Efficacy, Immunogenicity and Safety Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Various Dose Schedules in a Sporozoite Challenge Model in Healthy Malaria-naïve Adults
Phase: PHASE2
Conditions: Malaria
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart, Belgium
Primary Study vaccine

GlaxoSmithKline (GSK) Biologicals’ candidate 
Plasmodium falciparummalaria vaccine 
RTS,S/AS01E(SB257049).
Other Study vaccine

GlaxoSmithKline (GSK) Biologicals’ candidate 
Plasmodium falciparummalaria vaccine 
RTS,S/AS01B(SB257049).
eTrack study number and 
Abbreviated Title
205081(MALARIA-092)
Investigational New Drug 
(IND) number
17337
Date of protocol
Final Version 1: 09 March 2016
Date of protocol 
amendment/administrative 
change
Amendment 1 Final: 23 June2016
Administrative change1 Final: 19June2017
Title
Efficacy, immunogenicity and safety study of GSK 
Biologicals’ candidate malaria vaccine (SB257049) 
evaluating various dose schedules in a sporozoite 
challenge model in healthy malaria-naïve adults.
Detailed Title
A Phase IIa, open-label, controlled, mono-center study 
to evaluate the efficacy, immunogenicity and safety of 
GSK Biologicals’ candidate malaria vaccines 
RTS,S/AS01Eand RTS,S/AS01
Badministered as 
various dose schedules according to a 0, 1, 7-month or 
a 0, 7-month schedule in healthy malaria-naïve 
subjects aged 18-55years.
Co-ordinating author

 (Scientific Writer -Keyrus 
Biopharma contractor for GSK Biologicals)
Contributing authors

 (Clinical Research and 
Development Lead[CRDL])

, 
(Project Statisticians)

, 
(Study Delivery 
Leads)

, 
(Vaccine Supply 
Coordinator)
 
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eTrack study number and 
Abbreviated Title
205081(MALARIA-092)
Investigational New Drug 
(IND) number
17337
Detailed Title
A Phase IIa, open-label, controlled, mono-center study 
to evaluate the efficacy, immunogenicity and safety of 
GSK Biologicals’ candidate malaria vaccines 
RTS,S/AS01Eand RTS,S/AS01
Badministered as 
various dose schedules according to a 0, 1,7-month or 
a 0, 7-month schedule in healthy malaria-naïve 
subjects aged 18-55years.
Contributing authors 
(continued)

, 
(Clinical 
Laboratory Sciences Leads)

, 
(Clinical Safety 
representatives)

, 
(Study Data Managers)

 (Clinical Regulatory 
Affairs representative)

, 
(Global 
Patent Representatives)
GSK Biologicals’ Protocol DS v 14.1.1
Copyright 2016-2017the GlaxoSmithKline group of companies. All rights reserved. Unauthorized
copying or use of this information is prohibited.
(Amended 19June 2017)
 
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ProtocolAdministrative Change 1 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
205081(MALARIA-092)
Investigational New Drug 
(IND) number
17337
Date of protocol 
administrative change
Administrative change1 Final: 19June2017
Detailed Title 
A Phase IIa, open-label, controlled, mono-center 
study to evaluate the efficacy, immunogenicity and 
safety of GSK Biologicals’ candidate malaria 
vaccines RTS,S/AS01Eand RTS,S/AS01
B
administered as various dose schedules according to a 
0, 1, 7-month or a 0, 7-month schedule in healthy 
malaria-naïve subjects aged 18-55years.
Sponsorsignatory
François Roman, Clinical & Epidemiology Project 
Lead, DDW Vaccines
Signature
Date
 
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Protocol Administrative Change1 Rationale
Administrative change:
Administrative change1
Rationale/background for changes: 
The Investigational New Drug (IND) number,17337, has been added to the title page.
Q² Solutions,as a new partner,willmanage logisticalaspects of serum samples sent 
from site to GSK for testing. Theirdetails have been added to APPENDIX B
‘CLINICAL LABORATORIES’.
Minor errors and inconsistencies have been corrected and contributing authors updated.
Intensity grades for aspartate aminotransferasewere missing in Table 29 ‘Toxicity 
grading scales for blood testing’. These have been added.
 
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ProtocolAdministrative Change 1Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.
To assume responsibility for the proper conduct of the study at this site.
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccinesand 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 writteninformed 
consent of the subject and/or the subject’s legally acceptable representative. 
To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 
To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsoror the investigational vaccines, and more generally about his/her
financial ties with the sponsor. GSK Biologicals will use and disclose the 
information solely for the purpose of complying with regulatory requirements.
Hence I:
Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).
Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 
Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
205081(MALARIA-092)
Investigational New Drug 
(IND) number
17337
Date of protocol 
administrative change
Administrative change 1 Final: 19June 2017
Detailed Title
A Phase IIa, open-label, controlled, mono-center 
study to evaluate the efficacy, immunogenicity and 
safety of GSK Biologicals’ candidate malaria 
vaccines RTS,S/AS01Eand RTS,S/AS01
B
administered as various dose schedules according to a 
0, 1, 7-month or a 0, 7-month schedule in healthy 
malaria-naïve subjects aged 18-55years.
Investigator name
Signature
Date
 
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Sponsor Information
1. Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart, Belgium
2. Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3. Sponsor Study Monitor
Refer tothe local study contact information document.
4. Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer toprotocol 
Section 9.4.2.
 
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SYNOPSIS
Detailed Title
A Phase IIa, open-label, controlled, mono-center study to 
evaluate the efficacy, immunogenicity andsafety of GSK 
Biologicals’ candidate malaria vaccines RTS,S/AS01Eand 
RTS,S/AS01Badministered as various dose schedules 
according to a 0, 1, 7-month or a 0, 7-month schedule in 
healthy malaria-naïve subjects aged 18-55years.
Indication
Primary immunization against malaria diseasecaused by 
Plasmodium falciparum(P. falciparum).
Rationale for the 
study and study 
design
Rationale for the study
Results from controlled human malaria infection (CHMI) 
studies showeda simple way to improve the efficacy of the 
RTS,S/AS01 vaccine to the point where it might become 
useful either for improved malaria control in the pediatric 
population or as a tool to reduce malaria transmission. 
Combining several interventions such as vector control, 
prophylactic vaccination and mass drug administration, thus 
targeting different stages of the parasite cycle, may prove to 
offer the best control of malaria transmission.
This study aims to investigatewhether changes in dosing 
schedule are associated with increased or equivalent 
protection, and to evaluatethe immune mechanisms 
associated with vaccine efficacy under varying dosing 
schedules.
The study aims are the following:
a. Evaluation of the role of a fractional second and third 
dose.
b. Evaluation of a two-dose schedule where the second dose 
is fractional.
c. Evaluation of the use of the pediatric formulation to 
vaccinate adults, when a pediatric dose is delivered to 
adults.
d. Evaluation of the use of the pediatric formulation to 
vaccinate adults, when what has been considered so far as 
an adult dose is delivered using the pediatric formulation 
(increasing the volume of administration).
e. Evaluate the impact of varying dosing schedules on 
immune effectors and immune correlates of protection.
 
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The ability to use the pediatric formulation (RTS,S/AS01
E) 
for adults would be a very positive step when considering 
product availability and implementation feasibility of a mass 
vaccination program in the context of an elimination 
campaign, therefore study aims c) and d) are being 
investigated. The pediatric formulation of RTS,S/AS01 has 
never been used in adults, but there are indications from other 
programs that the AS01EAdjuvant System may not be 
substantially inferior to AS01
Bfor immunogenicity [EARLY-
CLINRES-002, data on file; Montoya, 2013].
Evaluation of a two-dose schedule, separated by seven
months, will contribute to explore the possibility that the close 
repetition of doses leads to some excessive priming that may 
be detrimental to the immune responses. If leading to 
sufficient protection, a two-dose strategy may be a great 
advantage when considering cost and logistics aspects in the 
contribution to malaria control and elimination efforts.
Rationale for the study design
This study is designed to evaluate efficacy, immunogenicity 
and safety of various dose schedules of GSK Biologicals
' 
candidate malaria vaccinesRTS,S/AS01B(adult formulation 
containing 50 µg RTS,S antigen and AS01
Bformulation with 
50 µg of MPL and 50 µg of QS-21 per 0.5 ml) and 
RTS,S/AS01E(pediatric formulation containing 25 µg RTS,S 
antigen and AS01
Eformulation with 25 µg of MPL and 25 µg 
of QS-21 per 0.5 ml) in healthy malaria-naïve subjects aged 
18-55years. The study proposed herein will include sixstudy 
groups. Four of these study groups will be vaccinated 
according to a 0, 1, 7-month schedule and one according to a 
0, 7-month schedule. The immunization schedule of reference 
will be the same as the one used in study MALARIA-071 
(117014), i.e. RTS,S/AS01
Bfull dose at Month 0 and Month 1 
and RTS,S/AS01
B1/5thdose at Month 7. Three months after 
the last dose of study vaccines, all subjects will undergo a 
sporozoite challenge and will be compared to an infectivity 
control group:

Group AduFxwill receive RTS,S/AS01Bfull dose at 
Month 0 and Month 1 + RTS,S/AS01Bfractional dose 
(1/5
thdose) at Month 7 (immunization schedule of 
reference).

Group 2PedFxwill receive double dose of RTS,S/AS01E
at Month 0 and Month 1 + double dose of RTS,S/AS01
E
fractional dose (1/5
thdose) at Month 7.

Group PedFxwill receive RTS,S/AS01Efull dose at 
Month 0 and Month 1 + RTS,S/AS01Efractional dose 
(1/5th dose) at Month 7.
 
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Group Adu2Fxwill receive RTS,S/AS01Bfull dose at 
Month 0 + RTS,S/AS01Bfractional dose (1/5
thdose) at 
Month 1 and Month 7.
Group Adu1Fxwill receive RTS,S/AS01Bfull dose at 
Month 0 + RTS,S/AS01Bfractional dose (1/5
thdose) at 
Month 7.

Group infectivity controlwill not receive any 
immunization but will undergo the sporozoite challenge.
The sporozoite challenge model, in the RTS,S/AS candidate 
vaccine development program, has demonstrated a high 
relevance in its ability to predict efficacy under conditions of 
natural exposure in malaria-endemic countries. The study 
design is similar to that of other past CHMI studies 
successfully conducted. To better discriminate levels of 
protection across study groups and assess durability of 
protection, CHMI will occur three months after the last 
vaccine dose rather than three weeks as in past RTS,S studies. 
About 150 healthy adults will be enrolled and followed up 
closely under controlled conditions by investigators 
experienced in P. falciparumchallenge studies. The 
proportion of immunized participants who remain free of P. 
falciparuminfection following sporozoite challenge and the 
delay in the pre-patent period leading to infection will be 
evaluated as indicators of vaccine-induced protection. 
Immunological investigations are planned with the intent to 
characterize qualitatively and quantitatively the immune 
response induced by the immunization regimen. This design 
takes into account logistical restrictions on the size of human 
challenge procedures.
Immunological assays will be selected for their ability to 
demonstrate whether the administration of a fractional vaccine 
dose can affect quantitatively or qualitatively the vaccine-
induced immune response, especially when considering the 
generation of antibodies against the circumsporozoite protein 
of P. falciparum(CS) antigen, but also the hepatitis B surface 
antigen (HBsAg) which is present in the vaccine construct. 
Qualitative aspect of the immune response will be 
characterized as much as possible (targeting different parts of 
the antigen and avidity). Samples from this study may be used 
in future assay development or testing to better understand the 
immune responses underlying vaccine induced protection, 
responses to the vaccine components and the disease under 
investigation.
 
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Objectives
Primary
Efficacy

To assess the vaccine efficacy against the occurrence of 
P. falciparumparasitemia (defined by a positive blood 
slide) for each vaccination schedule (AduFx, 2PedFx, 
PedFx, Adu2Fx, and Adu1Fx) versus the infectivity 
controls.
Secondary
Efficacy

To assess the time to onset of P. falciparumparasitemia 
(defined by a positive blood slide) for each vaccination 
schedule (AduFx, 2PedFx, PedFx, Adu2Fx, and Adu1Fx) 
versus the infectivity controls.

To assess the occurrence of P. falciparumparasitemia 
(defined by a positive blood slide) after vaccine 
administration for alternative vaccination schedules 
(2PedFx, PedFx, Adu2Fx, and Adu1Fx) versus the 
immunization schedule of reference (AduFx).

To assess the time to onset of P. falciparumparasitemia 
(defined by a positive blood slide) after vaccine 
administration for alternative vaccination schedules 
(2PedFx, PedFx, Adu2Fx, and Adu1Fx) versus the 
immunization schedule of reference (AduFx).
Immunogenicity
For each vaccination schedule:

To evaluate anti-CS repeat region antibody response at 
specified timepoints.

To evaluate anti-HBs immunoglobulin G (IgG) antibody 
response at specified timepoints.
Safety
For each vaccination schedule:

To assess the safety (unsolicited AEs/AEs of specific 
interest/serious adverse events [SAEs]) and 
reactogenicity (solicited AEs).
 
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Tertiary
Immunogenicity
For each vaccination schedule:
To evaluate anti-CS repeat region IgG avidity index at 
specified timepoints.

To evaluate anti-full length CS protein IgG 
concentrations and anti-C terminal portion of the protein 
(C-term) IgG concentrations at specified timepoints.

To evaluate anti-full length CS protein and anti-C-term 
IgG avidity at specified timepoints.
Note: other immuno-assays evaluating the immune response 
targeting the CS and HBsAgmight be performed.
Study design
Experimental design: Phase IIA, open, randomized, 
controlled, mono-centric, single-country study with five 
parallel groupsand one infectivity control group.

Duration of the study: Approximately 16months for each 
vaccinated subject and threemonths for the infectivity 
control subjects.
Epoch 001: Primary starting at Visit 1 (Screening)
(Screening for vaccinated subjects) and ending at 
Visit 10(Day 226).
Epoch 002: Challenge starting at Visit 11(Day 286) 
or Visit 1b (Screening)(Screening for infectivity 
controls), as applicable, and ending at Visit 31(Day 
376).
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 001Epoch 002
AduFx
RTS,S/AS01Bfu
l
l dose at Month 0, Month 1 + 
RTS,S/AS01B1/5
thdose at Month 7
26
18 years-55
years
X 
X
2PedFx
RTS,S/AS01Edoub
le dose at Month 0, Month 1 + 
doub
le dose RTS,S/AS01
E1/5
thdose at Month 7
26
18years-55
years
X 
X
PedFx
RTS,S/AS01Efu
l
l dose at Month 0, Month 1 + 
RTS,S/AS01E1/5
thdose at Month 7
26
18years-55
years
X 
X
Adu2Fx
RTS,S/AS01Bfu
l
l dose at Month 0 + RTS,S/AS01
B
1/5
thdose at Month 1, Month 7
26
18years-55
years
X 
X
Adu1Fx
RTS,S/AS01Bfu
l
l dose at Month 0 + RTS,S/AS01
B
1/5
thdose at Month 7
26
18years-55
years
X 
X
Infect
iv
ity 
contro
l
Sub
jects w
i
l
l not rece
ive any 
immun
izat
ion but w
i
l
l 
undergo sporozo
ite cha
l
lenge
30*
18years-55
years
X
* between 20 and 30 infect
iv
ity contro
ls 
w
i
l
l be enro
l
led.
 
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Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine/Product 
name
Injectable 
volume
Study Groups
AduFx
2PedFx PedFx Adu2Fx Adu1Fx Infectivity 
control
RTS,S/AS01B
(Fu
l
l dose)
RTS,S(50 µg)
0.5m
l
X
X
X
AS01B
X
X
X
RTS,S/AS01B
(1/5
thdose)
RTS,S(50 µg)
0.1m
l
X
X
X
AS01B
X
X
X
RTS,S/AS01E
(Fu
l
l dose)
RTS,S(25 µg)
0.5m
l
X*
X
AS01E
X*
X
RTS,S/AS01E
(1/5
thdose)
RTS,S(25 µg)
0.1m
l
X**
X
AS01E
X**
X
* In
jected vo
lume w
i
l
l be 1.0 m
l
** In
jected vo
lume w
i
l
l be 0.2 m
l
Control: active control(Group AduFx [RTS,S/AS01
Bfull 
dose at Month 0 and Month 1 + RTS,S/AS01Bfractional 
dose at Month 7] is the immunization schedule of 
reference) and infectivity controls for the challenge.
Vaccination schedule are provided in Synopsis Table 1.
Treatment allocation: randomized
Blinding:
Synopsis Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
open
Epoch 002
open
Sampling schedule:

Blood samples for assessment of anti-CS and anti-HBs 
immune response and for serum repository will be 
collected before vaccine administration (Day 0), one 
month post-Dose 2 (Day 58), six months post-Dose 2 
(Day 196), one month post-Dose 3 (Day 226), on the 
day of challenge (Day 286), 28 days post-challenge 
(Day 314), and at study end (Day 376) for subjects 
from AduFx, 2PedFx, PedFx, and Adu2Fx groups
and before vaccine administration (Day 0), before 
Dose 2 (Day 196), one month post-Dose 2 (Day 226), 
on the day of challenge (Day 286), 28 days post-
challenge (Day 314), and at study end (Day 376) for 
subjects from Adu1Fx group.
Blood samples for peripheral blood mononuclear cells 
(PBMC) and plasma repository will be collected 
before vaccine administration (Day 0), one month 
post-Dose 1 (Day 28), seven days post-Dose 2 (Day 
 
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35), one month post-Dose 2 (Day 58), six months post-
Dose 2 (Day 196), seven days post-Dose 3 (Day 203), 
one month post-Dose 3 (Day 226), on the day of 
challenge (Day 286), and at study end (Day 376) for 
subjects from AduFx, 2PedFx, PedFx, and Adu2Fx 
groupsand before vaccine administration (Day 0), one 
month post-Dose 1 (Day 28), before Dose 2 (Day 196), 
seven days post-Dose 2 (Day 203), one month post-
Dose 2 (Day 226), on the day of challenge (Day 286), 
and at study end (Day 376) for subjects from Adu1Fx 
group.
Blood samples for the evaluation of biochemistry 
(alanine aminotransferase [ALT], aspartate 
aminotransferase [AST] and creatinine) and 
hematology (hemoglobin, leukocytes [white blood 
cells; WBC] and platelets) parameters will be collected 
before vaccine administration (screening), seven days 
post-Dose 2 (Day 35), one month post-Dose 2 (Day 
58), seven days post-Dose 3 (Day 203), one month 
post-Dose 3 (Day 226), the day of first parasitemia, 
and 28 days post-challenge (Day 314) for subjects 
from AduFx, 2PedFx, PedFx, and Adu2Fx groups, 
before vaccine administration (screening), seven days 
post-Dose 2 (Day 203), one month post-Dose 2 (Day 
226), the day of first parasitemia, and 28 days post-
challenge (Day 314) for subjects from Adu1Fx group
and at screening, the day of first parasitemia and 28 
days post-challenge (Day 314) for the infectivity 
control subjects.
Blood samples for RNAsequencing (messenger 
ribonucleic acid [mRNA] sequencing analysis) will be 
collected before vaccine administration (Day 0), at
Dose 2 (Day 28), one day post-Dose 2 (Day 29), at
Dose 3 (Day 196), and one day post-Dose 3 (Day 197) 
for subjects from AduFx, 2PedFx, PedFx, and 
Adu2Fx groupsand before vaccine administration 
(Day 0), one month post-Dose 1 (Day 28), atDose 2 
(Day 196) and one day post-Dose 2 (Day 197) for 
subjects from Adu1Fx group.
Blood sample for assessment of parasitemia (PCR 
testing) will be collected on the day of subject entry 
into the hotel phase (Day 295[Visit 16]) to provide an 
estimate of the number of subjects likely to develop 
malaria within the first few days of the hotel phase.
 
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
Blood sample for assessment of parasitemia (blood 
smear) will be collected daily for 14 days (from Day 
291[Visit 12] to Day 304[Visit 25]) and then every 
two days for ninedays (Day 306[Visit 26], Day 308
[Visit 27], Day 310[Visit 28], Day 312[Visit 29], and 
Day 314[Visit 30]). For subjects who develop malaria,
blood smear may be discontinued once the subject has 
three consecutive negative smears (separated by more 
than 12 hours) following the initial treatment.
Blood samples for testing ofhuman immunodeficiency 
virus(HIV), hepatitis C virus (HCV) and HBsAg will 
be collected from all subjects at screening.
Urinary pregnancy test (urine beta-human chorionic 
gonadotropin [-HCG]) will be performed on all 
women atscreening, before each vaccine dose for 
vaccinated subjectsand on the day of challenge.

Type of study: self-contained.
Data collection: electronic Case Report Form (eCRF).

Safety monitoring:
Each subject will be observed for at least 30 minutes 
after vaccination to evaluate and treat any acute AEs.

Each subject will be observed for at least 30 minutes 
following completion of the sporozoite challenge to 
evaluate and treat any acute allergic reactions.

All SAEs (all, fatal, related to the investigational 
vaccine) and pregnancies will be reported until study 
end (Day 376).
All AEs and SAEs leading to withdrawal from further 
vaccination will be reported until study end (Day 376) 
for all vaccinated subjects (AduFx, 2PedFx, PedFx, 
Adu2Fx, and Adu1Fx groups).

Meningitis and potential immune-mediated diseases 
(pIMDs)are AEs of specific interest to be reported 
until study end (Day 376) for all vaccinated subjects 
(AduFx, 2PedFx, PedFx, Adu2Fx, and Adu1Fx 
groups).
Solicited local and general AEs will be collected from 
all vaccinated subjects (AduFx, 2PedFx, PedFx, 
Adu2Fx, and Adu1Fx groups) during seven days (day 
of vaccination and six subsequent days) after each dose 
of study vaccine.
 
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
Unsolicited AEs will be collected from all vaccinated 
subjects (AduFx, 2PedFx, PedFx, Adu2Fx, and 
Adu1Fx groups) during 30 days (day of vaccination 
and 29 subsequent days) after each dose of study 
vaccine.

AEspost-challengewill be collected from all subjects 
(AduFx, 2PedFx, PedFx, Adu2Fx, Adu1Fx, and 
infectivity control groups) during 30 days (day of 
challenge and 29 subsequent days) after the sporozoite 
challenge.
Biochemistry (ALT, AST and creatinine) and 
hematology (hemoglobin, WBC and platelets) 
parameters will be assessed as described in ‘Sampling 
schedule’.
Case definition
Case definition of P. falciparum infection:asexual blood 
stage P. falciparumparasite density > 0 detected by blood slide 
reading.
Number of subjects The target is to enroll approximately 150 subjects (26 subjects 
per vaccine group and between 20 and 30 subjects in the 
infectivity control group) aged 18 to 55years at the time of first 
vaccination.
Endpoints
Primary
Efficacy

Occurrence of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge, 
comparing RTS,S/AS01
Badministered as full doses at 
Month 0 and Month 1 and 1/5thdose at Month 7 (AduFx 
group) versus infectivity controls.

Occurrence of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge, 
comparing RTS,S/AS01
Eadministered as double dose at 
Month 0 and Month 1 and double 1/5thdose at Month 7 
(2PedFx group) versus infectivity controls.

Occurrence of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge, 
comparing RTS,S/AS01
Eadministered as full doses at 
Month 0 and Month 1 and 1/5thdose at Month 7 (PedFx 
group) versus infectivity controls.
Occurrence of P. falciparum parasitemia (defined by a 
positive blood slide) following sporozoite challenge, 
comparing RTS,S/AS01
Badministered as one full dose at 
Month 0 and 1/5th doses at Month 1 and Month 7 (Adu2Fx 
group) versus infectivity controls.
 
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Occurrence of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge, 
comparing RTS,S/AS01
Badministered as one full dose at 
Month 0 and 1/5thdoses at Month 7 (Adu1Fx group) versus 
infectivity controls.
Secondary
Efficacy
Occurrence of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge, 
comparing RTS,S/AS01
Eadministered as double dose at 
Month 0 and Month 1 and double 1/5thdose at Month 7 
(2PedFx group) versus immunization schedule of reference
(AduFx group).

Occurrence of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge, 
comparing RTS,S/AS01
Eadministered as full doses at 
Month 0 and Month 1 and 1/5th dose at Month 7 (PedFx) 
versus immunization schedule of reference (AduFx group).

Occurrence of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge, 
comparing RTS,S/AS01
Badministered as one full dose at 
Month 0 and 1/5thfull dose at Month 1 and Month 7 
(Adu2Fx) versus immunization schedule of reference 
(AduFx group).

Occurrence of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge, 
comparing RTS,S/AS01
Badministered as one full dose at 
Month 0 and 1/5thfull doses at Month 7 (Adu1Fx) versus 
immunization schedule of reference (AduFx group).

Time to onset of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge in each 
vaccination schedule versus immunization schedule of 
reference(AduFx group).
Time to onset of P. falciparumparasitemia (defined by a 
positive blood slide) following sporozoite challenge in each 
vaccination schedule versus infectivity controls.
Immunogenicity

For each vaccination schedule, the immune response tothe 
CS antigen of the investigational vaccine:
Anti-CS repeat region antibody concentrations before 
vaccine administration (Day 0), one month post-Dose 
 
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2 (Day 58), six months post-Dose 2 (Day 196), one 
month post-Dose 3 (Day 226), on the day of challenge 
(Day 286), 28 days post-challenge (Day 314), and at 
study end (Day 376) for subjects from AduFx, 2PedFx, 
PedFx, and Adu2Fx groups and before vaccine 
administration (Day 0), before Dose 2 (Day 196), one 
month post-Dose 2 (Day 226), on the day of challenge
(Day 286), 28 days post-challenge (Day 314), and at 
study end (Day 376) for subjects from Adu1Fx group.

For each vaccination schedule, the immune response to the 
hepatitis B antigen of the investigational vaccine:

Anti-HBs IgG antibody concentrations before vaccine 
administration (Day 0), one month post-Dose 2 (Day 
58), six months post-Dose 2 (Day 196), one month 
post-Dose 3 (Day 226), on the day of challenge (Day 
286), 28 days post-challenge (Day 314), and at study 
end (Day 376) for subjects from AduFx, 2PedFx, 
PedFx, and Adu2Fx groups and before vaccine 
administration (Day 0), before Dose 2 (Day 196), one 
month post-Dose 2 (Day 226), on the day of challenge 
(Day 286), 28 days post-challenge (Day 314), and at 
study end (Day 376) for subjects from Adu1Fx group.
Safety

Safety and reactogenicity of the investigational vaccine for 
each vaccination schedule:
Occurrence of solicited local and general AEs within 
seven days (day of vaccination and six subsequent 
days) after each vaccination.

Occurrence ofunsolicited AEs within 30 days (day of 
vaccination and 29 subsequent days) after each 
vaccination, according to the Medical Dictionary for 
Regulatory Activities (MedDRA) classification.

Occurrence of AEs within 30 days (day of challenge 
and 29 subsequent days) after challenge, according to 
the MedDRA classification.
Occurrence of SAEs (all, fatal, related to 
investigational vaccine) within 30 days (day of 
vaccination and 29 subsequent days) after each 
vaccination, according to the MedDRA classification.
Occurrence of SAEs (all, fatal, related to 
investigational vaccine) during the whole study period 
(from Dose 1 [Day 0] up to study conclusion [Day 
376]), according to the MedDRA classification.
 
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
Occurrence of AEs and SAEs leading to withdrawal 
from further vaccination from Dose 1 (Day 0) up to 
study conclusion (Day 376), according to the 
MedDRA classification, for each vaccinated subject.

Occurrence of pIMDs from Dose 1 (Day 0) up to study 
conclusion (Day 376), according to the MedDRA 
classification, for each vaccinated subject.
Occurrence of meningitis from Dose 1 (Day 0) up to 
study conclusion (Day 376), according to the 
MedDRA classification, for each vaccinated subject.
Occurrence of abnormal laboratory values at 
screening, Day 35, Day 58, Day 203, Day 226, the day 
of first parasitemia, and Day 314 for each vaccinated 
subject and at screening, the day of first parasitemia 
and Day 314 for the infectivity control subjects.

Safety after sporozoite challenge in the infectivity control 
group.
Occurrence of AEs within 30 days (day of challenge 
and 29 subsequent days) after challenge, according to 
the MedDRA classification.

Occurrence of SAEs (all, fatal, related) from day of 
challenge (Day 286) to the end of the challenge phase 
(Day 314), according to the MedDRA classification.
Tertiary
Immunogenicity

For each vaccination schedule, the immune response to the 
CS antigen of the investigational vaccine:

Anti-CS repeat region IgG avidity index before 
vaccine administration (Day 0), one month post-Dose 
2 (Day 58), six months post-Dose 2 (Day 196), one 
month post-Dose 3 (Day 226), on the day of challenge 
(Day 286), 28 days post-challenge (Day 314), and at 
study end (Day 376) for subjects from AduFx, 2PedFx, 
PedFx, and Adu2Fx groups and before vaccine 
administration (Day 0), before Dose 2 (Day 196), one 
month post-Dose 2 (Day 226), on the day of challenge 
(Day 286), 28 days post-challenge (Day 314), and at 
study end (Day 376) for subjects from Adu1Fx group.

Anti-full length CS protein IgG concentrations and 
anti-C-term IgG concentrations before vaccine 
administration (Day 0), one month post-Dose 2 (Day 
58), six months post-Dose 2 (Day 196), one month 
 
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post-Dose 3 (Day 226), on the day of challenge (Day 
286), 28 days post-challenge(Day 314), and at study 
end (Day 376) for subjects from AduFx, 2PedFx, 
PedFx, and Adu2Fx groups and before vaccine 
administration (Day 0), before Dose 2 (Day 196), one 
month post-Dose 2 (Day 226), on the day of challenge 
(Day 286), 28 days post-challenge (Day 314), and at 
study end (Day 376) for subjects from Adu1Fx group.

