neral A E will be ta b ulate d f or eac h d ose a n d f or t he w h ole s olicite d 
f oll o w-u p peri o d (i.e. f o ur da y s p ost-D ose 3, D ose 4, D ose 5 a n d D ose 6), wit h e xact 
9 5 % CI . Si milar ta bles will be ge nerate d f or Gra de 3 A Es, ca usal e ve nts a n d f or fe ver, 
te m perat ure i n 0. 5C i ncre me nts.
T he ver bati m re p orts of u ns olicite d s y m pt o ms will be re vie we d b y  a p hys icia n a n d t he 
sig ns a n d s y m pt o ms will be c o de d acc or di n g t o t he Me d D R A . T he perce nta ge of s u bjects 
wit h at least o ne re p ort of u ns olicite d A E classifie d b y  t he Me d D R A preferre d ter m le vel, 
occ urri n g wit hi n 3 0 da y s ( da y of vacci nati o n a n d 2 9 s u bse q ue nt da ys) after eac h d ose of 
st u d y vacci ne will be ta b ulate d wit h e xact 9 5 % CI.
T he perce nta ge of s u bjects re p orti n g a n S A E (all, fatal, relate d) occ urri n g wit hi n 3 0 da y s 
( da y of vacci nati o n a n d 2 9 s u bse q ue nt da ys) after eac h d ose of st u d y vacci ne, classifie d 
b y  t he Me d D R A preferre d ter m le vel will be ta b ulate d wit h e xact 9 5 % CI.
T he perce nta ge of s u bjects re p orti n g a n S A E (all, fatal, relate d) fr o m D ose 1 ( Da y  0) 
u ntil M o nt h 1 4, fr o m Da y 0 u ntil M o nt h 2 6 a n d o ver t he w h ole st u d y d urati o n ( D ose 1 
[ Da y 0] u ntil M o nt h 5 0), classified b y  t he Me d D R A preferre d ter m le vel, will be 
ta b ulate d wit h e xact 9 5 % CI.
C CI

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The percentage of subjects reporting an AE or SAE leading to withdrawal from further 
vaccination from Dose 1 (Day 0) until Month 50, classified by the MedDRA preferred 
term level, will be tabulated with exact 95% CI.
The percentage of subjects reporting severe malaria cases and cerebral malaria cases from 
Day 0 up to Month 14, Day 0 up to Month 26, Day 0 up to Month 50 and over successive 
years within the study will be tabulated with exact 95% CI. The percentage of subjects 
reporting pIMDs from Dose 1 (Day 0) until Month 14, from Day 0 until Month 26 and 
from Day 0 until Month 50, classified by the MedDRA preferred term level will be 
tabulated with exact 95% CI.
The percentage of subjects reporting meningitis from Dose 1 (Day 0) until Month 14, 
from Day 0 until Month 26 and from Day 0 until Month 50, classified by the MedDRA 
preferred term level will be tabulated with exact 95% CI.
The percentage of subjects reporting seizures occurring within 30 days (day of 
vaccination and 29 subsequent days) after each dose of study vaccine, classified by the 
MedDRA preferred term level will be tabulated with exact 95% CI.
For generalized convulsive seizures occurring within seven days following a dose of 
study vaccine, an analysis will be performed based on the Brighton Collaboration 
guidelines [Bonhoeffer, 2004]. This includes descriptive tables of the time relationship of 
seizures to vaccination, the duration of seizures and the level of diagnostic certainty.
Biochemistry (ALT, creatinine) and hematology (hemoglobin, WBC, platelets) values 
that are outside of the reference ranges (see Table 29) will be described in the 
reactogenicity sub-cohort (first 50 subjects enrolled in each group) before Dose 3, seven 
days post-Dose 3 and 30 days post-Dose 3. Frequency distribution of results by toxicity 
grades will be tabulated by group.
11.11.
Interpretation of analyses
Vaccine efficacy estimates with a lower limit of the 95% CI above 0 are to be considered 
statistically significant.
11.12.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
11.12.1.
Sequence of analyses
All analyses (including interim analyses) will be conducted on data as clean as possible.

Sequence of analyses and conditional continuation:

A first analysis will be performed on data collected up to Month 21 (Visit 25) to 
evaluate the primary objective (cleaned data) and relevant secondary objectives.

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
A second analysis will be performed on data collected up to Month 33 (Visit 31) 
to evaluate relevant secondary objectives.

A final analysis will be performed at study end (Month 50) on data collected up 
to Month 50. An integrated study report presenting all results until Month 50 
will be produced.

After the interim analyses, the IDMC will have the possibility to recommend the 
suspension of further vaccinations and termination of specific study group(s) upon 
consideration of the study results. In the event that the IDMC recommend the 
suspension of further vaccinations, the group(s) impacted will be followed up for 12 
months after their last study vaccination.
11.12.2.
Statistical considerations for interim analyses
The analysis of the primary endpoint will be performed after Month 21 (Visit 25) on 
cleaned data collected up to Month 14. No alpha adjustment is foreseen because final 
analysis of the primary endpoint will occur at the time of the first interim analysis after 
Month 21 (Visit 25) on cleaned data collected up to Month 14.
12.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled.
12.1.
Electronic case report form instructions
A validated GSK defined electronic data collection tool will be used as the method for
data collection.
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and 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.

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12.2.
Study monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a source document 
verification (SDV). By SDV we understand verifying eCRF 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 eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form.
For eCRF, the monitor freezes completed and approved screens at each visit.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
12.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.

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GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures.
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site.
12.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
12.5.
Posting of information on publicly available clinical trial 
registers and publication policy
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in 
compliance with the current regulations. The minimal requirement is to have primary 
endpoint summary results disclosed at latest 12 months post primary completion date 
and to have secondary endpoint disclosed at latest 12 months after the Last Subject 
Last Visit (LSLV) as described in the protocol.
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors.
Amended 14 November 2019
12.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.

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GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
13.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.

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14.
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Accessed: 25 January 2016.
WHO. Guidelines for the treatment of malaria. 3rd Edition. 2015. 
http://www.who.int/malaria/publications/atoz/9789241549127/en/. Accessed: 25 January 
2016.
WHO. Position paper on rabies vaccine - 6 August 2010. 
http://www.who.int/immunization/rabies_grad_efficacy.pdf?ua=1. Accessed: 25 January 
2016.
WHO. Verbal autopsy standards: Ascertaining and attributing cause of death. 2007. 
http://www.who.int/healthinfo/statistics/verbalautopsystandards/en/index2.html. 
Accessed 15 February 2016.
WHO. Weekly Epidemiological Record. Malaria vaccine WHO position paper. 2016; 
91:33-52. http://www.who.int/wer/2016/wer9104.pdf. Accessed: 10 February 2016.
WHO. Weekly Epidemiological Record. Rabies vaccines WHO position paper. 2007; 
82:425-436. http://www.who.int/wer/2007/wer8249_50.pdf?ua=1. Accessed: 25 January 
2016.

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APPENDIX A
LABORATORY ASSAYS
Anti-CS antibody
Antibody concentrations against P. falciparum CS-repeat region will be measured at 
CEVAC by a standard ELISA methodology using plate adsorbed recombinant R32LR 
antigen, as described by Clement et al. [Clement, 2012]. Anti-CS antibody concentrations
will be determined relative to a standard reference antibody as a control according to 
standard operating procedures from the laboratory. The cut-off for the assay is 0.5 EU/ml. 
Results will be reported in EU/ml.
Anti-HBs antibody
Anti-HBs antibody concentrations will be determined using commercially available 
CLIA kits ADVIA® Centaur anti-HBs2 manufactured by Siemens Healthcare. The cut-
off for the assay is 6.2 mIU/ml. Results will be reported in mIU/ml.
Anti-CS avidity
For the measurement of avidity of IgG against P. falciparum CS-repeat region, samples 
will be evaluated as described by Clement et al. [Clement, 2012], but in two different 
plates; one treated with a chaotropic agent and one untreated plate. As chaotropic agent a 
1 M solution of ammonium thiocyanate (NH4SCN) is added in the treatment plate while 
0.05% Tween-20 in phosphate buffered saline (PBS) is added in the untreated plate and 
both CS ELISA plates are further washed and developed as described [Clement, 2012]. 
The avidity index (AI) is calculated as the ratio of the concentration of anti-CS IgG 
(EU/ml) that remained bound to the coated antigen after treatment with NH4SCN, divided 
by the concentration of IgG (EU/ml) that remained bound to the coated antigen in the 
untreated plate.
Blood smear and filter paper for assessment of P. falciparum parasitemia
Blood slide preparation and slide reading will be performed according to standard 
operating procedure from the Malaria Diagnostics Centre of Excellence, Kisumu, Kenya.
Blood drops will be collected on a filter paper for the ancillary study that will evaluate 
the incidence of P. falciparum infection assessed by PCR and parasite genotyping.
Hemoglobin, WBC, platelets, ALT and creatinine
The measure of hematology and biochemistry parameters will be done at each study 
center using validated automated analyzers and according to the equipment 
specifications.

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APPENDIX B
CLINICAL LABORATORIES
Table 31
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Clinical Laboratory Services, Rixensart
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium
GSK Biologicals Clinical Laboratory Services, Rixensart
Avenue Fleming, 20 - B-1300 Wavre - Belgium
Table 32
Outsourced laboratories
Laboratory
Address
Clinical Laboratory Services, South Africa
4th Floor Spencer Lister Building
Corner of Hospital and de Korte Streets
Braamfontein
Johannesburg 2000, South Africa
CEVAC - University of Gent
De Pintelaan, 185 Gent
Belgium
Kenya Medical Research Institute / US Army Medical 
Research Unit Kenya, Walter Reed 
Project.(KEMRI/USAMRU-K, WRP), Malaria Diagnostics 
Center, Kisumu
PO Box 54, Kisumu 40100, 
Kenya
Collaborators for filter paper assessment of molecular detection and genotyping of 
Plasmodium falciparum parasites
This ancillary analysis will be carried out in partnership with the Harvard School of 
Public Health (Holyoke Center 727, 1350 Massachusetts Avenue, Cambridge, 
Massachusetts 02138, USA) and the Broad Institute (415 Main St, Cambridge, MA 
02142, USA).

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APPENDIX C
CASE DEFINITIONS OF SEVERE MALARIA AND 
CEREBRAL MALARIA
Cases of severe malaria and cerebral malaria will be reported as part of the safety 
surveillance. Case definitions adapted from the WHO case definitions of severe malaria 
and cerebral malaria will be used as reference for diagnosis.
Table 33
Case definition of severe P. falciparum malaria
Adapted from [WHO, 2015].
P. falciparum parasitemia > 0 detected by microscopy and/or rapid diagnostic test (RDT)
AND one or more of the following, occurring in the absence of an identified alternative cause:

Impaired consciousness: a Blantyre coma score < 3;

Prostration: generalized weakness so that the person is unable to sit, stand or walk without assistance;

Multiple convulsions: more than two episodes within 24h;

Acidosis: a base deficit of > 8 mEq/l or, if not available, a plasma bicarbonate level of < 15 mmol/l or 
venous plasma lactate ≥ 5 mmol/l. Severe acidosis manifests clinically as respiratory distress (rapid, 
deep, labored breathing).

Hypoglycemia: blood or plasma glucose < 2.2 mmol/l (< 40 mg/dl);

Severe malarial anemia: hemoglobin concentration ≤ 5 g/dl or a hematocrit of ≤ 15% in children < 12 
years of age with a parasite count > 10 000/μl;

Renal impairment: plasma or serum creatinine > 265 μmol/l (3 mg/dl) or blood urea > 20 mmol/l;

Jaundice: plasma or serum bilirubin > 50 μmol/l (3 mg/dl) with a parasite count > 100 000/μl;

Pulmonary edema: radiologically confirmed or oxygen saturation < 92% on room air with a respiratory rate 
> 30/min, often with chest indrawing and crepitations on auscultation;

Significant bleeding: including recurrent or prolonged bleeding from the nose, gums or venipuncture sites; 
hematemesis or melaena;

Shock: compensated shock is defined as capillary refill ≥ 3 s or temperature gradient on leg (mid to 
proximal limb), but no hypotension. Decompensated shock is defined as systolic blood pressure < 70 mm 
Hg in children, with evidence of impaired perfusion (cool peripheries or prolonged capillary refill);

Hyperparasitemia: P. falciparum parasitemia > 10% (i.e. percentage of infected red blood cells > 10%; 
corresponding to > 500 000/μl).
Table 34
Case definition of cerebral P. falciparum malaria
Adapted from [WHO, 2015].
Severe P. falciparum malaria with coma (Blantyre coma score < 3); 
AND
If malaria with seizure: coma persisting for > 30 min after the seizure.
Other treatable causes of coma should be excluded before diagnosing cerebral malaria (e.g. hypoglycaemia, 
bacterial meningitis).
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APPENDIX D
SAFETY LABORATORY TESTING: CLS SOUTH 
AFRICA
Cerebrospinal fluid (CSF) for meningitis testing
The recommended method for evaluation of meningitis will be through CSF analysis. 
For all suspected meningitis cases, a CSF sample will be sent to CLS South Africa for 
CSF polymerase chain reaction (PCR) testing for selected common aetiological 
pathogens of meningitis as listed below. An approximate volume of CSF should be 500 
µl.

CSF: PCR testing
TEST
Bacteria
Haemophilus influenzae**
Streptococcus pneumoniae**
Neisseria meningitidis**
Salmonella enterica
Mytobacterium tuberculosis
Viruses
Adenovirus*
Cytomegalovirus*
Enterovirus*
Epstein Bar virus*
Herpes simplex virus 1 & 2*
HHV 6 & 7*
Rabies
Mumps virus*
Parechovirus*
Parvovirus B19*
Varicella Zoster Virus*
Parasite
Plasmodium spp
*These tests are currently available as a single multiplex PCR.
**These tests are currently available as a single multiplex PCR.

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The following additional tests are available at CLS South Africa and can be requested by 
the treating clinician if required.

CSF: Other possible PCR testing 
TEST
Bacteria
Borrelia burgdorferi*
Brucella spp*
Coxiella burnetii*
Ehrlichia spp*
Leptospira spp*
Rickettsia spp*
Viruses
Chikungunya*
Crimean-Congo haemorrhagic fever virus*
Dengue virus*
Flavivirus genus*
Hepatitis A virus* 
Hepatitis B virus*
JC virus*
Measles virus*
Rift valley fever virus*
Sindbis virus*
Rubella virus*
Varicella zoster virus* 
West Nile virus*
Parasite
Toxoplasmosis
* These tests are performed in a single multiplex PCR.
Optionally, if indicated, an additional blood sample of approximately 5 ml whole blood 
may be taken by the treating clinician to aid in the diagnosis of meningitis through serum 
PCR or serum serology. The following tests will be available at CLS South Africa.

Serum: PCR
TEST
Bacteria
Rickettsia*
Viruses
Cytomegalovirus*
Enterovirus*
Haemophilus Influenza
Parvovirus
Varicella*
Parasite
Toxoplasmosis
*These tests are currently available as a single multiplex PCR.

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
Serum: Serology
TEST
Bacteria
Beta haemolytic streptococcus
Mycoplasma pneumoniae
Streptococcus pneumoniae
Viruses
CMV IgG & IgM
Epstein-Barr virus
HSV IgG
HSV IgM
Measles IgG/IgM
Mumps IgG/IgM
Rabies IgG/IgM
VZV IgG/IgM
Parasites
Cryptococcus
Analysis of potential Immune-Mediated Diseases (pIMDs)
The medical and scientific judgement of the investigator is required in deciding whether 
other disorders not mentioned in the list of pIMDs have enough evidence of an 
autoimmune origin. 
Optionally, if indicated, an additional blood sample of approximately 5 ml whole blood 
may be taken by the treating clinician to aid in the diagnosis of pIMDs. A list of potential 
serum autoimmune tests that can be performed at CLS South Africa is provided below. 

Serum: Autoimmune tests
TEST
Anti-insulin autoantibodies (IA2)*
Anti-glutamic acid decarboxylase autoantibodies (anti-GAD65)
Anti-Tyrosine phosphatase-like IA2 antibodies
Anti-islet cell antibodies
Anti-smooth muscle antibodies (ASMA) 
Anti-liver-kidney microsomal antibodies (anti-LKM)
Anti-soluble liver antigens (anti-SLA)
Anti-mitochondrial antibodies (AMA)
Anti-nuclear antibodies (ANA)
Anti-double stranded DNA (anti-dsDNA)
Rheumatoid factor (RF)
Anti-Glomerular Basement Membrane antibodies (anti-GBM)
Anti-neutrophil cytoplasmic autoantibodies (ANCAs)
Anti-streptolysin O / Anti-DNAse
Serum C3, C4 complement 
Anti-cyclic citrullinated peptide antibodies (anti-CCP)
Anti-skin basement membrane protein
IgA endomysial antibodies
Anticardiolipin (ELISA) IgM, IgG
Anti-beta 2 glycoprotein I
Anti-prothrombin
Amended 14 November 2019

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A P P E N DI X E
A M E N D M E N T S A N D A D M I NI S T R ATI V E 
C H A N G E S T O T H E P R O T O C O L
Gl a x o S mit h Kli n e Bi ol o gi c al s
Vacci ne Val ue & Healt h Scie nce ( V V H S)
Pr ot oc ol A me n d me nt 1
e Tr ac k st u d y n u m ber 
a n d A b bre vi ate d Title
2 0 4 8 8 9 ( M A L A RI A-0 9 4)
A m e n d me nt n u m ber:
A me n d me nt 1
A m e n d me nt d ate:
1 3 Se pte m ber 2 0 1 6
C o -or di n ati n g a ut h or:
Scie ntific Writer , Freela nce C o ntract or f or G S K 
Bi ol o gicals
R ati o n ale/ b ac k gr o u n d f or c h a n ges: 
T he sa m ple bl o o d v ol u me f or i m m u n o ge nicit y assess me nt has bee n i ncrease d fr o m 2 . 1 
ml t o 2. 5 ml t o e ns ure t hat a n a de q uate bl o o d v ol u me is o btai ne d f or t he a nal ysis. T he 
v ol u me of w h ole bl o o d t o be c ollecte d was i ncrease d t o ta ke i nt o acc o u nt t he dea d 
v ol u me d ue t o ali q u oti n g , a n d als o t o e na ble re peat testi n g of sa m ples i n case of i n vali d 
res ults
M ore detaile d i nstr ucti o ns ha ve bee n i ncl u de d f or e val uati o n of s us pecte d me ni n gitis 
cases a n d p I M D.
F oll o wi n g I n vesti gat or re q uest, t he e xcl usi o n criteria f or s u bjects wit h a hist or y  of 
seiz ure a n d/ or mal n utriti o n ha ve bee n re vise d t o pr o vi de clarificati o n.
Be d nets will be gi ve n t o all s u bjects scree ne d a n d n ot o nl y  t h ose e nr olle d.
A m e n de d te xt h as bee n i ncl u de d i n b ol d it alics a n d delete d te xt i n stri ket hr o u g h i n 
t he f oll o wi n g secti o ns:
P P D