Anti-full length CS protein and anti-C-term IgG 
avidity before vaccine administration (Day 0), one 
month post-Dose 2 (Day 58), six months post-Dose 2 
(Day 196), one month post-Dose 3 (Day 226), on the 
day of challenge (Day 286), 28 days post-challenge 
(Day 314), and at study end (Day 376) for subjects 
from AduFx, 2PedFx, PedFx, and Adu2Fx groups and 
before vaccine administration (Day 0), before Dose 2 
(Day 196), one month post-Dose 2 (Day 226), on the 
day of challenge (Day 286), 28 days post-challenge 
(Day 314), and at study end (Day 376) for subjects 
from Adu1Fx group.
Note: other immuno-assays evaluating the immune 
response targeting the CS and HBsAgmight be performed.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................30
GLOSSARY OF TERMS...............................................................................................34
TRADEMARKS.............................................................................................................38
1. INTRODUCTION....................................................................................................39
1.1.
Background................................................................................................39
1.2.
Rationale for the study and study design....................................................41
1.2.1.
Rationale for the study.................................................................41
1.2.2. 
Rationale for the study design......................................................42
1.3.
Benefit : Risk assessment...........................................................................43
1.3.1.
Risk assessment..........................................................................43
1.3.2.
Benefit assessment.....................................................................44
1.3.3.
Overall Benefit:Risk conclusion....................................................44
2. OBJECTIVES.........................................................................................................45
2.1.
Primary objective........................................................................................45
2.1.1.
Efficacy........................................................................................45
2.2.
Secondary objectives..................................................................................45
2.2.1.
Efficacy........................................................................................45
2.2.2.
Immunogenicity............................................................................45
2.2.3.
Safety..........................................................................................45
2.3.
Tertiary objectives.......................................................................................46
2.3.1.
Immunogenicity............................................................................46
3. STUDY DESIGN OVERVIEW ................................................................................47
4. CASE DEFINITION................................................................................................52
5. STUDY COHORT...................................................................................................53
5.1.
Number of subjects/centers........................................................................53
5.2.
Inclusion criteria for enrolment....................................................................53
5.3.
Exclusion criteria for enrolment...................................................................54
6. CONDUCT OF THE STUDY..................................................................................56
6.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................56
6.2.
Subject identification and randomization of treatment.................................57
6.2.1.
Subject identification....................................................................57
6.2.2.
Randomization of treatment.........................................................57
6.2.2.1.
Randomization of supplies..........................................57
6.2.2.2.
Treatment allocation to the subject.............................57
 
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6.2.2.2.1.
Study group and treatment 
number allocation...................................58
6.2.2.2.2.
Treatment number allocation for 
subsequent doses..................................58
6.3.
Method of blinding......................................................................................58
6.4.
General study aspects................................................................................58
6.4.1.
Mosquito challenge......................................................................59
6.4.1.1.
Contraindications to malaria challenge.......................59
6.4.1.2.
Parasite and mosquito strains....................................59
6.4.1.3.
Infection of human subjects........................................60
6.4.1.4.
Determining parasitemia.............................................60
6.4.1.5.
Management of infected human subjects...................60
6.4.1.6.
Malaria treatment.......................................................61
6.5.
Outline of study procedures........................................................................63
6.6.
Detailed description of study procedures....................................................72
6.6.1.
Informed consent.........................................................................72
6.6.2.
Check inclusion and exclusion criteria.........................................72
6.6.3.
Check screening laboratory results..............................................72
6.6.4.
Collect demographic data............................................................72
6.6.5.
Medical history.............................................................................72
6.6.6.
Record information on past hepatitis B immunization...................72
6.6.7.
Physical examination...................................................................72
6.6.8.
Urine pregnancy test....................................................................73
6.6.9.
Check contraindications to vaccination........................................73
6.6.10. Assess pre-vaccination body temperature...................................73
6.6.11. Randomization and treatment number allocation.........................73
6.6.12. Study vaccines administration......................................................74
6.6.13. Check contraindications to challenge...........................................74
6.6.14. Sporozoite challenge...................................................................74
6.6.15. Distribution of emergency notification card...................................74
6.6.16. Sampling......................................................................................74
6.6.17. Check and record concomitant medication/vaccination and 
intercurrent medical conditions....................................................75
6.6.18. Recording of AEs, SAEs, pregnancies and AEs of specific 
interest.........................................................................................76
6.6.19. Study conclusion..........................................................................76
6.7.
Biological sample handling and analysis.....................................................76
6.7.1.
Use ofspecified study materials..................................................77
6.7.2.
Biological samples.......................................................................77
6.7.3.
Laboratory assays.......................................................................81
6.7.4.
Biological samples evaluation......................................................83
6.7.4.1.
Immunological read-outs............................................83
6.7.4.2.
Hematology/Blood Chemistry.....................................87
6.7.4.3.
Molecular biology.......................................................88
6.7.4.4.
Parasitemia................................................................89
6.7.5.
Immunological correlates of protection.........................................89
7. STUDY VACCINES AND ADMINISTRATION........................................................90
7.1.
Description of study vaccines......................................................................90
7.2.
Storage and handling of study vaccines......................................................90
7.3.
Dosage and administration of study vaccines.............................................91
7.3.1.
Dosage of RTS,S/AS01...............................................................91
 
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7.3.1.1.
RTS,S/AS01E.............................................................91
7.3.1.2.
RTS,S/AS01B.............................................................92
7.3.2.
Administration of RTS,S/AS01.....................................................92
7.4.
Replacement of unusable vaccine doses....................................................93
7.5.
Contraindications to vaccination.................................................................93
7.6.
Concomitant medications/products and concomitant vaccinations..............94
7.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................94
7.6.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses........................94
7.7.
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses.........................................................................95
8. HEALTH ECONOMICS..........................................................................................95
9. SAFETY.................................................................................................................95
9.1.
Safety definitions........................................................................................96
9.1.1.
Definition of an adverse event......................................................96
9.1.2.
Definition of a serious adverse event...........................................97
9.1.3.
Solicited adverse events..............................................................98
9.1.3.1.
Solicited local (injection-site) adverse events..............98
9.1.3.2.
Solicited general adverse events................................98
9.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events............................................................................98
9.1.5. 
Adverse events of specific interest...............................................99
9.1.5.1.
Potential immune-mediated diseases.........................99
9.1.5.2.
Meningitis.................................................................101
9.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events.........................................................................................101
9.2.1.
Pregnancy.................................................................................101
9.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies.......................................................................................102
9.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies...................................102
9.3.2.
Post-Study adverse events and serious adverse events............105
9.3.3.
Evaluation of adverse events and serious adverse events.........105
9.3.3.1.
Active questioning to detect adverse events 
and serious adverse events......................................105
9.3.3.2.
Assessment of adverse events.................................106
9.3.3.2.1.
Assessment of intensity........................106
9.3.3.2.2.
Assessment of causality.......................108
9.3.3.3.
Assessment of outcomes..........................................110
9.4.
Reporting of serious adverse events, pregnancies, and other events.......110
9.4.1.
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals..........................................110
9.4.2. 
Contact information for reporting serious adverse events, 
pregnancies and adverse events of specific interest..................111
9.4.3.
Completion and transmission of serious adverse event 
reports to GSK Biologicals.........................................................111
9.4.3.1.
Back-up system in case the electronic 
reporting system does not work................................111
 
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9.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals.................................................................................112
9.4.5.
Reporting ofadverse events of specific interest to GSK 
Biologicals.................................................................................112
9.4.6.
Updating of SAE, pregnancy, and adverse events of 
specific interest information after removal ofwrite access 
to the subject’s eCRF.................................................................112
9.4.7.
Regulatory reporting requirements for serious adverse 
events........................................................................................113
9.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies..............................................................................................113
9.5.1.
Follow-up ofadverse events and serious adverse events..........113
9.5.1.1.
Follow-up during the study........................................113
9.5.1.2.
Follow-up after the subject is discharged from 
the study...................................................................113
9.5.2.
Follow-up of pregnancies...........................................................114
9.6.
Treatment of adverse events....................................................................114
9.7.
Subject card..............................................................................................114
10.SUBJECT COMPLETION AND WITHDRAWAL...................................................115
10.1. Subject completion...................................................................................115
10.2. Subject withdrawal....................................................................................115
10.2.1. Subject withdrawal from the study.............................................115
10.2.2. Subject withdrawal from investigational vaccines.......................116
10.3. Extension study........................................................................................116
10.4. Screen and baseline failures.....................................................................116
11.STATISTICAL METHODS....................................................................................117
11.1. Primary endpoint.......................................................................................117
11.1.1. Efficacy......................................................................................117
11.2. Secondary endpoints................................................................................117
11.2.1. Efficacy......................................................................................117
11.2.2. Immunogenicity..........................................................................118
11.2.3. Safety........................................................................................118
11.3. Tertiary endpoints.....................................................................................119
11.3.1. Immunogenicity..........................................................................119
11.4. Determination of sample size....................................................................120
11.5. Cohorts for analyses.................................................................................121
11.5.1. Total vaccinated cohort..............................................................121
11.5.2. According-to-protocol cohort for analysis of 
immunogenicity and efficacy......................................................121
11.6. Derived and transformed data...................................................................121
11.7. Analysis of demographics.........................................................................122
11.8. Analysis of efficacy...................................................................................122
11.9. Analysis of immunogenicity.......................................................................123
11.10.Analysis of safety......................................................................................123
11.11.Interpretation of analyses..........................................................................124
11.12.Conduct of analyses.................................................................................124
11.12.1. Sequence of analyses................................................................124
11.12.2. Statistical considerations for interim analyses............................124
12.ADMINISTRATIVE MATTERS.............................................................................125
 
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12.1. Electronic Case Report Form instructions.................................................125
12.2. Study Monitoring byGSK Biologicals........................................................125
12.3. Record retention.......................................................................................126
12.4. Quality assurance.....................................................................................126
12.5. Posting of information on publicly available clinical trial registers and 
publication policy......................................................................................127
12.6. Provision of study results to investigators.................................................127
13.COUNTRY SPECIFIC REQUIREMENTS.............................................................127
14.REFERENCES.....................................................................................................128
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................49
Table 2
Study groups and treatment foreseen in the study.................................49
Table 3
Overview of the vaccine administration per study groups.......................50
Table 4
Blinding of study epochs........................................................................50
Table 5
Case definition of P. falciparuminfection................................................52
Table 6
List of study procedures for the investigational vaccine groups: 
AduFx, 2PedFx, PedFx, and Adu2Fx.....................................................63
Table 7
List of study procedures for the investigational vaccine group: 
Adu1Fx..................................................................................................66
Table 8
List of study procedures for the infectivity control group.........................69
Table 9
Intervals between study visits for the investigational vaccine 
groups: AduFx, 2PedFx, PedFx, and Adu2Fx........................................71
Table 10
Intervals between study visits for the investigational vaccine 
groups: Adu1Fx......................................................................................71
Table 11
Intervals between study visits for the infectivity control group.................71
Table 12
Biological samples (whole blood)...........................................................78
Table 13
Assays for humoral immunity (antibody determination)..........................81
Table 14
Assessment of P. falciparumparasitemia...............................................82
Table15
Hematology, biochemistry and screening tests......................................82
Table 16
Immunological read-outs........................................................................83
Table 17
Hematology and biochemistry read-outs................................................87
Table 18
RNA sequencing (mRNA sequencing analysis)......................................88
Table 19
Parasitemia (blood smear).....................................................................89
Table 20
Study vaccines.......................................................................................90
Table 21
Dosage and administration.....................................................................92
Table 22
Solicited local adverse events................................................................98
 
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Table 23
Solicited general adverse events............................................................98
Table 24
List of potential immune-mediated diseases...........................................99
Table 25
Reporting periods for collecting safety information for the 
investigational vaccine groups: AduFx, 2PedFx, PedFx, and 
Adu2Fx)...............................................................................................103
Table 26
Reporting periods for collecting safety information for the 
investigational vaccine groups: Adu1Fx...............................................104
Table 27
Reporting periods for collecting safety information for the 
infectivity control group.........................................................................105
Table 28
Intensity scales for solicited symptoms in adults...................................106
Table 29
Toxicity grading scales for blood testing...............................................108
Table 30
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals...............................................110
Table 31
GSK Biologicals’ laboratories...............................................................132
Table 32
Outsourced laboratories.......................................................................132
 
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LIST OF FIGURES
PAGE
Figure 1
Study design..........................................................................................47
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS.....................................................................130
APPENDIX B CLINICAL LABORATORIES................................................................132
APPENDIX CNHANES I CARDIOVASCULAR RISK CRITERIA................................133
APPENDIX DAMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................136
 
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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/AS01Bat Month 0, Month 1 and Month 2.
AduFx:
Subjects receiving RTS,S/AS01Bfull dose at Month 0, 
Month 1 + RTS,S/AS01B1/5thdose at Month 7
Adu1Fx:
Subjects receiving RTS,S/AS01Bfull dose at Month 0 + 
RTS,S/AS01B1/5thdose at Month 7
Adu2Fx:
Subjects receiving RTS,S/AS01Bfull dose at Month 0 + 
RTS,S/AS01B1/5thdose at Month 1, Month 7
AE:
Adverse event
ALT:
Alanine aminotransferase
Anti-CS:
Antibody to the Plasmodium falciparum
circumsporozoite (CS) repeat domain
Anti-HBs:
Antibody to the hepatitis B surface antigen
AS01B:
GSK’s proprietary Adjuvant System containing MPL, 
QS-21 and liposome (50 µg MPL and 50 µg QS-21)
AS01E:
GSK’s proprietary Adjuvant System containing MPL, 
QS-21 and liposome (25 µg MPL and 25 µg QS-21)
AST:
Aspartate aminotransferase
ATP:
According-to-protocol
-HCG:
Beta-human chorionic gonadotropin
CEVAC:
Center for vaccinology, Ghent University, Belgium
CHMI:
Controlled human malaria infection
CI:
Confidence interval
CLIA:
Chemiluminescence enzyme immunoassay
CLS:
Clinical laboratory sciences
CS:
Circumsporozoite protein of Plasmodium falciparum
C-term:
CS terminal portion of the protein
 
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DoC:
Day of challenge
eCRF:
Electronic case report form
EDD:
Estimated date of delivery
EGA:
Estimated gestational age
ELISA:
Enzyme-linked immunosorbent assay
EPT:
Endpoint titer
eTDF:
Electronic temperature excursion decision form
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 (1/5
th
dose) at Month7.
GCP:
Good clinical practice
GMC:
Geometric mean concentration
GSK:
GlaxoSmithKline
HBsAg:
Hepatitis B surface antigen
HCV:
Hepatitis C virus
HIV:
Human immunodeficiency virus
IB:
Investigator brochure
ICF:
Informed consent form
ICH:
International conference on harmonization
IEC:
Independent ethics committee
IgG:
Immunoglobulin G
IM:
Intramuscular
IMP:
Investigational medicinal product
IND:
Investigational new drug
 
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IRB:
Institutional review board
LMP:
Last menstrual period
MedDRA:
Medical dictionary for regulatory activities
MPL:
3-O-desacyl-4’-monophosphoryl lipid A (produced by 
GSK)
mRNA:
messenger ribonucleic acid
NHANES I:
National health and nutrition examination survey I
PBMC:
Peripheral blood mononuclear cells
PCR:
Polymerase chain reaction
PedFx:
Subjects receiving RTS,S/AS01Efull dose at Month 0, 
Month 1 + RTS,S/AS01E1/5thdose at Month 7
2PedFx:
Subjects receiving RTS,S/AS01Edouble dose at Month 0, 
Month 1 + double dose RTS,S/AS01E1/5thdose at 
Month7
P. falciparum:
Plasmodium falciparum
pIMD:
Potential immune-mediated disease
QS-21:
(Quillaja saponaria Molina, fraction 21) (Licensed by GSK 
from Antigenics Inc, a wholly owned subsidiary of Agenus 
Inc., a Delaware, USA corporation)
RTS,S:
Particulate antigen, containing both RTS and S (hepatitis 
B surface antigen) proteins
RTS,S/AS01B:
GSK Biologicals’ candidate Plasmodium falciparum
malaria vaccine adjuvanted with GSK Biologicals’ 
proprietary Adjuvant System AS01
B
RTS,S/AS01E:
GSK Biologicals’ candidate Plasmodium falciparum
malaria vaccine adjuvanted with GSK Biologicals’ 
proprietary Adjuvant System AS01
E
SAE:
Serious adverse event
SBIR:
Randomization system on internet
SD:
Standard deviation
 
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SDV:
Source document verification
SOP:
Standard operatingprocedure
SPM:
Study procedures manual
TVC:
Total vaccinated cohort
ULN:
Upper limit of normal range
WBC:
White blood cells
WHB:
Whole blood
WRAIR:
Walter Reed Army Institute of Research
 
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GLOSSARY OF TERMS
Adequate contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example:
abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle, 
Oral contraceptives , either combined or progestogen 
alone, 
injectable progestogen, 
implants of etenogestrel or levonorgestrel, 
estrogenic vaginal ring, 
percutaneous contraceptive patches, 
intrauterine device or intrauterine system, 

male partner sterilization prior to the female subject’s 
entry into the study, and this male is the sole partner 
for that subject,
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history.

male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository

male condom combined with a female diaphragm, 
either with or without a vaginal spermicide (foam, 
gel, film, cream, or suppository).
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, when this 
is their preferred and usual lifestyle.
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.
 
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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.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
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.
Epoch:
An epoch is a self-contained set of consecutive timepoints 
or a single timepoint froma single protocol. Self-
contained means that data collected for all subjects at all 
timepoints within that epochallows to draw a complete 
conclusion to define or precise the targeted label of the 
product (e.g. primary, booster, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety).
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis.
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. 
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes
associated with puberty including breast development and 
pubic hair growth. Menarche usually occurs within 1-2 
years of breast development, thelarche. However, a young 
 
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female can become pregnant before her first menses. 
Thus, a conservative definition of non-childbearing 
potential in a pre-menarcheal female is a young female 
who has not yet entered puberty as evidenced by lack of 
breast development (palpable glandular breast tissue).
Menopause:
Menopause is the age associated with complete cessation 
of menstrual cycles, menses, and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses 
with an appropriate clinical profile at the appropriate age 
e.g. > 45 years.
Potential Immune-
Mediated Disease:
Potential immune-mediated diseases (pIMDs) are a subset 
of AEs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune etiology.
Primary completion 
date:
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated.
Protocol amendment:
The International Conference on Harmonization (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study.
Protocol administrative 
change:
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study. 
Randomization:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Self-contained study:
Study with objectives not linked to the data of another 
study.
Serious adverse event:
A serious adverse event (SAE) is any untoward medical 
occurrence that:
results in death;
is life-threatening;
requires hospitalization or prolongation of existing 
hospitalization;
results in disability/incapacity;
 
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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 following AEs of specific interest:
pIMDs and meningitis will be reported as SAEs.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
Solicited adverse event:
Adverse events to be recorded as endpoints in the clinical 
study. The presence/occurrence/intensity of these events 
is actively solicited from the subject or an observer during 
a specified post-vaccination follow-up period.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in theclinical study, either as a recipient of 
the vaccine(s)/product(s) or as a control.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomization or treatment allocation.
Treatment number:
A number identifying a treatment to a subject, according 
to the study randomizationor treatment allocation.
Unsolicited adverse 
event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specifiedperiod of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
 
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TRADEMARKS
The following trademarks are used in the present protocol.
Note: In the body of the protocol (including the synopsis), the names of the products will 
be written without the superscript symbol ™ or ® and in italics.
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
Ma
larone®
Atovaquone and proguan
i
l hydroch
lor
ide
Trademarks not owned by the 
GlaxoSmithKline group of companies
Generic description
QS-21(Qu
i
l
la
ja saponar
iaMo
l
ina, fract
ion 
21; l
icensed by GSK from Ant
igen
ics Inc, a 
who
l
ly owned subs
id
iary of Agenus Inc., a 
De
laware, USA corporat
ion)
Tr
iterpene g
lycos
ide 
immune enhancer
Imod
ium
®(Johnson & Johnson L
im
ited)
Loperam
ide
Coartem®(Novart
is Pharmaceut
ica
ls UK 
Ltd.)
Artemether/
lumefantr
ine
 
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1.
INTRODUCTION
1.1.
Background
GlaxoSmithKline (GSK) Biologicals in partnership with PATH is developing a first 
generation Plasmodium falciparum(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 several formulations of the candidate pre-erythrocytic 
P.falciparummalaria vaccine, RTS,S/AS01, which consists of sequences of the 
circumsporozoite (CS) protein of P. falciparumand hepatitis B surface antigen (HBsAg) 
adjuvanted with the adjuvant system AS01 containing two immuneenhancers MPL (3’-
O-desacyl-4’-monophosphoryl-lipid A) and QS-21 (Quillaja saponariaMolina, fraction 
21), in a liposomes suspension.
A large Phase III study (MALARIA-055 PRI [110021]), 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 vaccine efficacy of this pediatric formulation 
RTS,S/AS01E, (25 µg of RTS,S antigen with AS01
Econtaining 25 µg MPL, 25 µg 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; [TheRTS,S Clinical Trials Partnership, 2011]) and 
31.4% (95% CI: 24.2, 37.9) in infants aged 6-12 weeks [TheRTS,S Clinical Trials 
Partnership, 2012] over 12 months post-Dose 3. Vaccine efficacy for clinical malaria 
waned over time [TheRTS,S Clinical Trials Partnership, 2014; TheRTS,S Clinical Trials 
Partnership, 2015]. The administration of a RTS,S/AS01
Efourth dose enhanced 
protection.
While the Phase III evaluation of the pediatric candidate malaria vaccine RTS,S/AS01E
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 along-
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 
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 full 0.5 ml dose (fractional dose).
 
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Later in the RTS,S clinical development program, immunization scheduleswith 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), has been further investigated recently in a CHMI study in malaria-naïve 
adults (MALARIA-071). The biological hypothesis was that the delayed fractional dose 
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). Immunological investigations showed that the delayed fractional 
dose regimen did not generate higher absolute anti-CS antibody titers as compared to the 
standard regimen, but increased anti-CS antibody avidity. The mean (standard deviation) 
avidity index on day of challenge (using CS full length as target antigen, was 0.55 (0.08) 
in the 012M group vs 0.68 (0.1) in the Fx017M group (p<0.0001). Further 
immunological investigations are ongoing. 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 fourth dose 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.
Please refer to the current Investigator Brochure (IB) for information regarding the pre-
clinical and clinical studiesof RTS,S/AS01.
 
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1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
Results fromCHMI studies showeda simple way to improve the efficacy of the 
RTS,S/AS01 vaccine to the point where it might become useful either for improved 
malaria control in the pediatric population or as a tool to reduce malaria transmission. 
Combining several interventions such as vector control, prophylactic vaccination and 
mass drug administration, thus targeting different stages of the parasite cycle, may prove 
to offer the best control of malaria transmission.
This study aims to investigate whether changes in dosing schedule are associated with 
increased or equivalent protection, and to evaluate the immune mechanisms associated 
with vaccine efficacy under varying dosing schedules.
The study aims are the following:
a. Evaluation of the role of a fractional second and third dose.
b. Evaluation of a two-dose schedule where the second dose is fractional.
c. Evaluation of the use of the pediatric formulation to vaccinate adults, when a 
pediatric dose is delivered to adults.
d. Evaluation of the use of the pediatric formulation to vaccinate adults, when what has 
been considered so far as an adult dose is delivered using the pediatric formulation 
(increasing the volume of administration).
e. Evaluate the impact of varying dosing schedules on immune effectors and immune 
correlates of protection.
The ability to use the pediatric formulation (RTS,S/AS01E) for adults would be a very 
positive step when considering product availability and implementation feasibility of a 
mass vaccination program in the context of an elimination campaign, therefore study 
aims c) and d) are being investigated. The pediatric formulation of RTS,S/AS01 has 
never been used in adults, but there are indications from other programs that the AS01E
Adjuvant System may not be substantially inferior to AS01
Bfor immunogenicity 
[EARLY-CLINRES-002, data on file; Montoya, 2013].
Evaluation of a two-dose schedule, separated by sevenmonths, will contribute to explore 
the possibility that the close repetition of doses leads to some excessive priming that may 
be detrimental to the immune responses. If leading to sufficient protection, a two-dose 
strategy may be a great advantage when considering cost and logistics aspects in the 
contribution to malaria control and elimination efforts.
 
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1.2.2.
Rationale for the study design
This study is designed to evaluate efficacy, immunogenicity and safety of various dose 
schedules of GSK Biologicals’ candidate malaria vaccinesRTS,S/AS01B(adult 
formulation containing 50 µg RTS,S antigen and AS01
Bformulation with 50 µg of MPL 
and 50 µg of QS-21 per 0.5 ml) and RTS,S/AS01E(pediatric formulation containing 25 
µg RTS,S antigen and AS01Eformulation with 25 µg of MPL and 25 µg of QS-21 per 0.5 
ml) in healthy malaria-naïve subjects aged 18-55years.The study proposed herein will
include sixstudy groups. Four of these study groups will be vaccinated according to a 0, 
1, 7-month scheduleand one according to a 0, 7-month schedule.The immunization 
schedule of reference will be the same as the one used in study MALARIA-071 
(117014), i.e. RTS,S/AS01
Bfull dose at Month 0 and Month 1 and RTS,S/AS01
B1/5th
dose at Month 7. Three months after the last dose of study vaccines, all subjects will 
undergo a sporozoite challenge and will be compared to an infectivity control group:
Group AduFx will receive RTS,S/AS01Bfull dose at Month 0 and Month 1 + 
RTS,S/AS01Bfractional dose (1/5
th dose) at Month 7 (immunization schedule of 
reference).
Group 2PedFx will receive double dose of RTS,S/AS01Eat Month 0 and Month 1 + 
double dose of RTS,S/AS01Efractional dose (1/5
th dose) at Month 7.

Group PedFx will receive RTS,S/AS01Efull dose at Month 0 and Month 1 + 
RTS,S/AS01Efractional dose (1/5
th dose) at Month 7.
Group Adu2Fx will receive RTS,S/AS01Bfull dose at Month 0 + RTS,S/AS01
B
fractional dose (1/5
th dose) at Month 1 and Month 7.
Group Adu1Fx will receive RTS,S/AS01Bfull dose at Month 0 + RTS,S/AS01
B
fractional dose (1/5
th dose) at Month 7.

Group infectivity control will not receive any immunization but will undergo the 
sporozoite challenge.
The sporozoite challenge model, in the RTS,S/AS candidate vaccine development 
program, has demonstrated a high relevance in its ability to predict efficacy under 
conditions of natural exposure in malaria-endemic countries. The study design is similar 
to that of other past CHMI studies successfully conducted. To better discriminate levels 
of protection across study groups and assess durability of protection, CHMI will occur 
three months after the last vaccine dose rather than three weeks as in past RTS,S studies. 
About 150 healthy adults will be enrolled and followed up closely under controlled 
conditions by investigators experienced in P. falciparumchallenge studies. The 
proportion of immunized participants who remain free of P. falciparuminfection 
following sporozoite challenge and the delay in the pre-patent period leading to infection 
will be evaluated as indicators of vaccine-induced protection. Immunological 
investigations are planned with the intent to characterize qualitatively and quantitatively 
the immune response induced by the immunization regimen. This design takes into 
account logistical restrictions on the size of human challenge procedures.
 
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Immunological assays will be selected for their ability to demonstrate whether the 
administration of a fractional vaccine dose can affect quantitatively or qualitatively the 
vaccine-induced immune response, especially when considering the generation of 
antibodies against the CS antigen, but also the HBsAg which is present in the vaccine 
construct. Qualitative aspect of the immune response will be characterized as much as 
possible (targeting different parts of the antigen and avidity). Samples from this study
may be used in future assay development or testing to better understand the immune 
responses underlying vaccine induced protection, responses to the vaccine components 
and the disease under investigation.
1.3.
Benefit : Risk assessment
Please refer to the current IBfor the summary of potential risks and benefits of
RTS,S/AS01.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
1.3.1.
Risk assessment
Important Potential/Identified Risk
Data/Rationale for Risk
MitigationStrategy
Investigational study vaccine (RTS,S/AS01)
Important potent
ia
l r
isk: Meningitis
In the 
large Phase III study, 
MALARIA-055 PRI, an 
imba
lance of 
men
ing
it
is cases of any et
io
logy (
i.e. 
inc
lud
ing cases w
ith conf
irmed 
et
io
logy and cases w
ith no et
io
logy 
found), w
ith no c
luster 
in t
ime-to-
onset, has been observed 
in 
ch
i
ldren 5-17 months of age at f
irst 
dose. Men
ing
it
is has not been a 
safety concern 
in RTS,S stud
ies 
in 
adu
lts.
Sub
jects w
i
l
l be 
instructed on the 
need to attend the c
l
in
ic 
if they are
unwe
l
l. A h
igh 
leve
l of med
ica
l 
superv
is
ion 
is 
in p
lace to detect and 
treat men
ing
it
is 
if 
it occurs. 
Men
ing
it
is 
is an AEof spec
if
ic 
interest (see Sect
ion 
9.1.5). C
l
in
ica
l 
deta
i
ls of each case w
i
l
l be captured 
through the exped
ited AE report and 
in a spec
if
ic eCRF screen.
Important potent
ia
l r
isk: 
Hypersensitivity (including 
anaphylaxis)
As w
ith other vacc
ines, 
hypersens
it
iv
ity and anaphy
lax
is to 
one or severa
l components of the 
vacc
ine can rare
ly occur.
One case of erythema mu
lt
iforme 
and two cases of bronchospasm 
w
ith
in 30 days fo
l
low
ing 
RTS,S/AS01 vacc
inat
ion were 
reported as hypersens
it
iv
ity 
react
ions 
in past ped
iatr
ic stud
ies.
No case of anaphy
lax
is has been 
reported fo
l
low
ing RTS,S/AS01 
vacc
inat
ion to date.
Sub
jects w
i
l
l be observed c
lose
ly for 
at 
least 30 m
inutes fo
l
low
ing 
adm
in
istrat
ion of the vacc
ine w
ith 
appropr
iate med
ica
l treatment 
read
i
ly ava
i
lab
le 
in case of 
anaphy
lax
is.
H
istory of anaphy
lax
is post-
vacc
inat
ion and h
istory of any 
react
ion or hypersens
it
iv
ity 
l
ike
ly to 
be exacerbated by any component 
of the vacc
ine are exc
lus
ion cr
iter
ia 
in th
is study (see Sect
ion5.3).
Prev
ious anaphy
lact
ic react
ion to a 
vacc
ine 
is a contra
ind
icat
ion to 
further exper
imenta
l vacc
inat
ions 
in 
th
is study (see Sect
ion 7.5).
 
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Important Potential/Identified Risk
Data/Rationale for Risk
MitigationStrategy
Important potent
ia
l r
isk: potential 
immune-mediated disease (pIMD)
pIMD 
is a theoret
ica
l concern w
ith 
ad
juvanted vacc
ines as no ev
idence 
of auto
immune d
isease caused by 
RTS,S/AS01 has been observed.
Sub
jects w
i
l
l be 
informed of th
is 
theoret
ica
l r
isk and the need to 
attend the c
l
in
ic 
if they are unwe
l
l. 
pIMD 
is an AE of spec
if
ic 
interest 
(see Sect
ion 9.1.5). The occurrence 
of pIMD cases w
i
l
l be descr
ibed.
Study procedures
Pa
in when tak
ing b
lood samp
les
When tak
ing the b
lood samp
les, the 
sub
ject may fee
l fa
int; or exper
ience 
m
i
ld pa
in, bru
is
ing, 
irr
itat
ion or 
redness.
Sub
jects w
i
l
l be adv
ised to 
inform or 
ca
l
l the study doctor 
immed
iate
ly 
if 
they have any s
ide effects that they 
perce
ive as ser
ious.
R
isks assoc
iated w
ith ma
lar
ia 
cha
l
lenge
The r
isks assoc
iated w
ith the 
sporozoïte cha
l
lenge 
inc
lude 
loca
l 
inf
lammatory reac
t
ions or potent
ia
l 
a
l
lerg
ic react
ions to mosqu
ito b
ites 
as we
l
l as the deve
lopment of 
ma
lar
ia 
infect
ion. Trans
ient 
abnorma
l
it
ies, such as fever, 
headache, m
i
ld anem
ia, 
leukopen
ia, 
sp
lenomega
ly, hepat
ic tenderness 
and fat
igue, are expected 
consequences of ma
lar
ia.
The comp
l
icat
ions of ma
lar
ia wh
ich 
can 
lead to k
idney, 
l
iver or bra
in 
damage, and death, are seen dur
ing 
natura
l
ly acqu
ired ma
lar
ia when 
d
iagnos
is and treatment are de
layed 
and h
igh 
leve
ls of paras
item
ia 
deve
lop.
Ant
i-ma
lar
ia treatment w
i
l
l be 
adm
in
istered to ma
lar
ia 
infected 
sub
jects. Under the carefu
l
ly 
contro
l
led cond
it
ions of th
is study, 
the chance of ser
ious 
i
l
lness or 
death from ma
lar
ia 
infect
ion 
is very 
sma
l
l.
1.3.2.
Benefit assessment
No direct benefit is foreseen from the study participation. Possible indirect benefits may 
be possible since subjects will be screened for human immunodeficiency virus (HIV), 
hepatitis B and C and will receive a medical check-up.
1.3.3.
Overall Benefit:Risk conclusion
The potential risks in association with RTS,S/AS01 (SB257049) are considered 
acceptable and the potential risks associated with malaria challenges are minimized by 
the carefully controlled condition of this study.
 
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2.
OBJECTIVES
2.1.
Primary objective
2.1.1.
Efficacy
To assess the vaccine efficacy against the occurrence of P. falciparumparasitemia 
(defined by a positive blood slide) for each vaccination schedule (AduFx, 2PedFx, 
PedFx, Adu2Fx, and Adu1Fx) versus the infectivity controls.
Refer to Section 11.1for the definition of the primary endpoint.
2.2.
Secondary objectives
2.2.1.
Efficacy

To assess the time to onset of P. falciparumparasitemia (defined by a positive blood 
slide) for each vaccination schedule (AduFx, 2PedFx, PedFx, Adu2Fx, and Adu1Fx) 
versus the infectivity controls.
To assess the occurrence of P. falciparumparasitemia (defined by a positive blood 
slide) after vaccine administration for alternative vaccination schedules (2PedFx, 
PedFx, Adu2Fx, and Adu1Fx) versus the immunization schedule of reference 
(AduFx).
To assess the time to onset of P. falciparumparasitemia (defined by a positive blood 
slide) after vaccine administration for alternative vaccination schedules (2PedFx, 
PedFx, Adu2Fx, and Adu1Fx) versus the immunization schedule of reference 
(AduFx).
2.2.2.
Immunogenicity
For each vaccination schedule:
To evaluate anti-CS repeat region antibody response at specified timepoints.
To evaluate anti-HBs immunoglobulin G (IgG) antibody response at specified 
timepoints.
2.2.3.
Safety
For each vaccination schedule:

To assess the safety (unsolicited AEs/AEs of specific interest/serious adverse events 
[SAEs]) and reactogenicity (solicited AEs).
Refer to Section 11.2for the definition of the secondary endpoints.
 
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2.3.
Tertiary objectives
2.3.1.
Immunogenicity
For each vaccination schedule:
To evaluate anti-CS repeat region IgG avidity index at specified timepoints.
To evaluate anti-full length CS protein IgG concentrations and anti-C terminal 
portion of the protein (C-term) IgG concentrations at specified timepoints.
To evaluate anti-full length CS protein and anti-C-term IgG avidity at specified 
timepoints.
Note: other immuno-assays evaluating the immune response targeting the CS and HBsAg
might be performed.
Refer to Section 11.3for the definition of the tertiary endpoints.
 
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3.
STUDY DESIGN OVERVIEW
Figure 1
Study design
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Footnotes to Figure 1:
D: Day; Mth: month; R: RTS,S; SCR: Screen
ing; V: v
is
it. *B
lood samp
le for est
imat
ion of sub
jects w
ith paras
item
ia (PCR test
ing) w
i
l
l be co
l
lected on the day of sub
ject entry 
into the 
hote
l phase (Day 295 [V
is
it 16]); blood samp
le for b
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia and b
lood samp
le for assessment of 
paras
item
ia (b
lood smear) w
i
l
l be co
l
lected da
i
ly for 14 days (from Day 291[V
is
it 12] to Day 304[V
is
it 25]) and then every two days for n
inedays (Day 306[V
is
it 26], Day 308[V
is
it 
27], Day 310[V
is
it 28], Day 312[V
is
it 29], and Day 314[V
is
it 30]).
(Amended 19June 2017)
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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 IIA, open, randomized, controlled, mono-centric, single-
country study with five parallel groupsand one infectivity control group.
Duration of the study: Approximately 16months for each vaccinated subject and 
threemonths for the infectivity control subjects.
Epoch 001: Primary starting at Visit 1 (Screening)(Screening for vaccinated
subjects) and ending at Visit 10(Day 226).
Epoch 002: Challenge starting atVisit 11(Day 286) orVisit 1b (Screening)
(Screening for infectivity controls), as applicable,and ending at Visit 31(Day 
376).
Study groups:
Table 1
Study groups and epochs foreseen in the study
Study 
groups
Vaccination schedule
Number of 
subjects
Age 
(Min/Max)
Epochs
Epoch 001Epoch 002
AduFx
RTS,S/AS01Bfu
l
l dose at Month 0, Month 1 + 
RTS,S/AS01B1/5
thdose at Month 7
26
18 years-55
years
X 
X
2PedFx
RTS,S/AS01Edoub
le dose at Month 0, Month 1 + 
doub
le dose RTS,S/AS01
E1/5
thdose at Month 7
26
18years-55
years
X 
X
PedFx
RTS,S/AS01Efu
l
l dose at Month 0, Month 1 + 
RTS,S/AS01E1/5
thdose at Month 7
26
18years-55
years
X 
X
Adu2Fx
RTS,S/AS01Bfu
l
l dose at Month 0 + RTS,S/AS01
B
1/5
thdose at Month 1, Month 7
26
18years-55
years
X 
X
Adu1Fx
RTS,S/AS01Bfu
l
l dose at Month 0 + RTS,S/AS01
B
1/5
thdose at Month 7
26
18years-55
years
X 
X
Infect
iv
ity 
contro
l
Sub
jects w
i
l
l not rece
ive any 
immun
izat
ion but w
i
l
l 
undergo sporozo
ite cha
l
lenge
30*
18years-55
years
X
* between 20 and 30 
infect
iv
ity contro
ls w
i
l
l be enro
l
led.
Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine/Product 
name
Injectable 
volume
Study Groups
AduFx
2PedFx PedFx Adu2Fx Adu1Fx Infectivity 
control
RTS,S/AS01B
(Fu
l
l dose)
RTS,S(50 µg)
0.5m
l
X
X
X
AS01B
X
X
X
RTS,S/AS01B
(1/5
thdose)
RTS,S(50 µg)
0.1m
l
X
X
X
AS01B
X
X
X
RTS,S/AS01E
(Fu
l
l dose)
RTS,S(25 µg)
0.5m
l
X*
X
AS01E
X*
X
RTS,S/AS01E
(1/5
thdose)
RTS,S(25 µg)
0.1m
l
X**
X
AS01E
X**
X
* In
jected vo
lume w
i
l
l be 1.0 m
l
** In
jected vo
lume w
i
l
l be 0.2 m
l
 
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Table 3
Overview of the vaccine administration per study groups
Groups
Visit 2(Day 0)
Visit 3(Day 28)
Visit 7(Day 196)
AduFx
RTS,S/AS01B(Fu
l
l dose)(0.5 m
l) RTS,S/AS01B(Fu
l
l dose)(0.5 m
l) RTS,S/AS01B(1/5
thdose)(0.1 m
l)
2PedFx RTS,S/AS01E(Fu
l
l dose)(1.0 m
l) RTS,S/AS01E(Fu
l
l dose)(1.0 m
l) RTS,S/AS01E(1/5
thdose)(0.2 m
l)
PedFx
RTS,S/AS01E(Fu
l
l dose)(0.5 m
l) RTS,S/AS01E(Fu
l
l dose)(0.5 m
l) RTS,S/AS01E(1/5
thdose)(0.1 m
l)
Adu1Fx RTS,S/AS01B(Fu
l
l dose)(0.5 m
l)
-
RTS,S/AS01B(1/5th dose)(0.1 m
l)
Adu2Fx RTS,S/AS01B(Fu
l
l dose)(0.5 m
l) RTS,S/AS01B(1/5
thdose)(0.1 m
l) RTS,S/AS01B(1/5
thdose)(0.1 m
l)
Control: active control(Group AduFx [RTS,S/AS01
Bfull dose at Month 0 and Month 
1 + RTS,S/AS01Bfractional dose at Month 7] is the immunization schedule of 
reference) and infectivity controls for the challenge.
Vaccination schedule are provided in Table 1.
Treatment allocation: randomized
Table 4
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
open
Epoch 002
open
Sampling schedule:
Blood samples for assessment of anti-CS and anti-HBs immune response and for 
serum repository will be collected before vaccine administration (Day 0), one 
month post-Dose 2 (Day 58), six months post-Dose 2 (Day 196), one month 
post-Dose 3 (Day 226), on the day of challenge (Day 286), 28 days post-
challenge (Day 314), and at study end (Day 376) for subjects from AduFx, 
2PedFx, PedFx, and Adu2Fx groupsand before vaccine administration (Day 
0), before Dose 2 (Day 196), one month post-Dose 2 (Day 226), on the day of 
challenge (Day 286), 28 days post-challenge (Day 314), and at study end (Day 
376) for subjects from Adu1Fx group.
Blood samples for peripheral blood mononuclear cells (PBMC) and plasma 
repository will be collected before vaccine administration (Day 0), one month 
post-Dose 1 (Day 28), seven days post-Dose 2 (Day 35), one month post-Dose 2 
(Day 58), six months post-Dose 2 (Day 196), seven days post-Dose 3 (Day 203), 
one month post-Dose 3 (Day 226), on the day of challenge (Day 286), and at 
study end (Day 376) for subjects from AduFx, 2PedFx, PedFx, and Adu2Fx 
groups and before vaccine administration (Day 0), one month post-Dose 1 (Day 
28), before Dose 2 (Day 196), seven days post-Dose 2 (Day 203), one month 
post-Dose 2 (Day 226), on the day of challenge (Day 286), and at study end 
(Day 376) for subjects from Adu1Fx group.
 
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Blood samples for the evaluation of biochemistry (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST] and creatinine) and hematology 
(hemoglobin, leukocytes [white blood cells; WBC] and platelets) parameters 
will be collected before vaccine administration (screening), seven days post-
Dose 2 (Day 35), one month post-Dose 2 (Day 58), seven days post-Dose 3 
(Day 203), one month post-Dose 3 (Day 226), the day of first parasitemia, and 
28 days post-challenge (Day 314) for subjects from AduFx, 2PedFx, PedFx, 
and Adu2Fx groups, before vaccine administration (screening), seven days 
post-Dose 2 (Day 203), one month post-Dose 2 (Day 226), the day of first 
parasitemia, and 28 days post-challenge (Day 314) for subjects from Adu1Fx 
groupand at screening, the day of first parasitemia and 28 days post-challenge 
(Day 314) for the infectivity control subjects. Following a bleeding procedure 
failure or laboratory failure, repeat bleeds can be considered upon investigator 
discretion no more than three times, or if medically indicated for full 
investigation of a potential adverse event.
Blood samples for RNAsequencing(messenger ribonucleic acid [mRNA] 
sequencinganalysis)will be collected before vaccine administration (Day 0), at
Dose 2 (Day 28), one day post-Dose 2 (Day 29), at Dose 3 (Day 196), and one 
day post-Dose 3 (Day 197) for subjects from AduFx, 2PedFx, PedFx, and
Adu2Fx groupsand before vaccine administration (Day 0), one month post-
Dose 1 (Day 28), atDose 2(Day 196) and one day post-Dose 2 (Day 197) for 
subjects from Adu1Fx group.
Blood sample for assessment of parasitemia (PCR testing) will be collected on 
the day of subject entry into the hotel phase (Day 295[Visit 16]) to provide an 
estimate of the number of subjects likely to develop malaria within the first few 
days of thehotel phase.
Blood sample for assessment of parasitemia (blood smear) will be collected 
daily for 14 days (from Day 291[Visit 12] to Day 304[Visit 25]) and then 
every two days for ninedays (Day 306[Visit 26], Day 308[Visit 27], Day 310
[Visit 28], Day 312[Visit 29], and Day 314[Visit 30]). For subjects who 
develop malaria, blood smear may be discontinued once the subject has three 
consecutive negative smears (separated by more than 12 hours) following the 
initial treatment (see Section 6.4.1).

Blood samples for testing of HIV, hepatitis C virus (HCV) and HBsAg will be 
collected from all subjects at screening.

Urinary pregnancy test (urine beta-human chorionic gonadotropin [-HCG]) 
will be performed on all women at screening, before each vaccine dose for 
vaccinated subjectsand on the day of challenge.
Type of study: self-contained.
Data collection: electronicCase Report Form (eCRF).
 
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Safety monitoring:

Each subject will be observed for at least 30 minutes after vaccination to 
evaluate and treat any acute AEs.
Each subject will be observed for at least 30 minutes following completion of 
the sporozoite challenge to evaluate and treat any acute allergic reactions.
All SAEs (all, fatal, related to the investigational vaccine) and pregnancies will 
be reported until study end (Day 376).
All AEs and SAEs leading to withdrawal from further vaccination will be 
reported until study end (Day 376)for all vaccinated subjects (AduFx, 2PedFx, 
PedFx, Adu2Fx, and Adu1Fx groups).

Meningitis and pIMDs are AEs of specific interest to be reported until study end 
(Day 376; see Section 9.1.5)for all vaccinated subjects (AduFx, 2PedFx, PedFx, 
Adu2Fx, and Adu1Fx groups).

Solicited local and general AEs will be collected from all vaccinated subjects 
(AduFx, 2PedFx, PedFx, Adu2Fx, and Adu1Fx groups) during seven days (day 
of vaccination and six subsequent days) after each dose of study vaccine.
Unsolicited AEs will be collected from all vaccinated subjects (AduFx, 2PedFx, 
PedFx, Adu2Fx, and Adu1Fx groups) during 30 days (day of vaccination and 29 
subsequent days) after each dose of study vaccine.
AEs post-challengewill be collected from all subjects (AduFx, 2PedFx, PedFx,
Adu2Fx, Adu1Fx, and infectivity control groups) during 30 days (day of 
challenge and 29 subsequent days) after the sporozoite challenge.
Biochemistry (ALT, AST and creatinine) and hematology (hemoglobin, WBC 
and platelets) parameters will be assessed as described in ‘Sampling schedule’.
4.
CASE DEFINITION
Table 5
Case definition of P. falciparuminfection
Case definition
Asexua
l b
lood stage P. fa
lc
iparumparas
ite dens
ity > 0 detected by b
lood s
l
ide read
ing.
 
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5.
STUDY COHORT
5.1.
Number of subjects/centers
The target is to enroll approximately 150 subjects (26 subjects per vaccine group and 
between 20 and 30 subjects in the infectivity control group) aged 18 to 55years at the 
time of first vaccination. Refer to Section 11.4for the determination of sample size.
Overview of the recruitment plan
Recruitment will be conducted using multiple methods such as advertisements, flyers, 
posters, word of mouth and other institutional review board (IRB) approved methods. 
There will be an opportunity for subjects whoenroll in the study to receive compensation 
for recruitment of additional subjects.
Recruitment for the vaccine groupswill be terminated when 26 subjects per vaccine 
group have been enrolled (i.e. informed consent form signed), eligible per screening and
inclusion/exclusion criteria and available on the day of first vaccination.
Recruitment for infectivity control group will be terminated when a maximum of 30
subjects have been enrolled (i.e. informed consent form signed), eligible per screening 
and inclusion/exclusion criteria, and available on the day of challenge.For infectivity 
control group only, in the rare event that malaria-naïve volunteers cannot be recruited, 
subjects may be enrolled if they have not been diagnosed with malaria (clinical diseaseor 
parasitemia) within the last five years (inclusive).
5.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the diary cards, return for follow-up 
visits).

Written informed consent obtained from the subject prior to performingof any study 
specific procedure.
A male or female between, and including, 18 and 55years of age at the time of 
enrolment.
Healthy subjects as established by medical history and clinical examination before 
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Available to participate for the duration of the study (approximately 16months per 
vaccinated subject and approximately threemonths per subject in the infectivity 
control group).
Female subjects of non-childbearing potential may be enrolled in the study.

Non-childbearing potential is defined as pre-menarche, current tubal ligation, 
hysterectomy, ovariectomy or post-menopause.
Please refer to the glossary of termsfor the definition of menarche and menopause.
Female subjects of childbearing potential may be enrolled in the study, if the subject:
has practiced adequate contraception for 30 days prior to vaccination, and

has a negative pregnancy test atenrolment, and
has agreed to continue adequate contraception during the entire treatment period 
and for two months after completion of the vaccination seriesand/or malaria 
challenge.
Please refer to the glossary of termsfor the definition of adequate contraception.
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 ANYexclusion 
criterion applies, the subject must not be included in the study:
Use of any investigational or non-registered product (drug or vaccine) 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 (IM) 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 
≥20 mg/day (for adult subjects), or equivalent. Inhaled and topical steroids are 
allowed.
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab).

Chronic use of antibiotics with antimalarial effects (e.g. tetracyclines for 
dermatologic patients, sulfa for recurrent urinary tract infections, etc.).
Planned administration/administration ofa vaccine not foreseen by the study 
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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).
Seropositive for HBsAg or HCV.
Documented HIV-positive subject.
Previous vaccination against malaria.
History of malaria chemoprophylaxis within 60 days prior to vaccination.
Any history of malaria(for the vaccinegroups).
Planned travel to malaria endemic areas during the study period.
History of splenectomy.
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination.
Family history of congenital or hereditary immunodeficiency.
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine.
History of anaphylaxis post-vaccination.
Hypersensitivity to latex.
History of any reaction or hypersensitivity likely to be exacerbated by chloroquine.
History of psoriasis and porphyria, which may be exacerbated after chloroquine 
treatment.

Current use of medications known to cause drug reactions to chloroquine.
History of severe reactions to mosquito bites.
Major congenital defects.
Serious chronic illness.
History of any neurological disorders or seizures (except for a single episode of 
simple febrile seizure in childhood).

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.
Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by physical examination or laboratory 
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Any abnormal baseline laboratory screening tests: ALT, AST, creatinine, 
hemoglobin, platelet count, total WBC, out of normal range as defined in the 
protocol.

Evidence of increased cardiovascular disease risk, "moderate" or "high", according 
to the National health and nutrition examination survey I (NHANES I) criteria.
Note: NHANES I criteria will be applied for all subjects including subjects aged 18-
35 years old(seeAPPENDIX C).
An abnormal baseline screening electrocardiogram, defined as one showing 
pathologic Q waves and significant ST-T wave changes; left ventricular 
hypertrophy; any non-sinus rhythm excluding isolated premature atrial 
contractions;right or left bundle branch block; or advanced (secondary or 
tertiary) A-V heart block.

Hepatomegaly, right upper quadrant abdominal pain or tenderness.
Personal history of autoimmune disease.
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.
Pregnant or lactating female.
History of chronic alcohol consumption and/or drug abuse.

Female planning to become pregnant or planning to discontinue contraceptive 
precautions.

History of blood donation within 56 days preceding enrolment.
Any other significant finding that in the opinion of the investigator would increase 
the risk of having an adverse outcome fromparticipating in this study.
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 Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki. 
GSK will obtain favorableopinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
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Conduct of the study includes, but is not limited to, the following:
IRB/Independent Ethics Committee (IEC) review and favorableopinion/approval of 
study protocol and any subsequent amendments.
Subject 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, orboth.
Freely given and writtenor witnessed/ thumb printed informed consent must be obtained 
from each subject, as appropriate, priorto participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICHGCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgment, local regulations and requirements should guide the final 
structure and content of the local version of the ICF. 
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICFgenerated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
6.2.
Subject identification and randomizationof treatment
6.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented toparticipate in the study, according to the range of subject identification 
numbers allocated to the center.
6.2.2.
Randomizationof treatment
6.2.2.1.
Randomizationof supplies
The list of treatment numbers for the supplies is generated at GSK Biologicals, using 
MATerialEXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS) (Cary, NC, USA) by GSK Biologicals.
6.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
 
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6.2.2.2.1. Study group and treatment number allocation
The target is to enroll approximately 150 subjects (26 subjects per vaccine group and 
between 20 and 30 subjects in the infectivity control group). Randomization will be 
performed on the investigational vaccine groups (AduFx, 2PedFx, PedFx, Adu2Fx, and 
Adu1Fx) and not for the infectivity controls. The first enrolled 130 subjects will be 
allocated to the vaccine groups (AduFx, 2PedFx, PedFx, Adu2Fx, and Adu1Fx) and the 
subsequent subjects will be allocated to the infectivity controls group.
Allocation of thesubject to a study group at the investigator site will be performed using 
a randomizationsystem on internet (SBIR). The randomizationalgorithm will use a 
minimizationprocedure accounting for center.
After obtaining the signed and dated ICFfrom the subject and having checked the 
eligibility of the subject, the site staff in charge of the vaccineadministration will access 
SBIR. Upon providing the subject identification number, the randomizationsystem will
determine the study group and will provide the treatment number to be used for the first 
dose.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
6.2.2.2.2. Treatment number allocation for subsequent doses
For each dose subsequent to the first dose, the studystaff in charge of the vaccine
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
6.3.
Method of blinding
This study is 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.
 
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6.4.1.
Mosquitochallenge
Subjects from the five vaccine groups (AduFx, 2PedFx, PedFx, Adu2Fx, and Adu1Fx)
completing their immunization course will be challenged with sporozoite-infected 
mosquitoes to determine whether the expected protective response has developed. Such 
challenges are mandated by the absence of any laboratory tests that will unequivocally 
predict protection. The challenge is scheduled to occur approximately 90 days (three 
months) after the last vaccination (Day 286[Visit 11]).
Unimmunized infectivity control subjects will also be challenged to verify the adequacy 
of the challenge.
Subjects undergoing malaria challenge will receive an emergency notification card that 
outlines their participation in the study with details on the exposure to malaria, as well as 
the appropriate investigator contact telephone numbers. Details of this information may 
vary, depending on the venue selected for the hotel phase of the study.
6.4.1.1.
Contraindications to malaria challenge
The only absolute contraindication to mosquito challenge is pregnancy. If this occurs 
after immunization but before undergoing challenge, the subject must not be challenged 
and she will be followed for the duration of the study or pregnancy whichever is longer.
Asubject with a minor illness but who does not have fever during the pre-challenge 
assessmentmay be challenged at the discretion of the investigator. If the subject is 
moderately to severely ill with fever on the day of the challenge, he/she will not be 
challenged. Challenge can be performed within the time window defined in Table 9, 
Table 10and Table 11, at the discretion of the investigator if the subject becomes well. 
Subjects who will not be challenged will be followed for the duration of the study.
Any conditions which according to the judgment of the investigator would make the 
challenge unsafe.
6.4.1.2.
Parasite and mosquito strains
The 3D7 clone of P. falciparumis a human malaria isolate that has never been passed 
through monkeys, is well adapted to culture, is a good producer of gametocytes that can 
infect mosquitoes, is susceptible to currently available, approved, anti-malarial 
compounds, and has previously been used in the Walter Reed Army Institute of Research 
(WRAIR) challenge model to successfully infect human subjects under a Biologics 
Master File submitted to the Food and Drug Administration (FDA). Master seed lots of 
these parasites have been developed and stored at WRAIR. All blood products used for 
malaria and mosquito culturing will be commercially tested for HIV, HBsAg, HCV, and 
syphilis. The mosquitoes used will be laboratory-born and reared Anophelesstephensi.
 
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6.4.1.3.
Infection of human subjects
Mosquitoes infected approximately 2-3 weeks earlier that are likely to contain 
sporozoites in their salivary glands will be allowed to feed on the subjects. For each 
subject, five mosquitoes will be allowed to feed over five minutes, after which they will 
be dissected to confirm how many were infected, and the salivary glands scored. If 
required, additional mosquitoes will be allowed to feed until a total of five infected 
mosquitoes with a minimum 2+ salivary glands score have fed [Wirtz, 1987]. The 
mosquito feedings will be performed in a secure insectaryof the Department of 
entomology at WRAIR. Subjects will be observed for at least 30 minutes following 
completion of the sporozoite challenge in order to assess them for any evidence of acute 
allergic reactions related to mosquito exposure. To date, no severe allergic reactions 
related to mosquito bites have been documented in the context of the WRAIR malaria 
challengemodel. Routinely, transient local allergic reactions (itching, rash) typical of 
mosquito bites occur at sites of the bites.
6.4.1.4.
Determining parasitemia
Post-challenge, parasitemia will be determined by microscopy of Giemsa-stained thick 
blood films (smear). Microscopy will be performed on thick smears using a validated 
standard operation procedure.
All blood films (positive and negative) will be archived at the study centers for later re-
examination and confirmation, if required.
6.4.1.5.
Management of infected human subjects
The pre-patent period for P. falciparum in man normally averages 9-12 days. In previous 
studies, the pre-patent period in controls varied from 7-18 days. The shortest reported 
pre-patent period in man is five days, and the longest is 25 days [Ballou, 1987]. An 
immunized individual who does not have complete protection may have a prolongation of 
the parasite pre-patent period.
Beginning on Day 5 (Day 291[Visit 12]) after their challenge, subjects will be seen and 
evaluated daily by a study investigator and blood will be drawn for blood smears to check 
for the presence of parasites as described in Section 6.4.1.4. If fever or symptoms develop 
at any time, blood smears will be done more frequently (every 6 to 12 hours), and a study 
investigator will evaluate the subject. A confirmed positive result will be relayed 
immediately to the on-call investigator/study personnel by the microscopists. The 
infection will be treated early (i.e. as soon as parasites can be identified on thick smear) 
according to the treatment regimen outlined in Section 6.4.1.6.
Beginning on Day 9 post-challenge (Day 295[Visit 16]),a group of hotel rooms in the 
local area of WRAIR, will be reserved for malaria-challenged subjects. The subjects will 
be required to spend their nights there to allow for more rapid assessment of any potential 
symptoms of malaria during the hours that the study centers are closed. There will be an 
investigator present on-site and available for subject assessment. There will also be 
qualified study personnel on site 24 hours per day during the hotel phase of the study.
 
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A blood sample for assessment of parasitemia (PCR testing) will be collected on the day 
of subject entry into the hotelphase(Day 295[Visit 16]) to provide the study team an 
estimate of the number of subjects likely to develop malaria within the first few days of 
the hotel phase. This will allow the principal investigator and the study team to maximize 
subject safety byproperly allocating resources and medical personnel to meet any high 
demand periods (i.e. periods when a large number of subjects are/will become ill).These 
samples will be processed by and assessed at WRAIR.
During the hotel phase, all challenged subjects will be assessed on a daily basis in an 
identical manner. An evaluation will be done each morning (headache, muscle aches, 
etc.) and blood will be drawn for smear. All challenged subjects will beinstructedto 
check in with clinical staff by telephone call or in-person each evening during the hotel 
stay until they are positive for malaria. They will be asked if they feel any differently 
since they were seen in the morning.At any time required, the on-duty investigator will 
arrange for the timely production of blood smears, along with their examination and 
interpretation, in order to treat rapidly those subjects in whom therapy for malaria is 
indicated. Once a positive smear is identified, daily blood films will continue to be 
obtained until three consecutive films are negative (separated by more than 12 hours). A 
complete blood count and serum chemistry tests will be done when parasites are initially 
found in the blood(this could be done on the day of parasitemia detection or the day 
after).
The maximum hotel stay for malaria-challenged subjects should be approximately 10 
days (Day 295[Visit 16] to Day 304[Visit 25]). Asubject who develops malaria, is 
treated, and has three consecutive negative malaria smears (separated by more than 12 
hours), will not need to remain in the hotel. The investigators will be responsible for 
accounting for any subjects who do not arrive in the hotel during the challenge phase. If 
required, the investigators will physically locate and treat any malaria-infected subject 
who is unable to maintain the follow-up dictated by this study.
If infection does not develop within 18 days, the subject will be released from staying 
nightly at the hotel. Subjects who do not develop malaria will be required to come to the 
clinical center for evaluation and blood drawing for smears every two days up to 28 days 
post-challenge (Days 306[Visit 26], 308[Visit 27], 310[Visit 28], 312[Visit 29], and 
314[Visit 30]). A subject who develops malaria and has three consecutive (separated by 
more than 12 hours) negative smears following initial treatment may be excused from the 
remaining hotel visits and the late post-challenge clinic visits at Days 306, 308, 310,and 
312(20, 22, 24 and 26 days post-challenge), but will be required to come to the clinic 
center at Day 314(28 days post-challenge [Visit 30]). Telephone contact will be made if 
the subject does not keep a scheduled follow-up appointment. Symptomscreening via 
telephone may suffice in lieu of clinical visits for Days 306, 308, 310, or 312which fall 
upon a weekend.
6.4.1.6.
Malaria treatment
During the evaluation of protective efficacy, as soon as a malaria infection is documented 
in a subject, he/she will be treated with standard doses of oral chloroquine (a total of 
1500 mg chloroquine base: 600 mg base initially, followed by 300 mg base given 
approximately 6, 24, and 48 hours later) under direct observation. This regimen has been 
 
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100% effective in previous WRAIR malaria vaccine studies using the same malaria strain 
as will be used in this challenge model. Such early treatment minimizes the risk of 
developing a complicated malaria infection.Alternatively, atovaquone/proguanil 
(Malarone) standard oral dosage of 1 g/400 mg(four adult tablets per day for three 
consecutive days) or artemether/lumefantrine (Coartem) standard oral dosage of 80 
mg/480 mg (four tablets initial dose, four tablets 8 hours later, and then four tablets twice 
daily for the following two days) can be used to treat subjects.
The malaria strain used for challenge (P. falciparumstrain NF54/clone 3D7) is sensitive 
to several currently available, licensed, anti-malarial drugs that are safe, effective and 
have a low incidence of side effects. The investigators will have available approved 
antipyretics, such as acetaminophen and ibuprofen, for subjects experiencing fever and 
myalgias. In addition, other approved medications will be available to the investigators, 
which may include, but are not limited to: ondansetron andloperamide (Imodium) to treat 
other signs/symptoms as necessary. Investigators will always assure that subjects do not 
have underlying allergies to any of these medications prior to their use. An alternative 
antipyretic will be provided if the subject is allergic to a prescribed drug.
It is anticipated that treatment of malaria will be curative, since relapses do not occur 
after adequate treatment of P. falciparum infections. No previous P. falciparum subject
infected and treated by WRAIR has had a malaria relapse. Subjects will be advised to 
contact the study physician, or to advise their personal physician of their participation in 
this malaria study, if fever, headache, or other symptoms possibly related to malaria 
develop at any time within one year after completion of the study. In the unlikely event 
that malaria recurs, the subject will be retreated with chloroquine, atovaquone/proguanil 
(Malarone) standard oral dosage of 1 g/400 mg(four adult tablets per day for three 
consecutive days), or artemether/lumefantrine (Coartem) standard oral dosage of 80 
mg/480 mg (four tablets initial dose, four tablets 8 hours later, and then four tablets twice 
daily for the following two days).
No human viruses are known to be transmitted by colonized Anopheles mosquitoes. 
Blood purchased for malaria feedings has been commercially tested using FDA-approved 
test methods for antibodies to HIV, HCV, and syphilis, as well as for the presence of 
HBsAg; all blood has tested negatively for these tests. No documented cases of HIV or 
viral hepatitis transmission from mosquitoes to humans have occurred. The risk of 
accidentally transmitting malaria to a person in the community will be negligible 
because:
The infected mosquitoes will be raised insecure insectary at WRAIR.
All malaria challenges occur in a secure insectary.
The infected mosquitoes never leave the secured insectary area at any time.

Malaria infections in subjects will be treated promptly before gametocytes can 
develop (generally ten days after the development of patent malaria), thus the risk of 
transmission to local mosquitoes is reduced.
 