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Cli ni c al St u d y Pr ot o c ol
S p o n s or:
Gl a x o S mit h Kli n e Bi ol o gi c al s
R u e d e l’I n stit ut 8 9, 1 3 3 0 Ri x e n s art,
B el gi u m
Det aile d title
P hase II b ra n d o mize d, o pe n -la bel, c o ntr olle d, m ulti -
ce nter st u d y of t he efficac y, safet y a n d 
i m m u n o ge nicity of G S K Bi ol o gicals’ ca n di date 
malaria vacci ne R T S, S/ A S 0 1 E e val uati n g sc he d ules 
wit h or wit h o ut fracti o nal d oses, earl y D ose 4 a n d 
ye arl y d oses, i n c hil dre n 5 -1 7 m o nt hs of a ge li vi n g i n 
s u b- Sa hara n Africa.
C o or di n ati n g a ut h or
,
Pr oject Ma na ger Scie nce Writi n g, Malaria Vacci nes
C o ntri b uti n g a ut h ors

, Cli nic al L a b or at ory Scie nces 
St u dy M a n a ger

 
 B usi ness a n d Decisi o n Life Scie nces,
a n d 
, T C S, Pr oject Data Ma na ger s, 
c o ntract ors f or G S K Bi ol o gicals

S p o ns or re prese ntati ve: 
 
 Cli nical Researc h & 
De vel o p me nt, R & D Ce nter Bel gi u m a n d
, Cli nic al & E pi de mi ol o gy 
Pr oject Le a d, D D W V acci nes, Bel gi u m
P P D
P P D
P P D
P P D
P P D
P P D

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SYNOPSIS
Rationale for the 
study and study 
design
Rationale for the study
Rationale for the study design
A recent controlled human malaria infection (CHMI) study 
(MALARIA-071) demonstrated superior protection against 
malaria infection associated with the use of a fractional third 
dose in a 0, 1, 7-month schedule with a vaccine efficacy against 
infection of 86.7% (95% CI: 66.8; 94.6; p<0.0001) versus 
62.5% (95% CI: 29.4; 80.1; p=0.0009) in the standard 0, 1, 2-
month schedule. The incremental efficacy of the 0, 1, 7-month 
schedule over the 0, 1, 2-month schedule was 64.4% (95% CI: -
7.9; 88.3; p=0.0741) [Data on fileRegules, 2016]. The current 
study intends to establish POC for a fractional dose schedule 
under conditions of natural exposure. The study will be 
conducted in children 5-17 months old at first vaccination 
living in areas of mid to high malaria transmission, in line with 
the age group recommended by the World Health Organization 
(WHO) [WHO, 2016]. Infants 6-12 weeks old will not be 
included in this POC study to avoid interference of co-
administration with the standard Expanded Program on 
Immunization (EPI) vaccines.
Rationale for the inclusion of a control group
It is deemed unacceptable to use a placebo control when study 
participants are exposed to unacceptable levels of risk from 
delaying administration of a safe and effective vaccine that is 
accessible through the public health system of the country in 
which the study is planned. However, the Nuffield Council on 
Bioethics guidelines state that the use of placebos may be 
acceptable if participants are not deprived of a treatment they 
would have otherwise received, but are provided at a minimum 
with the standard of care that is the best available in the 
country’s public health system. CIOMS (Council for 
International Organizations of Medical Sciences), ICH 
(International Committee on Harmonization) and UNAIDS 
(Joint United Nations Programme on HIV/AIDS) guidelines
stipulate that researchers must take steps to minimize any risks 
associated with the use of controls. The protocol should explain 
clearly the scientific justification for using a placebo-controlled 
design, and specifically address whether (1) the study question 
cannot be answered with an active-controlled study design; and 
(2) the risks of delaying an existing efficacious vaccine are 
adequately minimized or mitigated; and (3) the use of a placebo 
control is justified by the potential public health value of the 

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1 5 2
researc h; a n d ( 4) t he researc h is res p o nsi ve t o l ocal healt h 
nee ds.
I n acc or da nce wit h t hese rec o m me n dati o ns, t he use of a n o n-
malaria c o m parat or vacci ne i n t his st u d y  is dee me d acce pta ble 
as:
1.
L oc al a v ail a bilit y. 
2.
R is k miti g ati o n. S u bjects will ha ve access t o t he best 
l ocall y a vaila ble malaria pre ve nti o n a n d treat me nt o pti o ns.
All scree ne d s u bjects will be pr ovi de d wit h a n Access t o
i nsectici de-treate d be d nets (IT Ns ) will be e ns ure d, a n d
t here will be ca pacity stre n gt he ni n g f or malaria dia g n osis 
a n d treat me nt will be e ns ure d . T he i nvesti g at or will m a ke 
every eff ort t o e ns ure t h at preve ntive me as ures as 
pr ovi de d by t he g over n me nt are a d here d t o a n d u n der 
circ u mst a nces w here t his is n ot p ossi ble disc ussi o ns wit h 
t he s p o ns or nee d t o t a ke pl ace. It is a ntici pate d t hat 
s u bjects will be nefit fr o m partici pati o n i n t he st u d y i n 
ter ms of facilitate d access t o care a n d relati vely i nte nse 
healt h m o nit ori n g. Re d uce d le vels of m or bi dit y  relate d t o 
partici pati o n i n a R T S, S/ A S 0 1 E st u d y has bee n d oc u me nte d 
[ Ha mel, 2 0 1 4].

S a m pli n g sc he d ule:

Bl o o d sa m ples f or i m m u n o ge nicit y will be ta ke n i n all 
s u bjects at ti me p oi nts descri be d i n S yn o psis Ta ble 4. 
F or t he e val uati o n of a nti -C S a n d a nti -H Bs res p o nses, 
a s u bset of 5 0 s u bjects ( 2 5 s u bjects per site) i n eac h 
gr o u p (i m m u n o ge nicit y s u bset) will be teste d at 
s pecifie d ti me p oi nts. 
 

I n a d diti o n t o t he bl o o d sa m ples liste d i n S yn o psis 
Ta ble 4, a s mall a m o u nt of bl o o d (f or bl o o d s mear a n d 
filter pa per) will be ta ke n e ver y m o nt h fr o m Da y 0 
u ntil M o nt h 2 3 a n d t he n e ver y  t hree m o nt hs fr o m 
M o nt h 2 3 u ntil M o nt h 5 0 i n all s u bjects f or t he 
e val uati o n of P. f alci p ar u m i nfecti o ns.

Bl o o d sa m ples f or t he e val uati o n of bi oc he mistr y  a n d 
he mat ol o g y  para meters will be ta ke n i n a s u b-c o h ort 
c o nsisti n g of t he first 5 0 s u bjects ( 2 5 s u bjects per site) 
e nr olle d i n eac h gr o u p (react o ge nicit y  s u b-c o h ort). 
Bi o c he mistr y ( A L T, creati ni ne) a n d he mat ol o g y 
( he m o gl o bi n, W B C, platelets) para meters will be 
assesse d bef ore D ose 3, se ve n da y s p ost-D ose 3 a n d 
3 0 da y s p ost-D ose 3 (see S y n o psis Ta ble 4). 
C CI

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
Efficacy surveillance:

The research team at each study center will provide all 
screened subjects with an ensure that ITN use is 
optimized and there will be capacity strengthening 
for malaria diagnosis and treatment will be ensured.
LIST OF ABBREVIATIONS
PVRV:
Purified Vero cell rabies vaccine
1
Introduction
1.2.1. Rationale for the study design
A recent CHMI study (MALARIA-071) 6 associated with the use of a fractional third 
dose in a 0, 1, 7-month schedule with a vaccine efficacy against infection of 86.7% (95% 
CI: 66.8; 94.6; p<0.0001) versus 62.5% (95% CI: 29.4; 80.1; p=0.0009) in the standard 0, 
1, 2-month schedule. The incremental efficacy of the 0, 1, 7-month schedule over the 0, 
1, 2-month schedule was 64.4% (95% CI: -7.9; 88.3; p=0.0741) [Regules, 2016Data on 
file]. The current study intends to establish POC for a fractional dose schedule under 
conditions of natural exposure. The study will be conducted in children 5-17 months old 
at first vaccination living in areas of mid to high malaria transmission, in line with the 
age group recommended by the World Health Organization (WHO) [WHO, 2016]. 
Infants 6-12 weeks old will not be included in this POC study to avoid interference of co-
administration with the standard Expanded Program on Immunization (EPI) vaccines.
1.2.2. Rationale for the inclusion of a control group
It is deemed unacceptable to use a placebo control when study participants are exposed to 
unacceptable levels of risk from delaying administration of a safe and effective vaccine 
that is accessible through the public health system of the country in which the study is 
planned. However, the Nuffield Council on Bioethics guidelines state that the use of 
placebos may be acceptable if participants are not deprived of a treatment they would 
have otherwise received, but are provided at a minimum with the standard of care that is 
the best available in the country’s public health system. CIOMS (Council for 
International Organizations of Medical Sciences), ICH (International Committee on 
Harmonization)and UNAIDS (Joint United Nations Programme on HIV/AIDS)
guidelines stipulate that researchers must take steps to minimize any risks associated with 
the use of controls. The protocol should explain clearly the scientific justification for 
using a placebo-controlled design, and specifically address whether (1) the study question 
cannot be answered with an active-controlled study design; and (2) the risks of delaying 
an existing efficacious vaccine are adequately minimized or mitigated; and (3) the use of 
a placebo control is justified by the potential public health value of the research; and (4) 
the research is responsive to local health needs.

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In accordance with these recommendations, the use of a non-malaria comparator vaccine 
in this study is deemed acceptable as:
1.
Local availability.
2.
Risk mitigation. Subjects will have access to the best locally available malaria 
prevention and treatment options. All screened subjects will be provided with an
Access to insecticide-treated bednets (ITNs) will be ensured, and there will be 
capacity strengthening for malaria diagnosis and treatment will be ensured. The 
investigator will make every effort to ensure that preventive measures as provided 
by the government are adhered to and under circumstances where this is not 
possible discussions with the sponsor need to take place. It is anticipated that 
subjects will benefit from participation in the study in terms of facilitated access to 
care and relatively intense health monitoring. Reduced levels of morbidity related to 
participation in a RTS,S/AS01E study has been documented [Hamel, 2014].
1.2.3. Rationale for the use of a rabies vaccine as a comparator vaccine
The efficacy of cell culture-derived rabies vaccines including human diploid cells vaccine 
(HDCV), purified Vero cell rabies vaccine (PVRV), purified chick embryo cells vaccine 
(PCECV), purified chick embryo cells vaccine (PHKCV) and purified duck embryo cells 
vaccine (PDEV) has been demonstrated [WHO, 2006]. In this study, a PCECV (Rabipur) 
will be used as comparator vaccine.

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3.
STUDY DESIGN OVERVIEW
Figure 1
Study design: clinic visits

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
S a m pli n g sc he d ule:

Bl o o d sa m ples f or i m m u n o ge nicit y  will be ta ke n i n all s u bjects at ti me p oi nts 
descri be d i n Ta ble 5 . F or t he e val uati o n of a nti-C S a n d a nti -H Bs res p o nses, a 
s u bset of 5 0 s u bjects ( 2 5 s u bjects per site) in eac h gr o u p (i m m u n o ge nicit y  
s u bset, see Secti o n 5) will be teste d at s pecifie d ti me p oi nts (see Ta ble 5 a n d 
Secti o n 6. 7. 4. 1 ). 
 

I n a d diti o n t o t he bl o o d sa m ples liste d i n Ta ble 5 , a s mall a m o u nt of bl o o d (f or 
bl o o d s mear a n d filter pa per) will be ta ke n e ver y  m o nt h fr o m Da y 0 u ntil M o nt h 
2 3 a n d t he n e ver y  t hree m o nt hs fr o m M o nt h 2 3 u ntil M o nt h 5 0 i n all s u bjects f or 
t he e val uati o n of P. f alci p ar u m i nfecti o ns (see Secti o n 6. 7. 4. 2 ).

Bl o o d sa m ples f or t he e val uati o n of bi oc he mistr y  a n d he mat ol o g y para meters 
will be ta ke n i n a s u b -c o h ort c o nsis ti n g of t he first 5 0 s u bjects ( 2 5 s u bjects per 
site) e nr olle d i n eac h gr o u p (react o ge nicit y s u b -c o h ort, see Secti o n 5). 
Bi oc he mistr y  ( A L T, creati ni ne) a n d he mat ol o g y ( he m o gl o bi n, W B C, platelets) 
para meters will be assesse d bef ore D ose 3, se ve n da y s p ost-D o se 3 a n d 3 0 da ys 
p ost -D ose 3 (see Ta ble 5 a n d Secti o n 6. 7. 4. 3 ).

Effic ac y s ur veill a nce:

T he researc h tea m at eac h st u d y  ce nter will pr ovi de all scree ne d s u bjects wit h 
a n e ns ure t hat I T N use is o pti mize d , a n d t here will be c a p acity stre n gt he ni n g 
f or m al ari a di a g n osis a n d tre at me nt will be e ns ure d . 
5. 1.
N u m b er of s u bj e ct s/ c e nt er s
T a bl e 9
S u b -c o h ort
S u b -c o h ort n a m e
D e s cri pti o n
E sti m at e d n u m b er of s u bj e ct s
R e act o g e nicity *
S olicit e d l oc al a n d g e n er al A Es will b e c oll ect e d i n a 
s u b-c o h ort c o nsisti n g of t h e first 5 0 s u bj ects 
e nr oll e d i n e ac h gr o u p. H e m at ol o gy a n d 
bi oc h e mistry p ar a m et ers will b e m e as ur e d i n t h e 
s a m e s u b-c o h ort.
2 5 0 ( 5 0 s u bj ects p er gr o u p, 2 5 
s u bj e ct s p er sit e )
* S u bj ects b el o n gi n g t o t his s u b-c o h ort will h av e s p ecific st u dy pr oc e d ur es p erf or me d f or t h e ass ess m e nt of 
r e act o g e nicity, h e m at ol o gy a n d bi oc h e mistry p ar a m et ers (r ef er t o T a bl e 1 1 , T a bl e 1 2 a n d T a bl e 1 3 ).
T a bl e 1 0
S u b s et
S u b s et n a m e
D e s cri pti o n
E sti m at e d n u m b er of s u bj e ct s
I m m u n o g e nicity*
A nti -C S a n d a nti -H Bs i m m u n e r es p o ns es will b e 
t est e d i n a s u bs et c orr es p o n di n g t o t h e first 5 0 
s u bj ects e nr oll e d i n e ac h gr o u p.
2 5 0 (5 0 s u bj ects p er gr o u p , 2 5 
s u bj e ct s p er sit e )
*I n t his st u dy, all s u bj ects e nr oll e d will h av e bl o o d s a m pl es t ak e n f or ass ess m e nt of i m m u n o g e nicity. N ot all s a m pl es 
will b e us e d f or t esti n g: a nti -C S a n d a nti -H Bs i m m u n e r es p o ns es will b e t est e d i n a s u bs et (i. e. t h e i m m u n o g e nicity 
s u bs et w hic h i ncl u d es t h e s a m e s u bj ects as i n t h e r e act o g e nicity s u b -c o h ort) 
 
C CI
C CI

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5.3.
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:

History of any neurological disorders or seizures. Children with a past history of a 
neurological disorder or atypical febrile seizure (a febrile seizure is atypical if it 
meets one of the following criteria: not associated with fever; lasts > 5 minutes; 
focal (not generalized); followed by transient or persistent neurological 
abnormality; occurs in a child < 6 months of age)

Moderate or severe malnutrition at screening defined as weight for age Z-score < -2 
(by WHO growth standard) [WHO, 2006].Moderate or severe malnutrition at 
screening defined as weight for age or weight for height Z-score < -2.

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6.5.
Outline of study procedures
Table 11
List of study procedures for clinic visits
Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit
25e
Visit 
28c
Visit 
29c
Visit 
31f
Visit 
32f
Visit 
34c
Visit 
35c
Visit 
39
Timepoints
D-28 to 
D0D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Control group
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
Measure and record length and weight
●
Issue subject's identification card
O
O
Check subject's identification card
O
O
O
O
O
O
O
Randomization
●
Distribute ITN n
O
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
Treatment number allocation
O
O
O
Administer study vaccine
●
●
●
Recording of administered treatment number
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.15 ml)
●
●
●
●
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit
25e
Visit 
28c
Visit 
29c
Visit 
31f
Visit 
32f
Visit 
34c
Visit 
35c
Visit 
39
Timepoints
D-28 to 
D0D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n,o,p
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p q
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
Study Conclusion
●
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
Group R012-20
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
O
Measure and record length and weight
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit
25e
Visit 
28c
Visit 
29c
Visit 
31f
Visit 
32f
Visit 
34c
Visit 
35c
Visit 
39
Timepoints
D-28 to 
D0D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Issue subject's identification card
O
O
Check subject's identification card
O
O
O
O
O
O
O
O
Randomization
●
Distribute ITN n
O
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
●
Treatment number allocation
O
O
O
O
Administer study vaccine
●
●
●
●
Recording of administered treatment number
●
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.15 ml)
●
●
●
●
●
●
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n,o,p
●
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p q
●
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
●
Study Conclusion
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit
25e
Visit 
28c
Visit 
29c
Visit 
31f
Visit 
32f
Visit 
34c
Visit 
35c
Visit 
39
Timepoints
D-28 to 
D0D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
●j
Groups R012-14-mD and Fx012-14-mFxD
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
O
O
O
O
O
Measure and record length and weight
●
Issue subject's identification card
O
O
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
Randomization
●
Distribute ITN n
O
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
●
●
●
Treatment number allocation
O
O
O
O
O
O
Administer study vaccine
●
●
●
●
●
●
Recording of administered treatment number
●
●
●
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.15 ml)
●
●
●
●
●
●
●
●
●
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit
25e
Visit 
28c
Visit 
29c
Visit 
31f
Visit 
32f
Visit 
34c
Visit 
35c
Visit 
39
Timepoints
D-28 to 
D0D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n,o,p
●
●
●
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
●k
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p q
●
●
●
●
●
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
●
●
●
●
●
Study Conclusion
●
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
●j
●j
●j
Group Fx017-mFxD
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
O
O
O
O
Measure and record length and weight
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit
25e
Visit 
28c
Visit 
29c
Visit 
31f
Visit 
32f
Visit 
34c
Visit 
35c
Visit 
39
Timepoints
D-28 to 
D0D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Issue subject's identification card
O
O
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
Randomization
●
Distribute ITN n
O
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
●
●
Treatment number allocation
O
O
O
O
O
Administer study vaccine
●
●
●
●
●
Recording of administered treatment number
●
●
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.15 ml)
●
●
●
●
●
●
●
●
●
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n,o,p
●
●
●
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p q
●
●
●
●
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
●
●
●
●
Study Conclusion
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit
25e
Visit 
28c
Visit 
29c
Visit 
31f
Visit 
32f
Visit 
34c
Visit 
35c
Visit 
39
Timepoints
D-28 to 
D0D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
●j
●j
Note: The double-line border following Month 21 (Visit 25) indicates the first analysis which will be performed on all data collected up to Month 21 (i.e. data that are as clean as 
possible). The final analysis will be performed on data collected up to study end (Month 50).
D: Day, M: Month.
●is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
a.
Clinic visit 5 (Month 2 + 7 days) and clinic visit 6 (Month 3) are only for groups R012-20, R012-14-mD, Fx012-14-mFxD and Control. The group FX017-mFXD has a field worker 
visit at Month 3 for assessment of parasitemia.
b.
Clinic visit 10 (Month 7), clinic visit 11 (Month 7 + 7 days) and clinic visit 12 (Month 8) are only for group Fx017-mFxD. The other groups have field worker visits at Month 7 and 
Month 8 respectively for assessment of parasitemia.
c.
Clinic visit 18 (Month 14), clinic visit 19 (Month 15), clinic visit 28 (Month 26), clinic visit 29 (Month 27), clinic visit 34 (Month 38) and clinic visit 35 (Month 39) are only for groups 
R012-14-mD and Fx012-14-mFxD. The other groups have field worker visits at Month 14, Month 15, Month 26 and Month 38 respectively for assessment of parasitemia. 
d.
Clinic visit 24 (Month 20) is only for groups R012-20, Fx017-mFxD and Control. The other groups have a field worker visit at Month 20 for assessment of parasitemia.
e.
Clinic visit 25 (Month 21) is only for groups R012-20 and Fx017-mFxD. The other groups have a field worker visit at Month 21 for assessment of parasitemia.
f.
Clinic visit 31 (Month 32) and clinic visit 32 (Month 33) are only for group Fx017-mFxD. The other groups have a field worker visit at Month 32 for assessment of parasitemia.
g.
The screening laboratory results (hemoglobin) must be checked during the screening activities and before randomization.
h.
There is no specific section in the eCRF to record the contraindications, warnings and precautions. The absolute contraindications to further administration of study vaccines have 
to be recorded in the AE or SAE section of the eCRF.
i.
At screening, hemoglobin will be assessed in all subjects screened.
j.
Solicited local and general AEs will be collected in the first 50 subjects enrolled in each group (reactogenicity sub-cohort) during four days (day of vaccination and three 
subsequent days) after vaccination as indicated in the table above. On the day of vaccination the evaluation will be carried out by the study physician at the study center. On Days 
1, 2 and 3 after vaccination, trained study personnel will visit the children to record solicited AEs on diary cards.
k.
Unsolicited AEs will be collected during 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine. Unsolicited AEs will be captured through passive
surveillance at inpatient and outpatient facilities and during study visits.
l.
AEs of specific interest include all seizures occurring within 30 days post-vaccination, meningitis and pIMDs (see Section 9.1.6). pIMDs will be reported via the electronic 
Expedited Adverse Events Report. Meningitis and seizures will be reported via the electronic Expedited Adverse Events Report and in addition clinical details of each case will be 
reported in a specific eCRF screen.