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6.5.
Outline of study procedures
Table 6
List of study procedures for the investigational vaccine groups: AduFx, 2PedFx, PedFx, and Adu2Fx
Epoch
Epoch 001
Epoch 002
Type of contact
Visit 1 
(Scree
ning)
Visit 2Visit 3Visit 4Visit 5Visit 6Visit 7Visit 8Visit 9 Visit 
10 Visit 11
Visit 12
to Visit 
29*
Visit 
Par**Visit 30Visit 
31
Study Month
0
1
7
10
13
Study Day
-90to 
0
0
28 
29 
35 
58 196 197 203 226
286 291to 
312
314 376
Vaccination timepoint
Vacc 1Vacc 2
Vacc 3
CHMI phase
Informed consent
●
Check 
inc
lus
ion/exc
lus
ion cr
iter
iaa
●
O
Check screen
ing 
laboratory resu
ltsb
●
Co
l
lect demograph
ic data
●
Med
ica
l h
istory
●
Record 
informat
ion on past hepat
it
is B 
immun
izat
ionc
●
Phys
ica
l exam
inat
ion
●
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Ur
ine pregnancy test (-HCG)
● 
● 
●
●
●
Check contra
ind
icat
ions to vacc
inat
iond
●
●
●
Record pre-vacc
inat
ion body temperature
●
●
●
Random
izat
ion
●
Treatment number a
l
locat
ion
O
O
O
Record
ing of adm
in
istered treatment number
●
●
●
Vacc
ines adm
in
istrat
ion
●
●
●
Check contra
ind
icat
ions to cha
l
lenged
●
Sporozo
ite cha
l
lenge
●
D
istr
ibut
ion of emergency not
if
icat
ion card
O
B
lood samp
l
ing for HIV, HCV and HBsAg (17 m
l)
●
B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear; 2.0 
m
l)
●***
●
B
lood samp
l
ing for assessment of paras
item
iaat start of hote
l 
phase(PCR; 2.0 m
l)
O****
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Epoch
Epoch 001
Epoch 002
Type of contact
Visit 1 
(Scree
ning)
Visit 2Visit 3Visit 4Visit 5Visit 6Visit 7Visit 8Visit 9 Visit 
10 Visit 11
Visit 12
to Visit 
29*
Visit 
Par**Visit 30Visit 
31
Study Month
0
1
7
10
13
Study Day
-90to 
0
0
28 
29 
35 
58 196 197 203 226
286 291to 
312
314 376
Vaccination timepoint
Vacc 1Vacc 2
Vacc 3
CHMI phase
B
lood samp
l
ing for assessment of ant
ibody determ
inat
ion and 
serum repos
itory (20.0 m
l)
●
● 
●
●
●
● 
●
B
lood samp
l
ing for RNAsequenc
ing (12 m
l)
● 
● 
●
● 
●
B
lood samp
l
ing for PBMC and p
lasma repos
itory (30.0 m
l)
● 
● 
● 
● 
● 
● 
●
●
●
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is (7.5 m
l)e
●
●
●
●
●
●
●
Record any concom
itant med
icat
ions/vacc
inat
ions
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Record any 
intercurrent med
ica
l cond
it
ions
●
●
●
●
●
●
●
●
●
●
●
●
●
●
D
istr
ibut
ion of d
iary cards
O
O
O
Return of d
iary cards
O
O
O
D
iary card transcr
ipt
ion by 
invest
igator
●
●
●
Record
ing of so
l
ic
ited 
loca
l and genera
l AEs (Days 0–6) post-
vacc
inat
ion
● 
●
●
Record
ing of unso
l
ic
ited AEs (Day 0-29) post-vacc
inat
ion
●
●
●
●
●
●
●
●
Record
ing of AEs (Day 0-29) post-cha
l
lenge
●
●
●
●
Record
ing of SAEs (a
l
l, fata
l, re
lated) and pregnanc
ies
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Record
ing of SAEs re
lated to study part
ic
ipat
ion, or to a concurrent 
GSK med
icat
ion/vacc
ine
● 
● 
● 
● 
● 
● 
● 
● 
● 
●
●
●
●
● 
●
Record
ing of a
l
l AEs and SAEs 
lead
ing to w
ithdrawa
l from further 
vacc
inat
ion
● 
● 
● 
● 
● 
● 
● 
● 
●
●
●
●
● 
●
Record
ing of AEs of spec
if
ic 
interestf
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Study Conc
lus
ion
●
-HCG: Beta-human chor
ion
ic gonadotrop
in; PBMC: per
iphera
l b
lood mononuc
lear ce
l
ls; Vacc: vacc
inat
ion.
* V
is
it 12= 291, V
is
it 13= Day 292, V
is
it 14= Day 293, V
is
it 15  = Day 294, V
is
it 16= Day 295, V
is
it 17= Day 296, V
is
it 18= Day 297, V
is
it 19= Day 298, V
is
it 20= Day 299, V
is
it 21
= Day 300, V
is
it 22= Day 301, V
is
it 23= Day 302, V
is
it 24= Day 303, V
is
it 25= Day 304, V
is
it 26= Day 306, V
is
it 27= Day 308, V
is
it 28= Day 310, V
is
it 29= Day 312.
** A b
lood samp
le for b
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia (between V
is
it 12[Day 291] and V
is
it 29[Day 312]).
*** B
lood samp
le for assessment of paras
item
ia (b
lood smear) w
i
l
l be co
l
lected da
i
ly for 14 days (from Day 291[V
is
it 12] to Day 304[V
is
it 25]) and then every two days for n
inedays 
(Day 306[V
is
it 26], Day 308[V
is
it 27], Day 310[V
is
it 28], Day 312[V
is
it 29], and Day 314 [V
is
it 30]). For sub
jects who deve
lop ma
lar
ia, b
lood smear may be d
iscont
inued once the 
sub
ject has three consecut
ive negat
ive smears (separated by more than 12 hours) fo
l
low
ing 
in
it
ia
l treatment.
CONFIDENTIAL
205081 (MALARIA-092)
Protocol Administrative Change 1 Final
5b13e9afe05d352f71d825e4727666a2d3a80e89
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205081 (MALARIA-092)
Protocol Administrative Change 1 Final
19-JUN-2017
65
**** B
lood samp
le for assessment of paras
item
ia (PCR test
ing) w
i
l
l be co
l
lected on the day of sub
ject entry 
into the hote
l (Day 295).
aInc
lud
ing a check of NHANES I cr
iter
ia and e
lectrocard
iogram(seeAPPENDIX C).
bThe screen
ing 
laboratory resu
lts (HIV, HCV, HBsAg, ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes [WBC], p
late
lets, and ur
ine -HCG) must be checked dur
ing the screen
ing 
act
iv
it
ies and before random
izat
ion.
cBased on best ev
idences ava
i
lab
le.
dThere 
is no spec
if
ic sect
ion 
in the eCRF to record the contra
ind
icat
ions, warn
ings and precaut
ions. The abso
lute contra
ind
icat
ions to further adm
in
istrat
ion of study vacc
inesor to 
cha
l
lengehave to be recorded 
in the AE or SAE sect
ion of the eCRF.
eB
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is 
inc
ludes ALT, AST, creat
in
ine,hemog
lob
in, 
leukocytes (WBC), and p
late
lets.
fAEs of spec
if
ic 
interest 
inc
lude men
ing
it
is and pIMDs (see Sect
ion 9.1.5).
● 
is used to 
ind
icate a study procedure that requ
ires documentat
ion 
in the 
ind
iv
idua
l eCRF.
○ 
is used to 
ind
icate a study procedure that does not requ
ire documentat
ion 
in the 
ind
iv
idua
l eCRF.
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Table 7
List of study procedures for the investigational vaccine group: Adu1Fx
Epoch
Epoch 001
Epoch 002
Type of contact
Visit 1 
(Screenin
g)
Visit 2 Visit 3 Visit 7 Visit 8 Visit 9
Visit 10Visit 11
Visit 12
to Visit 
29*
Visit 
Par**Visit 30Visit 
31
Study Month
0
1
7
10
13
Study Day
-90to 0 
0
28 
196 
197 
203 
226
286 291to 
312
314 376
Vaccination timepoint
Vacc 1
Vacc 2
CHMI phase
Informed consent
●
Check 
inc
lus
ion/exc
lus
ion cr
iter
iaa
●
O
Check screen
ing 
laboratory resu
ltsb
●
Co
l
lect demograph
ic data
●
Med
ica
l h
istory
●
Record 
informat
ion on past hepat
it
is B 
immun
izat
ionc
●
Phys
ica
l exam
inat
ion
●
O
O
O
O
O
O
O
O
O
O
O
Ur
ine pregnancy test (-HCG)
● 
●
●
●
Check contra
ind
icat
ions to vacc
inat
iond
●
●
Record pre-vacc
inat
ion body temperature
●
●
Random
izat
ion
●
Treatment number a
l
locat
ion
O
O
Record
ing of adm
in
istered treatment number
●
●
Vacc
ines adm
in
istrat
ion
●
●
Check contra
ind
icat
ions to cha
l
lenged
●
Sporozo
ite cha
l
lenge
●
D
istr
ibut
ion of emergency not
if
icat
ion card
O
B
lood samp
l
ing for HIV, HCV and HBsAg (17 m
l)
●
B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear; 2.0 
m
l)
●***
●
B
lood samp
l
ing for assessment of paras
item
ia at start of hote
l 
phase (PCR; 2.0 m
l)
O****
B
lood samp
l
ing for assessment of ant
ibody determ
inat
ion and 
serum repos
itory (20.0 m
l)
●
●
●
●
● 
●
B
lood samp
l
ing for RNAsequenc
ing (12 m
l)
● 
● 
● 
●
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Epoch
Epoch 001
Epoch 002
Type of contact
Visit 1 
(Screenin
g)
Visit 2 Visit 3 Visit 7 Visit 8 Visit 9
Visit 10Visit 11
Visit 12
to Visit 
29*
Visit 
Par**Visit 30Visit 
31
Study Month
0
1
7
10
13
Study Day
-90to 0 
0
28 
196 
197 
203 
226
286 291to 
312
314 376
Vaccination timepoint
Vacc 1
Vacc 2
CHMI phase
B
lood samp
l
ing for PBMC and p
lasma repos
itory (30.0 m
l)
● 
● 
●
● 
●
●
●
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is (7.5 m
l)e
●
●
●
●
●
Record any concom
itant med
icat
ions/vacc
inat
ions
●
●
●
●
●
●
●
●
●
●
●
Record any 
intercurrent med
ica
l cond
it
ions
●
●
●
●
●
●
●
●
●
●
●
D
istr
ibut
ion of d
iary cards
O
O
Return of d
iary cards
O
O
D
iary card transcr
ipt
ion by 
invest
igator
●
●
Record
ing of so
l
ic
ited 
loca
l and genera
l AEs (Days 0–6) post-
vacc
inat
ion
●
●
Record
ing of unso
l
ic
ited AEs (Day 0-29) post-vacc
inat
ion
●
●
●
●
●
Record
ing of AEs (Day 0-29) post-cha
l
lenge
●
●
●
●
Record
ing of SAEs (a
l
l, fata
l, re
lated) and pregnanc
ies
●
●
●
●
●
●
●
●
●
●
●
Record
ing of SAEs re
lated to study part
ic
ipat
ion, or to a concurrent 
GSK med
icat
ion/vacc
ine
● 
● 
● 
● 
● 
● 
●
●
●
●
● 
●
Record
ing of a
l
l AEs and SAEs 
lead
ing tow
ithdrawa
l from further 
vacc
inat
ion
● 
● 
● 
● 
● 
●
●
●
●
● 
●
Record
ing of AEs of spec
if
ic 
interestf
●
●
●
●
●
●
●
●
●
●
●
Study Conc
lus
ion
●
-HCG: Beta-human chor
ion
ic gonadotrop
in; PBMC: per
iphera
l b
lood mononuc
lear ce
l
ls; Vacc: vacc
inat
ion.
*V
is
it 12= Day 291,V
is
it 13= Day 292, V
is
it 14= Day 293, V
is
it 15  = Day 294, V
is
it 16= Day 295, V
is
it 17= Day 296, V
is
it 18= Day 297, V
is
it 19= Day 298, V
is
it 20= Day 299, V
is
it 
21= Day 300, V
is
it 22= Day 301, V
is
it 23= Day 302, V
is
it 24= Day 303, V
is
it 25= Day 304, V
is
it 26= Day 306, V
is
it 27= Day 308, V
is
it 28= Day 310, V
is
it 29= Day 312.
** A b
lood samp
le for b
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia (between V
is
it 12[Day 291] and V
is
it 29[Day 312]).
*** B
lood samp
le for assessment of paras
item
ia (b
lood smear) w
i
l
l be co
l
lected da
i
ly for 14 days (from Day 291[V
is
it 12] to Day 304[V
is
it 25]) and then every two days for n
inedays 
(Day 306[V
is
it 26], Day 308[V
is
it 27], Day 310[V
is
it28], Day 312[V
is
it 29], and Day 314 [V
is
it 30]). For sub
jects who deve
lop ma
lar
ia, b
lood smear may be d
iscont
inued once the 
sub
ject has three consecut
ive negat
ive smears (separated by more than 12 hours) fo
l
low
ing 
in
it
ia
l treatment.
**** B
lood samp
le for assessment of paras
item
ia (PCR test
ing) w
i
l
l be co
l
lected on the day of sub
ject entry 
into the hote
l (Day 295).
aInc
lud
ing a check of NHANES I cr
iter
ia and e
lectrocard
iogram(seeAPPENDIX C).
CONFIDENTIAL
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bThe screen
ing 
laboratory resu
lts (HIV, HCV, HBsAg, ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes [WBC], p
late
lets, and ur
ine -HCG) must be checked dur
ing the screen
ing 
act
iv
it
ies and before random
izat
ion.
cBased on best ev
idences ava
i
lab
le.
dThere 
is no spec
if
ic sect
ion 
in the eCRF to record the contra
ind
icat
ions, warn
ings and precaut
ions. The abso
lute contra
ind
icat
ions to further adm
in
istrat
ion of study vacc
inesor to 
cha
l
lengehave to be recorded 
in the AE or SAE sect
ion of the eCRF.
eB
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is 
inc
ludes ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes (WBC), and p
late
lets.
fAEs of spec
if
ic 
interest 
inc
lude men
ing
it
is and pIMDs (see Sect
ion 9.1.5).
● 
is used to 
ind
icate a study procedure that requ
ires documentat
ion 
in the 
ind
iv
idua
l eCRF.
○ 
is used to 
ind
icate a study procedure that does not requ
ire documentat
ion 
in the 
ind
iv
idua
l eCRF.
CONFIDENTIAL
205081 (MALARIA-092)
Protocol Administrative Change 1 Final
5b13e9afe05d352f71d825e4727666a2d3a80e89
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CONFIDENTIAL
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Protocol Administrative Change 1 Final
19-JUN-2017
69
Table 8
List of study procedures for the infectivity control group
Epoch
Epoch 002
Type of contact
Visit 1b 
(Screening)*
Visit 11
Visit 12to Visit 29** Visit Par***
Visit 30
Study Day
230to 286
286
291to 312
314
Informed consent
●
Check 
inc
lus
ion/exc
lus
ion cr
iter
iaa
●
O
Check screen
ing 
laboratory resu
ltsb
●
Co
l
lect demograph
ic data
●
Med
ica
l h
istory
●
Record 
informat
ion on past hepat
it
is B 
immun
izat
ion
c
●
Phys
ica
l exam
inat
ion
●
O
O
O
O
Ur
ine pregnancy test (-HCG)
●
●
Check contra
ind
icat
ions to cha
l
lenged
●
Sporozo
ite cha
l
lenge
●
D
istr
ibut
ion of emergency not
if
icat
ion card
O
B
lood samp
l
ing for HIV, HCV and HBsAg (17 m
l)
●
B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear; 2.0m
l)
●****
●
B
lood samp
l
ing for assessment of paras
item
ia at start of hote
l phase (PCR; 2.0 m
l)
O*****
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is (7.5 m
l)
e
●
●
●
Record any concom
itant med
icat
ions/vacc
inat
ions
●
●
●
●
Record any 
intercurrent med
ica
l cond
it
ions
●
●
●
●
Record
ing of AEs (Day 0-29) post-cha
l
lenge
●
●
●
●
Record
ing of SAEs (a
l
l, fata
l, re
lated) and pregnanc
ies
●
●
●
●
Record
ing of SAEs re
lated to study part
ic
ipat
ion, or to a concurrent GSK med
icat
ion/vacc
ine
●
●
●
●
●
Study Conc
lus
ion
●
-HCG: Beta-human chor
ion
ic gonadotrop
in; PBMC: per
iphera
l b
lood mononuc
lear ce
l
ls.
* Th
is v
is
it 
is on
ly app
l
icab
le to the 
infect
iv
ity contro
l group
**V
is
it 12= Day 291, V
is
it 13= Day 292, V
is
it 14= Day 293, V
is
it 15  = Day 294, V
is
it 16= Day 295, V
is
it 17= Day 296, V
is
it 18= Day 297, V
is
it 19= Day 298, V
is
it 20= Day 299, 
V
is
it 21= Day 300, V
is
it 22= Day 301, V
is
it 23= Day 302, V
is
it 24= Day 303, V
is
it 25= Day 304, V
is
it 26= Day 306, V
is
it 27= Day 308, V
is
it 28= Day 310, V
is
it 29= Day 312.
*** A b
lood samp
le for b
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia (between V
is
it 12[Day 291] and V
is
it 29[Day 312]).
**** B
lood samp
le for assessment of paras
item
ia (b
lood smear) w
i
l
l be co
l
lected da
i
ly for 14 days (from Day 291[V
is
it 12] to Day 304[V
is
it 25]) and then every two days for n
inedays 
(Day 306[V
is
it 26], Day 308[V
is
it 27], Day 310[V
is
it 28], Day 312[V
is
it 29], and Day 314 [V
is
it 30]). For sub
jects who deve
lop ma
lar
ia, b
lood smear may be d
iscont
inued once the 
sub
ject has three consecut
ive negat
ive smears (separated by more than 12 hours) fo
l
low
ing 
in
it
ia
l treatment.
***** B
lood samp
le for assessment of paras
item
ia (PCR test
ing) w
i
l
l be co
l
lected on the day of sub
ject entry 
into the hote
l (Day 295)
CONFIDENTIAL
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aInc
lud
ing a check of NHANES I cr
iter
ia and e
lectrocard
iogram(seeAPPENDIX C).
bThe screen
ing 
laboratory resu
lts (HIV, HCV, HBsAg, ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes [WBC], p
late
lets, and ur
ine -HCG) must be checked dur
ing the screen
ing 
act
iv
it
ies and before random
izat
ion.
cBased on best ev
idences ava
i
lab
le.
dThere 
is no spec
if
ic sect
ion 
in the eCRF to record the contra
ind
icat
ions, warn
ings and precaut
ions. The abso
lute contra
ind
icat
ions to cha
l
lenge have to be recorded 
in the AE or SAE 
sect
ion of the eCRF.
eB
lood samp
l
ingfor hemato
logy and b
iochem
istry ana
lys
is 
inc
ludes ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes (WBC), and p
late
lets.
● 
is used to 
ind
icate a study procedure that requ
ires documentat
ion 
in the 
ind
iv
idua
l eCRF.
○ 
is used to 
ind
icate a study procedure that does not requ
ire documentat
ion 
in the 
ind
iv
idua
l eCRF.
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Table 9
Intervals between study visits for the investigational vaccine 
groups: AduFx, 2PedFx, PedFx, and Adu2Fx
Interval
Optimal length of 
interval 
1
Allowed interval2
V
is
it 1 (Screen
ing)V
is
it 2(1
st
vacc
inat
ion)
0 to 90days
-
V
is
it 2V
is
it 3(2
ndvacc
inat
ion)
28days
7days
V
is
it 3V
is
it 5
7days
1day
V
is
it 3V
is
it 6
30days
7days
V
is
it 3V
is
it 7(3
rdvacc
inat
ion)
168days
14days
V
is
it 7V
is
it 9
7days
1day
V
is
it 7V
is
it 10
30days
7days
V
is
it 7V
is
it 11(Cha
l
lenge)
90days
+ 14days
V
is
it 11V
is
it 30
28days
7days
V
is
it 30V
is
it 31
62days
14days
1 Whenever poss
ib
le the 
invest
igator shou
ld arrange study v
is
its w
ith
in th
is 
interva
l.
2 Sub
jects maynot be e
l
ig
ib
le for 
inc
lus
ion 
in the accord
ing-to-protoco
l (ATP) cohort for ana
lys
is of 
immunogen
ic
ity
and eff
icacyif they make the study v
is
it outs
ide th
is 
interva
l.
Table 10
Intervals between study visits for the investigational vaccine 
groups: Adu1Fx
Interval
Optimal length of 
interval 
1
Allowed interval2
V
is
it 1 (Screen
ing)V
is
it 2(1
st
vacc
inat
ion)
0 to 90days
-
V
is
it 2 V
is
it 7 (2ndvacc
inat
ion)
196days
14days
V
is
it 7V
is
it 9
7days
1day
V
is
it 7V
is
it 10
30days
7days
V
is
it 7V
is
it 11(Cha
l
lenge)
90days
+ 14days
V
is
it 11V
is
it 30
28days
7days
V
is
it 30V
is
it 31
62days
14days
1 Whenever poss
ib
le the 
invest
igator shou
ld arrange study v
is
its w
ith
in th
is 
interva
l.
2 Sub
jects maynot be e
l
ig
ib
le for 
inc
lus
ion 
in the ATP cohort for ana
lys
is of 
immunogen
ic
ity and eff
icacyif they make 
the study v
is
it outs
ide th
is 
interva
l.
Table 11
Intervals between study visits for the infectivity control group
Interval
Optimal length of 
interval 
1
Allowed interval2
V
is
it 1b (Screen
ing)V
is
it 11(Cha
l
lenge)
0 to 56days
-
V
is
it 11V
is
it 30
28days
7days
1 Whenever poss
ib
le the 
invest
igator shou
ld arrange study v
is
its w
ith
in th
is 
interva
l.
2 Sub
jects maynot be e
l
ig
ib
le for 
inc
lus
ion 
in the ATP cohort for ana
lys
is of 
immunogen
ic
ity and eff
icacyif they make 
the study v
is
it outs
ide th
is 
interva
l.
 
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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 subjectmust be obtained 
before study participation. Refer to Section 6.1for 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 5.2and 5.3before 
enrolment.
The check of inclusion and exclusion criteria will include an electrocardiogram and the 
check of NHANES I criteria (seeAPPENDIX C).
6.6.3.
Check screening laboratory results
Checkthe results ofthe laboratory tests for HIV, HCV, HBsAg, ALT, AST, creatinine, 
hemoglobin, leukocytes (WBC), platelets, and urine -HCG to assess if the subject meets 
the related exclusion criteria as described in Section 5.3.
6.6.4.
Collect demographic data
Record demographic data such as date of birth, gender, and geographic ancestry in the 
subject’s eCRF.
6.6.5. 
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 firststudy vaccinationin the eCRF.
6.6.6.
Record information on past hepatitis B immunization
Record information on past hepatitis B immunization in the subject’s eCRF, based on 
best evidences available.
6.6.7.
Physical examination
Perform a physical examination of the subject, including assessment of body temperature
and recording of height and body weight.Collected information needs to be recorded in 
the eCRF.
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.
Urine pregnancy test
Female subjects areto have a urine pregnancy test at the screening visit and prior to any 
study vaccine administration. The study vaccinesmay only be administered if the 
pregnancy test is negative. Note: The urine pregnancy test mustbe performed even if the 
subject is menstruating at the time of the study visit.
Female subjects are also to have a urine pregnancy test prior to the sporozoite challenge. 
The sporozoite challengemay only be performed if the pregnancy test is negative.
6.6.9.
Check contraindicationsto vaccination
Contraindicationsto vaccination must be checked at the beginning of eachvaccination 
visit. Refer to Section7.5for more details.
This procedure is only applicable to subjects of the investigational vaccine groups, i.e.
AduFx, 2PedFx, PedFx, Adu2Fx,and Adu1Fx.
6.6.10.
Assess pre-vaccination body temperature
The axillary, rectal, oral or tympanicbody temperature of all subjects needs to be 
measured prior to any study vaccinesadministration. The preferred route for recording 
temperature in this study will be oral. If the subject has fever (fever is defined as 
temperature 37.5°C/99.5°F for oral, axillary or tympanicroute, or 38.0°C/100.4°F for 
rectal route)on the day of vaccination, the vaccination visit will be rescheduled within 
the allowed interval for this visit (see Table 9and Table 10).
This procedure is only applicable to subjects of the investigational vaccine groups, i.e.
AduFx, 2PedFx, PedFx, Adu2Fx,and Adu1Fx.
6.6.11.
Randomization and treatment number allocation
Study groupand 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.
This procedure is only applicable to subjects of the investigational vaccine groups, i.e.
AduFx, 2PedFx, PedFx, Adu2Fx,and Adu1Fx.
 
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6.6.12.
Study vaccines administration
After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly in the deltoid of the non-dominant arm 
(refer to Section 7.3for 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 (see Table 9andTable 10).

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.
This procedure is only applicable to subjects of the investigational vaccine groups, 
i.e. AduFx, 2PedFx, PedFx, Adu2Fx, and Adu1Fx.
6.6.13.
Check contraindications to challenge
Contraindications to sporozoite challenge are to be checkedfor all subjectsat the 
beginning of thechallenge visit as described in Section 6.4.1.1.
6.6.14.
Sporozoite challenge
After completing the prerequisite procedures prior to challenge, allsubjectswill be 
challenged with malaria as outlined in Section 6.4.1.3.
6.6.15.
Distribution of emergency notification card
Upon entry into the challenge phase of the study, all subjectswill be issuedan emergency 
notification card containing the subject’s name, details on the exposureto malaria and a 
24-hour emergency telephone contact numbers for study investigators.
6.6.16.
Sampling
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 HIV, HCV and HBsAg
A volume of approximately17.0 ml of whole blood should be drawn from all
subjects screened to assess HIV, HCV and HBsAg status (see Table 6, Table 7and 
Table 8).
Blood sampling for initial assessment of parasitemia (PCR)
A volume of approximately 2.0 ml should be drawn from all subjects on the day of 
subject entry to the hotel phase (Day 295[Visit 16])for the assessment of 
parasitemia by PCR testing toprovide the study team an estimate of the number of 
subjects likely to develop malaria within the first few days of the hotel phase (see 
Table 6, Table 7and Table 8). 
 
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Blood sampling for assessment of parasitemia(blood smear)
A volume of approximately 2.0 ml should be drawn from all subjects at each pre-
defined timepoint for the assessment of parasitemia by blood smear (see Table 6,
Table 7and Table 8). For subjects who develop malaria, blood samples for smears 
may be discontinuedonce the subjecthas three consecutive negativesmears 
(separated by more than 12 hours)following initial treatment.
Blood sampling for assessment of antibody determination and serum repository
For subjects of the investigational vaccine groups(AduFx, 2PedFx, PedFx, Adu2Fx, 
and Adu1Fx), avolume of at least 20.0ml of whole blood (to provide at least 10ml
of serum for anti-CS enzyme-linked immunosorbent assay [ELISA], anti-CS avidity, 
anti-HBs, and serum repository) should be drawn at each pre-defined timepoint (see 
Table 6andTable 7).After centrifugation, serum samples should be kept at –20°C/ –
4°F or below until shipment.
Blood sampling for RNAsequencing
For subjects of the investigational vaccine groups(AduFx, 2PedFx, PedFx, Adu2Fx, 
and Adu1Fx), avolume of approximately12.0ml of whole blood should be drawn at
each pre-defined timepoint for RNAsequencing (mRNA sequencing analysis; see 
Table 6andTable 7).The blood should be stored at room temperature (20 to 25°C) 
until they are transferred to the designated laboratory for further processing.
Blood sampling for PBMC and plasmarepository
For subjects of the investigational vaccine groups (AduFx, 2PedFx, PedFx, Adu2Fx, 
and Adu1Fx), avolume of approximately30.0ml of whole blood should be drawn at 
each pre-defined timepoint for the purpose of the PBMC and plasmarepository (see 
Table 6and Table 7). The blood should be stored at room temperatureuntil it is 
transferred to the designated laboratory for further processing.The purified PBMC 
should be stored in liquid nitrogen and plasma at -20°C or colder until further
processing.
Blood sampling for hematology and biochemistry analysis
A volume of approximately7.5 ml of whole blood should be drawn from all subjects 
at each pre-defined timepoint for the assessment of safety parameters (ALT, AST, 
creatinine, hemoglobin, leukocytes [WBC], and platelets; see Table 6, Table 7and 
Table 8).
6.6.17.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions
Concomitant medication/vaccination must be checked and recorded in the eCRFas 
described in Section 7.6.
Intercurrent medical conditions must be checked and recorded in the eCRFas described 
in Section 7.7.
 
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6.6.18.
Recording of AEs, SAEs, pregnancies and AEs of specific 
interest

For subjects of the investigational vaccine groups (AduFx, 2PedFx, PedFx, Adu2Fx, 
and Adu1Fx)
Refer to Section 9.3for procedures for the investigator to record AEs, SAEs, 
pregnancies and AEs of specific interest (meningitis and pIMDs). Refer to 
Section 9.4for guidelinesandhow to reportSAE, pregnancy and AEs of 
specific interest reports to GSK Biologicals.

The subjectswill be instructed to contactthe investigator immediately should 
theymanifest any signs or symptoms they perceive as serious.

At each vaccination visit, diary cards will be provided to the subject. The subject 
will record body (oral)temperature and any solicited local/general AEs (i.e. on 
the day of vaccination and during the next sixdays)or any unsolicited AEs (i.e. 
on the day of vaccination and during the next 29days)occurring after 
vaccination. The subjectwill be instructed to return the completed diary card to 
the investigator at the next study visit.

Collect and verify completed diary cards during discussion with the subject on 
Visit 3, Visit 6and Visit 10for subjects of AduFx, 2PedFx, PedFx,andAdu2Fx
groups and on Visit 3and Visit 10for subjects of Adu1Fxgroups.
Any unreturned diary cards will be sought from the subjectthrough telephone 
call(s) or any other convenient procedure. The investigator will transcribe the 
collected information into the eCRFin English.
For subjects of the infectivity controls group

Refer to Section 9.3for procedures for the investigator to record AEs,SAEsand 
pregnancies. Refer to Section 9.4for guidelines and how to report SAEand 
pregnancyreports to GSK Biologicals.
The subjects will be instructed to contact the investigator immediately should 
they manifest any signs or symptoms they perceive as serious.
6.6.19.
Study conclusion
The investigator will:
review data collected to ensure accuracy and completeness

complete the Study Conclusion screenin 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 labeledwith information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).
 
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Collected samples will be used forprotocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.
It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed, will be asked to give a specific 
consentto allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to the laws and regulations in the respective countries 
and will only be performed once an independent Ethics Committee or Review Board 
has approved this research.
Information on further investigations and their rationale can beobtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject. 
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 6.7.4may 
be changed.
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 MANDATORYthat all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 11.5for the definition of 
cohortsto be analyzed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision complywith this requirement. However, when 
GSK Biologicals does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM.
6.7.2.
Biological samples
Details of the quantity of biological sample to be taken at each timepoint during the study
are provided in Table 12.
 
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Table 12
Biological samples(whole blood)
Study Phase
Timepoint
Sample type
Total volume of blood per visit (ml)
AduFx
2PedFx 
PedFx
Adu2Fx 
Adu1Fx Infectivity 
control
Pre-vacc
inat
ion
V
is
it 1 (Screen
ing)
B
lood samp
l
ing for HIV, HCV and HBsAg
17.0 m
l
17.0 m
l
17.0 m
l
17.0 m
l
17.0 m
l
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
Total: 24.5 ml
24.5 ml
24.5 ml
24.5 ml
24.5 ml
-
V
is
it 2(Day 0)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for RNA sequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
B
lood samp
l
ing for PBMC and p
lasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
Total: 62.0 ml
62.0 ml
62.0 ml
62.0 ml
62.0 ml
-
Post-Dose 1
V
is
it 3(Day 28)
B
lood samp
l
ing for RNA sequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
B
lood samp
l
ing for PBMC and p
lasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
Total: 42.0 ml
42.0 ml
42.0 ml
42.0 ml
42.0 ml
-
Post-Dose 2* or 
Post-Dose 1**
V
is
it 4(Day 29)
B
lood samp
l
ing for RNA sequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
-
Total: 12.0 ml
12.0 ml
12.0 ml
12.0 ml
-
-
V
is
it 5(Day 35)
B
lood samp
l
ing for PBMC and p
lasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
-
Total: 37.5 ml
37.5 ml
37.5 ml
37.5 ml
-
-
V
is
it 6(Day 58)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
- 
-
B
lood samp
l
ing for PBMC and p
lasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
-
Total: 57.5 ml
57.5 ml
57.5 ml
57.5 ml
-
-
V
is
it 7(Day 196)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for RNA sequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
B
lood samp
l
ing for PBMC and p
lasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
Total: 62.0 ml
62.0 ml
62.0 ml
62.0 ml
62.0 ml
-
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Study Phase
Timepoint
Sample type
Total volume of blood per visit (ml)
AduFx
2PedFx 
PedFx
Adu2Fx 
Adu1Fx Infectivity 
control
Post-Dose 3* or 
Post-Dose 2**
V
is
it 8(Day 197)
B
lood samp
l
ing for RNA sequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
Total: 12.0 ml
12.0 ml
12.0 ml
12.0 ml
12.0 ml
-
V
is
it 9(Day 203)
B
lood samp
l
ing for PBMC and p
lasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
Total: 37.5 ml
37.5 ml
37.5 ml
37.5 ml
37.5 ml
-
V
is
it 10(Day 226)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for PBMC and p
lasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0m
l
30.0 m
l
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
Total: 57.5 ml
57.5 ml
57.5 ml
57.5 ml
57.5 ml
-
Pre-cha
l
lenge
V
is
it 1b (Screen
ing)
B
lood samp
l
ing for HIV, HCV and HBsAg
-
-
-
-
-
17.0 m
l
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
-
-
-
-
-
7.5 m
l
Total:
-
-
-
-
-
24.5 ml
V
is
it 11(Day 286)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing forPBMC and p
lasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
Total: 50.0 ml
50.0 ml
50.0 ml
50.0 ml
50.0 ml
-
Post-cha
l
lenge
V
is
it 12(Day 291) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 13(Day 292) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 14(Day 293) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 15(Day 294) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 16(Day 295)
B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
B
lood samp
l
ing for assessment of paras
item
ia at start of hote
l 
phase (PCR)****
2.0 m
l 
2.0 m
l 
2.0 m
l 
2.0 m
l 
2.0 m
l 
2.0 m
l
V
is
it 17(Day 296) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it18(Day 297) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 19(Day 298) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 20(Day 299) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 21(Day 300) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 22(Day 301) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 23(Day 302) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 24(Day 303) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
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Study Phase
Timepoint
Sample type
Total volume of blood per visit (ml)
AduFx
2PedFx 
PedFx
Adu2Fx 
Adu1Fx Infectivity 
control
V
is
it 25(Day 304) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)v
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 26(Day 306) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 27(Day 308) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 28(Day 310) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 29(Day 312) B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
V
is
it 30(Day 314)
B
lood samp
l
ing for assessment of paras
item
ia (b
lood smear)
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
2.0 m
l
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
Total: 29.5 ml
31.5 ml
31.5 ml
31.5 ml
31.5 ml
9.5 ml
V
is
it Par***
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
Total: 7.5 ml
7.5 ml
7.5 ml
7.5 ml
7.5 ml
7.5 ml
Study end
V
is
it 31(Day 376)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for PBMC and p
lasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
Total: 50.0 ml
50.0 ml
50.0 ml
50.0 ml
50.0 ml
-
Total blood collected over the entire study: 579.5 ml 579.5 ml 579.5 ml
579.5 ml
472.5 ml
79.5 ml
* For groups AduFx, 2PedFx, PedFx and Adu2Fx.
** For group Adu1Fx.
*** B
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia (between V
is
it 12[Day 291]and V
is
it 29[Day 312]).
**** B
lood samp
le for assessment of paras
item
ia by PCR w
i
l
l be co
l
lected on the day of sub
ject entry 
intothe hote
l (Day 295 [V
is
it 16]).
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6.7.3.
Laboratory assays
Please refer toAPPENDIX Afor a detailed description of the assays performed in the 
study. Please refer toAPPENDIX Bfor the address of the clinical laboratories used for 
sample analysis.
Serological assays for the determination of anti-CSantibodies will be performed by 
ELISAat laboratories designated by GSK Biologicals using standardized and validated 
procedures (refer to Table 13).
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 13).
Table 13
Assays for humoral immunity (antibody determination)
System Component
Method Kit/ 
Manufacturer
Unit
Cut-off
Laboratory
SERUM 
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
ELISA
In house
EU/m
l
0.5
CEVAC
SERUM 
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
ELISA
In house
%
Not 
app
l
icab
le
CEVAC
SERUM P
lasmod
ium fa
lc
iparum.ant
i-C-
Term C
ircumsporozo
ide Ab.IgG
ELISA
In house
EPT
100
WRAIR
SERUM 
P
lasmod
ium fa
lc
iparum.ant
i-C-
Term C
ircumsporozo
ide Ab.IgG 
av
id
ity
ELISA
In house
Av
id
ity 
Index
Not 
app
l
icab
le WRAIR
SERUM 
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite Fu
l
l 
length(N+C
-Term
ina
l) 
Recomb
inant+NANP 
Prote
in+NVDP Prote
in Ab.IgG
ELISA 
In house
1/DIL
Not 
app
l
icab
le WRAIR
SERUM
P
lasmod
ium fa
lc
iparum.ant
i-fu
l
l 
length C
ircumsporozo
ide Ab.IgG 
av
id
ity
ELISA 
In house
Av
id
ity 
Index
Not 
app
l
icab
le WRAIR
SERUM Hepat
it
is B V
irus.Surface Ab
CLIA
ADVIA Centaur 
ant
i-HBs2 
(S
iemens 
Hea
lthcare)
mIU/m
l 6.2
GSK
B
io
log
ica
ls*
CEVAC: Center for Vacc
ino
logy; CLIA: chem
i
lum
inescence enzyme 
immunoassay;ELISA: Enzyme-l
inked 
immunosorbent assay; EPT: endpo
int t
iter; IgG: Immunog
lobu
l
in G; WRAIR: Wa
lter Reed Army Inst
itute of 
Research
* GSK B
io
log
ica
ls 
laboratory refers to C
l
in
ica
l Laboratory Sc
iences (CLS) 
in R
ixensart, Be
lg
ium; Wavre, Be
lg
ium. 
Other assays on stored serum, PBMC and plasma samplesmay be performed based on 
results of ongoing studies to investigate the safety and/or vaccine induced anti-malaria 
and hepatitisB immune responses.
 
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Table 14
Assessment of P. falciparum parasitemia
System
Component
Method
Unit
Laboratory
WHOLE BLOOD
P
lasmod
ium fa
lc
iparum 
paras
ites* 
Not app
l
icab
le**paras
ite/l
WRAIR
WHOLE BLOOD
P
lasmod
ium fa
lc
iparum 
paras
ites*
Rea
l-t
ime PCRPos
it
ive/negat
ive***WRAIR
WRAIR: Wa
lter Reed Army Inst
itute of Research
* P. fa
lc
iparumparas
ite count 
inc
ludes b
lood-stage paras
ites.
** Method used w
i
l
l be b
lood s
l
ide m
icroscope read
ing.
*** For assessmentand process
ingby WRAIR of paras
item
ia on the day of sub
ject entry 
into the hote
l (Day 295 
[V
is
it16])
Table 15
Hematology, biochemistryand screening tests
System
Component
Method
Scale
Laboratory
SERUM
HIV-IgG + Ag (SER,GLR)
Immunoassay Qua
l
itat
ive
Quest D
iagnost
ics, Inc.
SERUM
Hepat
it
is B V
irus.Surface Ab
CLIA
Qua
l
itat
ive
Quest D
iagnost
ics, Inc.
SERUM
HCV Ab
Immunoassay Qua
l
itat
ive
Quest D
iagnost
ics, Inc.
URINE
-HCG* 
Immunoassay Qua
l
itat
ive
WRAIR
WHOLE BLOOD
Hemog
lob
in
Not app
l
icab
le
Quant
itat
ive
Quest D
iagnost
ics, Inc.
Leukocytes (Wh
ite B
lood Ce
l
ls)
P
late
lets
SERUM 
A
lan
ine Am
inotransferase
Not app
l
icab
le
Quant
itat
ive
Quest D
iagnost
ics, Inc.
Aspartate Am
inotransferase
Creat
in
ine
-HCG: Beta-human chor
ion
ic gonadotrop
in; CLIA: chem
i
lum
inescence enzyme immunoassay,HCV: hepat
it
is C 
v
irus, HIV: human 
immunodef
ic
iency v
irus, WRAIR: Wa
lter Reed Army Inst
itute of Research
*Ur
inary pregnancy test
PBMC for mRNAexpression profiling will be collectedand stored in a repositoryto 
allow mRNA sequencing or future next generation technologies, during the current study 
or in future research,to assess transcriptome signals.Scope of this assay will be based on 
ongoing investigations.
The repository laboratory for serum samples willbe GSK Biologicals’ clinical 
laboratories and for plasma and PBMC samples will be Precision Bioservices Inc.
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
 
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6.7.4.
Biological samples evaluation
6.7.4.1.
Immunological read-outs
Table 16
Immunological read-outs
Bloodsampling timepoint
Study 
groups
No. 
subjects
Sample
Component
Components 
priority rank
Type of 
contact 
and 
timepoint
Sampling 
timepoint
V
is
it 2
(Day 0)
Pre-
vacc
inat
ion
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
p
lasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 3
(Day 28)
One month 
post-Dose 1
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
PBMC and 
p
lasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 5
(Day 35)
Seven days 
post-Dose 2
AduFx, 
2PedFx,
PedFx, 
Adu2Fx
104
PBMC and 
p
lasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
 
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Bloodsampling timepoint
Study 
groups
No. 
subjects
Sample
Component
Components 
priority rank
Type of 
contact 
and 
timepoint
Sampling 
timepoint
V
is
it 6
(Day 58)
One month 
post-Dose 2
AduFx, 
2PedFx,
PedFx, 
Adu2Fx
104
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMCand 
p
lasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 7
(Day 196)
S
ix months 
post-Dose 2** 
or seven 
month post-
Dose 1***
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
p
lasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 9
(Day 203)
Seven days 
post-Dose 3** 
or post-Dose 
2***
AduFx, 
2PedFx,
PedFx,
Adu1Fx, 
Adu2Fx
130
PBMC and 
p
lasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
 
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Bloodsampling timepoint
Study 
groups
No. 
subjects
Sample
Component
Components 
priority rank
Type of 
contact 
and 
timepoint
Sampling 
timepoint
V
is
it 10
(Day 226)
One month 
post-Dose 3** 
or post-Dose 
2***
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
p
lasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 11
(Day 286)
Day of 
cha
l
lenge
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
p
lasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 30
(Day 314)
28 days post-
cha
l
lenge
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
 
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Bloodsampling timepoint
Study 
groups
No. 
subjects
Sample
Component
Components 
priority rank
Type of 
contact 
and 
timepoint
Sampling 
timepoint
V
is
it 31
(Day 376)
Study end
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
p
lasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
*Assays on stored serum,PBMC and p
lasma samp
les may be performed based on resu
lts of ongo
ing stud
ies to 
invest
igate the safety and/or vacc
ine 
induced ant
i-ma
lar
ia and hepat
it
is B 
immune responses.
** For groups AduFx, 2PedFx, PedFx and Adu2Fx.
***For group Adu1Fx.
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided inTable 16.
 
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6.7.4.2.
Hematology/Blood Chemistry
Table 17
Hematologyand biochemistry read-outs
Blood sampling timepoint
Study groups
No. subjects
Component
Type of contact 
and timepoint
Sampling 
timepoint
V
is
it 1 (Screen
ing)
Pre-vacc
inat
ion
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx
130
HIV-IgG + Ag (SER,GLR)
Hepat
it
is B V
irus.Surface Ab
HCV Ab
A
lan
ine Am
inotransferase
Aspartate Am
inotransferase
Creat
in
ine
Hemog
lob
in
Leukocytes (Wh
ite B
lood Ce
l
ls)
P
late
lets
V
is
it 5(Day 35) Seven days post-
Dose 2
AduFx, 2PedFx,
PedFx, Adu2Fx
104
A
lan
ine Am
inotransferase
Aspartate Am
inotransferase
Creat
in
ine
Hemog
lob
in
Leukocytes (Wh
ite B
lood Ce
l
ls)
P
late
lets
V
is
it 6(Day 58)
One month post-
Dose 2
AduFx, 2PedFx,
PedFx, Adu2Fx
104
A
lan
ine Am
inotransferase
Aspartate Am
inotransferase
Creat
in
ine
Hemog
lob
in
Leukocytes (Wh
ite B
lood Ce
l
ls)
P
late
lets
V
is
it 9(Day 203)
Seven days post-
Dose 3* or post-
Dose 2**
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx
130
A
lan
ine Am
inotransferase
Aspartate Am
inotransferase
Creat
in
ine
Hemog
lob
in
Leukocytes (Wh
ite B
lood Ce
l
ls)
P
late
lets
V
is
it 10(Day 226)
One month post-
Dose 3* or post-
Dose 2**
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx
130
A
lan
ine Am
inotransferase
Aspartate Am
inotransferase
Creat
in
ine
Hemog
lob
in
Leukocytes (Wh
ite B
lood Ce
l
ls)
P
late
lets
V
is
it 1b (Screen
ing)
Pre-cha
l
lenge
Infect
iv
ity contro
l
20***
HIV-IgG + Ag (SER,GLR)
Hepat
it
is B V
irus.Surface Ab
HCV Ab
A
lan
ine Am
inotransferase
Aspartate Am
inotransferase
Creat
in
ine
Hemog
lob
in
Leukocytes (Wh
ite B
lood Ce
l
ls)
P
late
lets
V
is
it Par
Event-dr
iven (f
irst 
paras
item
ia)
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx, Infect
iv
ity 
contro
l
150
A
lan
ine Am
inotransferase
Aspartate Am
inotransferase
Creat
in
ine
Hemog
lob
in
Leukocytes (Wh
ite B
lood Ce
l
ls)
P
late
lets
 
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Blood sampling timepoint
Study groups
No. subjects
Component
Type of contact 
and timepoint
Sampling 
timepoint
V
is
it 30(Day 314)
28 days post-
cha
l
lenge
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx, Infect
iv
ity 
contro
l
150
A
lan
ine Am
inotransferase
Aspartate Am
inotransferase
Creat
in
ine
Hemog
lob
in
Leukocytes (Wh
ite B
lood Ce
l
ls)
P
late
lets
* For groups AduFx, 2PedFx, PedFx and Adu2Fx.
** For group Adu1Fx.
***between 20 and 30 
infect
iv
ity contro
ls w
i
l
l be enro
l
led.
6.7.4.3.
Molecular biology
Table 18
RNAsequencing(mRNA sequencing analysis)
Blood sampling timepoint
Study groups
No. 
subjects
Component
Components 
priority rank
Type of contact 
and timepoint
Sampling 
timepoint
V
is
it 2(Day 0)
Pre-vacc
inat
ion AduFx, 2PedFx,PedFx,Adu1Fx,  
Adu2Fx
130
mRNA
Not app
l
icab
le
V
is
it 3(Day 28)
Day of Dose 2* or 
one month post-
Dose 1**
AduFx, 2PedFx,PedFx,Adu1Fx
Adu2Fx
130
mRNA
Not app
l
icab
le
V
is
it 4(Day 29)
One day post-
Dose 2
AduFx, 2PedFx,PedFx, Adu2Fx
104
mRNA
Not app
l
icab
le
V
is
it 7(Day 196) Day of Dose 3* or 
Dose 2**
AduFx, 2PedFx,PedFx,Adu1Fx,  
Adu2Fx
130
mRNA
Not app
l
icab
le
V
is
it 8(Day 197)
One day post-
Dose 3* or Dose 
2**
AduFx, 2PedFx,PedFx,Adu1Fx,  
Adu2Fx
130
mRNA
Not app
l
icab
le
mRNA: messenger r
ibonuc
le
ic ac
id
* For groups AduFx, 2PedFx, PedFx and Adu2Fx.
** For group Adu1Fx.
 
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6.7.4.4.
Parasitemia
Table 19
Parasitemia (blood smear)
Blood sampling 
timepoint
Study groups
No. 
subjectsComponentComponents 
priority rank 
V
is
it 12(Day 291)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 13(Day 292)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 14(Day 293)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 15(Day 294)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 16(Day 295) AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l
150
PCR*
2
V
is
it 17(Day 296)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 18(Day 297)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 19(Day 298)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 20(Day 299)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 21(Day 300)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 22(Day 301)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 23(Day 302)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 24(Day 303)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 25(Day 304)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 26(Day 306)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 27(Day 308)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 28(Day 310)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 29(Day 312)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 30(Day 314)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
* For assessment and process
ing by WRAIR of paras
item
ia on the day of sub
ject entry 
into the hote
l (Day 295 [V
is
it 
16])
6.7.5.
Immunological correlates of protection
No correlate of protection has been demonstrated so far for the CS antigen.
For the HBsAg, the conventional correlate of protection is anti-HBs antibody 
concentrationsabove 10 mIU/ml [EuropeanConsensus Group on Hepatitis B Immunity, 
2000].
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects.
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.
 
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7.
STUDY VACCINESAND ADMINISTRATION
7.1.
Description of study vaccines
The candidate RTS,S/AS01 vaccine to be used hasbeen developed and manufactured by 
GSK Biologicals.
The Quality Control Standards and Requirements for the candidate vaccineare described 
in separate Quality Assurance documents (e.g. release protocols,certificate of analysis) 
and the required approvals have been obtained.
The vaccinesare labeledand packed according to applicable regulatory requirements.
Table 20
Study vaccines
Treatment name
Vaccine 
name
Formulation
Presentation
Volume to be 
administered
Number 
of doses
RTS,S/AS01E
(Fu
l
l dose)
RTS,S
RTS,S=25µg
Lyoph
i
l
ized pe
l
let 
in 
a g
lass v
ia
l
0.5m
l
2*
AS01E
MPL=25µg; QS21=25µg; 
L
iposomes
L
iqu
id so
lut
ion 
in a 
g
lass v
ia
l
RTS,S/AS01E
(1/5
thdose)
RTS,S
RTS,S=25µg
Lyoph
i
l
ized pe
l
let 
in 
a g
lass v
ia
l
0.1m
l
1**
AS01E
MPL=25µg; QS21=25µg; 
L
iposomes
L
iqu
id so
lut
ion 
in a 
g
lass v
ia
l
RTS,S/AS01B
(Fu
l
l dose)
RTS,S
RTS,S=50µg
Lyoph
i
l
ized pe
l
let 
in 
a g
lass v
ia
l
0.5m
l
1 or 2***
AS01B
MPL=50µg; QS21=50µg; 
L
iposomes
L
iqu
id so
lut
ion 
in a 
g
lass v
ia
l
RTS,S/AS01B
(1/5t
hdose)
RTS,S
RTS,S=50µg
Lyoph
i
l
ized pe
l
let 
in 
a g
lass v
ia
l
0.1m
l
1 or 2****
AS01B
MPL=50µg; QS21=50µg; 
L
iposomes
L
iqu
id so
lut
ion 
in a 
g
lass v
ia
l
* RTS,S/AS01
Efu
l
l dose (0.5 m
l): Group 2PedFx w
i
l
l rece
ive two t
imes two doses; Group PedFx w
i
l
l rece
ive two 
doses.
** RTS,S/AS01
E1/5
thdose (0.1 m
l): Group 2PedFx w
i
l
l rece
ive one t
ime two doses; Group PedFx w
i
l
l rece
ive one 
dose.
*** RTS,S/AS01
Bfu
l
l dose (0.5 m
l): Group AduFx w
i
l
l rece
ive two doses; Group Adu1Fx and Adu2Fx w
i
l
l rece
ive 
one dose.
**** RTS,S/AS01
B1/5
thdose (0.1 m
l): Group AduFx and Adu1Fx w
i
l
l rece
ive one dose; Group Adu2Fx w
i
l
l rece
ive 
two doses.
7.2.
Storage and handling of study vaccines
The study vaccinesmust 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°Cimpacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°Flabel storage temperatureconditions.The impacted IMP(s) may still
be administered, but the site should avoid re-occurrence of such temperature excursion.
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take.
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.
Dosage of RTS,S/AS01
7.3.1.1.
RTS,S/AS01E
In this study, the commercial presentation of RTS,S/AS01E will be used, i.e. a two-doses 
glass vial of lyophilized RTS,S antigen (50 µg) to be reconstituted with a two-doses glass 
vial of AS01EAdjuvant 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 withdrawnto administer RTS,S/AS01Efull doses, or
0.1 ml will be withdrawn to administered RTS,S/AS01Efractional doses (1/5
thdose), 
or

1.0 ml will be withdrawn to administer RTS,S/AS01
Edouble doses, or
0.2ml will be withdrawn to administered double dose of RTS,S/AS01Efractional 
doses (1/5thdose).
All vials of vaccine provided in this study are intended for single use only.
 
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7.3.1.2.
RTS,S/AS01B
In this study, the clinical presentation of RTS,S/AS01
Bwill be used, i.e. a two-dose glass 
vial of lyophilized RTS,S antigen (50 µg) to be reconstituted with a mono-dose glass vial 
of AS01BAdjuvant System (0.5ml). The final product for administration will be 
prepared by reconstitution of the lyophilized antigen with the liquid adjuvant. Fromthe 
reconstituted vaccine vial:
0.5 ml will be withdrawn to administer RTS,S/AS01Bfull doses,or
0.1 ml will be withdrawn to administered RTS,S/AS01Bfractional doses (1/5
thdose).
All vials of vaccine provided in this study are intended for single use only.
7.3.2.
Administration of RTS,S/AS01
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 syringeand 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 the correct dose (see Section 7.3.1.1and Section 7.3.1.2). The full dose of 
RTS,S/AS01Eor RTS,S/AS01Bshould be administered using a fresh 25 gauge needle 
with a length of one inch (25 mm). For the fractional dose of RTS,S/AS01
Eor 
RTS,S/AS01B, a1ml syringe and fresh 25 gauge needle with a length of one inch (25 
mm)should be used and the volume administered should be as shown in Table 21. The 
reconstituted vaccine should be administered by slow IM injection into the non-dominant 
deltoid. The vaccine should be injected within four hours of reconstitution (storage at 
+2°C to +8°C).
Table 21
Dosage and administration
Type of contact 
and timepoint
Volume to be 
administered
Study 
group
Treatment name
Route
Site
Side
V
is
it 2(Day 0)
0.5m
l
AduFx
RTS,S/AS01B(Fu
l
l dose)
IM
De
lto
id
Non-dom
inant
1.0 m
l
2PedFx
RTS,S/AS01E(Fu
l
l dose)
IM
De
lto
id
Non-dom
inant
0.5m
l
PedFx
RTS,S/AS01E(Fu
l
l dose)
IM
De
lto
id
Non-dom
inant
0.5m
l
Adu2Fx
RTS,S/AS01B(Fu
l
l dose)
IM
De
lto
id
Non-dom
inant
0.5m
l
Adu1Fx
RTS,S/AS01B(Fu
l
l dose)
IM
De
lto
id
Non-dom
inant
V
is
it 3(Day 28)
0.5m
l
AduFx
RTS,S/AS01B(Fu
l
l dose)
IM
De
lto
id
Non-dom
inant
1.0 m
l
2PedFx
RTS,S/AS01E(Fu
l
l dose)
IM
De
lto
id
Non-dom
inant
0.5m
l
PedFx
RTS,S/AS01E(Fu
l
l dose)
IM
De
lto
id
Non-dom
inant
0.1m
l
Adu2Fx
RTS,S/AS01B(1/5
thdose)
IM
De
lto
id
Non-dom
inant
V
is
it 7(Day 196)
0.1m
l
AduFx
RTS,S/AS01B(1/5
thdose)
IM
De
lto
id
Non-dom
inant
0.2 m
l
2PedFx
RTS,S/AS01E(1/5
thdose)
IM
De
lto
id
Non-dom
inant
0.1m
l
PedFx
RTS,S/AS01E(1/5
thdose)
IM
De
lto
id
Non-dom
inant
0.1m
l
Adu2Fx
RTS,S/AS01B(1/5
thdose)
IM
De
lto
id
Non-dom
inant
0.1m
l
Adu1Fx
RTS,S/AS01B(1/5
thdose)
IM
De
lto
id
Non-dom
inant
IM: 
intramuscu
lar
 
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7.4.
Replacement of unusable vaccinedoses
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomizationwhen applicable), at least 15% additional vaccine doses will be 
supplied to replace those that are unusable. 
7.5.
Contraindications to vaccination
The following events constitute absolute contraindications toadministration of
RTS,S/AS01Band RTS,S/AS01
E. If any of these events occur during the study, the 
subject must not receive doses of vaccine but may continue other study procedures at the 
discretion ofthe investigator (see Section 9.5).
Anaphylaxis following the administration of vaccine(s).
Pregnancy (see Section 9.2.1).
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including HIV infection.
RTS,S/AS01Band RTS,S/AS01
E 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/AS01Bor RTS,S/AS01Emalaria vaccine or hepatitis B 
vaccines. Any subject who shows signs of hypersensitivity to the vaccine should not 
be given further doses.

Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe.

Occurrence of a new pIMD or the exacerbation of an existing pIMDthat, in the 
opinion of the investigator, expose the subject to unacceptable risk fromsubsequent 
vaccination. In such cases, the investigator should use his/her clinical judgmentprior 
to administering the next doseof the vaccine(s)/product(s). Refer to Section 9.1.5.1
for the definition of pIMDs.
The following events constitute contraindications to administration of RTS,S/AS01Band 
RTS,S/AS01Eat 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 9.5).
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 oral.
Subjects with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever can be administered all vaccines.
 
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7.6.
Concomitant medications/productsand concomitant 
vaccinations
At each study visit, the investigator should question the subject about any 
medications/productstaken and vaccinationsreceived by the subject.
7.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s)must be recorded in 
the eCRF.

All concomitant medications/products, except vitamins and dietary supplements, 
administered duringthe period starting within seven days followingeach dose of 
study vaccines(Day 0to Day 6) and during the entire sporozoite challenge (Day 286
to Day 314).

Any concomitant vaccination administered in the period starting seven days before 
the firstdose of study vaccinesand ending at the last study visit(Day -7to Day 376)
and during the entire sporozoite challenge (Day 286to Day 314).

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 7.6.2.
Any concomitant medications/products/vaccinesrelevant 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 Event report.
7.6.2.
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 11.5for cohorts to be analyzed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccinesused during the study period. 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 daysin total) during the study period. For corticosteroids, this will 
mean prednisone 20 mg/day (for adult subjects),or equivalent. Inhaled and topical 
steroids are allowed.
 
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Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab).
A vaccine not foreseen by the study protocol administered during the period starting
sevendays before each dose and ending seven days after each dose of vaccines
administration*.
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organizedby the public health authorities, outside the routine 
immunizationprogram, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Summary of Product 
Characteristics or Prescribing Informationand 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.
Drugs known to have anti-Plasmodiumproperties, used during the challenge period 
before identification of parasitemia.
7.7.
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses
For vaccinated subjects, at each study visit subsequent to the first vaccination/the 
vaccinationvisit, 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.
For the infectivity controls group, at each study visit subsequent to the sporozoite 
challenge 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 analysis of immunogenicity and 
efficacyif, during the study, they incur a condition that has the capability of altering their 
immune response or are confirmed to have an alteration of their initial immune status.
8.
HEALTH ECONOMICS
Not applicable
9.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAE as provided in 
this protocol. 
Each subject will be instructed to contact the investigator immediately should the subject 
manifest any signs or symptoms they perceive as serious.
 
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9.1.
Safety definitions
9.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavorableand unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. 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 vaccinesadministration 
even though they may have been present prior to the start of the study.
Signs, symptoms, or the clinical sequelae ofa suspected interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational vaccinesor a concurrent medication (overdose per se should not be 
reported as an AE/SAE).

Signs, symptoms temporally associated with vaccinesadministration.
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.
Examples of an AE DO NOT include:
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
firststudy vaccination. These events will be recorded in the medical history section 
of the eCRF.
 
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9.1.2.
Definition of a serious adverse event 
A SAEis any untoward medical occurrence that:
a. Results in death,
b. Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c. Requires hospitalizationor prolongation of existing hospitalization,
Note: In general, hospitalizationsignifies that the subject has been admitted at the 
hospital or 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 duringhospitalizationare also considered AEs. If a complication prolongs 
hospitalizationor fulfillsany other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the 
AE should be considered serious.
Hospitalizationfor elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d. Results in disability/incapacity, OR
Note: The termdisability 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.
e. Is a congenital anomaly/birth defect in the offspring of a study subject.
Medical or scientific judgmentshould be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalizationbut may jeopardizethe 
subject or may require medical or surgical intervention to prevent one of the other 
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 orat home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization.
 
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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 22 
Solicited local adverse events
All age groups
Pa
in at 
in
ject
ion s
ite
Redness at 
in
ject
ion s
ite
Swe
l
l
ing at 
in
ject
ion s
ite
9.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 23
Solicited general adverse events
Adult
Fat
igue
Fever
Gastro
intest
ina
l symptoms†
Headache
†Gastro
intest
ina
l symptoms 
inc
lude nausea, vom
it
ing, 
d
iarrhea and/or abdom
ina
l pa
in.
Note: Temperature will be recorded in the evening. Should additional temperature 
measurements be performed at other times of day, the highest temperature will be 
recorded in the eCRF.
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 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 Sections9.1.1and 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 exercisehis or her medical and scientific judgmentin deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
 
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9.1.5.
Adverse events of specific interest
AEs of specific interest for safety monitoring include meningitis and pIMDs.
9.1.5.1.
Potential immune-mediated diseases
pIMDs are a subset of AEsthat include autoimmune diseases and other inflammatory 
and/or neurologic disorders of interest which may or may not have an autoimmune 
etiology. AEs that need to be recorded and reported as pIMDs include those listed in 
Table 24.
However, the investigator will exercise his/her medical and scientific judgmentin 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.
Table 24 
List of potential immune-mediated diseases
Neuroinflammatorydisorders
Musculoskeletal disorders
Skin disorders

Cran
ia
l nerve d
isorders, 
inc
lud
ing 
para
lyses/pares
is (e.g. Be
l
l
’s pa
lsy) 

Opt
ic neur
it
is

Mu
lt
ip
le sc
leros
is

Transverse mye
l
it
is

Gu
i
l
la
in-Barré syndrome, 
inc
lud
ing 
M
i
l
ler F
isher syndrome and other 
var
iants

Acute d
issem
inated 
encepha
lomye
l
it
is, 
inc
lud
ing s
ite 
spec
if
ic var
iants: e.g. non-infect
ious 
encepha
l
it
is, encepha
lomye
l
it
is, 
mye
l
it
is, mye
lorad
icu
loneur
it
is

Myasthen
ia grav
is, 
inc
lud
ing 
Lambert-Eaton myasthen
ic 
syndrome 

Immune-med
iated per
iphera
l
neuropath
ies and p
lexopath
ies, 
(
inc
lud
ing chron
ic 
inf
lammatory 
demye
l
inat
ing po
lyneuropathy, 
mu
lt
ifoca
l motor neuropathy and 
po
lyneuropath
ies assoc
iated w
ith 
monoc
lona
l gammopathy).
Narco
lepsy

System
ic 
lupus erythematosus 
and assoc
iated cond
it
ions

System
ic sc
leroderma(System
ic 
sc
leros
is), 
inc
lud
ing d
iffuse 
system
ic form and CREST 
syndrome

Id
iopath
ic 
inf
lammatory 
myopath
ies, 
inc
lud
ing 
dermatomyos
it
is 

Po
lymyos
it
is 

Ant
isynthetase syndrome

Rheumato
id arthr
it
is, and 
assoc
iated cond
it
ions 
inc
lud
ing 
j
uven
i
le chron
ic arthr
it
isand 
St
i
l
l
’s d
isease

Po
lymya
lg
ia rheumat
ica

Spondy
loarthr
it
is, 
inc
lud
ing 
anky
los
ing spondy
l
it
is, react
ive 
arthr
it
is (Re
iter
's Syndrome) and 
und
ifferent
iated spondy
loarthr
it
is 

Psor
iat
ic arthropathy

Re
laps
ing po
lychondr
it
is

M
ixed connect
ivet
issue d
isorder

Psor
ias
is

V
it
i
l
igo

Erythema nodosum

Auto
immune bu
l
lous sk
in 
d
iseases (
inc
lud
ing 
pemph
igus, pemph
igo
id 
and dermat
it
is 
herpet
iform
is)

A
lopec
ia areata

L
ichen p
lanus

Sweet
’s syndrome

Loca
l
ised Sc
leroderma 
(Morphoea)
 
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Vasculitides
Blood disorders
Others

Large vesse
ls vascu
l
it
is 
inc
lud
ing: 
g
iant ce
l
l arter
it
is such as 
Takayasu
's arter
it
is and tempora
l 
arter
it
is. 

Med
ium s
ized and/or sma
l
l vesse
ls 
vascu
l
it
is 
inc
lud
ing: po
lyarter
it
is 
nodosa, Kawasak
i
's d
isease, 
m
icroscop
ic po
lyang
i
it
is, Wegener
's 
granu
lomatos
is, Churg–Strauss 
syndrome (a
l
lerg
ic granu
lomatous 
ang
i
it
is), Buerger
’s d
isease 
(thromboang
i
it
is ob
l
iterans), 
necrot
iz
ing vascu
l
it
is and ant
i-
neutroph
i
l cytop
lasm
ic ant
ibody 
(ANCA) pos
it
ive vascu
l
it
is (type 
unspec
if
ied), Henoch-Schon
le
in
purpura, Behcet
's syndrome, 
leukocytoc
last
ic vascu
l
it
is.

Auto
immune hemo
lyt
ic anem
ia

Auto
immune thrombocytopen
ia

Ant
iphospho
l
ip
id syndrome

Pern
ic
ious anem
ia

Auto
immune ap
last
ic anaem
ia

Auto
immune neutropen
ia 

Auto
immune pancytopen
ia

Auto
immune 
g
lomeru
lonephr
it
is 
(
inc
lud
ing IgA 
nephropathy, 
g
lomeru
lonephr
it
is 
rap
id
ly progress
ive, 
membranous 
g
lomeru
lonephr
it
is, 
membranopro
l
iferat
ive 
g
lomeru
lonephr
it
is, and 
mesang
iopro
l
iferat
ive 
g
lomeru
lonephr
it
is)

Ocu
lar auto
immune 
d
iseases (
inc
lud
ing 
auto
immune uve
it
is and 
auto
immune ret
inopathy)

Auto
immune 
myocard
it
is/card
iomyopa
thySarco
idos
is

Stevens-Johnson 
syndrome

S
jögren
’s syndrome

Id
iopath
ic pu
lmonary 
f
ibros
is

Goodpasture syndrome

Raynaud
’s phenomenon
Liver disorders
Gastrointestinal disorders
Endocrine disorders

Auto
immune hepat
it
is

Pr
imary b
i
l
iary c
irrhos
is

Pr
imary sc
leros
ing cho
lang
it
is

Auto
immune cho
lang
it
is

Inf
lammatory Bowe
l d
isease, 
inc
lud
ing Crohn
’s d
isease, 
u
lcerat
ive co
l
it
is, m
icroscop
ic 
co
l
it
is, u
lcerat
ive proct
it
is 

Ce
l
iac d
isease

Auto
immune pancreat
it
is

Auto
immune thyro
id
it
is 
(
inc
lud
ing Hash
imoto 
thyro
id
it
is)

Grave
's or Basedow
’s 
d
isease

D
iabetes me
l
l
itus type I

Add
ison
’s d
isease

Po
lyg
landu
lar 
auto
immune syndrome

Auto
immune 
hypophys
it
is
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as 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 and preferred termscodes corresponding to the 
above diagnoseswill be available to investigators at study start.
 
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9.1.5.2.
Meningitis
For the further evaluation of the safety signal of meningitis in the investigational vaccine 
groups (AduFx, 2PedFx, PedFx, Adu2Fx,and Adu1Fx), all cases of meningitis occurring 
during the studywill be reported as a SAE and clinical details of each case will be 
reported in a specific eCRF screen.
9.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
9.2.1.
Pregnancy
Female subjects who are pregnant or lactating at the time of vaccination must not receive 
additional doses of study vaccinesbut may continue other study procedures at the 
discretion of the investigator.
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE.
Note: The pregnancy itself should always be recorded on anelectronic pregnancy report.
The following should always be considered as SAE and will be reported asdescribed in 
Sections 9.4.1and 9.4.3:
Spontaneous pregnancy loss, including:

spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation)

ectopic and molar pregnancy

stillbirth (intrauterine death of fetusafter 22 weeks of gestation).
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006].It is recognized that national 
regulations might be different.
Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life). 
Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the fetusis delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion.
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the investigational vaccineswill be 
reported to GSK Biologicals as described in Section 9.4.3. While the investigator is not 
obligated to actively seek this information from former study participants, he/she may 
learn of a pregnancy through spontaneous reporting.
 
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9.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
9.3.1.
Time periodfor detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs starting within 30days following administration of each doseof study vaccines
(Day 0to Day 29) must be recorded intothe appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related.
For vaccinated subjects, the time period for collecting and recording SAEs will begin at 
the firstreceipt of study vaccine (Day 0) and will end at the last study visit(Day 376). 
For the infectivity controls group, the time period for collecting and recording SAEs will 
begin on the first day of the sporozoite challenge (Day 286) and will end at the last study 
visit (Day 314). See Section 9.4for instructions on reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the firstreceipt of study vaccines(Day 0) for AduFx,2PedFx, PedFx, 
Adu2Fx,and Adu1Fx groups.
In addition to the above-mentioned reporting requirements and in order to fulfill
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate (i.e. Screening) in the study until she/he is 
discharged from the study.
For vaccinated subjects, the time period for collecting and recording pregnancies will 
begin at the firstreceipt of study vaccines(Day 0) and will end at the last study visit (Day 
376). For the infectivity controls group, the time period for collecting and recording 
pregnancies will begin on the first day of the sporozoite challenge (Day 286) and will end 
at the last study visit (Day 314).See section 9.4for instructions on reporting of 
pregnancies.
For vaccinated subjects, the time period for collecting and recording of AEs of specific 
interest (meningitisand pIMDs)will begin at the first receipt of study vaccines (Day 0) 
and will end at the last study visit (Day 376). See section 9.4for instructions on reporting 
of pIMDs.
An overview of the protocol-required reporting periods for AEs, SAEs and pregnancies is 
given in Table 25, Table 26and Table 27.
 
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Table 25
Reporting periods for collecting safety information for the 
investigational vaccine groups: AduFx, 2PedFx, PedFx, and Adu2Fx)
Study visits
1
2
3
6
7
10
11 to 30
31
Study days
-90 
to 0
0 6
28 34 58
196 202
226
286 314315
376
So
l
ic
ited 
loca
l and 
genera
l AEs post-
vacc
inat
ion
Unso
l
ic
ited AEs 
post-vacc
inat
ion
AEs post-cha
l
lenge
AEs and SAEs 
lead
ing to w
ithdrawa
l 
from further 
vacc
inat
ion
SAEs (a
l
l, fata
l, 
re
lated)
SAEs re
lated to 
study part
ic
ipat
ion, 
or to a concurrent 
GSK 
med
icat
ion/vacc
ine
AEs of spec
if
ic 
interest (men
ing
it
is 
and pIMDs)
Pregnanc
ies
 
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Table 26
Reporting periods for collecting safety information for the 
investigational vaccine groups: Adu1Fx
Study visits
1
2
3
7
10
11 to 30
31
Study days
-90 
to 0
0 6
28
196 202
226
286 314 315
376
So
l
ic
ited 
loca
l and 
genera
l AEs post-
vacc
inat
ion
Unso
l
ic
ited AEs post-
vacc
inat
ion
AEs post-cha
l
lenge
AEs and SAEs 
lead
ing 
to w
ithdrawa
l from 
further vacc
inat
ion
SAEs (a
l
l, fata
l, 
re
lated)
SAEs re
lated to study 
part
ic
ipat
ion, or to a 
concurrent GSK 
med
icat
ion/vacc
ine
AEs of spec
if
ic 
interest 
(men
ing
it
is and pIMDs)
Pregnanc
ies
 
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Table 27
Reporting periods for collecting safety informationfor the infectivity 
control group
Study visits
1b
11 to 30
Study days
258 to 286
286
314
315
AEs post-cha
l
lenge
SAEs (a
l
l, fata
l, re
lated)
SAEs re
lated to study part
ic
ipat
ion, or to 
a concurrent GSK med
icat
ion/vacc
ine
Pregnanc
ies
9.3.2.
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 inTable 25, Table 26and 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 fromthe 
study, and he/she considers the event reasonably related to the investigational vaccines, 
the investigator will promptly notify the Study Contact for Reporting SAEs.
9.3.3.
Evaluation of adverse events and serious adverse events
9.3.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject should be asked a non-leading 
question such as:
‘Have you felt different in any way since receiving the vaccinesor since the previous 
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 theeCRF. 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.
 
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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.
9.3.3.2.
Assessment of adverse events
9.3.3.2.1. Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 28
Intensity scales for solicited symptoms in adults
Adults
Adverse Event
Intensity grade
Parameter
Pa
in at 
in
ject
ion s
ite
0
None
1
M
i
ld: Any pa
in ne
ither 
interfer
ing w
ith nor prevent
ing 
norma
l every day act
iv
it
ies.
2
Moderate: Pa
infu
l when 
l
imb 
is moved and 
interferes w
ith 
every day act
iv
it
ies.
3
Severe: S
ign
if
icant pa
in at rest. Prevents norma
l every 
day act
iv
it
ies.
Redness at 
in
ject
ion s
ite
Record greatest surface d
iameter 
in mm
Swe
l
l
ing at in
ject
ion s
ite
Record greatest surface d
iameter 
in mm
Fever*
Record temperature 
in °C/°F
Headache
0
Norma
l
1
M
i
ld: Headache that 
is eas
i
ly to
lerated
2
Moderate: Headache that 
interferes w
ith norma
l act
iv
ity
3
Severe: Headache that prevents norma
l act
iv
ity
Fat
igue
0
Norma
l
1
M
i
ld: Fat
igue that 
is eas
i
ly to
lerated
2
Moderate: Fat
igue that 
interferes w
ith norma
l act
iv
ity
3
Severe: Fat
igue that prevents norma
l act
iv
ity
Gastro
intest
ina
l symptoms
0
Norma
l
(nausea, vom
it
ing, d
iarrhea and/or 
abdom
ina
l pa
in)
1
M
i
ld: Gastro
intest
ina
l symptoms that are eas
i
ly to
lerated
2
Moderate: Gastro
intest
ina
l symptoms that 
interfere w
ith 
norma
l act
iv
ity
3
Severe: Gastro
intest
ina
l symptoms that prevent norma
l 
act
iv
ity
*Fever 
is def
ined as temperature 37.5°C / 99.5°F for ora
l, ax
i
l
lary or tympan
ic route, or 38.0°C / 100.4°F for recta
l 
route. The preferred route for record
ing temperature 
in th
is study w
i
l
l be ora
l.
The maximum intensity of local injection site rednessand swelling will be scored at GSK 
Biologicals as follows:
0 :
0 mm
1 :
> 0 to ≤ 50 mm
2 :
> 50 mm to ≤ 100 mm
3 :
> 100 mm
 
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The maximum intensity of feverwill be scored at GSK Biologicals as follows:
0 :
< 37.5°C (< 99.5°F)
1 :
≥ 37.5°C (≥ 99.5°F) to ≤ 38.0°C (100.4°F)
2 :
> 38.0°C(> 100.4°F) to ≤ 39.0°C (102.1°F)
3 :
> 39.0°C (102.1°F)
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgment.
The intensity should be assigned to one of the following categories:
1 (mild)
= An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
= An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
= An AE which prevents normal, everyday activities. In adults, such 
an AE would, for example, prevent attendance at work/school and 
would necessitate the administration of corrective therapy.
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.
 