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m.
If a subject is considered momentarily ineligible on the day of the screening visit (i.e. failing to meet one or more eligibility criteria) procedures for screening can be repeated one 
further time, within the time window allowed for screening (see Table 14). No more than one repeat is allowed.
n.
An ITN will be provided to each subject through the national program or where this is not available the ITN will be supplied by the investigatorsBlood for parasitemia (0.5 ml) 
includes the blood for the slide reading and for the filter paper. The parasitemia assessment by blood slide reading will include blood-stage parasites and gametocytes counts.
o.
In addition to the scheduled clinic visits, malaria cases will be captured by PCD throughout the study. All sick children presenting with fever and/or history of fever will have a blood 
sample taken for the evaluation of vaccine efficacy (for blood slide and filter paper for PCR).
p.
Case of severe malaria or cerebral malaria will be reported via the electronic Expedited Adverse Events Report (refer to Section 9.3.1) and in addition clinical details of each case 
will be reported in a specific eCRF screen.

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6.6.9. Issue subject’s identification card
At Visit 21 (Screening), take a picture of the subject and his/her parent(s)/LAR(s) to 
make an identification card with subject’s picture and number. Give this identification 
card to the subject’s parent(s)/LAR(s).
6.6.16.
Blood sampling for all subjects

Blood sampling for assessment of immunogenicity
A volume of approximately 2.5 ml of whole blood should be drawn from all 
subjects at each pre-defined timepoint. Out of this, a volume of at least 
approximately 1.11.5 ml of whole blood will provide 600 l of serum (to provide at 
least 1300 l of serum for anti-CS enzyme-linked immunosorbent assay [ELISA] + 
anti-CS avidity and at least 250 l of serum for anti-HBs) and serum from a volume 
of approximately In addition, 1.0 ml of whole blood will be stored should be drawn 
from all subjects at each pre-defined timepoint to support potential ancillary studies 
for the further characterization of the immune response and translational research for 
correlates of protection.
After centrifugation, serum samples should be kept at -20°C/ -4°F or below until 
shipment. Refer to the SPM for more details on sample storage conditions.

Blood sampling for assessment of hemoglobin at screening
A volume of approximately at least 0.5 ml of whole blood should be drawn from all 
subjects screened at Visit 1 (Screening) to measure hemoglobin concentration.

Blood sampling for assessment of parasitemia
A volume of approximately at least 0.5 ml of whole blood should be drawn from all 
subjects at each pre-defined timepoint for the assessment of P. falciparum
parasitemia (for blood slide and filter paper).
In addition to the scheduled clinic visits, malaria cases will be captured by PCD 
throughout the study. All sick children presenting with fever and/or history of fever 
will have a blood sample taken for the evaluation of vaccine efficacy (for blood slide 
and filter paper).
6.6.17.
Blood sampling for the reactogenicity sub-cohort

Blood sampling for assessment of safety
A volume of at least approximately 1.0 ml of whole blood should be drawn at each 
pre-defined timepoint for the assessment of hematology (hemoglobin, WBC, 
platelets) biochemistry (ALT, creatinine) parameters.
6.7.
Biological sample handling and analysis
6.7.2. Biological samples
Sample type to be collected in the study: whole blood.

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Table 15
Biological samples (whole blood)
Timepoint
Assessment
Total volume of blood per visit (ml)
R012-20
R012-14-mD
Fx012-14-
mFxD
Fx017-mFxD
Control
Visit 1 (Screening)
Safety 
(hemoglobin)†
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 2 (Day 0)
Immunogenicity 
2.15 ml
2.15 ml
2.15 ml
2.15 ml l
2.15 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
2.63.0 ml
2.63.0 ml
2.63.0 ml
2.63.0 ml
2.63.0 ml
Visit 3 (Month 1)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 4 (Month 2)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Immunogenicity 
2.15 ml
2.15 ml
2.15 ml
2.15 ml
2.15 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.64.0 or 
2.63.0 ml l**
3.64.0 or 
2.63.0 ml **
3.64.0 or 
2.63.0 ml **
2.63.0 ml
3.64.0 or 
2.63.0 ml **
Visit 5 (Month 2 + 7d) Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Visit 6 (Month 3)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Immunogenicity 
2.15 ml
2.15 ml
2.15 ml
-
2.15 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.64.0 or 
2.63.0 ml **
3.64.0 or 
2.63.0 ml **
3.64.0 or 
2.63.0 ml **
0.5 ml
3.64.0 or 
2.63.0 ml **
Visit 7 (Month 4)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 8 (Month 5)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 9 (Month 6)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 10 (Month 7)
Safety*
-
-
-
1.0 ml*
-
Immunogenicity 
-
-
-
2.15 ml
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
3.64.0 or 
2.63.0 ml **
0.5 ml
Visit 11 (Month 7 + 
7d)
Safety*
-
-
-
1.0 ml*
-
Visit 12 (Month 8)
Safety*
-
-
-
1.0 ml*
-
Immunogenicity 
-
-
-
2.15 ml l
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
3.64.0 or 
2.63.0 ml **
0.5 ml
Visit 13 (Month 9)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 14 (Month 10)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 15 (Month 11)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 16 (Month 12)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 17 (Month 13)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 18 (Month 14)
Immunogenicity 
-
2.15 ml
2.15 ml
-
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
2.63.0 ml
2.63.0 ml
0.5 ml
0.5 ml
Visit 19 (Month 15)
Immunogenicity 
-
2.15 ml
2.15 ml
-
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
2.63.0 ml
2.63.0 ml
0.5 ml
0.5 ml
Visit 20 (Month 16)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 21 (Month 17)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 22 (Month 18)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 23 (Month 19)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 24 (Month 20)
Immunogenicity 
2.15 ml
-
-
2.15 ml
2.15 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
2.63.0 ml
0.5 ml
0.5 ml
2.63.0 ml
2.63.0 ml

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Timepoint
Assessment
Total volume of blood per visit (ml)
R012-20
R012-14-mD
Fx012-14-
mFxD
Fx017-mFxD
Control
Visit 25 (Month 21)
Immunogenicity 
2.15 ml
-
-
2.15 ml
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
2.63.0 ml
0.5 ml
0.5 ml
2.63.0 ml
0.5 ml
Visit 26 (Month 22)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 27 (Month 23)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 28 (Month 26)
Immunogenicity 
-
2.15 ml
2.15 ml
-
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
2.63.0 ml
2.63.0 ml
0.5 ml
0.5 ml
Visit 29 (Month 27)
Immunogenicity 
-
2.15 ml
2.15 ml
-
-
Visit 30 (Month 29)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 31 (Month 32)
Immunogenicity 
-
-
-
2.15 ml
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
2.63.0 ml
0.5 ml
Visit 32 (Month 33)
Immunogenicity 
-
-
-
2.15 ml
-
Visit 33 (Month 35)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 34 (Month 38)
Immunogenicity 
-
2.15 ml
2.15 ml
-
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
2.63.0 ml
2.63.0 ml
0.5 ml
0.5 ml
Visit 35 (Month 39)
Immunogenicity 
-
2.15 ml
2.15 ml
-
-
Visit 36 (Month 41)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 37 (Month 44)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 38 (Month 47)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 39 (Month 50)
Immunogenicity
2.15 ml
2.15 ml
2.15 ml
2.15 ml
2.15 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
2.63.0 ml
2.63.0 ml
2.63.0 ml
2.63.0 ml
2.63.0 ml
† At screening, hemoglobin will be assessed in all subjects screened.
* Blood samples for hematology and biochemistry will be taken only in subjects belonging to the reactogenicity sub-
cohort.
** The total volume of blood to be taken depends if the subject belongs to the reactogenicity sub-cohort or not.
d: day
6.7.3. Laboratory assays
Table 17
Assessment of P. falciparum infection
System
Component
Method
Unit
Laboratory
Whole 
Blood*
Plasmodium falciparum
parasites**
Not applicable***
Not applicable
KEMRI/USAMRU-K, 
WRP, Malaria 
Diagnostics Center, 
Kisumu§
KEMRI/USAMRU-K, WRP: Kenya Medical Research Institute / US Army Medical Research Unit Kenya, Walter Reed 
Project.
* The incidence of P. falciparum infection assessed by PCR and parasite genotyping will be evaluated in an ancillary 
study, using samples collected as described in the present concept protocol (see Table 20).
** P. falciparum parasite count includes blood-stage parasites and gametocytes counts.
*** Method used will be blood slide microscope reading.
§ And/or other GSK designated laboratory.

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7.3.
Dosage and administration of study vaccines
7.3.1. RTS,S/AS01E
Disinfect the top of the vaccine vial (pellet) and adjuvant vial with alcohol swabs and let 
dry. Withdraw the content of the adjuvant vial in a syringe and inject the adjuvant into the 
vial of lyophilized antigen. The pellet is then dissolved by gently shaking the vial. Wait 
for one minute to ensure the complete dissolution of the vial content before withdrawing 
one full dose of RTS,S/AS01E (0.5 ml) or a fractional dose of RTS,S/AS01E (0.1 ml). For 
the full dose of RTS,S/AS01E, 0.5 ml should be administered using a fresh 25 gauge 
needle with a length of one inch (25 mm). For the fractional dose of RTS,S/AS01E, 
0.1 ml should be administered using a 1 ml syringe and fresh 25 gauge needle with a 
length of one inch (25 mm). The reconstituted vaccine should be administered by slow 
intramuscular injection into the left deltoid. The vaccine should be injected within four 
hours of reconstitution (storage at +2°C to +8°C). Refer to the SPM for full details of 
how to fill the syringe and inject the fractional dose.
9.1.
Safety definitions
9.1.6.1.
Potential immune-mediated diseases
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start. Tests for further evaluation of 
pIMDs may be conducted at Clinical Laboratory Sciences (CLS) South Africa if there 
is an indication for the test (see APPENDIX D for details of tests available at CLS 
South Africa).
9.1.6.3.
Meningitis
The recommended method for evaluation of meningitis will be through CSF analysis.
Lumbar puncture should be performed by qualified medical personnel in subjects 
when there is an indication for testing. The initial CSF testing to aid in the diagnosis of 
meningitis including, and not limited to, microscopy and gram staining, differential 
white cell and red blood cell count, CSF biochemistry, antigen/agglutination tests and 
culture, amongst others, is to be carried out by the site. For every suspected meningitis 
case, a CSF sample will be collected and from this approximately 500 µl will be sent to 
CLS South Africa for CSF polymerase chain reaction (PCR) testing for selected 
common aetiological pathogens of meningitis (see APPENDIX D for details of 
additional tests available at CLS South Africa for the evaluation of meningitis).
9.2.
Detecting and recording adverse events and serious adverse 
events
9.2.1. Time period for detecting and recording adverse events and serious 
adverse events
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 27.

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Table 27
Reporting periods for collecting safety information
Study visits
1
2
3
4
10
18
24
28
31
34
39
Event
Scr* Vac 
1
Vac 
2
Vac 
3
Vac 
4
Vac 
5
Vac 
6
Vac 
7
Vac 
8
Vac 
9
Study 
end
Study timepoint:
D -28 
to 0
-1
D0
D0 + 
3d
D0 + 
29d
M1 M1 + 
3d
M1 + 
29d
M2 M2 + 
3d
M2 + 
29d
M7 M7 + 
3d
M7 + 
29d
M14 M14 
+ 3d
M14 
+ 
29d
M20 M20 
+ 3d
M20 
+ 
29d
M26 M26 
+ 3d
M26 
+ 
29d
M32 M32 
+ 3d
M32 
+ 
29d
M38 M38 
+ 3d
M38 
+ 
29d
M50
For ALL groups
AEs/SAEs leading to 
withdrawal from 
further vaccination
SAEs related to 
study participation or 
concurrent GSK 
medication/vaccine
SAEs (All, fatal, 
related to the 
investigational 
vaccine)
AEs of specific 
interest**
Group R012-20 
Solicited local and 
general AEs***
Unsolicited AEs
Group R012-14-mD and Fx012-14-mFxD 
Solicited local and 
general AEs***

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Study visits
1
2
3
4
10
18
24
28
31
34
39
Event
Scr* Vac 
1
Vac 
2
Vac 
3
Vac 
4
Vac 
5
Vac 
6
Vac 
7
Vac 
8
Vac 
9
Study 
end
Study timepoint:
D -28 
to 0
-1
D0
D0 + 
3d
D0 + 
29d
M1 M1 + 
3d
M1 + 
29d
M2 M2 + 
3d
M2 + 
29d
M7 M7 + 
3d
M7 + 
29d
M14 M14 
+ 3d
M14 
+ 
29d
M20 M20 
+ 3d
M20 
+ 
29d
M26 M26 
+ 3d
M26 
+ 
29d
M32 M32 
+ 3d
M32 
+ 
29d
M38 M38 
+ 3d
M38 
+ 
29d
M50
Unsolicited AEs
Group Fx017-mFxD
Solicited local and 
general AEs***
Unsolicited AEs
Control group
Solicited local and 
general AEs***
Unsolicited AEs
* i.e. consent obtained.
** AEs of specific interest include seizures occurring within 30 days post-vaccination, meningitis and pIMDs.
*** Solicited local and general AEs will be collected in the first 50 subjects enrolled in each group (reactogenicity sub-cohort).
Scr: Screening; Vac: Vaccination; D: Day; M: Month; 3d: 3 days; 29d: 29 days.

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9.5.
Treatment of adverse events
Cases of suspected malaria will be tested with a rapid diagnostic test (RDT) or blood 
slide and managed on the basis of their result. These tests are separate to samples 
taken for determination of efficacy against P. falciparum infection by blood slide 
reading and filter paper for PCR (see Section 6.7.3).
14.
REFERENCES
Regules JA, Cicatelli SB, Bennett JW et al. Fractional third and fourth dose of 
RTS,S/AS01 malaria candidate vaccine: a phase 2a controlled human malaria parasite 
infection and immunogenicity study. J Infect Dis. 2016; 214:762–71.
APPENDIX B
CLINICAL LABORATORIES
Table 31
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Global Vaccine Clinical Laboratory
Services, Rixensart
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium
GSK Biologicals Global Vaccine Clinical Laboratory
Services, Rixensart
Avenue Fleming, 20 - B-1300 Wavre - Belgium
Table 32
Outsourced laboratories
Laboratory
Address
Clinical Laboratory Services, South Africa
4th Floor Spencer Lister Building
Corner of Hospital and de Korte Streets
Braamfontein
Johannesburg 2000, South Africa
CEVAC - University of Gent
De Pintelaan, 185 Gent
Belgium
Kenya Medical Research Institute / US Army Medical 
Research Unit Kenya, Walter Reed 
Project.(KEMRI/USAMRU-K, WRP), Malaria Diagnostics 
Center, Kisumu
PO Box 54, Kisumu 40100, 
Kenya
Collaborators for filter paper assessment of molecular detection and genotyping of 
Plasmodium falciparum parasites
This ancillary analysis will be carried out in partnership with the Harvard School of 
Public Health (Holyoke Center 727, 1350 Massachusetts Avenue, Cambridge, 
Massachusetts 02138, USA) and the Broad Institute (415 Main St, Cambridge, MA 
02142, USA).

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APPENDIX D
SAFETY LABORATORY TESTING: CLS South Africa
Cerebrospinal fluid (CSF) for meningitis testing
The recommended method for evaluation of meningitis will be through CSF analysis. 
For all suspected meningitis cases, a CSF sample will be sent to CLS South Africa for 
CSF polymerase chain reaction (PCR) testing for selected common aetiological 
pathogens of meningitis as listed below. An approximate volume of CSF should be 500 
µl.

CSF: PCR testing
TEST
Bacteria
Haemophilus influenzae
Streptococcus pneumoniae
Neisseria meningitidis
Salmonella enterica
Mytobacterium tuberculosis
Viruses
Adenovirus
Cytomegalovirus
Enterovirus
Epstein Bar virus
Herpes simplex virus 1 & 2
HHV 6
Rabies
Mumps virus
Parasite
Plasmodium spp
The following additional tests are available at CLS South Africa and can be requested 
by the treating clinician if required.

CSF: Other possible PCR testing 
TEST
Bacteria
Borrelia burgdorferi*
Brucella spp *
Coxiella burnetii*
Ehrlichia spp*
Leptospira spp*
Rickettsia spp *
Viruses
Chikungunya*
Crimean-Congo haemorrhagic fever virus*
Dengue virus*
Flavivirus genus*
Hepatitis A virus* 
Hepatitis B virus *
JC virus *
Measles virus *
Rift valley fever virus*
Sindbis virus*
Rubella virus*
Varicella zoster virus* 
West Nile virus*
Parasite
Toxoplasmosis
* These tests are performed in a multiplex PCR.