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The normal ranges and toxicity grading for laboratory safety parameters used in this 
study are presented inTable 29.
Table 29
Toxicity grading scales for blood testing
Adverse event
Intensity grade
Intensity*
Hemog
lob
in (ma
les)
Norma
l range 
12.5 -17.0 g/d
l
1
< 12.5 but 11.0 g/d
l
2
< 11.0 but 10.0 g/d
l
3
< 10.0 g/d
l
Hemog
lob
in (fema
les)
Norma
l range 
11.5 -15.0 g/d
l
1
< 11.5 but 10.5 g/d
l
2
< 10.5 but 9.5 g/d
l
3
< 9.5 g/d
l
Increase 
in 
leukocytes 
Norma
l range
3200 -10799 ce
l
ls/mm
3
(WBC)
1
10800 -15000 ce
l
ls/mm
3
2
15001 -20000 ce
l
ls/mm
3
3
> 20001 ce
l
ls/mm3
Decrease 
in 
leukocytes 
Norma
l range
3200 -10800 ce
l
ls/mm
3
(WBC)
1
2500 -3199 ce
l
ls/mm
3
2
1500 -2499 ce
l
ls/mm
3
3
< 1500 ce
l
ls/mm3
Decrease 
in p
late
lets
Norma
l
140000 -400000 ce
l
ls/mm
3
1
125000 -139000 ce
l
ls/mm
3
2
100000 -124000 ce
l
ls/mm
3
3
< 100000 ce
l
ls/mm3
A
lan
ine Am
inotransferase 
Norma
l range
Be
low ULN (60 U/
l for ma
les; 40 U/
l for fema
les 
1
1.1 -2.5 x ULN
2
2.6 –5 x ULN
3
> 5 x ULN
Aspartate Am
inotransferase Norma
l range
Be
low ULN (40 U/
l for ma
les; 35 U/
l for fema
les
1
1.1 -2.5 x ULN
2
2.6 –5 x ULN
3
> 5 x ULN
Creat
in
ine (ma
les)
Norma
l range 
0.5 -1.39 mg/d
l
1
1.4 -1.79 mg/d
l
2
1.8 -2.0 mg/d
l
3
> 2.0 mg/d
l
Creat
in
ine (fema
les)
Norma
l range
0.5 -1.29 mg/d
l
1
1.3 –1.69 mg/d
l
2
1.7 –1.9 mg/d
l
3
>1.9 mg/d
l
ULN: upper 
l
im
it of norma
l range
*Grad
ing sca
le adapted from [FDAgu
idance for 
industry: tox
ic
ity grad
ing sca
le for hea
lthy adu
lt and ado
lescent 
vo
lunteers enro
l
led 
in prevent
ive vacc
ine c
l
in
ica
l tr
ia
ls(September 2007)].
(Amended 19June 2017)
9.3.3.2.2. Assessment ofcausality
The investigator is obligated to assess the relationship between investigational vaccines
and the occurrence of each AE/SAE. The investigator will use clinical judgmentto 
determine the relationship. Alternative plausible causes, such as naturalhistory of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational vaccineswill be considered and 
 
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investigated. The investigator will also consult the IB and/or Summary of Product 
Characteristicsto determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Reportto GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of general AEs to the individual vaccineadministered. 
The investigator should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccine.
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine?
YES
: There is a reasonable possibility that the vaccinescontributed to the 
AE.
NO
: There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccines. There are other, more 
likely causes and administration of the study vaccinesis not 
suspected to have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 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).
 
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9.3.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
9.4.
Reporting of serious adverse events, pregnancies, and 
other events
9.4.1.
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals
SAEs that occur in the time period defined in Section 9.3will 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.
Pregnancies that occur in the time period defined in Section 9.3will be reported promptly 
to GSK within the timeframes described in Table 30, once the investigator becomes 
aware of the pregnancy. 
AEs of specific interest (meningitis and pIMDs) that occur in the time period defined in 
Section 9.3will 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 
AEs of specific interest.
Table 30
Timeframes for submitting serious adverse event, pregnancy 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*
‡
e
lectron
icExped
ited 
Adverse Events Report
24 hours*
e
lectron
icExped
ited Adverse 
Events Report
Pregnanc
ies
2 weeks*
e
lectron
ic pregnancy report
2 weeks*
e
lectron
ic pregnancy report
AEs of spec
if
ic 
interest 
(men
ing
it
is and 
pIMDs)
24 hours**
‡
e
lectron
icExped
ited 
Adverse Events Report
24 hours*
e
lectron
icExped
ited Adverse 
Events Report
* T
imeframe a
l
lowed after rece
iptor awareness of the 
informat
ion.
**T
imeframe a
l
lowed once the 
invest
igator determ
ines that the event meets the protoco
l def
in
it
ion of an AEs of spec
if
ic 
interest
.
‡ The 
invest
igator w
i
l
l be requ
ired to conf
irm rev
iew of the SAE/AEs of spec
if
ic 
interest causa
l
ity by t
ick
ing the 
‘rev
iewed
’ box 
in the e
lectron
ic Exped
ited Adverse Events Report w
ith
in 72 hours of subm
iss
ion of the SAE/AEs of 
spec
if
ic 
interest.
 
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9.4.2.
Contact information for reporting serious adverse events,
pregnancies and adverse eventsof specific interest
Study Contact for Reporting SAEs, AEs of specific interestand pregnancies
Refer to the localstudycontact information document.
Back-up Study Contact for Reporting SAEs, AEs of specific interestand 
pregnancies
24/24 hour and 7/7day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
US sitesonly:
Fax: 
9.4.3.
Completion and transmission of serious adverse eventreports to 
GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events ReportWITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report.The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
9.4.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Reportand fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.
This back-up system should only be used if the electronic reporting system is not working 
and NOTif the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Reportwithin 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.
 
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9.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report.
9.4.5.
Reporting of adverse events of specific interestto GSK 
Biologicals
Oncean AE of specificinterest (meningitis and pIMDs)is diagnosed (serious or non-
serious) in a study subject, the investigator (or designate) must complete the information 
in the electronic Expedited Adverse Events ReportWITHIN 24 HOURS after he/she 
becomes aware of the diagnosis. The report allows to specify that the event is a pIMD 
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 thecausalityof an AE 
of specific interestby 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 9.4.3.1for back-up system in case the electronic reporting system does 
not work.
9.4.6.
Updating of SAE, pregnancy, and adverse events of specific 
interestinformation after removal of write access to the subject’s
eCRF
When additional SAE, pregnancy, or AEs of specific interestinformation is received after
removal of the write access tothe subject’s eCRF, new or updated information should be 
recorded on the appropriatepaper report, with all changes signed and dated by the 
investigator. The updated report should be faxed to the Study Contact for Reporting 
SAEs (refer to the Sponsor Information) or to GSK Biologicals Clinical Safety and 
Pharmacovigilance department within the designated reporting time frames specified in
Table 30.
 
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9.4.7.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 9.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safetyreports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccines and unexpected. The 
purpose of the report is to fulfillspecific regulatory and GCP requirements, regarding the 
product under investigation.
9.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies
9.5.1.
Follow-up of adverse events and serious adverse events 
9.5.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 30).
All SAEs and AEs of specific interest (meningitis and pIMDs)(serious or non-serious)
documented at a previous visit/contact and designated as not recovered/not resolved or 
recovering/resolving will be reviewed at subsequent visits/contacts until the end of the 
study.
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 
daysafter the last vaccination.
9.5.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:
with SAEs, AEs of specific interest (meningitis and pIMDs) (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 Reportand/or pregnancy report as applicable.
 
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GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognizedfollow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
9.5.2.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the electronic pregnancy report and 
the Expedited Adverse Events Reportif applicable. Generally, the follow-up period 
doesn’t need to be longer than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
9.6.
Treatmentof adverse events
Treatment of any AE is at the sole discretion of the investigator and according tocurrent 
good medical practice.Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF(refer to Section 7.6).
9.7.
Subject card
Study subjects 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. In 
an emergency situation this card serves to inform the responsible attending physician that 
the subject is in a clinical study and that relevant information may be obtained by 
contacting the investigator.
Subjects must be instructed to keep subject cards in their possession at all times.
 
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10.
SUBJECT COMPLETION AND WITHDRAWAL
10.1.
Subject completion
A subject who returns for the concluding visitforeseen 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 visitforeseen 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 andno 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 himself/herself, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:
SAE.

Non-SAE.
Protocol violation (specify).

Consent withdrawal, not due to an AE*.
Moved from the study area.
Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because he/shehas withdrawn consent, the 
investigator will document the reason for withdrawal of consent, if specified by the 
subject, in the eCRF.
 
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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 9.5.1.2).
10.2.2.
Subject withdrawal from investigational vaccines
A ‘withdrawal’ from the investigational vaccinesrefers 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 vaccinesmay 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 vaccineswill be 
documented on the Vaccine Administration screen of theeCRF. The investigator will 
document whether the decision to discontinue further vaccination/treatment was made by 
the subject himself/herself,or bythe investigator, as well as which of the following 
possible reasons was responsible for withdrawal:
SAE.
Non-SAE.

Other (specify).
10.3.
Extension study
At the end of the study (study conclusion visit), the investigator will ask each subjectif 
they are interested to participate in a booster study/long-term study. If a subjectis not 
interested in participating in the booster study/long-term study the reason for refusal will 
be documented in the subject’s eCRF.
10.4.
Screen and baseline failures
Screening failures are defined as subjects who are withdrawn from the study after giving 
informed consent, but who do not meet the inclusion and exclusion criteria. Reason for 
screening failure will be collected.
 
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11.
STATISTICAL METHODS
11.1.
Primary endpoint
11.1.1.
Efficacy
Occurrence of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge, comparing RTS,S/AS01
Badministered as full doses 
at Month 0 and Month 1 and 1/5
thdose at Month 7 (AduFx group) versus infectivity 
controls.

Occurrence of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge, comparing RTS,S/AS01
Eadministered as double 
dose at Month 0 and Month 1 and double 1/5thdose at Month 7 (2PedFx group) 
versus infectivity controls.
Occurrence of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge, comparing RTS,S/AS01
Eadministered as full doses 
at Month 0 and Month 1 and 1/5
thdose at Month 7 (PedFx group) versus infectivity 
controls.

Occurrence of P. falciparum parasitemia (defined by a positive blood slide) 
following sporozoite challenge, comparing RTS,S/AS01
Badministered as one full 
dose at Month 0 and 1/5th doses at Month 1 and Month 7 (Adu2Fx group) versus 
infectivity controls.
Occurrence of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge, comparing RTS,S/AS01
Badministered as one full 
dose at Month 0 and 1/5thdoses at Month 7 (Adu1Fx group) versus infectivity 
controls.
11.2.
Secondary endpoints
11.2.1.
Efficacy
Occurrence of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge, comparing RTS,S/AS01
Eadministered as double 
dose at Month 0 and Month 1 and double 1/5thdose at Month 7 (2PedFx group) 
versus immunization schedule of reference (AduFx group).
Occurrence of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge, comparing RTS,S/AS01
Eadministered as full doses 
at Month 0 and Month 1 and 1/5
th dose at Month 7 (PedFx) versus immunization 
schedule of reference (AduFx group).
Occurrence of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge, comparing RTS,S/AS01
Badministered as one full 
dose at Month 0 and 1/5thfull dose at Month 1 and Month 7 (Adu2Fx) versus 
immunization schedule of reference (AduFx group).
 
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Occurrence of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge, comparing RTS,S/AS01
Badministered as one full
dose at Month 0 and 1/5thfull doses at Month 7 (Adu1Fx) versus immunization 
schedule of reference (AduFx group).
Time to onset of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge in each vaccination schedule versus immunization 
schedule of reference (AduFx group).
Time to onset of P. falciparumparasitemia (defined by a positive blood slide) 
following sporozoite challenge in each vaccination schedule versus infectivity 
controls.
11.2.2.
Immunogenicity
For each vaccination schedule, the immune response to the CS antigen of the 
investigational vaccine:
Anti-CS repeat region antibody concentrations before vaccine administration 
(Day 0), one month post-Dose 2 (Day 58), six months post-Dose 2 (Day 196), 
one month post-Dose 3 (Day 226), on the day of challenge (Day 286), 28 days 
post-challenge (Day 314), and at study end (Day 376) for subjects from AduFx, 
2PedFx, PedFx, and Adu2Fx groups and before vaccine administration (Day 0), 
before Dose 2 (Day 196), one month post-Dose 2 (Day 226), on the day of 
challenge (Day 286), 28 days post-challenge (Day 314), and at study end (Day 
376) for subjects from Adu1Fx group.
For each vaccination schedule, the immune response to the hepatitis B antigen of the 
investigational vaccine:

Anti-HBs IgG antibody concentrations before vaccine administration (Day 0), 
one month post-Dose 2 (Day 58), six months post-Dose 2 (Day 196), one month 
post-Dose 3 (Day 226), on the day of challenge (Day 286), 28 days post-
challenge (Day 314), and at study end (Day 376) for subjects from AduFx, 
2PedFx, PedFx, and Adu2Fx groups and before vaccine administration (Day 0), 
before Dose 2 (Day 196), one month post-Dose 2 (Day 226), on the day of 
challenge (Day 286), 28 days post-challenge (Day 314), and at study end (Day 
376) for subjects from Adu1Fx group.
11.2.3.
Safety
Safety and reactogenicity of the investigational vaccine for each vaccination 
schedule:
Occurrence of solicited local and general AEs within seven days (day of 
vaccination and six subsequent days) after each vaccination.

Occurrence of unsolicited AEs within 30 days (day of vaccination and 29 
subsequent days) after each vaccination, according to the Medical Dictionary for 
Regulatory Activities (MedDRA) classification.
 
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Occurrence of AEs within 30 days (day of challenge and 29 subsequent days) 
after challenge, according to the MedDRA classification.
Occurrence of SAEs (all, fatal, related to investigational vaccine) within 30 days 
(day of vaccination and 29 subsequent days) after each vaccination, according to 
the MedDRA classification.
Occurrence of SAEs (all, fatal, related to investigational vaccine) during the 
whole study period (from Dose 1 [Day 0] up to study conclusion [Day 376]), 
according to the MedDRA classification.

Occurrence of AEs and SAEs leading to withdrawal from further vaccination 
from Dose 1 (Day 0) up to study conclusion (Day 376), according to the 
MedDRA classification, for each vaccinated subject.

Occurrence of pIMDs from Dose 1 (Day 0) up to study conclusion (Day 376), 
according to the MedDRA classification, for each vaccinated subject.
Occurrence of meningitis from Dose 1 (Day 0) up to study conclusion (Day 
376), according to the MedDRA classification, for each vaccinated subject.
Occurrence of abnormal laboratoryvalues at screening, Day 35, Day 58, Day 
203, Day 226, the day of first parasitemia, and Day 314 for each vaccinated 
subject and at screening, the day of first parasitemia and Day 314 for the 
infectivity control subjects.
Safety after sporozoite challenge in the infectivity control group.
Occurrence of AEs within 30 days (day of challenge and 29 subsequent days) 
after challenge, according to the MedDRA classification.
Occurrence of SAEs (all, fatal, related) from day of challenge (Day 286) to the 
endof the challenge phase (Day 314), according to the MedDRA classification.
11.3.
Tertiary endpoints
11.3.1.
Immunogenicity
For each vaccination schedule, the immune response to the CS antigen of the 
investigational vaccine:

Anti-CS repeat region IgG avidity index before vaccine administration (Day 0), 
one month post-Dose 2 (Day 58), six months post-Dose 2 (Day 196), one month 
post-Dose 3 (Day 226), on the day of challenge (Day 286), 28 days post-
challenge (Day 314), and at study end (Day 376) for subjects from AduFx, 
2PedFx, PedFx, and Adu2Fx groups and before vaccine administration (Day 0), 
before Dose 2 (Day 196), one month post-Dose 2 (Day 226), on the day of 
challenge (Day 286), 28 days post-challenge (Day 314), and at study end (Day 
376) for subjects from Adu1Fxgroup.
 
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Anti-full length CS protein IgG concentrations and anti-C-term IgG 
concentrations before vaccine administration (Day 0), one month post-Dose 2 
(Day 58), six months post-Dose 2 (Day 196), one month post-Dose 3 (Day 226), 
on the day of challenge (Day 286), 28 days post-challenge (Day 314), and at 
study end (Day 376) for subjects from AduFx, 2PedFx, PedFx, and Adu2Fx 
groups and before vaccine administration (Day 0), before Dose 2 (Day 196), one 
month post-Dose 2 (Day 226), on the day of challenge (Day 286), 28 days post-
challenge (Day 314), and at study end (Day 376) for subjects from Adu1Fx 
group.

Anti-full length CS protein and anti-C-term IgG avidity before vaccine 
administration (Day 0), one month post-Dose 2 (Day 58), six months post-Dose 
2 (Day 196), one month post-Dose 3 (Day 226), on the day of challenge (Day 
286), 28 days post-challenge (Day 314), and at study end (Day 376) for subjects 
from AduFx, 2PedFx, PedFx, and Adu2Fx groups and before vaccine 
administration (Day 0), before Dose 2 (Day196), one month post-Dose 2 (Day 
226), on the day of challenge (Day 286), 28 days post-challenge (Day 314), and 
at study end (Day 376) for subjects from Adu1Fx group.
Note: other immuno-assays evaluating the immune response targeting the CS and HBsAg
might be performed.
11.4.
Determination of sample size
The target enrollment for this study will be approximately 150 subjects (26 subjects per 
vaccine group and between 20 and 30subjects in the infectivity control group) to ensure 
at least 20 subjects in each group will undergo sporozoite challenge, given an 
approximate 20% estimated drop-out rate in vaccinees, based on past experience.
Assuming at least 19/20 controls and 6/20 vaccinees become positive (vaccine efficacy 
approximately 68%) the trial has 99% powerto detect statistically significant vaccine 
efficacy of each of the vaccination groups over the infectivity controls for an overall 
power of 96% for the primary endpoint (p-value < 0.05).
For secondary efficacy endpoints the power of the trial to detect incremental vaccine 
efficacy of one schedule over any other is presented below:
Vaccine efficacy group 
x over controls
Vaccine efficacy group y 
over controls
Incremental Vaccine 
efficacy of group yover x
Power
50%
75%
50%
27%
50%
80%
60%
41%
50%
85%
70%
57%
50%
90%
80%
74%
 
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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. All challenged infectivity control will also be included and will be 
presented as a separate study group.
11.5.2.
According-to-protocol cohort for analysis of immunogenicityand 
efficacy
The ATP cohortfor analysis of immunogenicityand efficacywill 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,did not have any reported underlying medical 
condition influencing immune responses, and underwent sporozoite challenge.
11.6.
Derived and transformed data
Immunogenicity
A subject seropositive for anti-CS antibody will be a subject whose antibody 
concentrationwill 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 concentrationgreater than or equal to an established cut-
off (anti-HBs 10 mIU/ml).
The geometric mean concentrations(GMC)calculations will be performed by 
taking the anti-log of the mean of the log transformations (base 10). Antibody 
concentrationsbelow the cut-off of the assay will be given an arbitrary value of 
half the cut-off for the purpose of GMCcalculation.

Handling of missing data: for a given subject and a given immunogenicity 
measurement, missing or non-evaluable measurements will notbe 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.
 
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
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 TVCwill include only subjects/doses with documented safety data (i.e. 
symptom screen/sheet completed).
11.7.
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.
The analysis of demographics will be performed on the TVC and on the ATP cohort for 
immunogenicity and efficacy.
Demographic characteristics (age at vaccination in years, gender, and race) will be 
summarized by group using descriptive statistics:
Frequency tables will be generated for categorical variable such as race.

Mean, median, standard deviation (SD) and range will be provided for continuous 
data such as age.
Withdrawal status will be summarized by group using descriptive statistics:

The number of subjects enrolled into the study as well as the number of subjects 
excluded from ATP analyses will be tabulated.
The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal.
11.8.
Analysis of efficacy
The analysis of efficacy will be performed on the ATP cohort for immunogenicity and 
efficacy.
Efficacy will be assessed by comparison of P. falciparumparasitemia and time to onset 
of parasitemia after sporozoite challenge. Vaccine efficacy is defined as 100*(1-Relative 
Risk). Relative risk of infection and 95% CI will be calculated. Fisher’s Exact test will be 
used for the comparison of P. falciparumparasitemia between each one of the vaccine 
groups (AduFx, 2PedFx, PedFx, Adu2Fx, and Adu1Fx) and the infectivity control group. 
Kaplan-Meier analysis will be performed on time to onset of parasitemia, for 
comparisons between each one of the vaccine groups (AduFx, 2PedFx, PedFx, Adu2Fx, 
and Adu1Fx) and the infectivity control group, using the log-rank statistic. The same 
methodology will be applied for the evaluation of the vaccinated groups versus the 
immunization schedule of reference (AduFx group).All statistical tests will be two-tailed 
at 5% significance level.
 
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11.9.
Analysis of immunogenicity
The analysis of immunogenicity will be performed on the ATP cohort for 
immunogenicity and efficacy.
For each study group, at each timepoint that a blood sample result is available:
The percentage of subjects with seropositive levels of anti-CS (proportion of subjects 
with anti-CS antibody concentrations 0.5 EU/ml) with 95% CI will be determined 
at specified blood sampling timepoints in each groups (AduFx, 2PedFx, PedFx, 
Adu2Fx, and Adu1Fx; see Table 6and Table 7). Anti-CS antibody concentrations
will be summarized by GMC. Anti-CS antibody concentrationswill be displayed 
using reverse cumulative curves. Similar analysis will be performed for anti-CS 
repeat region, anti-full length CS protein and anti-C-term antibodies.

The percentage of subjects with seroprotection levels of anti-HBs (anti-HBs antibody 
concentrations10 mIU/ml) with 95% CI will be determined at specified blood 
sampling timepoints in each groups (AduFx, 2PedFx, PedFx, Adu2Fx, and Adu1Fx; 
see Table 6and Table 7). Anti-HBs antibody concentrationswill be summarized by 
GMC. Anti-HBs antibody concentrationswill be displayed using reverse cumulative 
curves.
For the analysis of secondary and tertiary objectives, avidity index will be summarized by 
mean, SD, median and quartile.
11.10.
Analysis of safety
The analysis of safety will be performed on the TVC.
The percentage of subjects with at least one local AE (solicited and unsolicited), with at 
least one general AE (solicited and unsolicited) and with any AE during the 7-day or 
30-day follow-up period after each vaccine dose and overall will be tabulated with exact 
95% CI. The percentage of doses followed by at least one local AE (solicited and 
unsolicited), by at least one general AE (solicited and unsolicited) and by any AE during 
the 7-day or 30-day follow-up period will be tabulated with exact 95% CI. The same 
computations will be done for Grade 3 AEs, for any AEs considered related to 
vaccination and for any Grade 3 AEs considered related to vaccination.
The percentage of subjects reporting each individual solicited local AE (any grade and 
Grade 3) and solicited general AE (any grade, Grade 3, any related, Grade 3 related, 
resulting in medically attended visit) during the 7-day follow-up period (Day 0-6) after 
each vaccine dose and overall will be tabulated for each group. Similarly, the percentage 
of doses followed by each individual solicited local and general AE will be tabulated, 
overall vaccination course, with exact 95% CI.
For fever, the number and percentage of subjects reporting fever by half degree (°C) 
cumulative increments during the first seven days (Day 0-6) after each vaccine dose and 
overall will be tabulated. Similar tabulations will be performed for anyfever with a 
causal relationship to vaccination and Grade 3 (> 39.5°C) causally related fever.
 
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The percentage of subjects reporting unsolicited AEs within 30 days (Day 0-29) after 
each vaccine dose (overall doses) and percentage of subjects reporting AEs after the 
sporozoite challenge will be tabulated by group and by MedDRA preferred term with 
exact 95% CI. Similar tabulation will be done for Grade 3 unsolicited AEs, for any 
causally related unsolicited AEs and for Grade 3 causally related unsolicited AEs.
The percentage of subjects reporting SAEs and pregnancies will be described in detail.
The percentage of vaccinated subjects reporting AEs of specific interest (meningitis and 
pIMDs) will be described in detail.
Biochemistry (ALT, AST and creatinine) andhematological (hemoglobin, WBC and 
platelets) laboratory values will be presented according to toxicity grading scales and 
tabulated by group.
The percentage of subjects using concomitant medication (any medication, any 
antipyretic and any antipyretic taken prophylactically, respectively) during the 7-day 
follow-up period (Day 0-6) after vaccination will be summarized by group after each
dose and overall. The percentage of subjects using concomitant medication during the 
entire sporozoite challenge will besummarized by group.
11.11.
Interpretation of analyses
For the primary efficacy evaluations the aim will be to establish significant vaccine 
efficacy over infectivity controls whereas secondary efficacy evaluations between 
vaccination schedules will be descriptive with the aim to characterize the difference in 
immunogenicity, efficacy and safety between groups.
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
The analysis will be performed when all data up to Day376are available. An integrated 
study report presenting all results until Day 376will be written.
11.12.2. Statistical considerations for interim analyses
No interim analyses are planned.
 
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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 Forminstructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties.
12.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the: 
Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform aneCRFreview and a Source Document 
Verification (SDV). By SDV we understand verifying eCRFentries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
 
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The Source Documentation Agreement Form describes the source data for the different 
data in theeCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRFwill serve as the source must be identified, agreed and 
documented in the source documentation agreement form.
For eCRF, the monitor freezescompleted andapproved screens at each visit.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
12.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures. 
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.
 
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12.5.
Posting of information on publicly available clinical trial 
registers and publication policy
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within 12 months of the primary completion date.
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.
12.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
13.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
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14.
REFERENCES
AsanteKP, Abdulla S, Agnandji S, et al. Safety and efficacy of the RTS,S/AS01
E
candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 
19 month follow-up of a randomised, open-label, phase 2 trial. Lancet Infect Dis.2011; 
11:741-49.
BallouWR, Sherwood JA, Neva FA, et al. Safety and efficacy of a recombinant DNA
Plasmodium falciparumsporozoite vaccine. Lancet1987;8545:1277-1281.
Centersfor Disease Control and Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf(last access: 
09-MAR-2016)
ClementF, Dewar V, Van Braeckel E et al. Validation of an enzyme-linked 
immunosorbent assay for the quantification of human IgG directed against the repeat 
region of the circumsporozoite protein of the parasite Plasmodium falciparum. Malar J.
2012; 11:384.
EMAGuideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005 ) ‘adopted at Community level 
in May 2006);
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf(last access: 09-MAR-2016)
EuropeanConsensus Group on Hepatitis B Immunity. Are booster immunisations needed 
for lifelong hepatitis B immunity? Lancet.2000; 355(9203):561-565.
FDAguidance for industry: toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials (September 2007). 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformatio
n/Guidances/Vaccines/ucm074775.htm(last access: 09-MAR-2016).
MalariaVaccine Funders Group. Malaria Vaccine Technology Roadmap. 2013. 
http://www.who.int/immunization/topics/malaria/vaccine_roadmap/TRM_update_nov13.
pdf?ua=1 (last access: 09-MAR-2016).
MontoyaJ, Solon JA, Cunanan SR, et al. A randomized, controlled dose-finding phase II 
study of the M72/AS01 candidate tuberculosis vaccine in healthy PPD-positive adults. J 
Clin Immunol 2013; 33(8): 1360-75.
StouteJA, Slaoui M, Heppner DG et al. A preliminary evaluation of a recombinant 
circumsporozoite protein vaccine against Plasmodium falciparummalaria. N Engl J Med.
1997; 336:86-91.
TheRTS,S Clinical Trials Partnership. First results of a phase 3 trial of RTS,S/AS01 
malaria vaccine in African children. N Engl J Med. 2011; 365:1863-75.
 
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TheRTS,S Clinical Trials Partnership. A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine
in African Infants. N Engl J Med. 2012; 367:2284-2295.
TheRTS,S Clinical Trials Partnership. The RTS,S/AS01 Malaria Vaccine Phase 3 Trial: 
18 Month Efficacy and Safety in Children and Young Infants at 11 African Sites. PLoS 
Med. 2014; 11(7):e1001685.
TheRTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria 
vaccine with or without a booster dose in infants and children in Africa: final results of a 
phase 3, individually randomised, controlled trial. Lancet. 2015;386(9988):31-45.
Wirtz RA, Ballou WR, Schneider I et al. Plasmodium falciparum: Immunogenicity of
circumsporozoite protein constructs produced in Escherichia coli. Exp Parasitol 
1987;63:166-72.
 
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APPENDIX A
LABORATORY ASSAYS
Anti-CS antibody
Antibody concentrations against P. falciparumCS-repeat region will be measured at 
CEVAC by a standard ELISA methodology using plate adsorbed recombinant R32LR 
antigen, as described by Clement 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.
Avidity assays against CS repeat region, CS full length and C-term antigens
The anti-CS repeat region avidity assay uses NH
4SCN to demonstrate the avidity of the 
antibodies in the assay, according to standard operatingprocedures (SOPs)from the 
laboratory. Briefly, one extra step is introduced in the classic anti-CS quantification 
assay. After addition and incubation of the serum sample an extra incubation with the 
chaotropic reagent (NH
4SCN at 1M) is inserted in order to introduce a detaching force to 
the antigen-antibody complex. The remaining antibodies, demonstrating a higher binding 
force to the antigen, are further quantified and the avidity index % (anti-CS repeat region 
concentrationunder chaotropic reagent/anti-CS repeat regionconcentrationwithout 
chaotropic reagent) is calculated and reported.
The avidity assay against full length CSproteinand C-term uses 4M urea as chaotropic 
reagent and the result is also reported as avidity index % (anti-CSP full length 
concentrationunder chaotropic reagent/anti-CSproteinfull length concentrationwithout 
chaotropic reagentand anti-C-term concentrationunder chaotropic reagent/anti-C-term 
titer without chaotropic reagent, respectively).
Blood smear and PCR testing for assessment of P. falciparumparasitemia
Blood slide preparation and reading and PCR testing will be performed according to 
laboratory SOPs.
Hematological and biochemical testing
Hematological and biochemical testing will be performed at Quest Diagnostics, Inc.
using laboratory SOPs.
RNAsequencing(mRNA expression analysis)
mRNAsequencingis a technique using next generation sequencing technology to 
sequence and quantify mRNA samples. It concerns analysis of mRNA transcription, not 
genetic testingas the data obtained is used to assess relative abundance of mRNA 
molecules. The Illumina Genome Analyzer II uses clonal array formation and reversible 
terminator technology to generate 20-30 million short sequence reads per sample lane. 
 
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These short sequences are aligned with the genome and counted to provide a relative 
frequency of sequences in the library population. The experiments will be instructed by 
the results obtained from systems biology results in previous CHMI studies.
 
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APPENDIX B 
CLINICAL LABORATORIES
Table 31
GSK Biologicals’ laboratories
Laboratory
Address
GSK B
io
log
ica
ls C
l
in
ica
l Laboratory 
Sc
iences, R
ixensart
B
iospec
imen Recept
ion -B7/44
Rue de 
l
'Inst
itut, 89 -B-1330 R
ixensart -Be
lg
ium
GSK B
io
log
ica
ls C
l
in
ica
l Laboratory 
Sc
iences, Wavre-Nord No
ir Ep
ine
Avenue F
lem
ing, 20 -B-1300 Wavre -Be
lg
ium
Table 32
Outsourced laboratories
Laboratory
Address
CEVAC -Un
ivers
ity of Gent
De P
inte
laan, 185 Gent
Be
lg
ium
D
iv
is
ion of Ma
lar
ia Vacc
ine 
Deve
lopment -WRAIR
Wa
lter Reed Army Inst
itute of Research
S
i
lver Spr
ing, MD 20910, Un
ited States
Prec
is
ion B
ioserv
ices, Inc.
8425 Progress Dr
ive
Freder
ick, MD 21701, Un
ited States
Quest D
iagnost
ics, Inc.
1901 Su
lphur Spr
ing Road
Ba
lt
imore, MD 21227, Un
ited States
Q² Solutions
27027 Tourney Road, Suite 2E
Valencia, CA 91355
United States
(Amended 19June 2017)
 
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APPENDIX C
NHANES I CARDIOVASCULAR RISK CRITERIA
Volunteers will be screened for cardiac risk factors and be given a screening 
electrocardiogram. The information will be recorded on a source document with the 
following noted:
Study ID # ______________
Risk factors
Weight___ kg
Blood pressure ________
Height_____ 
Smoker Y / N
Calculated BMI (kg/m2)_____
Diabetes Y / N
Using Table A (males) or Table B (females), 5-year cardiovascular risk:
□  Low
□  Moderate
□  High
Electrocardiogram (EKG)
12-lead EKG taken?  Y / N
If not, 
reason__________________________________________________________________
Electrocardiogram interpreted by 
__________________________________________________
Electrocardiogram interpretation 
___________________________________________________
Only volunteers with NHANES I low risk criteria as well as non-significant EKG, as 
determined by expert consultant cardiologist, are accepted in the study.
 
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Table A (for Males)
 
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Table B (for Females)
 
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APPENDIX D
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
205081 (MALARIA-092)
Amendment number:
Amendment 1
Amendment date:
23 June2016
Co-ordinating author:
, 
Scientific Writer, FreelanceContractor forGSK 
Biologicals
Rationale/background for changes: 
An additionalblood sample of approximately 2 ml for assessment of parasitemia 
(polymerase chain reaction [PCR]testing) will be collected on the day of subject entry 
into the hotel phase (Day 295 [Visit 16]) to provide the study team an estimate of the 
number of subjects likely to develop malaria within the first few days of the hotel 
phase. This will allow the principal investigator and the study team to maximize 
subject safety by properly allocating resources and medical personnel to meet any high 
demand periods (i.e. periods when a large number of subjects are/will become ill).
These samples will be processed byand assessed at WRAIR.
The text has been revised to provide clarification that blood samples for both PBMC 
and plasmawill be collected for repository storage.
The final protocol dated 09 March 2016details that 1 ml whole blood samples will be 
taken for parasitemia assessment. EDTA tubes of 1 ml volume are unavailable in the 
US hence2 ml EDTA tubes will be provided. Whole blood samples of 2 ml will be 
drawn and the required sample volumes will be extracted for the blood slide smear.
In Section 6.6.8, the text has been revised to clarify that urine pregnancy tests will be 
conducted for all females and not just those of childbearing potential.
On Day 1 post day of challenge no blood samples are scheduled. As there is no safety 
concern at this timepoint and no specific assessments are scheduled, this visit has been 
deleted from the protocol.
The proposed genetic testing will investigate the immune response to the vaccine or to 
malaria through RNA sequencing, which looks at the signature for immune molecules 
being produced by the body’s cells. Deep sequencing refers to sequencing a genomic 
region multiple times in order to detect rare events in the subject’s genome, identifying 
rare genetic mutations and specific hereditary characteristics. Deep sequencing is not 
proposed in this study, reference to which has been replaced by RNA sequencing.
 
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Amended text has been included in bold italicsand deleted text in strikethroughin 
the following sections:
SYNOPSIS
Study design
Experimental design: Phase IIA, open, randomized, 
controlled, mono-centric, single-country study with five 
parallel groups and one infectivity control group.

Duration of the study: Approximately 16 months for each 
vaccinated subject and three months for the infectivity 
control subjects.
Epoch 001: Primary starting at Visit 1 (Screening) 
(Screening for vaccinated subjects) and ending at Visit 
10 (Day 226).

Epoch 002: Challenge starting at Visit 11 (Day 286) or 
Visit 1b (Screening) (Screening for infectivity controls), as 
applicable, and ending at Visit 312(Day 376).

Sampling schedule:
Blood samples for peripheral blood mononuclear cells 
(PBMC) and plasmarepository will be collected 
before vaccine administration (Day 0), one month 
post-Dose 1 (Day 28), seven days post-Dose 2 (Day 
35), one month post-Dose 2 (Day 58), six months post-
Dose 2 (Day 196), seven days post-Dose 3 (Day 203), 
one month post-Dose 3 (Day 226), on the day of 
challenge (Day 286), and at study end (Day 376) for 
subjects from AduFx, 2PedFx, PedFx, and Adu2Fx 
groupsand before vaccine administration (Day 0), one 
month post-Dose 1 (Day 28), before Dose 2 (Day 196), 
seven days post-Dose 2 (Day 203), one month post-
Dose 2 (Day 226), on the day of challenge (Day 286), 
and atstudy end (Day 376) for subjects from Adu1Fx 
group.

Blood samples for deepRNAsequencing (messenger 
ribonucleic acid [mRNA] sequencing analysis) will be 
collected before vaccine administration (Day 0), at 
Dose 2 (Day 28), one day post-Dose 2 (Day 29), at 
Dose 3 (Day 196), and one day post-Dose 3 (Day 197) 
for subjects from AduFx, 2PedFx, PedFx, and 
Adu2Fx groupsand before vaccine administration 
(Day 0), one month post-Dose 1 (Day 28), at Dose 2 
(Day 196) and one day post-Dose 2 (Day 197) for 
subjects from Adu1Fx group.
 
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Blood sample for assessment of parasitemia (PCR 
testing) will be collected on the day of subject entry 
into the hotel phase (Day 295[Visit 16]) to provide an 
estimate of the number of subjects likely to develop 
malaria within the first few days of the hotel phase. 

Blood sample for assessment of parasitemia (blood 
smear) will be collected daily for 14 days (from Day 
291 [Visit 123] to Day 304 [Visit 256]) and then every 
two days for nine days (Day 306 [Visit 267], Day 308 
[Visit 278], Day 310 [Visit 289], Day 312 [Visit 2930], 
and Day 314 [Visit 301]). For subjects who develop 
malaria, blood smear may be discontinued once the 
subject has three consecutive negative smears 
(separated by morethan 12 hours) following the initial 
treatment.

Safety monitoring:
Biochemistry (ALT, AST and creatinine) and 
hematology (hemoglobin, WBC and platelets) 
parameters will be assessed before vaccine 
administration (screening), seven days post-Dose 2 
(Day 35), one month post-Dose 2 (Day 58), seven days 
post-Dose 3 (Day 203), one month post-Dose 3 (Day 
226), the day of first parasitemia, and 28 days post-
challenge (Day 314) for subjects from AduFx, 2PedFx, 
PedFx, and Adu2Fx groups, before vaccine 
administration (screening), seven days post-Dose 2 
(Day 203), one month post-Dose 2 (Day 226), the day 
of first parasitemia, and 28 days post-challenge (Day 
314) for subjects from Adu1Fx group and at screening, 
the day of first parasitemia and 28 days post-challenge 
(Day 314) for the infectivity control subjectsas 
described in ‘Samplingschedule’.

LIST OF ABBREVIATIONS
PCR:
Polymerase chain reaction
 
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3.
STUDY DESIGN OVERVIEW
Figure 1
Study design
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Footnotes to Figure 1:
D: Day; Mth: month; R: RTS,S; SCR: Screen
ing; V: v
is
it. *Blood sample for estimation of subjects with parasitemia (PCR testing) will be collected on the day of subject entry 
into the hotel phase (Day 295 [Visit 16]);bBlood samp
le f
or b
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia and b
lood samp
le for assessment 
of paras
item
ia (b
lood smear) w
i
l
l be co
l
lected da
i
ly for 14 days (from Day 291 [V
is
it 123] to Day 304 [V
is
it 254]) and then every two days for n
inedays (Day 306 [V
is
it 267], Day 308 
[V
is
it 278], Day 310 [V
is
it 289], Day 312 [V
is
it 2930], and Day 314 [V
is
it 301]).
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Experimental design: Phase IIA, open, randomized, controlled, mono-centric, single-
country study with five parallel groups and one infectivity control group.
Duration of the study: Approximately 16 months for each vaccinated subject and 
three months for the infectivity control subjects.
Epoch 001: Primary starting at Visit 1 (Screening) (Screening for vaccinated
subjects) and ending at Visit 10 (Day 226).
Epoch 002: Challenge starting at Visit 11 (Day 286) or Visit 1b (Screening) 
(Screening for infectivity controls), as applicable, and ending at Visit 312(Day 
376).
Sampling schedule:
Blood samples for peripheral blood mononuclear cells (PBMC) and plasma 
repository will be collected before vaccine administration (Day 0), one month 
post-Dose 1 (Day 28), seven days post-Dose 2 (Day 35), one month post-Dose 2 
(Day 58), six months post-Dose 2 (Day 196), seven days post-Dose 3 (Day 203), 
one month post-Dose 3 (Day 226), on the day of challenge (Day 286), and at 
study end (Day 376) for subjects from AduFx, 2PedFx, PedFx, and Adu2Fx 
groups and before vaccine administration (Day 0), one month post-Dose 1 (Day 
28), before Dose 2 (Day 196), seven days post-Dose 2 (Day 203), one month 
post-Dose 2 (Day 226), on the day of challenge (Day 286), and at study end 
(Day 376) for subjects from Adu1Fx group.
Blood samples for deepRNAsequencing (messenger ribonucleic acid [mRNA] 
sequencing analysis) will be collected before vaccine administration (Day 0), at 
Dose 2 (Day 28), one day post-Dose 2 (Day 29), at Dose 3 (Day 196), and one 
day post-Dose 3 (Day 197) for subjects from AduFx, 2PedFx, PedFx, and 
Adu2Fx groupsand before vaccine administration (Day 0), one month post-
Dose 1 (Day 28), at Dose 2 (Day 196) and one day post-Dose 2 (Day 197) for 
subjects from Adu1Fx group.
Blood sample for assessment of parasitemia (PCR testing) will be collected on 
the day of subject entry into the hotel phase (Day 295[Visit 16]) to provide an 
estimate of the number of subjects likely to develop malaria within the first 
few days of the hotel phase.

Blood sample for assessment of parasitemia (blood smear) will be collected 
daily for 14 days (from Day 291 [Visit 123] to Day 304 [Visit 256]) and then 
every two days for nine days (Day 306 [Visit 267], Day 308 [Visit 278], Day 
310 [Visit 289], Day 312 [Visit 2930], and Day 314 [Visit 301]). For subjects 
who develop malaria, blood smear may be discontinued once the subject has 
three consecutive negative smears (separated by morethan 12 hours) following 
the initial treatment.
Safety monitoring:
Biochemistry (ALT, AST and creatinine) and hematology (hemoglobin, WBC 
and platelets) parameters will be assessed before vaccine administration 
(screening), seven days post-Dose 2 (Day 35), one month post-Dose 2 (Day 58), 
 
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seven days post-Dose 3 (Day 203), one month post-Dose 3 (Day 226), the day of 
first parasitemia, and 28 days post-challenge (Day 314) for subjects from 
AduFx, 2PedFx, PedFx, and Adu2Fx groups, before vaccine administration 
(screening), seven days post-Dose 2 (Day 203), one month post-Dose 2 (Day 
226), the day of first parasitemia, and 28 days post-challenge (Day 314) for 
subjects from Adu1Fx group and at screening, the day of first parasitemia and 
28 days post-challenge (Day 314) for the infectivity control subjectsas described 
in ‘Sampling schedule’.
5.2. Inclusion criteriafor enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:
Female subjects of childbearing potential may be enrolled in the study, if the subject:
has practiced adequate contraception for 30 days prior to vaccination, and

has a negative pregnancy test at enrolment, and
has agreed to continue adequate contraception during the entire treatment period 
and for two months after completion of the vaccination series and/or malaria 
challenge.
6.4.1.5.
Management of infected human subjects
The pre-patent period for P. falciparum in man normally averages 9-12 days. In previous 
studies, the pre-patent period in controls varied from 7-18 days. The shortest reported 
pre-patent period in man is five days, and the longest is 25 days [Ballou, 1987]. An 
immunized individual who does not have complete protection may have a prolongation of 
the parasite pre-patent period.
Subjects will return at the study clinic on Day 1 (Day 287 [Visit 12]) after their primary 
phase challenge for evaluation by a study investigator. If for any reason subjects do not 
come at the study clinic, they can be contacted by phone to collect information on their 
well-being. Beginning on Day 5 (Day 291 [Visit 123]) after their challenge, subjects will 
be seen and evaluated daily by a study investigator and blood will be drawn for blood 
smears to check for the presence of parasites as described in Section 6.4.1.4. If fever or 
symptoms develop at any time, blood smears will be done more frequently (every 6 to 12 
hours), and a study investigator will evaluate the subject. A confirmed positive result will 
be relayed immediately to the on-call investigator/study personnel by the microscopists. 
The infection will be treated early (i.e. as soon as parasites can be identified on thick 
smear) according to the treatment regimen outlined in Section 6.4.1.6.
Beginning on Day 9 post-challenge (Day 295 [Visit 167]), a group of hotel rooms in the 
local area of WRAIR, will be reserved for malaria-challenged subjects. The subjects will 
be required to spend their nights there to allow for more rapid assessment of any potential 
 
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symptoms of malaria during the hours that the study centers are closed. There will be an 
investigator presenton-site and available for subject assessment. There will also be 
qualified study personnel on site 24 hours per day during the hotel phase of the study.
A blood sample for assessment of parasitemia (PCR testing) will be collected on the day 
of subject entry into the hotel phase (Day 295[Visit 16]) to provide the study team an 
estimate of the number of subjects likely to develop malaria within the first few days of 
the hotel phase. This will allow the principal investigator and the study team to 
maximize subject safety by properly allocating resources and medical personnel to meet 
any high demand periods (i.e. periods when a large number of subjects are/will become 
ill). These samples will be processed by and assessed at WRAIR.
During the hotel phase, all challenged subjects will be assessed on a daily basis in an 
identical manner. An evaluation will be done each morning (headache, muscle aches, 
etc.) and blood will be drawn for smear. All challenged subjects will be instructed to 
check in with clinical staff by telephone call or in-person each evening during the hotel 
stay until they are positive for malariaor post day of challenge Day 28 whichever comes 
first. They will be asked if they feel any differently since they were seen in the morning. 
At any time required, the on-duty investigator will arrange for the timely production of 
blood smears, along with their examination and interpretation, in order to treat rapidly 
those subjects in whom therapy for malaria is indicated. Once a positive smear is 
identified, daily blood films will continue to be obtained until three consecutive films are 
negative (separated by more than 12 hours). A complete blood count and serum 
chemistry tests will be done when parasites are initially found in the blood (this could be 
done on the day of parasitemia detection or the day after).
The maximum hotel stay for malaria-challenged subjects should be approximately 10 
days (Day 295 [Visit 167] to Day 304 [Visit 256]). A subject who develops malaria, is 
treated, and has three consecutive negative malaria smears (separated by more than 12 
hours), will not need to remain in the hotel. The investigators will be responsible for 
accounting for any subjects who do not arrive in the hotel during the challenge phase. If 
required, the investigators will physically locate and treat any malaria-infected subject 
who is unable to maintain the follow-up dictated by this study.
If infection does not develop within 18 days, the subject will be released from staying 
nightly at the hotel. Subjects who do not develop malaria will be required to come to the 
clinical center for evaluation and blood drawing for smears every two days up to 28 days 
post-challenge (Days 306 [Visit 267], 308[Visit 278], 310 [Visit 289], 312 [Visit 2930], 
and 314 [Visit 301]). A subject who develops malaria and has three consecutive 
(separated by more than 12 hours) negative smears following initial treatment may be 
excused from the remaining hotel visits and the late post-challenge clinic visits at Days 
306, 308,310, and 312(20, 22, 24 and 26 days post-challenge), but will be required to 
come to the clinic center at Day 314(28 days post-challenge[Visit 301]). Telephone 
contact will be made if the subject does not keep a scheduled follow-up appointment. 
Symptom screening via telephone may suffice in lieu of clinical visits for Days 306, 308,
310, or 312which fall upon a weekend.
 
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6.5. Outline of study procedures
Table 6
List of study procedures for the investigational vaccine groups: AduFx, 2PedFx, PedFx, and Adu2Fx
Epoch
Epoch 001
Epoch 002 
Type of contact
Visit 1 
(Scree
ning)
Visit 2Visit 3Visit 4 Visit 5Visit 6Visit 7Visit 8 Visit 9 Visit 
10 Visit 11
Visit 12 
to Visit 
3029*
Visit 
Par**
Visit 
3130
Visit 
3231
Study Month
0
1
7
10
13
Study Day
-90 to 
0
0
28 
29  35 
58 196 197  203 226
286 28791
to 312
314 376
Vaccination timepoint
Vacc 1Vacc 2
Vacc 3
CHMI phase
Informed consent
●
Check 
inc
lus
ion/exc
lus
ion cr
iter
iaa
●
O
Check screen
ing 
laboratory resu
ltsb
●
Co
l
lect demograph
ic data
●
Med
ica
l h
istory
●
Record 
informat
ion on past hepat
it
is B immun
izat
ion
c
●
Phys
ica
l exam
inat
ion
●
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Ur
ine pregnancy test (-HCG)
● 
● 
●
●
●
Check contra
ind
icat
ions to vacc
inat
iond
●
●
●
Record pre-vacc
inat
ion body temperature
●
●
●
Random
izat
ion
●
Treatment number a
l
locat
ion
O
O
O
Record
ing of adm
in
istered treatment number
●
●
●
Vacc
ines adm
in
istrat
ion
●
●
●
Check contra
ind
icat
ions to cha
l
lenged
●
Sporozo
ite cha
l
lenge 
●
D
istr
ibut
ion of emergency not
if
icat
ion card 
O
B
lood samp
l
ing for HIV, HCV and HBsAg (17 m
l) 
●
B
lood samp
l
ing for assessment of paras
item
ia (blood smear; 21.0
m
l)
●***
●
Blood sampling for assessment of parasitemia at start of hotel 
phase (PCR; 2.0 ml)
O****
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Epoch
Epoch 001
Epoch 002 
Type of contact
Visit 1 
(Scree
ning)
Visit 2Visit 3Visit 4 Visit 5Visit 6Visit 7Visit 8 Visit 9 Visit 
10 Visit 11
Visit 12 
to Visit 
3029*
Visit 
Par**
Visit 
3130
Visit 
3231
Study Month
0
1
7
10
13
Study Day
-90 to 
0
0
28 
29  35 
58 196 197  203 226
286 28791
to 312
314 376
Vaccination timepoint
Vacc 1Vacc 2
Vacc 3
CHMI phase
B
lood samp
l
ing for assessment of ant
ibody determ
inat
ion and 
serum repos
itory (20.0 m
l)
●
● 
●
●
●
● 
●
B
lood samp
l
ing for deepRNAsequenc
ing (12 m
l) 
● 
● 
●
● 
●
B
lood samp
l
ing for PBMC and plasmarepos
itory (30.0 m
l) 
● 
● 
● 
● 
● 
● 
●
●
●
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is (7.5 m
l)e
●
●
●
●
●
●
●
Record any concom
itant med
icat
ions/vacc
inat
ions
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Record any 
intercurrent med
ica
l cond
it
ions
●
●
●
●
●
●
●
●
●
●
●
●
●
●
D
istr
ibut
ion of d
iary cards
O
O
O
Return of d
iary cards
O
O
O
D
iary card transcr
ipt
ion by 
invest
igator
●
●
●
Record
ing of so
l
ic
ited 
loca
l and genera
l AEs (Days 0–6) post-
vacc
inat
ion
● 
●
●
Record
ing of unso
l
ic
ited AEs (Day 0-29) post-vacc
inat
ion
●
●
●
●
●
●
●
●
Record
ing of AEs (Day 0-29) post-cha
l
lenge 
●
●
●
●
Record
ing of SAEs (a
l
l, fata
l, re
lated) and pregnanc
ies
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Record
ing of SAEs re
lated to study part
ic
ipat
ion, or to a concurrent 
GSK med
icat
ion/vacc
ine
● 
● 
● 
● 
● 
● 
● 
● 
● 
●
●
●
●
● 
●
Record
ing of a
l
l AEs and SAEs 
lead
ing to w
ithdrawa
l from further 
vacc
inat
ion 
● 
● 
● 
● 
● 
● 
● 
● 
●
●
●
●
● 
●
Record
ing of AEs of spec
if
ic 
interestf
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Study Conc
lus
ion
●
-HCG: Beta-human chor
ion
ic gonadotrop
in; PBMC: per
iphera
l b
lood mononuc
lear ce
l
ls; Vacc: vacc
inat
ion.
* V
is
it 12 = Day 287, V
is
it 123= Day 291, V
is
it 134= Day 292, V
is
it 145= Day 293, V
is
it 156  = Day 294, V
is
it 167= Day 295, V
is
it 178= Day 296, V
is
it 189= Day 297, V
is
it 1920= 
Day 298, V
is
it 201= Day 299, V
is
it 212= Day 300, V
is
it 223= Day 301, V
is
it 234= Day 302, V
is
it 245= Day 303, V
is
it 256= Day 304, V
is
it 267= Day 306, V
is
it 278= Day 308, V
is
it 
289= Day 310, V
is
it 2930= Day 312.
** A b
lood samp
le for b
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia (between V
is
it 12 [Day 28791] and V
is
it 2930[Day 312]).
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*** B
lood samp
le for assessment of paras
item
ia (b
lood smear) w
i
l
l be co
l
lected da
i
ly for 14 days (from Day 291 [V
is
it 123] to Day 304 [V
is
it 256]) and then every two days for n
inedays 
(Day 306 [V
is
it 267], Day 308 [V
is
it 278], Day 310 [V
is
it 289], Day 312 [V
is
it 2930], and Day 314 [V
is
it 301]). For sub
jects who deve
lop ma
lar
ia, b
lood smear may be d
iscont
inued once 
the sub
ject has three consecut
ive negat
ive smears (separated by more than 12 hours) fo
l
low
ing 
in
it
ia
l treatment.
**** Blood sample for assessment of parasitemia (PCR testing) will be collected on the day of subject entry into the hotel (Day 295).
aInc
lud
ing a check of NHANES I cr
iter
ia and e
lectrocard
iogram(see Append
ix C).
bThe screen
ing 
laboratory resu
lts (HIV, HCV, HBsAg, ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes [WBC], p
late
lets, and ur
ine -HCG) must be checked dur
ing the screen
ing 
act
iv
it
ies and before random
izat
ion.
cBased on best ev
idences ava
i
lab
le.
dThere 
is no spec
if
ic sect
ion 
in the eCRF to record the contra
ind
icat
ions, warn
ings and precaut
ions. The abso
lute contra
ind
icat
ions to further adm
in
istrat
ion of study vacc
ines or to 
cha
l
lenge have to be recorded 
in the AE or SAE sect
ion of the eCRF.
eB
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is 
inc
ludes ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes (WBC), and p
late
lets.
fAEs of spec
if
ic 
interest 
inc
lude men
ing
it
is and pIMDs (see Sect
ion 9.1.5).
● is used to 
ind
icate a study procedure that requ
ires documentat
ion 
in the 
ind
iv
idua
l eCRF.
○ 
is used to 
ind
icate a study procedure that does not requ
ire documentat
ion 
in the 
ind
iv
idua
l eCRF.
Table7
List of study procedures for the investigational vaccine group: Adu1Fx
Epoch
Epoch 001
Epoch 002 
Type of contact
Visit 1 
(Screenin
g)
Visit 2 Visit 3 Visit 7
Visit 8 
Visit 9
Visit 10Visit 11
Visit 12 
to Visit 
2930*
Visit 
Par**
Visit 
301
Visit 
312
Study Month
0
1
7
10
13
Study Day
-90 to 0
0
28 
196 
197  
203 
226
286 29187
to 312
314 376
Vaccination timepoint
Vacc 1
Vacc 2
CHMI phase
Informed consent
●
Check 
inc
lus
ion/exc
lus
ion cr
iter
iaa
●
O
Check screen
ing 
laboratory resu
ltsb
●
Co
l
lect demograph
ic data
●
Med
ica
l h
istory
●
Record 
informat
ion on past hepat
it
is B 
immun
izat
ionc
●
Phys
ica
l exam
inat
ion
●
O
O
O
O
O
O
O
O
O
O
O
Ur
ine pregnancy test (-HCG)
● 
●
●
●
Check contra
ind
icat
ions to vacc
inat
iond
●
●
Record pre-vacc
inat
ion body temperature
●
●
Random
izat
ion
●
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Epoch
Epoch 001
Epoch 002 
Type of contact
Visit 1 
(Screenin
g)
Visit 2 Visit 3 Visit 7
Visit 8 
Visit 9
Visit 10Visit 11
Visit 12 
to Visit 
2930*
Visit 
Par**
Visit 
301
Visit 
312
Study Month
0
1
7
10
13
Study Day
-90 to 0
0
28 
196 
197  
203 
226
286 29187
to 312
314 376
Vaccination timepoint
Vacc 1
Vacc 2
CHMI phase
Treatment number a
l
locat
ion
O
O
Record
ing of adm
in
istered treatment number
●
●
Vacc
ines adm
in
istrat
ion
●
●
Check contra
ind
icat
ions to cha
l
lenged
●
Sporozo
ite cha
l
lenge 
●
D
istr
ibut
ion of emergency not
if
icat
ion card 
O
B
lood samp
l
ing for HIV, HCV and HBsAg (17 m
l) 
●
B
lood samp
l
ing for assessment of paras
item
ia (blood smear;21.0 
m
l)
●***
●
Blood sampling for assessment of parasitemia at start of hotel 
phase (PCR; 2.0 ml)
O****
B
lood samp
l
ing for assessment of ant
ibody determ
inat
ion and 
serum repos
itory (20.0 m
l)
●
●
●
●
● 
●
B
lood samp
l
ing for deepRNAsequenc
ing (12 m
l) 
● 
● 
● 
●
B
lood samp
l
ing for PBMC and plasmarepos
itory (30.0 m
l) 
● 
● 
●
● 
●
●
●
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is (7.5 m
l)e
●
●
●
●
●
Record any concom
itant med
icat
ions/vacc
inat
ions
●
●
●
●
●
●
●
●
●
●
●
Record any 
intercurrent med
ica
l cond
it
ions
●
●
●
●
●
●
●
●
●
●
●
D
istr
ibut
ion of d
iary cards
O
O
Return of d
iary cards
O
O
D
iary card transcr
ipt
ion by 
invest
igator
●
●
Record
ing of so
l
ic
ited 
loca
l and genera
l AEs (Days 0–6) post-
vacc
inat
ion
●
●
Record
ing of unso
l
ic
ited AEs (Day 0-29) post-vacc
inat
ion
●
●
●
●
●
Record
ing of AEs (Day 0-29) post-cha
l
lenge 
●
●
●
●
Record
ing of SAEs (a
l
l, fata
l, re
lated) and pregnanc
ies
●
●
●
●
●
●
●
●
●
●
●
Record
ing of SAEs re
lated to study part
ic
ipat
ion, or to a concurrent 
GSK med
icat
ion/vacc
ine
● 
● 
● 
● 
● 
● 
●
●
●
●
● 
●
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Epoch
Epoch 001
Epoch 002 
Type of contact
Visit 1 
(Screenin
g)
Visit 2 Visit 3 Visit 7
Visit 8 
Visit 9
Visit 10Visit 11
Visit 12 
to Visit 
2930*
Visit 
Par**
Visit 
301
Visit 
312
Study Month
0
1
7
10
13
Study Day
-90 to 0
0
28 
196 
197  
203 
226
286 29187
to 312
314 376
Vaccination timepoint
Vacc 1
Vacc 2
CHMI phase
Record
ing of a
l
l AEs and SAEs 
lead
ing to w
ithdrawa
l from further 
vacc
inat
ion 
● 
● 
● 
● 
● 
●
●
●
●
● 
●
Record
ing of AEs of spec
if
ic 
interest
f
●
●
●
●
●
●
●
●
●
●
●
Study Conc
lus
ion
●
-HCG: Beta-human chor
ion
ic gonadotrop
in; PBMC: per
iphera
l b
lood mononuc
lear ce
l
ls; Vacc: vacc
inat
ion.
* V
is
it 12 = Day 287, V
is
it 123= Day 291, V
is
it 134= Day 292, V
is
it 145= Day 293, V
is
it 156  = Day 294, V
is
it 167= Day 295, V
is
it 178= Day 296, V
is
it 189= Day 297, V
is
it 1920= 
Day 298, V
is
it 201= Day 299, V
is
it 212= Day 300, V
is
it 223= Day 301, V
is
it 234= Day 302, V
is
it 245= Day 303, V
is
it 256= Day 304, V
is
it 267= Day 306, V
is
it 278= Day 308, V
is
it 
289= Day 310, V
is
it 2930= Day 312.
** A b
lood samp
le for b
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia (between V
is
it 12[Day 28791] and V
is
it 2930[Day 312]).
*** B
lood samp
le for assessment of paras
item
ia (b
lood smear) w
i
l
l be co
l
lected da
i
ly for 14 days (from Day 291 [V
is
it 123] to Day 304 [V
is
it 256]) and then every two days for n
inedays 
(Day 306 [V
is
it 267], Day 308 [V
is
it 278], Day 310 [V
is
it 289], Day 312 [V
is
it 2930], and Day 314 [V
is
it 301]). For sub
jects who deve
lop ma
lar
ia, b
lood smear may be d
iscont
inued once 
the sub
ject has three consecut
ive negat
ive smears (separated by more than 12 hours) fo
l
low
ing 
in
it
ia
l treatment.
**** Blood sample for assessment of parasitemia (PCR testing) will be collected on the day of subject entry into the hotel (Day 295).
aInc
lud
ing a check of NHANES I cr
iter
ia and e
lectrocard
iogram(see Append
ix C).
bThe screen
ing 
laboratory resu
lts (HIV, HCV, HBsAg, ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes [WBC], p
late
lets, and ur
ine -HCG) must be checked dur
ing the screen
ing 
act
iv
it
ies and before random
izat
ion.
cBased on best ev
idences ava
i
lab
le.
dThere 
is no spec
if
ic sect
ion 
in the eCRF to record the contra
ind
icat
ions, warn
ings and precaut
ions. The abso
lute contra
ind
icat
ions to further adm
in
istrat
ion of study vacc
ines or to 
cha
l
lenge have to be recorded 
in the AE or SAE sect
ion of the eCRF.
eB
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is 
inc
ludes ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes (WBC), and p
late
lets.
fAEs of spec
if
ic 
interest 
inc
lude men
ing
it
is and pIMDs (see Sect
ion 9.1.5).
● 
is used to 
ind
icate a study procedure that requ
ires documentat
ion 
in the 
ind
iv
idua
l eCRF.
○ 
is used to 
ind
icate a study procedure that does not requ
ire documentat
ion 
in the 
ind
iv
idua
l eCRF.
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Table 8
List of study procedures for the infectivity control group
Epoch
Epoch 002
Type of contact
Visit 1b 
(Screening)*
Visit 11
Visit 12 to Visit 
2930**
Visit Par***
Visit 301
Study Day
230 to 286
286
29187to 312
314
Informed consent
●
Check 
inc
lus
ion/exc
lus
ion cr
iter
iaa
●
O
Check screen
ing 
laboratory resu
ltsb
●
Co
l
lect demograph
ic data
●
Med
ica
l h
istory
●
Record 
informat
ion on past hepat
it
is B 
immun
izat
ionc
●
Phys
ica
l exam
inat
ion
●
O
O
O
O
Ur
ine pregnancy test (-HCG)
●
●
Check contra
ind
icat
ions to cha
l
lenged
●
Sporozo
ite cha
l
lenge 
●
D
istr
ibut
ion of emergency not
if
icat
ion card 
O
B
lood samp
l
ing for HIV, HCV and HBsAg (17 m
l)
●
B
lood samp
l
ing for assessment of paras
item
ia (blood smear;21.0m
l)
●****
●
Blood sampling for assessment of parasitemia at start of hotel phase (PCR; 2.0 ml)
O*****
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is (7.5 m
l)e
●
●
●
Record any concom
itant med
icat
ions/vacc
inat
ions
●
●
●
●
Record any 
intercurrent med
ica
l cond
it
ions
●
●
●
●
Record
ing of AEs (Day 0-29) post-cha
l
lenge 
●
●
●
●
Record
ing of SAEs (a
l
l, fata
l, re
lated) and pregnanc
ies
●
●
●
●
Record
ing of SAEs re
latedto study part
ic
ipat
ion, or to a concurrent GSK med
icat
ion/vacc
ine
●
●
●
●
●
Study Conc
lus
ion
●
-HCG: Beta-human chor
ion
ic gonadotrop
in; PBMC: per
iphera
l b
lood mononuc
lear ce
l
ls.
* Th
is v
is
it 
is on
ly app
l
icab
le to the 
infect
iv
ity contro
l group
**V
is
it 12 = Day 287, V
is
it 123= Day 291, V
is
it 134= Day 292, V
is
it 145= Day 293, V
is
it 156  = Day 294, V
is
it 167= Day 295, V
is
it 178= Day 296, V
is
it 189= Day 297, V
is
it 1920= 
Day 298, V
is
it 201= Day 299, V
is
it 212= Day 300, V
is
it 223= Day 301, V
isit 2
34= Day 302, V
is
it 245= Day 303, V
is
it 256= Day 304, V
is
it 267= Day 306, V
is
it 278= Day 308, V
is
it 
289= Day 310, V
is
it 2930= Day 312.
*** A b
lood samp
le for b
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia (between V
is
it 12 [Day 28791] and V
is
it 2930[Day 312]).
**** B
lood samp
le for assessment of paras
item
ia (b
lood smear) w
i
l
l be co
l
lected da
i
ly for 14 days (from Day 291 [V
is
it 123] to Day 304 [V
is
it 256]) and then every two days for n
ine
days (Day 306 [V
is
it 267], Day 308 [V
is
it 278], Day 310 [V
is
it 289], Day 312 [V
is
it 2930], and Day 314 [V
is
it 301]).For sub
jects who deve
lop ma
lar
ia, b
lood smear may be d
iscont
inued 
once the sub
ject has three consecut
ive negat
ive smears (separated by more than 12 hours) fo
l
low
ing 
in
it
ia
l treatment.
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***** Blood sample for assessment of parasitemia (PCR testing) will be collected on the day of subject entry into the hotel (Day 295).
aInc
lud
ing a check of NHANES I cr
iter
ia and e
lectrocard
iogram(see Append
ix C).
bThe screen
ing 
laboratory resu
lts (HIV, HCV, HBsAg, ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes [WBC], p
late
lets, and ur
ine -HCG) must be checked dur
ing the screen
ing 
act
iv
it
ies and before random
izat
ion.
cBased on best ev
idences ava
i
lab
le.
dThere 
is no spec
if
ic sect
ion 
in the eCRF to record the contra
ind
icat
ions, warn
ings and precaut
ions. The abso
lute contra
ind
icat
ions to cha
l
lenge have to be recorded 
in the AE or SAE 
sect
ion of the eCRF.
eB
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is 
inc
ludes ALT, AST, creat
in
ine, hemog
lob
in, 
leukocytes (WBC), and p
late
lets.
● 
is used to 
ind
icate a study procedure that requ
ires documentat
ion 
in the 
ind
iv
idua
l eCRF.
○ 
is used to 
ind
icate a study procedure that does not requ
ire documentat
ion 
in the 
ind
iv
idua
l eCRF.
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Table 9
Intervals between study visits for the investigational vaccine 
groups: AduFx, 2PedFx, PedFx, and Adu2Fx
Interval
Optimal length of 
interval 
1
Allowed interval2
V
is
it 1 (Screen
ing) V
is
it 2 (1st
vacc
inat
ion)
0 to 90 days
-
V
is
it 2 V
is
it 3 (2ndvacc
inat
ion)
28 days
7 days
V
is
it 3 V
is
it 5 
7 days 
1 day
V
is
it 3 V
is
it 6 
30 days
7 days
V
is
it 3 V
is
it 7 (3rdvacc
inat
ion)
168 days
14 days
V
is
it 7 V
is
it 9 
7 days
1 day
V
is
it 7 V
is
it 10 
30 days
7 days
V
is
it 7 V
is
it 11 (Cha
l
lenge)
90 days 
+  14 days
V
is
it 11 V
is
it 301
28 days 
7 days
V
is
it 301V
is
it 312
62 days
14 days
1 Whenever poss
ib
le the 
invest
igator shou
ld arrange study v
is
its w
ith
in th
is 
interva
l.
2 Sub
jects w
i
l
lmaynot be e
l
ig
ib
le for 
inc
lus
ion 
in the accord
ing-to-protoco
l (ATP) cohort for ana
lys
is of 
immunogen
ic
ityand eff
icacyif they make the study v
is
it outs
ide th
is 
interva
l.
Table 10
Intervals between study visits for the investigational vaccine 
groups: Adu1Fx
Interval
Optimal length of 
interval 
1
Allowed interval2
V
is
it 1 (Screen
ing) V
is
it 2 (1st
vacc
inat
ion)
0 to 90 days
-
V
is
it 2 V
is
it 7 (2ndvacc
inat
ion)
196 days 
14days
V
is
it 7 V
is
it 9 
7 days
1 day
V
is
it 7 V
is
it 10 
30 days
7 days
V
is
it 7 V
is
it 11 (Cha
l
lenge)
90 days 
+  14 days
V
is
it 11 V
is
it 301
28 days 
7 days
V
is
it 301V
is
it 312
62 days
14 days
1 Whenever poss
ib
le the 
invest
igator shou
ld arrange study v
is
its w
ith
in th
is 
interva
l.
2 Sub
jects w
i
l
lmaynot be e
l
ig
ib
le for 
inc
lus
ion 
in the ATP cohort for ana
lys
is of 
immunogen
ic
ity and eff
icacyif they 
make the study v
is
it outs
ide th
is 
interva
l.
Table11
Intervals between study visits for the infectivity control group
Interval
Optimal length of 
interval 
1
Allowed interval2
V
is
it 1b (Screen
ing) V
is
it 11 (Cha
l
lenge)
0 to 56 days
-
V
is
it 11 V
is
it 301
28 days 
7 days
1 Whenever poss
ib
le the invest
igator shou
ld arrange study v
is
its w
ith
in th
is 
interva
l.
2 Sub
jects w
i
l
lmaynot be e
l
ig
ib
le for 
inc
lus
ion 
in the ATP cohort for ana
lys
is of 
immunogen
ic
ity and eff
icacyif they 
make the study v
is
it outs
ide th
is 
interva
l.
6.6.8.Urine pregnancy test
Female subjects of childbearing potentialare to have a urine pregnancy test at the 
screening visit and prior to any study vaccine administration. The study vaccines may 
only be administered if the pregnancy test is negative. Note: The urine pregnancy test 
must be performed even if the subject is menstruating at the time of the study visit.
 