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Optionally, if indicated, an additional blood sample of approximately 5 ml whole blood 
may be taken by the treating clinician to aid in the diagnosis of meningitis through 
serum PCR or serum serology. The following tests will be available at CLS South 
Africa.

Serum: PCR
TEST
Viruses
Cytomegalovirus
Enterovirus
Haemophilus Influenza
Varicella
Parasite
Toxoplasmosis

Serum: Serology
TEST
Bacteria
Beta haemolytic streptococcus
Mycoplasma pneumoniae
Streptococcus pneumoniae
Viruses
CMV IgG & IgM
Epstein-Barr virus
HSV IgG
HSV IgM
Measles IgG/IgM
Mumps IgG/IgM
Rabies IgG/IgM
VZV IgG/IgM
Parasites
Cryptococcus
Analysis of potential Immune-Mediated Diseases (pIMDs)
The medical and scientific judgement of the investigator is required in deciding 
whether other disorders not mentioned in the list of pIMDs have enough evidence of an 
autoimmune origin. 
Optionally, if indicated, an additional blood sample of approximately 5 ml whole blood 
may be taken by the treating clinician to aid in the diagnosis of pIMDs. A list of 
potential serum autoimmune tests that can be performed at CLS South Africa is 
provided below.

Serum: Autoimmune tests
TEST
Anti-insulin autoantibodies (IA2)*
Anti-glutamic acid decarboxylase autoantibodies (anti-GAD65)
Anti-Tyrosine phosphatase-like IA2 antibodies
Anti-islet cell antibodies
Anti-smooth muscle antibodies (ASMA) 
Anti-liver-kidney microsomal antibodies (anti-LKM)
Anti-soluble liver antigens (anti-SLA)
Anti-mitochondrial antibodies (AMA)
Anti-nuclear antibodies (ANA)
Anti-double stranded DNA (anti-dsDNA)

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TEST
Rheumatoid factor (RF)
Anti-Glomerular Basement Membrane antibodies (anti-GBM)
Anti-neutrophil cytoplasmic autoantibodies (ANCAs)
Anti-streptolysin O / Anti-DNAse
Serum C3, C4 complement 
Anti-cyclic citrullinated peptide antibodies (anti-CCP)
Anti-skin basement membrane protein
IgA endomysial antibodies
Anticardiolipin (ELISA) IgM, IgG
Anti-beta 2 glycoprotein I
Anti-prothrombin

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
1 7 6
Gl a x o S mit h Kli n e Bi ol o gi c al s
Vacci ne Val ue & Healt h Scie nce ( V V H S)
Pr ot oc ol A me n d me nt 2
e Tr ac k st u d y n u m ber 
a n d A b bre vi ate d Title
2 0 4 8 8 9 ( M A L A RI A-0 9 4)
A m e n d me nt n u m ber:
A me n d me nt 2
A m e n d me nt d ate:
0 6 A pril 2 0 1 7
C o -or di n ati n g a ut h or:
, 
Scie ntific Writer , Freela nce C o ntract or f or G S K 
Bi ol o gicals
R ati o n ale/ b ac k gr o u n d f or c h a n ges: 
T o ali g n wit h Malaria -0 9 5, t he a ncillar y  st u d y t o Malaria-0 9 4, i n w hic h a n efficac y  
a nal ys es will be c o n d ucte d at M o nt h 3 2, a n a d diti o nal i nteri m a nalys is has bee n a d de d 
t o Malaria-0 9 4 at M o nt h 3 3, 1 m o nt h p ost fracti o nal b o oster d ose ( Gr o u p F x 0 1 7 -
m F x D). I n a d diti o n m o nt hl y  cr oss-secti o nal visits will ta ke place u p u ntil M o nt h 2 0 
i nstea d of M o nt h 2 3 a n d t hereafter e ver y 3 m o nt hs.  
At t he re q uest of t he G ha na Healt h Ser vice Et hics Re vie w C o m mittee , clarificati o n has 
bee n pr o vi de d t hat s u bjects s h o ul d c o nti n ue wit h t heir r o uti ne E PI i m m u nizati o ns as 
a p plica ble t o t heir a ge w hilst partici pati n g i n t he st u d y.
F oll o wi n g a re q uest b y  t he G ha na F D A, t he sec o n dar y o bjecti ves a n d e n d p oi nts ha ve 
bee n si m plifie d.
A m e n de d te xt h as bee n i ncl u de d i n b ol d it alics a n d delete d te xt i n stri ket hr o u g h i n 
t he f oll o wi n g secti o ns:
Cli ni c al St u d y Pr ot o c ol
S p o n s or:
Gl a x o S mit h Kli n e Bi ol o gi c al s
R u e d e l’I n stit ut 8 9, 1 3 3 0 Ri x e n s art,
B el gi u m
Pri m ar y st u d y 
v acci ne/ pr o d uct a n d 
n u m ber

Gla x o S mit h Kli ne ( G S K) Bi ol o gicals’ ca n di date 
Pl as m o di u m f alci p ar u m malaria vacci ne 
R T S, S/ A S 0 1 E ( S B 2 5 7 0 4 9).
Ot her st u d y 
v acci ne/ pr o d uct

Ra bies vacci ne ( Ra bi p ur ™)
e Tr ac k st u d y n u m ber a n d 
a b bre vi ate d title
2 0 4 8 8 9 (M A L A RI A -0 9 4 )
E u dr a C T n u m ber
2 0 1 6 -0 0 0 2 9 0 -2 0
D ate of pr ot oc ol
Fi nal Versi o n 1: 1 6 Fe br uar y  2 0 1 6
P P D

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
1 7 7
D ate of pr ot oc ol 
a me n d me nt
A me n d me nt 1 Fi nal: 1 3 Se pte m ber 2 0 1 6 
A me n d me nt 2 Fi n al: 0 6 A pril 2 0 1 7
Title
Efficac y , safet y a n d i m m u n o ge nicit y st u d y of G S K 
Bi ol o gicals’ ca n di date malaria vacci ne ( S B 2 5 7 0 4 9) 
e val uati n g sc he d ules wit h or wit h o ut fracti o nal d oses, 
earl y D ose 4 a n d ye arl y d oses, i n c hil dre n 5 -1 7 m o nt hs 
of a ge.
Det aile d title
P hase II b ra n d o mize d, o pe n -la bel, c o ntr olle d, m ulti-
ce nter st u d y of t he efficac y, safet y a n d 
i m m u n o ge nicity of G S K Bi ol o gicals’ ca n di date 
malaria vacci ne R T S, S/ A S 0 1 E e val uati n g sc he d ules 
wit h or wit h o ut fracti o nal d oses, earl y D ose 4 a n d 
ye arl y d oses, i n c hil dre n 5 -1 7 m o nt hs of a ge li vi n g i n 
s u b-Sa hara n Africa.
C o or di n ati n g a ut h or
 
Pr oject Ma na ger Scie nce Writi n g, Malaria Vacci nes
C o ntri b uti n g a ut h ors

, St u d y Data Ma na ger, T C S, 
c o ntract or f or G S K Bi ol o gicals

 St u d y Deli ver y 
Lea d s

 Vacci ne S u p pl y C o or di nat or

, Bi ostatistics

, Safety P h y sicia n

, Cli nical La b orat or y Scie nces Lea d 

, Cli nical La b orat or y Scie nces 
St u d y  Ma na ger

, Lea d Statisticia n 

, 
Cli nical Researc h a n d De vel o p me nt Lea ds 

, Se ni or Local Deli ver y  Lea d

, Gl o bal Pate nt re prese ntati ve

 
B usi ness a n d Decisi o n L ife Scie nces, a n d 
 T C S, Pr oject Data Ma na gers, 
c o ntract ors f or G S K Bi ol o gicals

, Pr oject St atistici a n 

, Cli nical Re g ulat or y 
Affairs re prese ntati ve
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
1 7 8

, Cli nical Researc h a n d 
De vel o p me nt Lea d

, St u dy Deli ver y  Ma na ger

, Cli nical 
Researc h & De vel o p me nt, R & D Ce nter Bel gi u m 
a n d 
, Cli nical & E pi de mi ol o g y  
Pr oject Lea d, D D W Vacci nes, Bel gi u m
G S K Bi ol o gic als’ Pr ot oc ol D S v 1 4. 1. 1
C o p yri g ht 2 0 1 6 7 t he Gl a x o S mit h Kli ne gr o u p of c o m p a nies. All ri g hts reser ve d. U n a ut h orize d 
c o p yi n g or use of t his i nf or m ati o n is pr o hi bite d.
S Y N O P SI S
Det aile d Title
P hase II b ra n d o mize d, o pe n -la bel, c o ntr olle d, m ulti-ce nter 
st u d y of t he efficac y, safet y a n d i m m u n o ge nicit y of G S K 
Bi ol o gicals’ ca n di date malaria vacci ne R T S, S/ A S 0 1 E
e val uati n g sc he d ules wit h or wit h o ut fracti o nal d oses, earl y 
D ose 4 a n d ye arl y d oses, i n c hil dre n 5 -1 7 m o nt hs of a ge li vi n g 
i n s u b-Sa hara n Africa.
R ati o n ale f or t he 
st u d y a n d st u d y 
desi g n
R ati o n ale f or t he use of a r a bies v acci ne as a c o m p ar at or 
v acci ne
...........
T he efficac y  of cell c ult ure-deri ve d ra bies vacci nes i ncl u di n g 
h u ma n di pl oi d cells vacci ne ( H D C V), p urifie d Ver o cells 
vacci ne ( P V R V), p urifie d c hic k e m br y o cells vacci ne 
( P C E C V), p urifie d ha mster ki d ne y cells vacci ne ( P H K C V) a n d 
p urifie d d uc k e m br y o cells vacci ne ( P D E V) has bee n 
de m o nstrate d [ W H O , 2 00 6 1 0 ]. In t his st u d y , a P C E C V 
(R a bi p ur ) will be use d as c o m parat or vacci ne.
..............
O bjecti ves
Sec o n d ar y

Effic ac y

T o assess t he i ncre me nt al v acci ne effic acy a g ai nst 
cli nic al m al ari a of a sc he d ule wit h a fr acti o n al t hir d 
d ose at M o nt h 2 vers us a sc he d ule wit h 3 f ull d oses 
( pri m ary a n d sec o n d ary c ase defi niti o ns) over 1 2 
m o nt hs p ost -D ose 3.

T o assess t he i ncre me nt al v acci ne effic acy a g ai nst 
cli nic al m alari a, over 7 a n d 1 2 m o nt hs p ost -D ose 3, 
P P D
P P D
P P D
P P D

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of a schedule with a fractional third dose at Month 7 
versus a schedule with a fractional third dose at 
Month 2.

To assess the incremental vaccine efficacy against 
clinical malaria, over 7 and 12 months post-Dose 3, 
of a schedule with a fractional third dose at Month 7 
versus a schedule with 3 full doses.

To assess the incremental vaccine efficacy against 
clinical malaria, over 12 months post-Dose 4, post-
Dose 5 and post-Dose 6 of a schedule with a 
fractional third dose at Month 2 and yearly fractional 
doses versus a schedule with full doses at Month 0, 
Month 1, Month 2 and yearly full doses.

To assess the incremental vaccine efficacy against 
clinical malaria, over 12 months post-Dose 4, of a 
schedule with a fractional third dose at Month 7 
versus a standard schedule with 4 full doses at 
0,1,2,20 months.

To assess the vaccine efficacy and impact of each 
RTS,S/AS01E schedule over the entire study period
by measuring the efficacy against clinical malaria at 
Months 14, 20, 26, 32, 38 and 50.

To assess the prevalence of P. falciparum infections 
(defined by a positive blood slide) of each 
RTS,S/AS01E schedule at cross-sectional visits 
(monthly from Month 0-20 and every three months 
thereafter till study end).

To assess the vaccine efficacy against incident 
P. falciparum infections defined by positive blood 
slide over the entire study period.

Efficacy: Incremental efficacy of a schedule with a 
fractional third dose at Month 2 over the standard 
schedule (primary and secondary case definitions)

To assess the incremental vaccine efficacy against 
clinical malaria (primary and secondary case 
definitions), over 12 months post-Dose 3, of a 
schedule with a fractional third dose at Month 2 versus 
the standard schedule.

To assess the incremental vaccine efficacy against 
incident P. falciparum infections (defined by a 
positive blood slide), over 12 months post-Dose 3, of a 

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schedule with a fractional third dose at Month 2 versus 
the standard schedule.

Efficacy: Efficacy of each RTS,S/AS01E schedule up to 
one year post-Dose 3

To assess the vaccine efficacy against clinical malaria, 
over seven months post-Dose 3, of a schedule with a 
fractional third dose at Month 2.

To assess the vaccine efficacy against incident 
P. falciparum infections (defined by a positive blood 
slide), over seven months post-Dose 3, of a schedule 
with a fractional third dose at Month 2.

To assess the vaccine efficacy against clinical malaria, 
over seven months post-Dose 3, of a schedule with a 
fractional third dose at Month 7.

To assess the vaccine efficacy against incident 
P. falciparum infections (defined by a positive blood 
slide), over seven months post-Dose 3, of a schedule 
with a fractional third dose at Month 7.

To assess the vaccine efficacy against clinical malaria, 
over seven months post-Dose 3, of the standard 0, 1, 2-
month schedule.

To assess the vaccine efficacy against incident 
P. falciparum infections (defined by a positive blood 
slide), over seven months post-Dose 3, of the standard 
0, 1, 2-month schedule.

To assess the vaccine efficacy against clinical malaria, 
over 12 months post-Dose 3, of a schedule with a 
fractional third dose at Month 2.

To assess the vaccine efficacy against incident 
P. falciparum infections (defined by a positive blood 
slide), over 12 months post-Dose 3, of a schedule with 
a fractional third dose at Month 2.

To assess the vaccine efficacy against clinical malaria, 
over 12 months post-Dose 3, of a schedule with a 
fractional third dose at Month 7. 

To assess the vaccine efficacy against incident 
P. falciparum infections (defined by a positive blood 
slide), over 12 months post-Dose 3, of a schedule with 
a fractional third dose at Month 7.

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
To assess the vaccine efficacy against clinical malaria, 
over 12 months post-Dose 3, of the standard 0, 1, 2-
month schedule.

To assess the vaccine efficacy against incident 
P. falciparum infections (defined by a positive blood 
slide), over 12 months post-Dose 3, of the standard 0, 
1, 2-month schedule.

Efficacy: Timing of the fractional third dose

To assess the incremental vaccine efficacy against 
clinical malaria, over seven months post-Dose 3, of a 
schedule with a fractional third dose at Month 7 versus 
a schedule with a fractional third dose at Month 2.

To assess the incremental vaccine efficacy against 
incident P. falciparum infections (defined by a 
positive blood slide), over seven months post-Dose 3, 
of a schedule with a fractional third dose at Month 7 
versus a schedule with a fractional third dose at
Month 2.

To assess the incremental vaccine efficacy against 
clinical malaria, over seven months post-Dose 3, of a 
schedule with a fractional third dose at Month 7 versus 
the standard schedule.

To assess the incremental vaccine efficacy against 
incident P. falciparum infections (defined by a 
positive blood slide), over seven months post-Dose 3, 
of a schedule with a fractional third dose at Month 7 
versus the standard schedule.

To assess the incremental vaccine efficacy against 
clinical malaria, over 12 months post-Dose 3, of a 
schedule with a fractional third dose at Month 7 versus 
a schedule with a fractional third dose at Month 2.

To assess the incremental vaccine efficacy against 
incident P. falciparum infections (defined by a 
positive blood slide), over 12 months post-Dose 3, of a 
schedule with a fractional third dose at Month 7 versus 
a schedule with a fractional third dose at Month 2.

To assess the incremental vaccine efficacy against 
clinical malaria, over 12 months post-Dose 3, of a 
schedule with a fractional third dose at Month 7 versus 
the standard schedule.

To assess the incremental vaccine efficacy against 
incident P. falciparum infections (defined by a 

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positive blood slide), over 12 months post-Dose 3, of a 
schedule with a fractional third dose at Month 7 versus 
the standard schedule.

Efficacy: Incremental efficacy of fractional Dose 4, 
Dose 5 and Dose 6 versus full doses

To assess the incremental vaccine efficacy against 
clinical malaria, over 12 months post-Dose 4, of a 
schedule with a fractional third dose at Month 7 versus 
the standard schedule.

To assess the incremental vaccine efficacy against 
incident P. falciparum infections (defined by a 
positive blood slide), over 12 months post-Dose 4, of a 
schedule with a fractional third dose at Month 7 versus 
the standard schedule.

To assess the incremental vaccine efficacy against 
clinical malaria, over 12 months post-Dose 4, post-
Dose 5 and post-Dose 6 of a schedule with a fractional 
third dose at Month 2 and yearly fractional doses 
versus a schedule with full doses at Month 0, Month 1, 
Month 2 and yearly full doses.

To assess the incremental vaccine efficacy against 
incident P. falciparum infections (defined by a 
positive blood slide), over 12 months post-Dose 4, 
post-Dose 5 and post-Dose 6 of a schedule with a 
fractional third dose at Month 2 and yearly fractional 
doses versus a schedule with full doses at Month 0, 
Month 1, Month 2 and yearly full doses.

Efficacy: Efficacy and impact of each RTS,S/AS01E 
schedule over the entire study period

To assess the vaccine efficacy against clinical malaria 
of each RTS,S/AS01E schedule up to Month 14.

To assess the vaccine efficacy and impact against 
clinical malaria of each RTS,S/AS01E schedule up to 
Month 20, Month 26, Month 38 and up to study end 
(Month 50).

To assess the vaccine efficacy against incident 
P. falciparum infections (defined by a positive blood 
slide) of each RTS,S/AS01E schedule up to Month 14, 
Month 20, Month 26, Month 38 and up to study end 
(Month 50).

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
Efficacy: Efficacy against prevalent P. falciparum 
infections

To assess the occurrence of prevalent P. falciparum 
infections (defined by a positive blood slide) of each 
RTS,S/AS01E schedule at Month 14, Month 20, Month 
26, Month 38 and up to study end (Month 50).
Study design

...............

Duration of the study: Approximately 50 months, with an
two interim analysis analyses and option for conditional 
continuation (see next bullet point).

Epoch 001: Starting at Visit 1 (Screening) and ending 
at Visit 17 (Month 13). Note: the data up to Visit 18 
(Month 14) pertains to Epoch 001.

Epoch 002: Starting at Visit 18 (Month 14) and ending 
at Visit 276 (Month 23). Note: the data up to Visit 287
(Month 26) pertains to Epoch 002.

Epoch 003: Starting at Visit 287 (Month 26) and 
ending at Visit 332 (Month 35). Note: the data up to 
Visit 343 (Month 38) pertains to Epoch 003.

Epoch 004: Starting at Visit 343 (Month 38) and 
ending at Visit 398 (Month 50).

Sequence of analyses and conditional continuation:

A first analysis will be performed on data collected up 
to Month 21 (Visit 25) to evaluate the primary 
objective and relevant secondary objectives.

A second analysis will be performed on data collected 
up to Month 33 (Visit 31) to evaluate relevant 
secondary objectives.

A second final analysis will be performed at study end 
(Month 50) on data collected up to Month 50. An 
integrated study report presenting all results until 
Month 50 will be produced.
After the first interim analysisanalyses, the Independent Data 
Monitoring Committee (IDMC) will have the possibility to 
recommend the suspension of further vaccinations and 
termination of specific study group(s) upon consideration of the 
study results. In the event that the IDMC recommend the 
suspension of further vaccinations, the group(s) impacted will 
be followed up for 12 months after their last study vaccination. 

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
Sampling schedule:

........

In addition to the blood samples listed in Synopsis 
Table 4, a small amount of blood (for blood smear and 
filter paper) will be taken every month from Day 0 
until Month 23 20 and then thereafter every three 
months from Month 23 until Month 50 in all subjects 
for the evaluation of P. falciparum infections.

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Synopsis Table 4
Blood sampling timepoints
Visit 
1
Visit 
2
Visit 
4
Visit 
5
Visit 
6
Visit 
10
Visit 
11
Visit 
12
Visit 
18
Visit 
19
Visit 
24
Visit 
25
Visit 
287
Visit 
298
Visit 
310
Visit 
321
Visit 
343
Visit 
354
Visit 
398
Study group
Type of blood 
sampling
Scr
D0
M2
M2 + 
7d
M3
M7
M7 + 
7d
M8
M14
M15
M20
M21
M26
M27
M32
M33
M38
M39
M50
R012-20
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
R012-14-mD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
x
Fx012-14-mFxD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
x
Fx017-mFxD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
Control
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
* At screening, hemoglobin will be assessed in all subjects screened.
** Blood samples for hematology and biochemistry will be taken in a sub-cohort consisting of the first 50 subjects enrolled in each group.
§ Blood samples for immunogenicity will be taken in all subjects enrolled.
Scr: Screening
M: Month
D: Day

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
Efficacy surveillance:

...............

Cross-sectional surveys: to evaluate the vaccine 
efficacy against incident and prevalent P. falciparum
infections, monthly cross-sectional surveys will be 
performed from Day 0 until Month 23 20 to measure 
P. falciparum parasitemia. From Month 23 Thereafter
until study end (Month 50) parasitemia will be 
measured every three months. Blood slides from cross-
sectional surveys will not be read in real time.

Safety monitoring:

...........

Where possible autopsies will be performed. Verbal 
autopsy will be performed on all cases of mortality 
occurring outside hospital if autopsies cannot be 
performed.
Synopsis Table 6
Case definition of incident P. falciparum infection*
Case definition 1
A documented P. falciparum asexual parasite density > 0 detected by blood slide reading at a 
cross-sectional survey or as captured by the secondary case definition of clinical malaria (active 
a detection of infection and passive case detection of infection).
* Note, the incidence of P. falciparum infection defined by 
positive PCR and parasite genotyping will be evaluated in the 
context of an ancillary study, using samples collected as 
described in the present protocol.
Endpoints
Primary

Efficacy: Incremental efficacy of a schedule with a 
fractional third dose at Month 2 over the standard 
schedule

The occurrence of clinical malaria meeting the primary 
case definition from Month 2.5 up to Month 14 in group 
Fx012-14-mFxD and groups R012-20 + R012-14-mD.
Secondary

Efficacy: Incremental efficacy of a schedule with a 
fractional third dose at Month 2 over the standard 
schedule (primary and secondary case definitions)

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
The occurrence of clinical malaria meeting the 
primary and secondary case definitions from Day 0 up 
to Month 50.

The occurrence of incident P. falciparum infections 
from Day 0 to Month 50.

The prevalence of P. falciparum infections defined by 
positive blood slide at each cross-sectional survey.

Efficacy: Efficacy of each RTS,S/AS01E schedule up to 
one year post-Dose 3

The occurrence of clinical malaria meeting the primary 
and secondary case definitions from Month 2.5 up to 
Month 9 in group Fx012-14-mFxD and Control group.

The occurrence of incident P. falciparum infections 
from Month 2.5 up to Month 9 in group Fx012-14-
mFxD and Control group.

The occurrence of clinical malaria meeting the primary 
and secondary case definitions from Month 7.5 up to 
Month 14 in group Fx017-mFxD and Control group.

The occurrence of incident P. falciparum infections 
from Month 7.5 up to Month 14 in group Fx017-mFxD 
and Control group.

The occurrence of clinical malaria meeting the primary 
and secondary case definitions from Month 2.5 up to 
Month 9 in groups R012-20 + R012-14-mD and Control 
group.

The occurrence of incident P. falciparum infections 
from Month 2.5 up to Month 9 in groups R012-20 + 
R012-14-mD and Control group.

The occurrence of clinical malaria meeting the primary 
and secondary case definitions from Month 2.5 up to 
Month 14 in group Fx012-14-mFxD and Control group.

The occurrence of incident P. falciparum infections 
from Month 2.5 up to Month 14 in group Fx012-14-
mFxD and Control group.

The occurrence of clinical malaria meeting the primary 
and secondary case definitions from Month 7.5 up to 
Month 19 in group Fx017-mFxD and Control group.

The occurrence of incident P. falciparum infections 
from Month 7.5 up to Month 19 in group Fx017-mFxD 
and Control group.

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
The occurrence of clinical malaria meeting the primary 
and secondary case definition from Month 2.5 up to 
Month 14 in groups R012-20 + R012-14-mD and 
Control group.

The occurrence of incident P. falciparum infections 
from Month 2.5 up to Month 14 in groups R012-20 + 
R012-14-mD and Control group.

Efficacy: Timing of the fractional third dose

The occurrence of clinical malaria meeting the primary 
and secondary case definitions, from Month 7.5 up to 
Month 14 in group Fx017-mFxD and from Month 2.5 up 
to Month 9 in group Fx012-14-mFxD.

The occurrence of incident P. falciparum infections, 
from Month 7.5 up to Month 14 in group Fx017-mFxD 
and from Month 2.5 up to Month 9 in group Fx012-14-
mFxD.

The occurrence of clinical malaria meeting the primary 
and secondary case definitions, from Month 7.5 up to 
Month 14 in group Fx017-mFxD and from Month 2.5 up 
to Month 9 in groups R012-20 + R012-14-mD.

The occurrence of incident P. falciparum infections, 
from Month 7.5 up to Month 14 in group Fx017-mFxD 
and from Month 2.5 up to Month 9 in groups R012-20 + 
R012-14-mD.

The occurrence of clinical malaria meeting the primary 
and secondary case definitions, from Month 7.5 up to 
Month 19 in group Fx017-mFxD and from Month 2.5 up 
to Month 14 in group Fx012-14-mFxD.

The occurrence of incident P. falciparum infections, 
from Month 7.5 up to Month 19 in group Fx017-mFxD 
and from Month 2.5 up to Month 14 in group Fx012-14-
mFxD.

The occurrence of clinical malaria meeting the primary 
and secondary case definitions, from Month 7.5 up to 
Month 19 in group Fx017-mFxD and from Month 2.5 up 
to Month 14 in groups R012-20 + R012-14-mD.

The occurrence of incident P. falciparum infections, 
from Month 7.5 up to Month 19 in group Fx017-mFxD 
and from Month 2.5 up to Month 14 in groups R012-20 
+ R012-14-mD.

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
Efficacy: Incremental efficacy of fractional Dose 4, Dose 
5 and Dose 6 versus full doses

The occurrence of clinical malaria meeting the primary 
and secondary case definitions, from Month 20 up to 
Month 32 in groups Fx017-mFxD and R012-20.

The occurrence of incident P. falciparum infections, 
from Month 20 up to Month 32 in groups Fx017-mFxD 
and R012-20.

The occurrence of clinical malaria meeting the primary 
and secondary case definitions, from Month 14 up to 
Month 26, from Month 26 up to Month 38 and from 
Month 38 up to Month 50 in groups Fx012-14-mFxD 
and R012-14-mD.

The occurrence of incident P. falciparum infections, 
from Month 14 up to Month 26, from Month 26 up to 
Month 38 and from Month 38 up to Month 50 in groups 
Fx012-14-mFxD and R012-14-mD.

Efficacy: Efficacy and impact of each RTS,S/AS01E
schedule over the entire study period

The occurrence of clinical malaria meeting the primary 
and secondary case definitions from Day 0 up to 
Month 14, Day 0 up to Month 20, Day 0 up to 
Month 26, Day 0 up to Month 38 and Day 0 up to 
Month 50 in each group.

The occurrence of incident P. falciparum infections 
from Day 0 up to Month 14, Day 0 up to Month 20, 
Day 0 up to Month 26, Day 0 up to Month 38 and Day 0 
up to Month 50 in each group.

Efficacy: Efficacy against prevalent P. falciparum
infections

The occurrence of prevalent P. falciparum infections at each 
cross sectional survey.

Immunogenicity: Immune response to the CS and HBs 
antigens (immunogenicity subset)

..............

Safety

The occurrence of SAEs (all, fatal and related) during 
the whole study period from Dose 1 (Day 0) up to 
Month 20 and from Day 0 up to Month 50 according to 

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the Medical Dictionary for Regulatory Activities 
(MedDRA) classification.

The occurrence of SAEs (all, fatal and related) within 30 
days (day of vaccination and 29 subsequent days) after 
each dose of study vaccine, according to the MedDRA 
classification.

The occurrence of AEs and SAEs leading to withdrawal 
from further vaccination from Dose 1 (Day 0) up to 
Month 50, according to the MedDRA classification.

The occurrence of severe malaria cases and cerebral 
malaria cases from Day 0 up to Month 20, Day 0 up to 
Month 50 and over successive years within the 
studyduring the whole study period.

The occurrence of pIMDs from Day 0 up to Month 20 
and from Day 0 up to Month 50, according to the 
MedDRA classification.

The occurrence of meningitis from Day 0 up to Month 
20 and from Day 0 up to Month 50, according to the 
MedDRA classification.

.....

Reactogenicity (reactogenicity sub-cohort)

The occurrence of solicited local and general AEs in a 
the first 50 subjects enrolled in each group 
(reactogenicity sub-cohort) within four days (day of 
vaccination and three subsequent days) after Dose 3 of 
study vaccine (all groups including controls), after Dose 
4 (groups R012-20, R012-14-mD, Fx012-14-mFxD and 
Fx017-mFxD), after Dose 5 (groups R012-14-mD, 
Fx012-14-mFxD and Fx017-mFxD) and after Dose 6 
(groups R012-14-mD and Fx012-14-mFxD).
1.2.3. Rationale for the use of a rabies vaccine as a comparator vaccine
............
The efficacy of cell culture-derived rabies vaccines including human diploid cells vaccine 
(HDCV), purified Vero cell rabies vaccine (PVRV), purified chick embryo cells vaccine 
(PCECV), purified chick embryo cells vaccine (PHKCV) and purified duck embryo cells 
vaccine (PDEV) has been demonstrated [WHO, 200610]. In this study, a PCECV 
(Rabipur) will be used as comparator vaccine.
..............

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2.2.
Secondary objectives
See synopsis for changes in secondary objectives.

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3.
STUDY DESIGN OVERVIEW
Figure 1
Study design: clinic visits

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Figure 2
Study design: visits for assessment of parasite prevalence

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
..............

Duration of the study: Approximately 50 months, with an two interim analysis
analyses and option for conditional continuation (see next bullet point).

Epoch 001: Starting at Visit 1 (Screening) and ending at Visit 17 (Month 13). 
Note: the data up to Visit 18 (Month 14) pertains to Epoch 001.

Epoch 002: Starting at Visit 18 (Month 14) and ending at Visit 276 (Month 23). 
Note: the data up to Visit 287 (Month 26) pertains to Epoch 002.

Epoch 003: Starting at Visit 287 (Month 26) and ending at Visit 332 (Month 
35). Note: the data up to Visit 343 (Month 38) pertains to Epoch 003.

Epoch 004: Starting at Visit 343 (Month 38) and ending at Visit 398 (Month 
50).

Sequence of analyses and conditional continuation:

A first analysis will be performed on data collected up to Month 21 (Visit 25) to 
evaluate the primary objective and relevant secondary objectives.

A second analysis will be performed on data collected up to Month 33 (Visit 
31) to evaluate relevant secondary objectives.

A second final analysis will be performed at study end (Month 50) on data 
collected up to Month 50. An integrated study report presenting all results until 
Month 50 will be produced.
After the interimfirst analysisanalyses, the Independent Data Monitoring Committee 
(IDMC) will have the possibility to recommend the suspension of further vaccinations 
and termination of specific study group(s) upon consideration of the study results. In the 
event that the IDMC recommend the suspension of further vaccinations, the group(s) 
impacted will be followed up for 12 months after their last study vaccination.

Sampling schedule:

...............

In addition to the blood samples listed in Table 5, a small amount of blood (for 
blood smear and filter paper) will be taken every month from Day 0 until Month 
23 20 and then thereafter every three months from Month 23 until Month 50 in 
all subjects for the evaluation of P. falciparum infections (see Section 6.7.4.2).

...........

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Table 5
Blood sampling timepoints
Visit 
1
Visit 
2
Visit 
4
Visit 
5
Visit 
6
Visit 
10
Visit 
11
Visit 
12
Visit 
18
Visit 
19
Visit 
24
Visit 
25
Visit 
287
Visit 
298
Visit 
310
Visit 
321
Visit 
343
Visit 
354
Visit 
398
Study group
Type of blood 
sampling
Scr
D0
M2
M2 + 
7d
M3
M7
M7 + 
7d
M8
M14
M15
M20
M21
M26
M27
M32
M33
M38
M39
M50
R012-20
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
R012-14-mD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
x
Fx012-14-mFxD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
x
Fx017-mFxD
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
x
x
x
x
Control
Safety
x*
x**
x**
x**
Immunogenicity§
x
x
x
x
x
* At screening, hemoglobin will be assessed in all subjects screened.
** Blood samples for hematology and biochemistry will be taken in a sub-cohort consisting of the first 50 subjects enrolled in each group.
§ Blood samples for immunogenicity will be taken in all subjects enrolled.
Scr: Screening
M: Month
D: Day

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
Efficacy surveillance:

............

Cross-sectional surveys: to evaluate the vaccine efficacy against incident and 
prevalent P. falciparum infections, monthly cross-sectional surveys will be 
performed from Day 0 until Month 23 20 to measure P. falciparum parasitemia. 
From Month 23 Thereafter until study end (Month 50) parasitemia will be 
measured every three months. Blood slides from cross-sectional surveys will not 
be read in real time.

............ 

Safety monitoring:

.............

Where possible autopsies will be performed. Verbal autopsy will be performed 
on all cases of mortality occurring outside hospital if autopsies cannot be 
performed.
4.2. Case definitions of P. falciparum infection
Table 7
Case definition of incident P. falciparum infection*
Case definition 1
A documented P. falciparum asexual parasite density > 0 detected by blood slide reading at a 
cross-sectional survey or as captured by the secondary case definition of clinical malaria (active 
detection of infection and passive case detection of infection).
*Note, the incidence of P. falciparum infection defined by positive PCR and parasite 
genotyping will be evaluated in the context of an ancillary study, using samples collected 
as described in the present protocol (see Section 6.7.4.2).
6.2.3. Allocation of subjects to assay subsets
Blood samples for immunogenicity will be taken in all subjects at timepoints described in 
Table 5. Not all samples will be used for testing:

Anti-CS and anti-HBs immune responses will be tested in a subset which 
includesing the same subjects as in the reactogenicity sub-cohortcorresponding to 
(the first 50 subjects enrolled in each group).

............
6.4.2. Standard of care provided to the subjects during the study
During the study, subjects will receive standard medical care according to national 
guidelines.
Subjects should continue with their routine EPI immunizations as applicable to their 
age whilst participating in the study. 

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Clinical malaria episodes are detected by PCD and treatment will be guided by rapid 
diagnostic test (RDT)/clinical evaluation at the discretion of the investigator. Blood 
slides will also be collected, however, these will not be read in real time but sent to a 
central laboratory (see Table 17) where all blood samples will be read according to a 
standardized method. Case definitions of clinical malaria will be based on final 
parasite density obtained from this process.
Malaria infections will be detected through active detection of infections through 
cross-sectional blood sampling. Blood slides obtained will not be read in real time and 
will follow the same process as described above. As a result, non-febrile parasite 
positive children with no symptoms will not be treated for malaria at the time of cross-
sectional visits.

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6.5.
Outline of study procedures
Table 11
List of study procedures for clinic visits
Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
287c
Visit 
298c
Visit 
310f
Visit 
321f
Visit 
343c
Visit 
354c
Visit 
398
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Control group
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
Measure and record length and weight
●
Issue subject's identification card
O
Check subject's identification card
O
O
O
O
O
O
Randomization
●
Distribute ITN
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
Treatment number allocation
O
O
O
Administer study vaccine
●
●
●
Recording of administered treatment number
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.5 ml)
●
●
●
●
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
287c
Visit 
298c
Visit 
310f
Visit 
321f
Visit 
343c
Visit 
354c
Visit 
398
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n,o
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
Study Conclusion
●
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
Group R012-20
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
O
Measure and record length and weight
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
287c
Visit 
298c
Visit 
310f
Visit 
321f
Visit 
343c
Visit 
354c
Visit 
398
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Issue subject's identification card
O
Check subject's identification card
O
O
O
O
O
O
O
Randomization
●
Distribute ITN
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
●
Treatment number allocation
O
O
O
O
Administer study vaccine
●
●
●
●
Recording of administered treatment number
●
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.5 ml)
●
●
●
●
●
●
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n, o
●
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p
●
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
●
Study Conclusion
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
287c
Visit 
298c
Visit 
310f
Visit 
321f
Visit 
343c
Visit 
354c
Visit 
398
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
●j
Groups R012-14-mD and Fx012-14-mFxD
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
O
O
O
O
O
Measure and record length and weight
●
Issue subject's identification card
O
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
Randomization
●
Distribute ITN
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
●
●
●
Treatment number allocation
O
O
O
O
O
O
Administer study vaccine
●
●
●
●
●
●
Recording of administered treatment number
●
●
●
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.5 ml)
●
●
●
●
●
●
●
●
●
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
287c
Visit 
298c
Visit 
310f
Visit 
321f
Visit 
343c
Visit 
354c
Visit 
398
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n, 0
●
●
●
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
●k
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p
●
●
●
●
●
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
●
●
●
●
●
Study Conclusion
●
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
●j
●j
●j
Group Fx017-mFxD
Informed consent
●
Check inclusion/exclusion criteria
●
O
Check the subject's vaccination card
O
Check screening lab results (hemoglobin)
●g
Collect demographic data
●
Check medical history
●
Physical examination
●
O
O
O
O
O
O
O
O
O
O
O
Measure and record length and weight
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
287c
Visit 
298c
Visit 
310f
Visit 
321f
Visit 
343c
Visit 
354c
Visit 
398
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
Issue subject's identification card
O
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
Randomization
●
Distribute ITN
O
Record if the subject belongs to the reactogenicity 
sub-cohort
●
Check contraindications and warnings and 
precautions
●h
●h
●h
●h
●h
Record pre-vaccination body temperature
●
●
●
●
●
Treatment number allocation
O
O
O
O
O
Administer study vaccine
●
●
●
●
●
Recording of administered treatment number
●
●
●
●
●
Blood sampling for assessment of immunogenicity 
for ALL subjects (2.5 ml)
●
●
●
●
●
●
●
●
●
Blood sampling for assessment of hemoglobin at 
screening (0.5 ml)
●i
Blood sampling for assessment of parasitemia for 
ALL subjects (0.5 ml) n, o
●
●
●
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
●
●
●
Record unsolicited AEs (Days 0-29)
●k
●k
●k
●k
●k
●k
●k
●k
●k
●k
Record AEs/SAEs leading to withdrawal from 
further vaccination
●
●
●
●
●
●
●
●
●
●
●
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
Record SAEs (All, fatal, related to the 
investigational vaccine) p
●
●
●
●
●
●
●
●
●
●
●
Record AEs of specific interest l
●
●
●
●
●
●
●
●
●
●
●
Study Conclusion
●