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Female subjects are also to have a urine pregnancy test prior to the sporozoite challenge. 
The sporozoite challengemay only be performed if the pregnancy test is negative.
6.6.16.
Sampling
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 HIV, HCV and HBsAg
A volume of approximately17.0 ml of whole blood should be drawn from all 
subjects screened to assess HIV, HCV and HBsAg status (see Table 6, Table 7and 
Table 8).
Blood sampling for initial assessment of parasitemia (PCR)
A volume of approximately 2.0 ml should be drawn from all subjects on the day of 
entry to the hotel phase (Day 295[Visit 16]) for the assessment of parasitemia by 
PCR testing to provide the study team an estimate of the number of subjects likely 
to develop malaria within the first few days of the hotel phase (see Table 6, Table 7 
and Table 8).

Blood sampling for assessment of parasitemia(blood smear)
A volume of approximately21.0 ml should be drawn from allsubjects at each pre-
defined timepoint for the assessment of parasitemia by blood smear(see Table 6, 
Table 7and Table 8). For subjects who develop malaria, blood samples for smears 
may be discontinuedonce the subjecthas three consecutive negativesmears 
(separated by more than 12 hours)following initial treatment.
Blood sampling for assessment of antibody determination and serum repository
For subjects of the investigational vaccine groups(AduFx, 2PedFx, PedFx, Adu2Fx, 
and Adu1Fx), avolume of at least 20.0ml of whole blood (to provide at least 10ml
of serum for anti-CS enzyme-linked immunosorbent assay [ELISA], anti-CS avidity, 
anti-HBs, and serum repository) should be drawn at each pre-defined timepoint (see 
Table 6 andTable 7).After centrifugation, serum samples should be kept at –20°C/ –
4°F or below until shipment.

Blood sampling for deepRNAsequencing
For subjects of the investigational vaccine groups(AduFx, 2PedFx, PedFx, Adu2Fx, 
and Adu1Fx), a volume of approximately12.0 ml of whole blood should be drawn at 
each pre-defined timepoint for deepRNAsequencing (mRNA sequencing analysis; 
see Table 6 andTable 7).The blood should be stored at room temperature (20 to 
25°C) until they are transferred to the designated laboratory for further processing.

Blood sampling for PBMC and plasmarepository
For subjects of the investigational vaccine groups(AduFx, 2PedFx, PedFx, Adu2Fx, 
and Adu1Fx), a volume of approximately30.0 ml of whole blood should be drawn at 
each pre-defined timepoint for the purpose of the PBMC and plasmarepository (see 
Table 6 andTable 7). The blood should be stored at room temperature until it is 
transferred to the designated laboratory for further processing. The purified PBMC 
 
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should be stored in liquid nitrogen and plasma at -20°C or colderuntil further 
processing.
Blood sampling for hematology and biochemistry analysis
A volume of approximately7.5 ml of whole blood should be drawn from all subjects 
at each pre-defined timepoint for the assessment of safety parameters (ALT, AST, 
creatinine, hemoglobin, leukocytes [WBC], and platelets; see Table 6,Table 7and 
Table 8).
6.7.2.Biological samples
Details of the quantity of biological sample to be taken at each timepoint during the study
are provided in Table 12.
 
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Table 12
Biological samples (whole blood)
Study Phase
Timepoint
Sample type
Total volume of blood per visit (ml)
AduFx
2PedFx 
PedFx
Adu2Fx 
Adu1Fx Infectivity 
control
Pre-vacc
inat
ion
V
is
it 1 
(Screen
ing) 
B
lood samp
l
ing for HIV, HCV and HBsAg
17.0 m
l
17.0 m
l
17.0 m
l
17.0 m
l
17.0 m
l
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
Total: 24.5 ml
24.5 ml
24.5 ml
24.5 ml
24.5 ml
-
V
is
it 2 (Day 0)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for deepRNAsequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
B
lood samp
l
ing for PBMCand plasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
Total: 62.0 ml
62.0 ml
62.0 ml
62.0 ml
62.0 ml
-
Post-Dose 1
V
is
it 3 (Day 28)
B
lood samp
l
ing for deepRNAsequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
B
lood samp
l
ing for PBMCand plasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
Total: 42.0 ml
42.0 ml
42.0 ml
42.0 ml
42.0 ml
-
Post-Dose 2* or 
Post-Dose 1**
V
is
it 4 (Day 29) B
lood samp
l
ing for deepRNAsequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
-
Total: 12.0 ml
12.0 ml
12.0 ml
12.0 ml
-
-
V
is
it 5 (Day 35)
B
lood samp
l
ing for PBMC and plasmarepos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
-
Total: 37.5 ml
37.5 ml
37.5 ml
37.5 ml
-
-
V
is
it 6 (Day 58)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
- 
-
B
lood samp
l
ing for PBMC and plasmarepos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
-
Total: 57.5 ml
57.5 ml
57.5 ml
57.5 ml
-
-
V
is
it 7 (Day 196)
B
lood samp
l
ing for ant
ibody determ
inat
ion andserum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for deepRNAsequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
B
lood samp
l
ing for PBMC and plasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
Total: 62.0 ml
62.0ml
62.0 ml
62.0 ml
62.0 ml
-
Post-Dose 3* or 
Post-Dose 2**
V
is
it 8 (Day 197)B
lood samp
l
ing for deepRNAsequenc
ing
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
12.0 m
l
-
Total: 12.0 ml
12.0 ml
12.0 ml
12.0 ml
12.0 ml
-
V
is
it 9 (Day 203)B
lood samp
l
ing for PBMC and plasmarepos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
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Study Phase
Timepoint
Sample type
Total volume of blood per visit (ml)
AduFx
2PedFx 
PedFx
Adu2Fx 
Adu1Fx Infectivity 
control
Total: 37.5 ml
37.5 ml
37.5 ml
37.5 ml
37.5 ml
-
V
is
it 10 (Day 
226)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for PBMC and plasmarepos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
-
Total: 57.5 ml
57.5 ml
57.5 ml
57.5 ml
57.5 ml
-
Pre-cha
l
lenge
V
is
it 1b 
(Screen
ing) 
B
lood samp
l
ing for HIV, HCV and HBsAg
-
-
-
-
-
17.0 m
l
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
-
-
-
-
-
7.5 m
l
Total:
-
-
-
-
-
24.5 ml
V
is
it 11 (Day 
286)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for PBMC and plasma repos
itory
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
30.0 m
l
-
Total: 50.0 ml
50.0 ml
50.0 ml
50.0 ml
50.0 ml
-
Post-cha
l
lenge
V
is
it 123(Day 
291)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 134(Day 
292)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 145(Day 
293)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 156(Day 
294)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 167(Day 
295)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
Blood sampling for assessment of parasitemia at start of 
hotel phase (PCR)****
2.0 ml 
2.0 ml 
2.0 ml 
2.0 ml 
2.0 ml 
2.0 ml
V
is
it 178(Day 
296)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 189(Day 
297)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 1920(Day 
298)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 201(Day 
299)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 212(Day B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
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Study Phase
Timepoint
Sample type
Total volume of blood per visit (ml)
AduFx
2PedFx 
PedFx
Adu2Fx 
Adu1Fx Infectivity 
control
300)
V
is
it 223(Day 
301)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 234(Day 
302)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 245(Day 
303)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 256(Day 
304)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)v 21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 267(Day 
306)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 278(Day 
308)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 289(Day 
310)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 2930(Day 
312)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
V
is
it 301(Day 
314)
B
lood samp
l
ing for assessment of paras
item
ia (blood smear)
21.0m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
21.0 m
l
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
Total: 298.5m
l
298.5m
l
298.5m
l
298.5m
l
298.5m
l
98.5 m
l
V
is
it Par***
B
lood samp
l
ing for hemato
logy and b
iochem
istry ana
lys
is
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
7.5 m
l
Total: 7.5 ml
7.5 ml
7.5 ml
7.5 ml
7.5 ml
7.5 ml
Study end
V
is
it 312(Day 
376)
B
lood samp
l
ing for ant
ibody determ
inat
ion and serum 
repos
itory
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l 
20.0 m
l
-
B
lood samp
l
ing for PBMCand plasmarepos
itory
30.0 m
l
30.0 m
l
30.0m
l
30.0 m
l
30.0 m
l
-
Total: 50.0 ml
50.0 ml
50.0 ml
50.0 ml
50.0 ml
-
Total blood collected over the entire study:57958.5 ml57958.5 m57958.5 m 57958.5 m 57958.5 m7958.5ml
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6.7.3.Laboratory assays
Other assays on stored serum, PBMC and plasma samplesand PBMCmay be performed 
based on results of ongoing studies to investigate the safety and/or vaccine induced anti-
malaria and hepatitisB immune responses.
Table 14
Assessment of P. falciparumparasitemia
System
Component
Method
Unit
Laboratory
WHOLE BLOOD
P
lasmod
ium fa
lc
iparum paras
ites* Not 
app
l
icab
le**
paras
ite/l
WRAIR
WHOLE BLOOD
Plasmodium falciparum 
parasites* 
Real-time 
PCR
Positive/negative***WRAIR
WRAIR: Wa
lter Reed Army Inst
itute of Research
* P. fa
lc
iparumparas
ite count 
inc
ludes b
lood-stage paras
ites.
** Method used w
i
l
l be b
lood s
l
ide m
icroscope read
ing.
*** For assessment and processing by WRAIR of parasitemia on the day of subject entry into the hotel (Day 
295 [Visit 16])
PBMC for geneRNAexpression profiling will be collected and stored in a repository to 
allow mRNA sequencing or future next generation technologies, during the current 
study or in future research,to assess transcriptome signals. Scope of this assay will be 
based on ongoing investigations.
The repository laboratory for serum samples will be GSK Biologicals’ clinical 
laboratories and for plasma and PBMC samples will be Precision Bioservices Inc.
6.7.4.Biological samples evaluation
6.7.4.1.
Immunological read-outs
Table 16
Immunological read-outs
Blood sampling timepoint
Study 
groups
No. 
subjects
Sample
Component
Components 
priority rank
Type of 
contact 
and 
timepoint
Sampling 
timepoint
V
is
it 2 
(Day 0)
Pre-
vacc
inat
ion
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
To be determ
ined
Not app
l
icab
le
 
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Blood sampling timepoint
Study 
groups
No. 
subjects
Sample
Component
Components 
priority rank
Type of 
contact 
and 
timepoint
Sampling 
timepoint
plasma
repos
itory*
V
is
it 3 
(Day 28)
One month 
post-Dose 1
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
PBMCand 
plasma
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 5 
(Day 35)
Seven days 
post-Dose 2
AduFx, 
2PedFx,
PedFx, 
Adu2Fx
104
PBMC and 
plasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 6 
(Day 58)
One month 
post-Dose 2
AduFx, 
2PedFx,
PedFx, 
Adu2Fx
104
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
plasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 7 
(Day 196)
S
ix months 
post-Dose 2** 
or seven 
month post-
Dose 1***
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
plasma
repos
itory*
To bedeterm
ined
Not app
l
icab
le
 
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Blood sampling timepoint
Study 
groups
No. 
subjects
Sample
Component
Components 
priority rank
Type of 
contact 
and 
timepoint
Sampling 
timepoint
V
is
it 9 
(Day 203)
Seven days 
post-Dose 3** 
or post-Dose 
2***
AduFx, 
2PedFx,
PedFx,
Adu1Fx, 
Adu2Fx
130
PBMC and 
plasma
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 10 
(Day 226)
One month 
post-Dose 3** 
or post-Dose 
2***
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
plasma
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 11 
(Day 286)
Day of 
cha
l
lenge
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
plasma
repos
itory*
To be determ
ined
Not app
l
icab
le
 
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Blood sampling timepoint
Study 
groups
No. 
subjects
Sample
Component
Components 
priority rank
Type of 
contact 
and 
timepoint
Sampling 
timepoint
V
is
it 301
(Day 314)
28 days post-
cha
l
lenge
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
V
is
it 312
(Day 376)
Study end
AduFx, 
2PedFx,
PedFx, 
Adu2Fx, 
Adu1Fx
130
Serum
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ite 
Prote
in.R32LR Ab.IgG
1
P
lasmod
ium 
fa
lc
iparum.C
ircumsporozo
ide 
Prote
in.R32LR Ab.IgG Av
id
ity
2
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG
3
P
lasmod
ium fa
lc
iparum.ant
i-
C-Term C
ircumsporozo
ide 
Ab.IgG av
id
ity
4
Hepat
it
is B V
irus.Surface Ab
5
Serum 
repos
itory*
To be determ
ined
Not app
l
icab
le
PBMC and 
plasma 
repos
itory*
To be determ
ined
Not app
l
icab
le
*Assays on stored serum, PBMC and plasma samp
lesor stored PBMC samp
lesmay be performed based on resu
lts 
of ongo
ing stud
ies to 
invest
igate the safety and/or vacc
ine 
induced ant
i-ma
lar
ia and hepat
it
is B 
immune responses.
** For groups AduFx, 2PedFx, PedFx and Adu2Fx.
*** For group Adu1Fx.
 
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6.7.4.2.
Hematology/Blood Chemistry
Table 17
Hematology and biochemistry read-outs
Blood sampling timepoint
Study groups
No. subjects
Component
Type of contact 
and timepoint
Sampling 
timepoint
V
is
it 1 (Screen
ing)
Pre-vacc
inat
ion
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx 
130
HIV-IgG + Ag (SER,GLR)
Hepat
it
is B V
irus.Surface Ab
HCV Ab 
A
lan
ine Am
inotransferase 
Aspartate Am
inotransferase 
Creat
in
ine 
Hemog
lob
in 
Leukocytes (Wh
ite B
lood Ce
l
ls) 
P
late
lets 
V
is
it 5 (Day 35)
Seven days post-
Dose 2
AduFx, 2PedFx,
PedFx, Adu2Fx
104
A
lan
ine Am
inotransferase 
Aspartate Am
inotransferase 
Creat
in
ine 
Hemog
lob
in 
Leukocytes (Wh
ite B
lood Ce
l
ls) 
P
late
lets 
V
is
it 6 (Day 58)
One month post-
Dose 2
AduFx, 2PedFx,
PedFx, Adu2Fx
104
A
lan
ine Am
inotransferase 
Aspartate Am
inotransferase 
Creat
in
ine 
Hemog
lob
in 
Leukocytes (Wh
ite B
lood Ce
l
ls) 
P
late
lets 
V
is
it 9 (Day 203)
Seven days post-
Dose 3* or post-
Dose 2**
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx 
130
A
lan
ine Am
inotransferase 
Aspartate Am
inotransferase 
Creat
in
ine 
Hemog
lob
in 
Leukocytes (Wh
ite B
lood Ce
l
ls) 
P
late
lets 
V
is
it 10 (Day 226)
One month post-
Dose 3* or post-
Dose 2**
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx 
130
A
lan
ine Am
inotransferase 
Aspartate Am
inotransferase 
Creat
in
ine 
Hemog
lob
in 
Leukocytes (Wh
ite B
lood Ce
l
ls) 
P
late
lets 
V
is
it 1b (Screen
ing)
Pre-cha
l
lenge 
Infect
iv
ity contro
l 
20***
HIV-IgG + Ag (SER,GLR)
Hepat
it
is B V
irus.Surface Ab
HCV Ab 
A
lan
ine Am
inotransferase 
Aspartate Am
inotransferase 
Creat
in
ine 
Hemog
lob
in 
Leukocytes (Wh
ite B
lood Ce
l
ls) 
P
late
lets 
V
is
it Par 
Event-dr
iven (f
irst 
paras
item
ia)
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx, Infect
iv
ity 
contro
l
150
A
lan
ine Am
inotransferase 
Aspartate Am
inotransferase 
Creat
in
ine 
Hemog
lob
in 
Leukocytes (Wh
ite B
lood Ce
l
ls) 
P
late
lets 
 
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Blood sampling timepoint
Study groups
No. subjects
Component
Type of contact 
and timepoint
Sampling 
timepoint
V
is
it 301(Day 314) 28 days post-
cha
l
lenge
AduFx, 2PedFx,
PedFx, Adu2Fx, 
Adu1Fx, Infect
iv
ity 
contro
l
150
A
lan
ine Am
inotransferase 
Aspartate Am
inotransferase 
Creat
in
ine 
Hemog
lob
in 
Leukocytes (Wh
ite B
lood Ce
l
ls) 
P
late
lets 
* For groups AduFx, 2PedFx, PedFx and Adu2Fx.
** For group Adu1Fx.
***between 20 and 30 
infect
iv
ity contro
ls w
i
l
l be enro
l
led.
6.7.4.3.
Molecular biology
Table 18
DeepRNA sequencing (mRNA sequencing analysis)
Blood sampling timepoint
Study groups
No. 
subjects
Component
Components 
priority rank
Type of contact 
and timepoint
Sampling 
timepoint
V
is
it 2 (Day 0)
Pre-vacc
inat
ion AduFx, 2PedFx,PedFx,Adu1Fx,  
Adu2Fx
130
mRNA
Not app
l
icab
le
V
is
it 3 (Day 28)
Day of Dose 2* or 
one month post-
Dose 1**
AduFx, 2PedFx,PedFx,Adu1Fx 
Adu2Fx
130
mRNA
Not app
l
icab
le
V
is
it 4 (Day 29)
One day post-
Dose 2
AduFx, 2PedFx,PedFx, Adu2Fx
104
mRNA
Not app
l
icab
le
V
is
it 7 (Day 196) Day of Dose 3* or 
Dose 2**
AduFx, 2PedFx,PedFx,Adu1Fx,  
Adu2Fx
130
mRNA
Not app
l
icab
le
V
is
it 8 (Day 197)
One day post-
Dose 3* or Dose 
2**
AduFx, 2PedFx,PedFx,Adu1Fx,  
Adu2Fx
130
mRNA
Not app
l
icab
le
mRNA: messenger r
ibonuc
le
ic ac
id
* For groups AduFx, 2PedFx, PedFx and Adu2Fx.
** For group Adu1Fx.
 
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6.7.4.4.
Parasitemia
Table 19
Parasitemia (blood smear)
Blood sampling 
timepoint
Study groups
No. 
subjectsComponentComponents 
priority rank 
V
is
it 123(Day 291)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 134(Day 292)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 145(Day 293)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 156(Day 294)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 167(Day 295)
AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infectivity 
control
150
PCR*
2
V
is
it 178(Day 296)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 189(Day 297)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 1920(Day 
298)
AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 201(Day 299)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 212(Day 300)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 223(Day 301)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 234(Day 302)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 245(Day 303)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 256(Day 304)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 267(Day 306)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 278(Day 308)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 289(Day 310)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 2930(Day 
312)
AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
V
is
it 301(Day 314)AduFx, 2PedFx,PedFx, Adu2Fx,Adu1Fx, Infect
iv
ity contro
l 150 B
lood smear
1
* For assessmentand processing by WRAIR of parasitemia on the day of subject entry into the hotel (Day 295 
[Visit 16])
6.7.5.Immunological correlates of protection
No correlate of protection has been demonstrated so far for the CS antigen.
For the HBsAg, the conventional correlate of protection is anti-HBs antibody 
concentrationsabove 10 mIU/ml [European Consensus Group on Hepatitis B Immunity, 
2000].
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects/subjects’parent(s)/LAR(s).
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.
 
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9.3.1.Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
Table 25
Reporting periods for collecting safety information for the 
investigational vaccine groups: AduFx, 2PedFx, PedFx, and Adu2Fx)
Study visits
1
2
3
6
7
10
11 to 301
312
Study days
-90 
to 0
0 6
28 34 58
196 202
226
286 314315
376
So
l
ic
ited 
loca
l and 
genera
l AEs post-
vacc
inat
ion
Unso
l
ic
ited AEs 
post-vacc
inat
ion
AEs post-cha
l
lenge
AEs and SAEs 
lead
ing to w
ithdrawa
l 
from further 
vacc
inat
ion
SAEs (a
l
l, fata
l, 
re
lated)
SAEs re
lated to 
study part
ic
ipat
ion, 
or to a concurrent 
GSK 
med
icat
ion/vacc
ine
AEs of spec
if
ic 
interest (men
ing
it
is 
and pIMDs)
Pregnanc
ies
 
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Table 26
Reporting periods for collecting safety information for the 
investigational vaccine groups: Adu1Fx
Study visits
1
2
3
7
10
11 to 301
312
Study days
-90 
to0
0 6
28
196 202
226
286 314 315
376
So
l
ic
ited 
loca
l and 
genera
l AEs post-
vacc
inat
ion
Unso
l
ic
ited AEs post-
vacc
inat
ion
AEs post-cha
l
lenge
AEs and SAEs 
lead
ing 
to w
ithdrawa
l from 
further vacc
inat
ion
SAEs (a
l
l, fata
l, 
re
lated)
SAEs re
lated to study 
part
ic
ipat
ion, or to a 
concurrent GSK 
med
icat
ion/vacc
ine
AEs of spec
if
ic 
interest 
(men
ing
it
is and pIMDs)
Pregnanc
ies
 
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Table 27
Reporting periods for collecting safety information for the infectivity 
control group
Study visits
1b
11 to 301
Study days
258 to 286
286
314
315
AEs post-cha
l
lenge
SAEs (a
l
l, fata
l, re
lated)
SAEs re
lated to study part
ic
ipat
ion, or to 
a concurrent GSK med
icat
ion/vacc
ine
Pregnanc
ies
APPENDIX A
LABORATORY ASSAYS
Blood smear and PCR testingfor assessment of P. falciparumparasitemia
Blood slide preparation andslidereading and PCR testing will be performed according to 
laboratory SOPs.
DeepRNA sequencing(mRNA expression analysis)
mRNAsequencingis a technique using next generation sequencing technology to 
sequence and quantify mRNA samples. It concerns analysis of mRNA transcription, not 
genetic testingas the data obtained is used to assess relative abundance of mRNA 
molecules. The Illumina Genome Analyzer II uses clonal array formation and reversible 
terminator technology to generate 20-30 million short sequence reads per sample lane. 
These short sequences are aligned with the genome and counted to provide a relative 
frequency of sequences in the library population. The experiments will be instructed by 
the results obtained from systems biology results in previous CHMI studies.
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Administrative Change 1
eTrack study number 
and Abbreviated Title
205081 (MALARIA-092)
IND number
17337
EudraCT number
205081 (MALARIA-092)
Administrative change 
number:
Administrative change 1
Administrative change 
date:
19June 2017
Co-ordinating author:
, 
Scientific Writer, Freelance Contractor for GSK 
Biologicals
Rationale/background for changes: 
The Investigational New Drug (IND) number,17337, has been added to the title page.
Q² Solutions,as a new partner,willmanage logisticalaspects of serum samples sent 
from site to GSK for testing.Their details have been added to APPENDIX B 
‘CLINICAL LABORATORIES’.
Minor errors and inconsistencies have been corrected and contributing authors updated.
Intensity grades for aspartate aminotransferasewere missing in Table 29 ‘Toxicity 
grading scalesfor blood testing’. These have been added.
Amended text has been included in bold italicsand deleted text in strikethroughin 
the following sections:
 
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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart, Belgium
Primary Study vaccine

GlaxoSmithKline (GSK) Biologicals’ candidate 
Plasmodium falciparummalaria vaccine 
RTS,S/AS01E(SB257049).
Other Study vaccine

GlaxoSmithKline (GSK) Biologicals’ candidate 
Plasmodium falciparummalaria vaccine 
RTS,S/AS01B(SB257049).
eTrack study number and 
Abbreviated Title
205081 (MALARIA-092)
Investigational New Drug 
(IND) number
17337
Date of protocol
Final Version 1: 09 March 2016
Date of protocol 
amendment/administrative 
change
Amendment 1 Final: 23 June 2016
Administrative change1 Final: 19June2017
Title
Efficacy, immunogenicity and safety study of GSK 
Biologicals’ candidate malaria vaccine (SB257049) 
evaluating various dose schedules in a sporozoite 
challenge model in healthy malaria-naïve adults.
Detailed Title
A Phase IIa, open-label, controlled, mono-center study 
to evaluate the efficacy, immunogenicity and safety of 
GSK Biologicals’ candidate malaria vaccines 
RTS,S/AS01Eand RTS,S/AS01
Badministered as 
various dose schedules according to a 0, 1,7-month or 
a 0, 7-month schedule in healthy malaria-naïve 
subjects aged 18-55 years.
Co-ordinating author

 (Scientific Writer -Keyrus 
Biopharma contractor for GSK Biologicals)
Contributing authors

 (Clinical Research and 
Development Lead [CRDL])

, 
(Project Statisticians)

, 
(Study Delivery 
Leads)

, 
(Vaccine Supply 
Coordinator)
 
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eTrack study number and 
Abbreviated Title
205081 (MALARIA-092)
Investigational New Drug 
(IND) number
17337
Detailed Title
A Phase IIa, open-label, controlled, mono-center study 
to evaluate the efficacy, immunogenicity and safety of 
GSK Biologicals’ candidate malaria vaccines 
RTS,S/AS01Eand RTS,S/AS01
Badministered as 
various dose schedules according to a 0, 1, 7-month or 
a 0, 7-month schedule in healthy malaria-naïve 
subjects aged 18-55 years.
Contributing authors 
(continued)

, 
(Clinical 
Laboratory Sciences Leads)

, 
(Clinical Safety 
representatives)

, 
(Study Data Managers)

 (Clinical Regulatory 
Affairs representative)

, 
(Global 
Patent Representatives)
GSK Biologicals’ Protocol DS v 14.1.1
Copyright 2016-2017the GlaxoSmithKline group of companies. All rights reserved. Unauthorized 
copying or use of this information is prohibited.
 
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3.
Study Design Overview
Figure1
Study design
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Footnotes to Figure 1:
D: Day; Mth: month; R: RTS,S; SCR: Screen
ing; V: v
is
it. * B
lood samp
le for est
imat
ion of sub
jects w
ith paras
item
ia (PCR test
ing) w
i
l
l be co
l
lected on the day of sub
ject entry 
into the 
hote
l phase (Day 295 [V
is
it 16]); b
lood samp
le for b
iochem
istry and hemato
logy parameters w
i
l
l be co
l
lected the day of f
irst paras
item
ia and b
lood samp
le for assessment of 
paras
item
ia (b
lood smear) w
i
l
l be co
l
lected da
i
ly for 14 days (from Day 291  [V
is
it 12] to Day 304 [V
is
it 25]) and then every two days for n
ine days (Day 306 [V
is
it 26], Day 308 [V
is
it 
27], Day 310 [V
is
it 28], Day 312 [V
is
it 29], and Day 314 [V
is
it 30]).
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9.3. Detecting and recording adverse events, serious adverse 
events and pregnancies
9.3.3.2.
Assessment of adverse events
9.3.3.2.1.
Assessment of intensity
Table 29
Toxicity grading scales for blood testing
Adverse event
Intensity grade
Intensity*
Hemog
lob
in (ma
les)
Norma
l range 
12.5 -17.0 g/d
l
1
< 12.5 but 11.0 g/d
l
2
< 11.0 but 10.0 g/d
l
3
< 10.0 g/d
l
Hemog
lob
in (fema
les)
Norma
l range 
11.5 -15.0 g/d
l
1
< 11.5 but 10.5 g/d
l
2
< 10.5 but 9.5 g/d
l
3
< 9.5 g/d
l
Increase 
in 
leukocytes 
Norma
l range
3200 -10799 ce
l
ls/mm
3
(WBC)
1
10800 -15000 ce
l
ls/mm
3
2
15001 -20000 ce
l
ls/mm
3
3
> 20001 ce
l
ls/mm3
Decrease 
in 
leukocytes 
Norma
l range
3200 -10800 ce
l
ls/mm
3
(WBC)
1
2500 -3199 ce
l
ls/mm
3
2
1500 -2499 ce
l
ls/mm
3
3
< 1500 ce
l
ls/mm3
Decrease 
in p
late
lets
Norma
l
140000 -400000 ce
l
ls/mm
3
1
125000 -139000 ce
l
ls/mm
3
2
100000 -124000 ce
l
ls/mm
3
3
< 100000 ce
l
ls/mm3
A
lan
ine Am
inotransferase 
Norma
l range
Be
low ULN (60 U/
l for ma
les; 40 U/
l for fema
les 
1
1.1 -2.5 x ULN
2
2.6 –5 x ULN
3
> 5 x ULN
Aspartate Am
inotransferase Norma
l range
Be
low ULN (40 U/
l for ma
les; 35 U/
l for fema
les
1
1.1 -2.5 x ULN
2
2.6 –5 x ULN
3
> 5 x ULN
Creat
in
ine (ma
les)
Norma
l range 
0.5 -1.39 mg/d
l
1
1.4 -1.79 mg/d
l
2
1.8 -2.0 mg/d
l
3
> 2.0 mg/d
l
Creat
in
ine (fema
les)
Norma
l range
0.5 -1.29 mg/d
l
1
1.3 –1.69 mg/d
l
2
1.7 –1.9 mg/d
l
3
>1.9 mg/d
l
ULN: upper 
l
im
it of norma
l range
*Grad
ing sca
le adapted from [FDA gu
idance for 
industry: tox
ic
ity grad
ing sca
le for hea
lthy adu
lt and ado
lescent 
vo
lunteers enro
l
led 
in prevent
ive vacc
ine c
l
in
ica
l tr
ia
ls (September 2007)].
 
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APPENDIX B 
CLINICAL LABORATORIES
Table 32
Outsourced laboratories
Laboratory
Address
CEVAC -Un
ivers
ity of Gent
De P
inte
laan, 185 Gent
Be
lg
ium
D
iv
is
ion of Ma
lar
ia Vacc
ine 
Deve
lopment -WRAIR
Wa
lter Reed Army Inst
itute of Research
S
i
lver Spr
ing, MD 20910, Un
ited States
Prec
is
ion B
ioserv
ices, Inc.
8425 Progress Dr
ive
Freder
ick, MD 21701, Un
ited States
Quest D
iagnost
ics, Inc.
1901 Su
lphur Spr
ing Road
Ba
lt
imore, MD 21227, Un
ited States
Q² Solutions
27027 Tourney Road, Suite 2E
Valencia, CA 91355
United States
 
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