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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Type of contact: Clinic visits
Visit 1m
Screening
Visit 2 Visit 
3
Visit 
4
Visit 
5a
Visit 
6a
Visit 
10b
Visit 
11b
Visit 
12b
Visit 
18c
Visit 
19c
Visit 
24d
Visit 
25e
Visit 
287c
Visit 
298c
Visit 
310f
Visit 
321f
Visit 
343c
Visit 
354c
Visit 
398
Timepoints
D-28 to 
D-1
D0
M1
M2
M2
+ 7d
M3
M7
M7
+ 7d
M8
M14 M15 M20 M21 M26 M27 M32 M33 M38 M39 M50
Children age (Months)
5-17 
m
For the reactogenicity sub-cohort only:
Blood sampling for assessment of safety (1.0 ml)
●
●
●
Record solicited local and general AEs 
(Days 0-3)
●j
●j
●j
Note: The double-line border following Month 21 (Visit 25) and Month 33 (Visit 31) indicates the two interim first analyseis which will be performed on all data collected up to 
respectively Month 21 and up to Month 33 (i.e. data that are as clean as possible, except clinical malaria fully cleaned up to Month 14). The final analysis will be performed on 
fully cleaned data collected up to study end (Month 50).
D: Day, M: Month.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
a. Clinic visit 5 (Month 2 + 7 days) and clinic visit 6 (Month 3) are only for groups R012-20, R012-14-mD, Fx012-14-mFxD and Control. The group FX017-mFXD has a field worker 
visit at Month 3 for assessment of parasitemia.
b. Clinic visit 10 (Month 7), clinic visit 11 (Month 7 + 7 days) and clinic visit 12 (Month 8) are only for group Fx017-mFxD. The other groups have field worker visits at Month 7 and 
Month 8 respectively for assessment of parasitemia.
c. Clinic visit 18 (Month 14), clinic visit 19 (Month 15), clinic visit 287 (Month 26), clinic visit 298 (Month 27), clinic visit 343 (Month 38) and clinic visit 354 (Month 39) are only for 
groups R012-14-mD and Fx012-14-mFxD. The other groups have field worker visits at Month 14, Month 15, Month 26 and Month 38 respectively for assessment of parasitemia. 
d. Clinic visit 24 (Month 20) is only for groups R012-20, Fx017-mFxD and Control. The other groups have a field worker visit at Month 20 for assessment of parasitemia.
e. Clinic visit 25 (Month 21) is only for groups R012-20 and Fx017-mFxD. The other groups have a field worker visit at Month 21 for assessment of parasitemia.
f.
Clinic visit 310 (Month 32) and clinic visit 321 (Month 33) are only for group Fx017-mFxD. The other groups have a field worker visit at Month 32 for assessment of parasitemia.
g. The screening laboratory results (hemoglobin) must be checked during the screening activities and before randomization.
h. There is no specific section in the eCRF to record the contraindications, warnings and precautions. The absolute contraindications to further administration of study vaccines have 
to be recorded in the AE or SAE section of the eCRF.
i.
At screening, hemoglobin will be assessed in all subjects screened.
j.
Solicited local and general AEs will be collected in the first 50 subjects enrolled in each group (reactogenicity sub-cohort) during four days (day of vaccination and three subsequent 
days) after vaccination as indicated in the table above. On the day of vaccination the evaluation will be carried out by the study physician at the study center. On Days 1, 2 and 3 
after vaccination, trained study personnel will visit the children to record solicited AEs on diary cards.
k. Unsolicited AEs will be collected during 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine. Unsolicited AEs will be captured through passive 
surveillance at inpatient and outpatient facilities and during study visits.

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l.
AEs of specific interest include all seizures occurring within 30 days post-vaccination, meningitis and pIMDs (see Section 9.1.6). pIMDs will be reported via the electronic Expedited 
Adverse Events Report. Meningitis and seizures will be reported via the electronic Expedited Adverse Events Report and in addition clinical details of each case will be reported in 
a specific eCRF screen.
m. If a subject is considered momentarily ineligible on the day of the screening visit (i.e. failing to meet one or more eligibility criteria) procedures for screening can be repeated one 
further time, within the time window allowed for screening (see Table 14). No more than one repeat is allowed.
n. Blood for parasitemia (0.5 ml) includes the blood for the slide reading and for the filter paper. The parasitemia assessment by blood slide reading will include blood-stage parasites 
and gametocytes counts.
o. In addition to the scheduled clinic visits, malaria cases will be captured by PCD throughout the study. All sick children presenting with fever and/or history of fever will have a blood 
sample taken for the evaluation of vaccine efficacy (for blood slide and filter paper for PCR).
p. Case of severe malaria or cerebral malaria will be reported via the electronic Expedited Adverse Events Report (refer to Section 9.3.1) and in addition clinical details of each case 
will be reported in a specific eCRF screen.
Table 13
List of study procedures for field worker visits - Part 2 (Month 20 to Month 50)
Epochs
Epoch 002
Epoch 003
Epoch 004
Type of contact: Field worker visits
Visit 
24
Visit 
j*
Visit 
k*
Visit 
l*
Visit 
25
Visit 
26
Visit 
276
Visit 
287
Visit 
m*
Visit 
n*
Visit 
o*
Visit 
298
Visit 
3029
Visit 
310
Visit 
p*
Visit 
q*
Visit 
r*
Visit 
332
Visit 
343
Visit 
s*
Visit 
t*
Visit 
u*
Visit 
365
Visit 
376
Visit 
387
Timepoints
M20 M20 
+ 1d
M20 
+ 2d
M20 
+ 3d
M21 M22 M23 M26 M26 
+ 1d
M26 
+ 2d
M26 
+ 3d
M27 M29 M32 M32
+ 1d
M32 
+ 2d
M32 
+ 3d
M35 M38 M38 
+ 1d
M38 
+ 2d
M38 
+ 3d
M41 M44 M47
Control group
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort 
only: 
Record solicited local and general AEs 
(Days 0-3)
Group R012-20
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort 
only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●

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Epochs
Epoch 002
Epoch 003
Epoch 004
Type of contact: Field worker visits
Visit 
24
Visit 
j*
Visit 
k*
Visit 
l*
Visit 
25
Visit 
26
Visit 
276
Visit 
287
Visit 
m*
Visit 
n*
Visit 
o*
Visit 
298
Visit 
3029
Visit 
310
Visit 
p*
Visit 
q*
Visit 
r*
Visit 
332
Visit 
343
Visit 
s*
Visit 
t*
Visit 
u*
Visit 
365
Visit 
376
Visit 
387
Timepoints
M20 M20 
+ 1d
M20 
+ 2d
M20 
+ 3d
M21 M22 M23 M26 M26 
+ 1d
M26 
+ 2d
M26 
+ 3d
M27 M29 M32 M32
+ 1d
M32 
+ 2d
M32 
+ 3d
M35 M38 M38 
+ 1d
M38 
+ 2d
M38 
+ 3d
M41 M44 M47
Groups R012-14-mD and Fx012-14-
mFxD
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort 
only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●
●
●
●
Group Fx017-mFxD
Check subject's identification card
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Blood sampling for assessment of 
parasitemia for ALL subjects (0.5 ml) †, §
●
●
●
●
●
●
●
●
●
●
For the reactogenicity sub-cohort 
only: 
Record solicited local and general AEs 
(Days 0-3)
●
●
●
●
●
●
M: Month, d: day.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
*
Visits a-u are restricted to the subjects in the reactogenicity sub-cohort; these visits are for the recording of solicited local and general AEs in the three days following each 
vaccination.
†
Blood for parasitemia (0.5 ml) includes the blood for the slide reading and for the filter paper. The parasitemia assessment by blood slide reading will include blood-stage parasites 
and gametocytes counts.
§
In addition to the scheduled clinic visits, malaria cases will be captured by PCD throughout the study. All sick children presenting with fever and/or history of fever will have a blood 
sample taken for the evaluation of vaccine efficacy (for blood slide and filter paper for PCR).

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Table 14
Intervals between study visits
Interval
Optimal length of 
interval 1
Allowed interval2
Visit 1Visit 2 (Vacc)
0 to 28 days
0 - 28 days
Visit 2Visit 3 (Vacc)
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 3Visit 4 (Vacc)
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 4Visit 5
7 days
Minimum 6 days - Maximum 8 days
Visit 4Visit 6
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 6Visit 7
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 7Visit 8
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 8Visit 9
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 3Visit 10 (Vacc)
6 months
Minimum 161 days (23 weeks) - Maximum 203 days (29 weeks)
Visit 10Visit 11
7 days
Minimum 6 days - Maximum 8 days
Visit 10Visit 12
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 12Visit 13
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 13Visit 14
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 14Visit 15
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 15Visit 16
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 16Visit 17
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 4Visit 18 (Vacc)
12 months
Minimum 336 days (48 weeks) - Maximum 392 days (56 weeks)
Visit 18Visit 19
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 19Visit 20
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 20Visit 21
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 21Visit 22
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 22Visit 23
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 4Visit 24 (Vacc)*
18 months
Minimum 518 days (74 weeks) - Maximum 574 days (82 weeks)
Visit 10Visit 24 (Vacc)**
13 months
Minimum 364 days (52 weeks) - Maximum420 days (60 weeks)
Visit 24Visit 25
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 254Visit 26
13 months
Minimum 2177 days (311 weeks) - Maximum 35105 days (515
weeks)
Visit 26Visit 27
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 18Visit 287 (Vacc)
12 months
Minimum 336 days (48 weeks) - Maximum 392 days (56 weeks)
Visit 287Visit 298
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 287Visit 3029
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 24Visit 310 (Vacc)
12 months
Minimum 336 days (48 weeks) - Maximum 392 days (56 weeks)
Visit 310Visit 321
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 310Visit 332
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 287Visit 343 (Vacc)
12 months
Minimum 336 days (48 weeks) - Maximum 392 days (56 weeks)
Visit 343Visit 354
1 month
Minimum 21 days (3 weeks) - Maximum 35 days (5 weeks)
Visit 343Visit 365
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 365Visit 376
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 376Visit 387
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
Visit 387Visit 398
3 months
Minimum 77 days (11 weeks) - Maximum 105 days (15 weeks)
1. Whenever possible the investigator should arrange study visits within this interval.
2. Subjects will not be eligible for inclusion in the according-to-protocol (ATP) cohorts if they make the study visit 
outside this interval: to be included in the ATP cohort for efficacy, subjects should receive all vaccinations within the 
protocol specified intervals; to be included in the ATP cohort for immunogenicity, subjects should receive all 
vaccinations within the protocol specified intervals and perform all blood samplings for immunogenicity within the 
protocol specified intervals.
* Interval between Visit 4 and Visit 24 is for groups Control and R012-20.
** Interval between Visit 10 and Visit 24 is for group Fx017-mFxD.
Vacc: vaccination in at least one group.

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6.6.19. Recording of unsolicited AEs, SAEs and AEs of specific interest
.............
Where possible autopsies will be performed. Verbal autopsy will be performed on all 
cases of mortality occurring outside hospital if it is not possible to perform the autopsies
(Refer to Section 9.2.3.6).
6.7.2. Biological samples
Table 15
Biological samples (whole blood)
Timepoint
Assessment
Total volume of blood per visit (ml)
R012-20
R012-14-
mD
Fx012-14-
mFxD
Fx017-mFxD
Control
Visit 1 (Screening)
Safety 
(hemoglobin)†
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 2 (Day 0)
Immunogenicity 
2.5 ml
2.5 ml
2.5 ml
2.5 ml l
2.5 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0 ml
3.0 ml
3.0 ml
3.0 ml
3.0 ml
Visit 3 (Month 1)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 4 (Month 2)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Immunogenicity 
2.5 ml
2.5 ml
2.5 ml
2.5 ml
2.5 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total: 4.0 or 3.0 ml**
4.0 or 3.0 
ml**
4.0 or 3.0 ml**
3.0 ml
4.0 or 3.0 
ml**
Visit 5 (Month 2 + 7d)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Visit 6 (Month 3)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Immunogenicity 
2.5 ml
2.5 ml
2.5 ml
-
2.5 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total: 4.0 or 3.0 ml**
4.0 or 3.0 
ml**
4.0 or 3.0 ml**
0.5 ml
4.0 or 3.0 
ml**
Visit 7 (Month 4)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 8 (Month 5)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 9 (Month 6)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 10 (Month 7)
Safety*
-
-
-
1.0 ml*
-
Immunogenicity 
-
-
-
2.5 ml
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
4.0 or 3.0 ml**
0.5 ml
Visit 11 (Month 7 + 
7d)
Safety*
-
-
-
1.0 ml*
-
Visit 12 (Month 8)
Safety*
-
-
-
1.0 ml*
-
Immunogenicity 
-
-
-
2.5 ml
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
4.0 or 3.0 ml**
0.5 ml
Visit 13 (Month 9)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 14 (Month 10)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 15 (Month 11)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 16 (Month 12)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 17 (Month 13)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 18 (Month 14)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml

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Timepoint
Assessment
Total volume of blood per visit (ml)
R012-20
R012-14-
mD
Fx012-14-
mFxD
Fx017-mFxD
Control
Visit 19 (Month 15)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 20 (Month 16)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 21 (Month 17)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 22 (Month 18)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 23 (Month 19)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 24 (Month 20)
Immunogenicity 
2.5 ml
-
-
2.5 ml
2.5 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0 ml
0.5 ml
0.5 ml
3.0 ml
3.0 ml
Visit 25 (Month 21)
Immunogenicity 
2.5 ml
-
-
2.5 ml
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0  ml
0.5 ml
0.5 ml
3.0 ml
0.5 ml
Visit 26 (Month 22)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 276 (Month 23)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 287 (Month 26)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 298 (Month 27)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Visit 3029 (Month 29)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 310 (Month 32)
Immunogenicity 
-
-
-
2.5 ml
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
3.0 ml
0.5 ml
Visit 321 (Month 33)
Immunogenicity 
-
-
-
2.5 ml
-
Visit 332 (Month 35)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 343 (Month 38)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 354 (Month 39)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Visit 365 (Month 41)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 376 (Month 44)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 387 (Month 47)
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 398 (Month 50)
Immunogenicity
2.5 ml
2.5 ml
2.5 ml
2.5 ml
2.5 ml
Parasitemia
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0 ml
3.0 ml
3.0 ml
3.0 ml
3.0 ml
† At screening, hemoglobin will be assessed in all subjects screened.
* Blood samples for hematology and biochemistry will be taken only in subjects belonging to the reactogenicity sub-
cohort.
** The total volume of blood to be taken depends if the subject belongs to the reactogenicity sub-cohort or not.
d: day

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6.7.4. Biological samples evaluation
6.7.4.1.
Immunological read-outs
Table 19
Immunological read-outs
Blood sampling timepoint
Study groups
Subset name
No. 
subjects
Component
Components 
priority rank 
Type of contact 
and timepoint
Sampling 
timepoint
Visit 2 (Day 0)
Pre-Vacc
All groups
Immunogenicity
250
Anti- CS
1
All groups
Immunogenicity
250
Anti-CS avidity
2
All groups
Immunogenicity
250
Anti-HBs
3
Visit 4 (Month 2)
Post-Dose 2 
(Fx017-mFxD) 
/ Pre-Dose 3 
(other groups)
All groups
Immunogenicity
250
Anti-CS
1
All groups
Immunogenicity
250
Anti-CS avidity
2
All groups
Immunogenicity
250
Anti-HBs
3
Visit 6 (Month 3)
Post-Dose 3
R012-20
R012-14-mD
Fx012-14-mFxD
Control
Immunogenicity
200
Anti-CS
1
R012-20
R012-14-mD
Fx012-14-mFxD
Control
Immunogenicity
200
Anti-CS avidity
2
R012-20
R012-14-mD
Fx012-14-mFxD
Control
Immunogenicity
200
Anti-HBs
3
Visit 10
Pre-Dose 3
Fx017-mFxD
Immunogenicity
50
Anti-CS
1
(Month 7)
Fx017-mFxD
Immunogenicity
50
Anti-CS avidity
2
Fx017-mFxD
Immunogenicity
50
Anti-HBs
3
Visit 12
Post-Dose 3
Fx017-mFxD
Immunogenicity
50
Anti-CS
1
(Month 8)
Fx017-mFxD
Immunogenicity
50
Anti-CS avidity
2
Fx017-mFxD
Immunogenicity
50
Anti-HBs
3
Visit 18
(Month 14)
Pre-Dose 4
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS
1
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS avidity
2
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-HBs
3
Visit 19
(Month 15)
Post-Dose 4
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS
1
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-CS avidity
2
R012-14-mD
Fx012-14-mFxD
Immunogenicity
100
Anti-HBs
3
Visit 24
(Month 20)
Pre-Dose 4
R012-20
Fx017-mFxD
Control
Immunogenicity
150
Anti-CS
1
R012-20
Fx017-mFxD
Control
Immunogenicity
150
Anti-CS avidity
2
R012-20
Fx017-mFxD
Control
Immunogenicity
150
Anti-HBs
3

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
2 1 1
Bl o o d s a m pli n g ti m e p oi nt
St u d y gr o u p s
S u b s et n a m e
N o. 
s u bj e ct s
C o m p o n e nt
C o m p o n e nt s 
pri orit y r a n k 
T y p e of c o nt a ct 
a n d ti m e p oi nt
S a m pli n g 
ti m e p oi nt
Visit 2 5
( M o nt h 2 1)
P ost -D os e 4
R 0 1 2 -2 0
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S
1
R 0 1 2 -2 0
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S avi dity
2
R 0 1 2 -2 0
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -H Bs
3
Visit 2 8 7
( M o nt h 2 6)
Pr e -D os e 5
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S
1
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S avi dity
2
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -H Bs
3
Visit 2 9 8
( M o nt h 2 7)
P ost -D os e 5
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S
1
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S avi dity
2
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -H Bs
3
Visit 3 1 0
Pr e -D os e 5
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -C S
1
( M o nt h 3 2)
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -C S avi dity
2
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -H Bs
3
Visit 3 2 1
P ost -D os e 5
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -C S
1
( M o nt h 3 3)
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -C S avi dity
2
Fx 0 1 7 -m Fx D
I m m u n o g e nicity
5 0
A nti -H Bs
3
Visit 3 4 3
( M o nt h 3 8)
Pr e -D os e 6
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S
1
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S avi dity
2
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -H Bs
3
Visit 3 5 4
( M o nt h 3 9)
P ost -D os e 6
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S
1
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -C S avi dity
2
R 0 1 2 -1 4 -m D
Fx 0 1 2 -1 4 -m Fx D
I m m u n o g e nicity
1 0 0
A nti -H Bs
3
Visit 3 9 8
St u dy e n d
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -C S
1
( M o nt h 5 0)
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -C S avi dity
2
All gr o u ps
I m m u n o g e nicity
2 5 0
A nti -H Bs
3
.................
C CI

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6.7.4.2.
Parasitemia
Table 20
Parasitemia (blood smear)
Blood sampling timepoint
Study groups
No. subjects
Component
Components 
priority rank 
Visit 2 (Day 0)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 3 (Month 1)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 4 (Month 2)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 6 (Month 3)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 7 (Month 4)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 8 (Month 5)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 9 (Month 6)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 10 (Month 7)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 12 (Month 8)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 13 (Month 9)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 14 (Month 10)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 15 (Month 11)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 16 (Month 12)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 17 (Month 13)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 18 (Month 14)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 19 (Month 15)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 20 (Month 16)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 21 (Month 17)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 22 (Month 18)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 23 (Month 19)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 24 (Month 20)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 25 (Month 21)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 26 (Month 22)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 276 (Month 23)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 287 (Month 26)
All groups
1500
Blood smear 
+ blood for ancillary study*
1

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Blood sampling timepoint
Study groups
No. subjects
Component
Components 
priority rank 
Visit 3029 (Month 29)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 310 (Month 32)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 332 (Month 35)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 343 (Month 38)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 365 (Month 41)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 376 (Month 44)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 387 (Month 47)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 398 (Month 50)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
* The incidence of P. falciparum infection assessed by PCR and parasite genotyping will be evaluated in an ancillary 
study, using samples collected as described in the present protocol. The blood for the ancillary study will be collected 
on filter paper.
7.3.2. Rabies vaccine
Table 23
Dosage and administration
Type of contact 
and timepoint
Volume to be 
administered
Study group
Treatment name
Route 1
Site
Side
Visit 2 (Day 0)
0.5 ml
R012-20
R012-14-mD
Fx012-14-mFxD
Fx017-mFxD
RTS,S/AS01E (Full dose)
IM 
Deltoid
Left
1.0 ml
Control
Rabies vaccine
IM
Deltoid 
Left
Visit 3 (Month 1)
0.5 ml
R012-20
R012-14-mD
Fx012-14-mFxD
Fx017-mFxD
RTS,S/AS01E (Full dose)
IM 
Deltoid
Left
1.0 ml
Control
Rabies vaccine
IM
Deltoid 
Left
Visit 4 (Month 2)
0.5 ml
R012-20
R012-14-mD
RTS,S/AS01E (Full dose)
IM 
Deltoid
Left
0.1 ml
Fx012-14-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
1.0 ml
Control
Rabies vaccine
IM
Deltoid 
Left
Visit 10 (Month 7)
0.1 ml
Fx017-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 18 (Month 14)
0.5 ml
R012-14-mD
RTS,S/AS01E (Full dose)
IM 
Deltoid
Left
0.1 ml
Fx012-14-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 24 (Month 20)
0.5 ml
R012-20
RTS,S/AS01E (Full dose)
IM 
Deltoid
Left
0.1 ml
Fx017-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 287 (Month 26)
0.5 ml
R012-14-mD
RTS,S/AS01E (Full dose)
IM 
Deltoid
Left
0.1 ml
Fx012-14-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 310 (Month 32)
0.1 ml
Fx017-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
Visit 343 (Month 38)
0.5 ml
R012-14-mD
RTS,S/AS01E (Full dose)
IM 
Deltoid
Left
0.1 ml
Fx012-14-mFxD
RTS,S/AS01E (1/5th dose)
IM
Deltoid
Left
1 Intramuscular (IM)

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9.2.1. Time period for detecting and recording adverse events and serious 
adverse events
.................
fulfil
...............

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Table 27
Reporting periods for collecting safety information
Study visits
1
2
3
4
10
18
24
287
310
343
398
Event
Scr* Vac 
1
Vac 
2
Vac 
3
Vac 
4
Vac 
5
Vac 
6
Vac 
7
Vac 
8
Vac 
9
Study 
end
Study timepoint:
D -28 
to -1
D0
D0 + 
3d
D0 + 
29d
M1 M1 + 
3d
M1 + 
29d
M2 M2 + 
3d
M2 + 
29d
M7 M7 + 
3d
M7 + 
29d
M14 M14 
+ 3d
M14 
+ 
29d
M20 M20 
+ 3d
M20 
+ 
29d
M26 M26 
+ 3d
M26 
+ 
29d
M32 M32 
+ 3d
M32 
+ 
29d
M38 M38 
+ 3d
M38 
+ 
29d
M50
For ALL groups
AEs/SAEs leading to 
withdrawal from 
further vaccination
SAEs related to 
study participation or 
concurrent GSK 
medication/vaccine
SAEs (All, fatal, 
related to the 
investigational 
vaccine)
AEs of specific 
interest**
Group R012-20 
Solicited local and 
general AEs***
Unsolicited AEs
Group R012-14-mD and Fx012-14-mFxD 
Solicited local and 
general AEs***

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Study visits
1
2
3
4
10
18
24
287
310
343
398
Event
Scr* Vac 
1
Vac 
2
Vac 
3
Vac 
4
Vac 
5
Vac 
6
Vac 
7
Vac 
8
Vac 
9
Study 
end
Study timepoint:
D -28 
to -1
D0
D0 + 
3d
D0 + 
29d
M1 M1 + 
3d
M1 + 
29d
M2 M2 + 
3d
M2 + 
29d
M7 M7 + 
3d
M7 + 
29d
M14 M14 
+ 3d
M14 
+ 
29d
M20 M20 
+ 3d
M20 
+ 
29d
M26 M26 
+ 3d
M26 
+ 
29d
M32 M32 
+ 3d
M32 
+ 
29d
M38 M38 
+ 3d
M38 
+ 
29d
M50
Unsolicited AEs
Group Fx017-mFxD
Solicited local and 
general AEs***
Unsolicited AEs
Control group
Solicited local and 
general AEs***
Unsolicited AEs
* i.e. consent obtained.
** AEs of specific interest include seizures occurring within 30 days post-vaccination, meningitis and pIMDs.
*** Solicited local and general AEs will be collected in the first 50 subjects enrolled in each group (reactogenicity sub-cohort).
Scr: Screening; Vac: Vaccination; D: Day; M: Month; 3d: 3 days; 29d: 29 days.

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9.2.3.6.
Verbal autopsy process
Where possible autopsies will be performed. Verbal autopsies will be carried out on all 
children who die outside a health facility to ascribe the cause of death if it is not possible 
to perform the autopsies. The questionnaire used will be based on the INDEPTH 
standard and adapted to be locally appropriate [WHO, 2007].
11.
Statistical methods
11.1. Primary endpoint
See synopsis for changes in Primary endpoint.
11.2. Secondary endpoint
See synopsis for changes in Secondary endpoints.
11.7.6.
Secondary analyses of efficacy
A) Clinical malaria:
................
Analysis performed at Month 33:

Vaccine efficacy and impact of R012-20 versus Control group over D0-M26 
(all episodes, TVC).

Vaccine efficacy and impact of R012-14-mD versus Control group over 
D0-M26 (all episodes, TVC).

Vaccine efficacy and impact of Fx012-14-mFxD versus Control group over 
D0-M26 (all episodes, TVC).

Vaccine efficacy and impact of Fx017-mFxD versus Control group over 
D0-M26 (all episodes, TVC).

Incremental efficacy of Fx017-mFxD versus R012-20 over M20-M32 (all 
episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M14-M26 
(all episodes, ATP).
Analysis performed at Month 50:

Vaccine efficacy and impact of R012-20 versus Control group over D0-M26 (all 
episodes, TVC).

Vaccine efficacy and impact of R012-20 versus Control group over D0-M38 (all 
episodes, TVC).

Vaccine efficacy and impact of R012-20 versus Control group over D0-M50 (all 
episodes, TVC).

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
Vaccine efficacy and impact of R012-14-mD versus Control group over 
D0-M26 (all episodes, TVC).

Vaccine efficacy and impact of R012-14-mD versus Control group over 
D0-M38 (all episodes, TVC).

Vaccine efficacy and impact of R012-14-mD versus Control group over 
D0-M50 (all episodes, TVC).

Vaccine efficacy and impact of Fx012-14-mFxD versus Control group over 
D0-M26 (all episodes, TVC).

Vaccine efficacy and impact of Fx012-14-mFxD versus Control group over 
D0-M38 (all episodes, TVC).

Vaccine efficacy and impact of Fx012-14-mFxD versus Control group over 
D0-M50 (all episodes, TVC).

Vaccine efficacy and impact of Fx017-mFxD versus Control group over 
D0-M26 (all episodes, TVC).

Vaccine efficacy and impact of Fx017-mFxD versus Control group over 
D0-M38 (all episodes, TVC).

Vaccine efficacy and impact of Fx017-mFxD versus Control group over 
D0-M50 (all episodes, TVC).

Incremental efficacy of Fx017-mFxD versus R012-20 over M20-M32 (all 
episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M14-M26 
(all episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M26-M38 
(all episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M38-M50 
(all episodes, ATP).
B) Incident P. falciparum infections
...............
Analysis performed at Month 33:

Vaccine efficacy of R012-20 versus Control group over D0-M26 (all episodes, 
TVC).

Vaccine efficacy of R012-14-mD versus Control group over D0-M26 (all 
episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M26 (all 
episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M26 (all 
episodes, TVC).

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
Incremental efficacy of Fx017-mFxD versus R012-20 over M20-M32 (all 
episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M14-M26 
(all episodes, ATP).
Analysis performed at Month 50:

Vaccine efficacy of R012-20 versus Control group over D0-M26 (all episodes, 
TVC).

Vaccine efficacy of R012-20 versus Control group over D0-M38 (all episodes, 
TVC).

Vaccine efficacy of R012-20 versus Control group over D0-M50 (all episodes, 
TVC).

Vaccine efficacy of R012-14-mD versus Control group over D0-M26 (all 
episodes, TVC).

Vaccine efficacy of R012-14-mD versus Control group over D0-M38 (all 
episodes, TVC).

Vaccine efficacy of R012-14-mD versus Control group over D0-M50 (all 
episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M26 (all 
episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M38 (all 
episodes, TVC).

Vaccine efficacy of Fx012-14-mFxD versus Control group over D0-M50 (all 
episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M26 (all 
episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M38 (all 
episodes, TVC).

Vaccine efficacy of Fx017-mFxD versus Control group over D0-M50 (all 
episodes, TVC).

Incremental efficacy of Fx017-mFxD versus R012-20 over M20-M32 (all 
episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M14-M26 
(all episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M26-M38 
(all episodes, ATP).

Incremental efficacy of Fx012-14-mFxD versus R012-14-mD over M38-M50 
(all episodes, ATP).

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C) Prevalent P. falciparum infections
..............
Analysis performed at Month 33:

Prevalent P. falciparum infections at each cross-sectional survey at Month 26 
(TVC).
Analysis performed at Month 50:

Prevalent P. falciparum infections at each cross sectional survey at Month 26 
(TVC).

Prevalent P. falciparum infections at each cross-sectional survey at Month 38 
(TVC).

Prevalent P. falciparum infections at each cross-sectional survey at Month 50 
(TVC).
11.12.1.
Sequence of analyses
All analyses (including interim analysisanalyses) will be conducted on data as clean as 
possible.

Sequence of analyses and conditional continuation:

A first analysis will be performed on data collected up to Month 21 (Visit 25) to 
evaluate the primary objective (cleaned data) and relevant secondary objectives.

A second analysis will be performed on data collected up to Month 33 (Visit 
31) to evaluate relevant secondary objectives.

A second final analysis will be performed at study end (Month 50) on data 
collected up to Month 50. An integrated study report presenting all results until 
Month 50 will be produced.

After the interim first analysisanalyses, the IDMC will have the possibility to 
recommend the suspension of further vaccinations and termination of specific study 
group(s) upon consideration of the study results. In the event that the IDMC 
recommend the suspension of further vaccinations, the group(s) impacted will be 
followed up for 12 months after their last study vaccination.
11.12.2.
Statistical considerations for interim analyses
The analysis of the primary endpoint will be performed on data collected up to Month 14. 
No alpha adjustment is foreseen because the primary endpoint will be analyzed at the 
time of the first interim analysis.The analysis of the primary endpoint will be performed 
after Month 21 (Visit 25) on cleaned data collected up to Month 14. No alpha 
adjustment is foreseen because final analysis of the primary endpoint will occur at the 
time of the first interim analysis after Month 21 (Visit 25) on cleaned data collected up 
to Month 14.

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14.
REFERENCES
WHO Child Growth Standards (2006): 
http://www.who.int/childgrowth/standards/cht_wfa_girls_p_0_2.pdf and 
http://www.who.int/childgrowth/standards/cht_wfa_boys_p_0_2.pdf. Accessed: 25 
January 2016.

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
2 2 2
Gl a x o S mit h Kli n e Bi ol o gi c al s
Vacci ne Val ue & Healt h Scie nce ( V V H S)
Pr ot oc ol A me n d me nt 3
e Tr ac k st u d y n u m ber 
a n d A b bre vi ate d Title
2 0 4 8 8 9 ( M A L A RI A-0 9 4)
A m e n d me nt n u m ber:
A me n d me nt 3
A m e n d me nt d ate:
1 4 N o ve m ber 2 0 1 9
C o -or di n ati n g a ut h or:
 
Scie ntific Writer , Freela nce C o ntract or f or G S K 
Bi ol o gicals
R ati o n ale/ b ac k gr o u n d f or c h a n ges: 
Case defi niti o n of se vere P. f alci p ar u m malaria: Per pr ot oc ol, i m paire d c o nsci o us ness 
was t o be e val uate d usi n g t he Glas g o w c o ma sc ore f or c hil dre n ≥ 2 y ears a n d usi n g t he 
Bla nt yre c o ma sc ore f or c hil dre n < 2 ye ars ( A p pe n di x C: Case defi niti o n of se vere P. 
f alci p ar u m malaria). H o we ver, l ocal practice is t o use t he Bla nt yr e c o ma sc ore f or 
c hil dre n. After disc ussi o n wit h t he I nde pe n de nt Data M o nit ori n g C o m mittee (I D M C),
o nl y  t he Bla ntyre c o ma sc ore is t o be use d f or assess me nt of i m paire d c o nsci o us ness i n 
all a ge gr o u ps i n t he st u d y. 
Per pr ot oc ol, filter pa per bl o o d s p ots were t o be c ollecte d f or use i n t he a ncillar y  st u d y, 
M A L A RI A -0 9 5, t o l o o k at vacci ne efficac y  a gai nst cli nical a n d asy m pt o matic malaria 
i nfecti o n usi n g ultra-se nsiti ve m olec ular a m plificati o n a n d se q uenci n g met h o d ol o g y . 
H o we ver, t he M A L A RI A- 0 9 5 pr ot oc ol will use sa m ples o nl y u p t o M o nt h 3 2. T he 
M A L A RI A -0 9 4 pr ot oc ol has bee n a me n de d t o reflect filter pa per sa m pli n g u p u ntil t he 
M o nt h 3 2 ti me p oi nt.
I n t he assess me nt of vacci ne efficac y a gai nst all e pis o des of malaria ( Secti o n 1 1. 7. 2 ), 
a n esti mate d se ve n da ys f or dr u g cleara nce ( half-life) f oll o wi n g a n e pis o de meeti n g t he 
case defi niti o n u n der e val uati o n was t o be s u btracte d fr o m t he f oll o w-u p ti me . T his has 
bee n c ha n ge d t o 1 4 da y s t o be i n li ne wit h act ual cleara nce a n d als o t o all o w f or 
c o m paris o n wit h pre vi o us P hase III efficac y  data i n t he sa me p o p ulati o n ( M A LA RI A -
0 5 5 data).
T he a nti -C S i m m u n o ge nicit y  e n d p oi nt f or t he i m m u n o ge nicit y sec o n dar y o bjecti ve 
‘Im m u ne res p o nse t o t he C S a nti ge n’ was i na d verte ntl y o mitte d bet wee n pr ot oc ol 
a me n d me nt 1 a n d pr ot oc ol a me n d me nt 2 a n d has bee n rei nstate d.
Acc or di n g t o E U re g ulati o n, t he defi niti o n of e n d of st u d y  ( E o S) m ust be i ncl u de d i n 
t he cli nical pr ot oc ol, a n d t he st u d y re p ort s u b mitte d i n a pre defi ne d ti mefra me base d o n 
t he E o S milest o ne. Per G S K p olicies, a s u m mar y of t he st u d y res ults ha ve t o be 
p u blicl y  discl ose d, t he refere nce milest o ne f or w hic h is base d o n t he pri mar y 
c o m pleti o n date. T he defi niti o ns f or t he E o S a n d pri mar y  c o m pleti o n date ha ve bee n 
clarifie d. Details f or t he discl os ure of pr ot oc ol i nf or mati o n a n d st u d y  res ults ha ve bee n 
u p date d ( Secti o n 1 2. 5 ).
P P D

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
2 2 3
A P P E N DI X D Safet y La b orat or y  Testi n g: C LS S o ut h Africa: t he n u m ber of tests t hat 
ca n be perf or me d b y p ol y merase c hai n reacti o n ( P C R) o n cere br os pi nal fl ui d ( C S F) 
a n d ser u m sa m ples has i ncrease d. T he A p pe n di x has bee n a me n de d t o s h o w t he 
brea dt h of a nal ys es a vaila ble.
A m e n de d te xt h as bee n i ncl u de d i n b ol d it alics a n d delete d te xt i n stri ket hr o u g h i n 
t he f oll o wi n g secti o ns:
Cli ni c al St u d y Pr ot o c ol
S p o n s or:
Gl a x o S mit h Kli n e Bi ol o gi c al s
R u e d e l’I n stit ut 8 9, 1 3 3 0 Ri x e n s art,
B el gi u m
Pri m ar y st u d y 
v acci ne/ pr o d uct a n d 
n u m ber

Gla x o S mit h Kli ne ( G S K) Bi ol o gicals’ ca n di date 
Pl as m o di u m f alci p ar u m malaria vacci ne 
R T S, S/ A S 0 1 E ( S B 2 5 7 0 4 9).
Ot her st u d y 
v acci ne/ pr o d uct

Ra bies vacci ne ( Ra bi p ur ™)
e Tr ac k st u d y n u m ber a n d 
a b bre vi ate d title
2 0 4 8 8 9 (M A L A RI A -0 9 4 )
E u dr a C T n u m ber
2 0 1 6 -0 0 0 2 9 0 -2 0
D ate of pr ot oc ol
Fi nal Versi o n 1 : 1 6 Fe br uar y  2 0 1 6
D ate of pr ot oc ol 
a me n d me nt
A me n d me nt 1 Fi nal: 1 3 Se pte m ber 2 0 1 6
A me n d me nt 2 Fi nal: 0 6 A pril 2 0 1 7
A me n d me nt 3 Fi n al : 1 4 N ove m ber 2 0 1 9
C o or di n ati n g a ut h or
, 
Pr oject Ma na ger Scie nce Writi n g, Malaria Vacci nes
C o ntri b uti n g a ut h ors / 
Revie wers

 T C S, a n d 
, I C O N, St u d y  Data Ma na gers, 
c o ntract ors f or G S K Bi ol o gicals

a n d
 
, St u d y Deli ver y Lea ds

, Vacci ne S u p pl y C o or di nat or

, Bi ostatistics

 
 Safet y P h ysicia ns

 Cli nical La b orat or y Scie nces Lea d

, 
Cli nical L a b orat or y Scie nces St u d y  Ma na gers
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

C O N FI D E N TI A L
2 0 4 8 8 9 ( M A L A RI A -0 9 4)
Pr ot o c ol A m e n d m e nt 3 Fi n al
1 4- N O V -2 0 1 9
2 2 4

, Lea d 
Statisticia n s

 
Cli nical Researc h a n d De vel o p me nt Lea ds 

, Se ni or 
L ocal Deli ver y  Lea ds

 Gl o bal Pate nt re prese ntati ve

 B usi ness a n d Decisi o n Life 
Scie nces, a n d 
 T C S, Pr oject Data 
Ma na gers, c o ntract ors f or G S K Bi ol o gicals

, Pr oject 
Statisticia n s

, Cli nical Re g ulat or y 
Affairs re prese ntati ve

, St u dy Deli ver y  Ma na ger

, Cli nical 
Researc h & De vel o p me nt, R & D Ce nter Bel gi u m 
a n d 
, Cli nical & E pi de mi ol o g y  
Pr oject Lea d, D D W Vacci nes, Bel gi u m
G S K Bi ol o gic als’ Pr ot oc ol D S v 1 4. 1. 1
C o p yri g ht 2 0 1 6 -2 0 1 7 2 0 1 9 t he Gl a x o S mit h Kli ne gr o u p of c o mp a nies. All ri g hts reser ve d. 
U n a ut h orize d c o p yi n g or use of t his i nf or m ati o n is pr o hi bite d.
S Y N O P SI S
R ati o n ale f or t he st u d y a n d 
st u d y desi g n
R ati o n ale f or t he use of a r a bies v acci ne as a 
c o m p ar at or v acci ne
… … … … …
T he efficac y  of cell c ult ure-deri ve d ra bies vacci nes 
i ncl u di n g h u ma n di pl oi d cells vacci ne ( H D C V), 
p urifie d Ver o cell s r a bies vacci ne ( P V R V), p urifie d 
c hic k e m br yo cells vacci ne ( P C E C V), p urifie d ha mster 
ki d ne y  cells vacci ne ( P H K C V) a n d p urifie d d uc k 
e m br yo cells vacci ne ( P D E V) has bee n de m o nstrate d 
[ W H O, 2 0 1 0]. In t his st u d y , a P C E C V ( Ra bi p ur) will 
be use d as c o m parat or vacci ne.
… … … … …..
St u d y desi g n

Pri m ary c o m pleti o n d ate: Visit 1 8 ( M o nt h 1 4 ) or 
l ast visit of E p oc h 0 01 .
Refer t o t he G L O S S A R Y O F T E R M S f or t he 
defi niti o n of pri m ary c o m pleti o n d ate.
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

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
End of Study (EoS): Last testing results released 
of samples collected at Visit 38 (Month 50).
Refer to the GLOSSARY OF TERMS for the 
definition of EoS.

Sampling schedule:

…….

In addition to the blood samples listed in 
Synopsis Table 4, a small amount of blood 
(for blood smear and filter paper) will be 
taken every month from Day 0 until Month 
20, and thereafter every three months until 
Month 50 for blood smear and until Month 
32 for filter paper in all subjects for the 
evaluation of P. falciparum infections.

……..

Efficacy surveillance:

….. All children with fever and/or history of 
fever will have a blood sample taken for the 
evaluation of vaccine efficacy (blood slide 
throughout the study and filter paper for 
polymerase chain reaction [PCR] up until 
month 32). All anti-malaria treatments 
administered during the study should be 
recorded in the subject’s eCRF.
Endpoints
Secondary

Immunogenicity: Immune response to the CS 
and HBs antigens (immunogenicity subset)

Anti-CS antibody concentrations and 
seropositivity measured before Dose 1, one 
month post-Dose 2 (group Fx017-mFxD 
only), before and one month post-Dose 3, 
before and one month after Dose 4, before 
and one month after each yearly dose and at 
study end (Month 50).

……
LIST OF ABBREVIATIONS
EoS:
End of study

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GLOSSARY OF TERMS
End of Study (EoS):
(Synonym of End of 
Trial)
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last Visit 
(LSLV).
For studies with collection of Human Biologicals Samples 
or imaging data, EoS is defined as the date of the last 
testing/reading released of the Human Biologicals Samples 
or imaging data, related to primary and secondary 
endpoints. EoS must be achieved no later than 8 months 
after LSLV.
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 will be written without the superscript symbol ™ or ® and in italics.
Trademark of the GlaxoSmithKline group 
of companies
Generic description
Rabipur™
Purified chick embryo cell culture rabies 
vaccine
Trademark not owned by the 
GlaxoSmithKline group of companies
Generic description
QS-21 (Quillaja saponaria Molina, fraction 
21) (Licensed by GSK from Antigenics Inc., 
a wholly owned subsidiary of Agenus Inc., a 
Delaware, USA corporation)
Triterpene glycoside immune enhancer
1.2.1 Rationale for the study design
A recent CHMI study (MALARIA-071) demonstrated superior protection against 
malaria infection6 associated with the use of a fractional third dose in a 0, 1, 7-month 
schedule with a vaccine efficacy against infection of 86.7% (95% CI: 66.8; 94.6; 
p<0.0001) versus 62.5% (95% CI: 29.4; 80.1; p=0.0009) in the standard 0, 1, 2-month 
schedule. …………

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1.2.3. Rationale for the use of a rabies vaccine as a comparator vaccine
…………
The efficacy of cell culture-derived rabies vaccines including human diploid cells vaccine 
(HDCV), purified Vero cell rabies vaccine (PVRV), purified chick embryo cells vaccine 
(PCECV), purified hamster kidneychick embryo cells vaccine (PHKCV) and purified 
duck embryo cells vaccine (PDEV) has been demonstrated [WHO, 2010]. In this study, a 
PCECV (Rabipur) will be used as comparator vaccine.
3.
STUDY DESIGN OVERVIEW

Primary completion date: Visit 18 (Month 14) or last visit of Epoch 001.
Refer to the GLOSSARY OF TERMS for the definition of primary completion 
date.

End of Study (EoS): Last testing results released of samples collected at Visit 38
(Month 50).
Refer to the GLOSSARY OF TERMS for the definition of EoS.

Sampling schedule:

……………….

In addition to the blood samples listed in Table 5, a small amount of blood (for 
blood smear and filter paper) will be taken every month from Day 0 until Month 
20, and thereafter every three months until Month 50 for blood smear and until 
Month 32 for filter paper in all subjects for the evaluation of P. falciparum
infections (see Section 6.7.4.2).

Efficacy surveillance:

…… All children with fever and/or history of fever will have a blood sample 
taken for the evaluation of vaccine efficacy (blood slide throughout the study
and filter paper for polymerase chain reaction [PCR] up until month 32). …….
6.5.
Outline of study procedures
Table 11
List of study procedures for clinic visits
Footnotes to Table 11:
n. Blood for parasitemia (0.5 ml) includes the blood for the slide reading (to Month 50) and for the filter paper (to 
Month 32). The parasitemia assessment by blood slide reading will include blood-stage parasites and gametocytes 
counts.
o. In addition to the scheduled clinic visits, malaria cases will be captured by PCD throughout the study. All sick 
children presenting with fever and/or history of fever will have a blood sample taken for the evaluation of vaccine 
efficacy (for blood slide to Month 50 and filter paper for PCR to Month 32).

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Table 13
List of study procedures for field worker visits - Part 2 (Month 20 to 
Month 50)
Footnotes to Table 13:
† Blood for parasitemia (0.5 ml) includes the blood for the slide reading (to Month 50) and for the filter paper (to Month 
32). The parasitemia assessment by blood slide reading will include blood-stage parasites and gametocytes counts.
§ In addition to the scheduled clinic visits, malaria cases will be captured by PCD throughout the study. All sick children 
presenting with fever and/or history of fever will have a blood sample taken for the evaluation of vaccine efficacy (for 
blood slide to Month 50 and filter paper for PCR to Month 32).
6.6.16.
Blood sampling for all subjects

Blood sampling for assessment of parasitemia
A volume of approximately 0.5 ml of whole blood should be drawn from all subjects
at each pre-defined timepoint for the assessment of P. falciparum parasitemia (until 
Month 50 for blood slide and until Month 32 for filter paper).
In addition to the scheduled clinic visits, malaria cases will be captured by PCD 
throughout the study. All sick children presenting with fever and/or history of fever 
will have a blood sample taken for the evaluation of vaccine efficacy (until Month 
50 for blood slide and until Month 32 for filter paper).
6.7.2.
Biological samples
Table 15
Biological samples (whole blood)
Timepoint
Assessment
Total volume of blood per visit (ml)
R012-20
R012-14-mD
Fx012-14-
mFxD
Fx017-mFxD
Control
Visit 1 (Screening)
Safety 
(hemoglobin)†
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 2 (Day 0)
Immunogenicity 
2.5 ml
2.5 ml
2.5 ml
2.5 ml l
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0 ml
3.0 ml
3.0 ml
3.0 ml
3.0 ml
Visit 3 (Month 1)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 4 (Month 2)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Immunogenicity 
2.5 ml
2.5 ml
2.5 ml
2.5 ml
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total: 4.0 or 3.0 ml** 4.0 or 3.0 ml** 4.0 or 3.0 ml**
3.0 ml
4.0 or 3.0 ml**
Visit 5 (Month 2 + 
7d)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Visit 6 (Month 3)
Safety*
1.0 ml*
1.0 ml*
1.0 ml*
-
1.0 ml*
Immunogenicity 
2.5 ml
2.5 ml
2.5 ml
-
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total: 4.0 or 3.0 ml** 4.0 or 3.0 ml** 4.0 or 3.0 ml**
0.5 ml
4.0 or 3.0 ml**
Visit 7 (Month 4)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 8 (Month 5)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 9 (Month 6)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 10 (Month 7)
Safety*
-
-
-
1.0 ml*
-
Immunogenicity 
-
-
-
2.5 ml
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
4.0 or 3.0 ml**
0.5 ml

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Timepoint
Assessment
Total volume of blood per visit (ml)
R012-20
R012-14-mD
Fx012-14-
mFxD
Fx017-mFxD
Control
Visit 11 (Month 7 + 
7d)
Safety*
-
-
-
1.0 ml*
-
Visit 12 (Month 8)
Safety*
-
-
-
1.0 ml*
-
Immunogenicity 
-
-
-
2.5 ml
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
4.0 or 3.0 ml**
0.5 ml
Visit 13 (Month 9)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 14 (Month 10)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 15 (Month 11)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 16 (Month 12)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 17 (Month 13)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 18 (Month 14)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 19 (Month 15)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 20 (Month 16)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 21 (Month 17)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 22 (Month 18)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 23 (Month 19)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 24 (Month 20)
Immunogenicity 
2.5 ml
-
-
2.5 ml
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0 ml
0.5 ml
0.5 ml
3.0 ml
3.0 ml
Visit 25 (Month 21)
Immunogenicity 
2.5 ml
-
-
2.5 ml
-
Visit 26 (Month 23)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 27 (Month 26)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 28 (Month 27)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Visit 29 (Month 29)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 30 (Month 32)
Immunogenicity 
-
-
-
2.5 ml
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
0.5 ml
0.5 ml
3.0 ml
0.5 ml
Visit 31 (Month 33)
Immunogenicity 
-
-
-
2.5 ml
-
Visit 32 (Month 35)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 33 (Month 38)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
0.5 ml
3.0 ml
3.0 ml
0.5 ml
0.5 ml
Visit 34 (Month 39)
Immunogenicity 
-
2.5 ml
2.5 ml
-
-
Visit 35 (Month 41)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 36 (Month 44)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 37 (Month 47)
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Visit 38 (Month 50)
Immunogenicity
2.5 ml
2.5 ml
2.5 ml
2.5 ml
2.5 ml
Parasitemia‡
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
Total:
3.0 ml
3.0 ml
3.0 ml
3.0 ml
3.0 ml
† At screening, hemoglobin will be assessed in all subjects screened.
* Blood samples for hematology and biochemistry will be taken only in subjects belonging to the reactogenicity sub-
cohort.
** The total volume of blood to be taken depends if the subject belongs to the reactogenicity sub-cohort or not.
d: day.
‡ Blood for parasitemia (0.5 ml) includes the blood for the slide reading (to Month 50) and for the filter paper (to 
Month 32).

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† At screening, hemoglobin will be assessed in all subjects screened.
* Blood samples for hematology and biochemistry will be taken only in subjects belonging to the reactogenicity sub-
cohort.
** The total volume of blood to be taken depends if the subject belongs to the reactogenicity sub-cohort or not.
d: day
6.7.4.2.
Parasitemia
Table 20
Parasitemia (blood smear and blood for ancillary study)
Blood sampling timepoint
Study groups
No. subjects
Component
Components 
priority rank 
Visit 2 (Day 0)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 3 (Month 1)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 4 (Month 2)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 6 (Month 3)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 7 (Month 4)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 8 (Month 5)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 9 (Month 6)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 10 (Month 7)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 12 (Month 8)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 13 (Month 9)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 14 (Month 10)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 15 (Month 11)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 16 (Month 12)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 17 (Month 13)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 18 (Month 14)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 19 (Month 15)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 20 (Month 16)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 21 (Month 17)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 22 (Month 18)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 23 (Month 19)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 24 (Month 20)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 26 (Month 23)
All groups
1500
Blood smear 
+ blood for ancillary study*
1

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Blood sampling timepoint
Study groups
No. subjects
Component
Components 
priority rank 
Visit 27 (Month 26)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 29 (Month 29)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 30 (Month 32)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 32 (Month 35)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 33 (Month 38)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 35 (Month 41)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 36 (Month 44)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 37 (Month 47)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
Visit 38 (Month 50)
All groups
1500
Blood smear 
+ blood for ancillary study*
1
* The incidence of P. falciparum infection assessed by PCR and parasite genotyping will be evaluated in an ancillary 
study, using samples collected until Month 32 as described in the present protocol. The blood for the ancillary study 
will be collected on filter paper.
11.2.
Secondary endpoints

Immunogenicity: Immune response to the CS and HBs antigens 
(immunogenicity subset)

Anti-CS antibody concentrations and seropositivity measured before Dose 1, 
one month post-Dose 2 (group Fx017-mFxD only), before and one month 
post-Dose 3, before and one month after Dose 4, before and one month after 
each yearly dose and at study end (Month 50).

…………..
11.7.2.
Measures of incidence (P. falciparum infection and clinical 
malaria)

All episodes
………….. Seven Fourteen days following an episode meeting the case definition under 
evaluation will be subtracted from the follow-up time. The distribution of the total 
number of events per subject will be tabulated by group.
12.5.
Posting of information on publicly available clinical trial 
registers and publication policy
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.

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Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within six months of the primary completion date for 
studies of authorized vaccines and 18 months for studies of non-authorized vaccines.
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit. At the time of publication, this protocol will be fully 
disclosed.GSK assures that the key design elements of this protocol will be posted on 
the GSK website and in publicly accessible database(s) such as clinicaltrials.gov, in 
compliance with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in 
compliance with the current regulations. The minimal requirement is to have primary 
endpoint summary results disclosed at latest 12 months post primary completion date 
and to have secondary endpoint disclosed at latest 12 months after the Last Subject 
Last Visit (LSLV) as described in the protocol.
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors.
APPENDIX C CASE DEFINITIONS OF SEVERE MALARIA AND 
CEREBRAL MALARIA
Table 33
Case definition of severe P. falciparum malaria
Adapted from [WHO, 2015].
P. falciparum parasitemia > 0 detected by microscopy and/or rapid diagnostic test (RDT)
AND one or more of the following, occurring in the absence of an identified alternative cause:

Impaired consciousness: a Glasgow coma score < 11 in children two years of age or older (2 years)
                                        or a Blantyre coma score < 3 in children less than two years of age (< 2 years);

……….
Table 34
Case definition of cerebral P. falciparum malaria
Adapted from [WHO, 2015].
Severe P. falciparum malaria with coma (Glasgow coma score < 11 in children two years of age or older [2 years] 
or Blantyre coma score < 3 in children less than two years of age [(< 2 years]); 
AND
If malaria with seizure: coma persisting for > 30 min after the seizure.
Other treatable causes of coma should be excluded before diagnosing cerebral malaria (e.g. hypoglycaemia, 
bacterial meningitis).

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APPENDIX D
SAFETY LABORATORY TESTING: CLS SOUTH 
AFRICA

CSF: PCR testing
TEST
Bacteria
Haemophilus influenzae**
Streptococcus pneumoniae**
Neisseria meningitidis**
Salmonella enterica
Mytobacterium tuberculosis
Viruses
Adenovirus*
Cytomegalovirus*
Enterovirus*
Epstein Bar virus*
Herpes simplex virus 1 & 2*
HHV 6 & 7*
Rabies
Mumps virus*
Parechovirus*
Parvovirus B19*
Varicella Zoster Virus*
Parasite
Plasmodium spp
*These tests are currently available as a single multiplex PCR.
**These tests are currently available as a single multiplex PCR.

CSF: Other possible PCR testing 
TEST
Bacteria
Borrelia burgdorferi*
Brucella spp*
Coxiella burnetii*
Ehrlichia spp*
Leptospira spp*
Rickettsia spp*
Viruses
Chikungunya*
Crimean-Congo haemorrhagic fever virus*
Dengue virus*
Flavivirus genus*
Hepatitis A virus* 
Hepatitis B virus*
JC virus*
Measles virus*
Rift valley fever virus*
Sindbis virus*
Rubella virus*
Varicella zoster virus* 
West Nile virus*
Parasite
Toxoplasmosis
*These tests are performed in a single multiplex PCR.

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
Serum: PCR
TEST
Bacteria
Rickettsia*
Viruses
Cytomegalovirus*
Enterovirus*
Haemophilus Influenza
Parvovirus
Varicella*
Parasite
Toxoplasmosis
*These tests are currently available as a single multiplex PCR.

Serum: Autoimmune tests
TEST
Anti-insulin autoantibodies (IA2)*
Anti-glutamic acid decarboxylase autoantibodies (anti-GAD65)
Anti-Tyrosine phosphatase-like IA2 antibodies
Anti-islet cell antibodies
Anti-smooth muscle antibodies (ASMA) 
Anti-liver-kidney microsomal antibodies (anti-LKM)
Anti-soluble liver antigens (anti-SLA)
Anti-mitochondrial antibodies (AMA)
Anti-nuclear antibodies (ANA)
Anti-double stranded DNA (anti-dsDNA)
Rheumatoid factor (RF)
Anti-Glomerular Basement Membrane antibodies (anti-GBM)
Anti-neutrophil cytoplasmic autoantibodies (ANCAs)
Anti-streptolysin O / Anti-DNAse
Serum C3, C4 complement 
Anti-cyclic citrullinated peptide antibodies (anti-CCP)
Anti-skin basement membrane protein
IgA endomysial antibodies
Anticardiolipin (ELISA) IgM, IgG
Anti-beta 2 glycoprotein I
Anti-prothrombin