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

C O N FI D E N TI A L
2 6 -S E P -2 0 1 8
1
Cli ni c al St u d y Pr ot o c ol
S p o n s or:
Gl a x o S mit h Kli n e Bi ol o gi c al s S A
R u e d e l’I n stit ut 8 9,
1 3 3 0, Ri x e n s art, B el gi u m
Pri m ar y st u d y v acci ne a n d 
n u m ber

Gla x o S mit h Kli ne ( G S K) Bi ol o gicals’ ca n di date 
Pl as m o di u m f alci p ar u m (P. f alci p ar u m ) malaria 
vacci ne R T S, S/ A S 0 1 E ( S B 2 5 7 0 4 9)
e Tr ac k st u d y n u m ber a n d 
A b bre vi ate d Title
2 0 9 0 0 3 ( M A L A R I A-1 0 2 B S T: 0 9 2 )
I n vesti g ati o n al Ne w Dr u g 
(I N D) n u m ber
1 7 3 3 7
D ate of P r ot oc ol
Fi nal Versi o n 2 : 2 6 Se pte m ber 2 0 1 8
Title
Efficac y , i m m u n o ge nicit y a n d safety st u d y e val uati n g a 
fracti o nal ( F x) b o oster d ose of G S K Bi ol o gicals' 
ca n di date malaria vacci ne ( S B 2 5 7 0 4 9) i n a s p or oz oite 
c halle n ge m o del i n healt h y malaria-naï ve a d ults.
Det aile d Title
A P hase IIa, o pe n-la bel, n o n- ra n d o mize d, c o ntr olle d, 
m o n o -ce nter st u d y t o e val uate t he efficac y, 
i m m u n o ge nicity a n d safet y of a fracti o nal ( F x) b o oster 
d ose of Gla x o S mit h Kli ne Bi ol o gicals’ malaria 
ca n di date vacci ne R T S, S/ A S 0 1 E w he n gi ve n t o healt h y  
a d ults s u bjects pre vi o usl y recei vi n g vari o us pri mar y  
d ose sc he d ules i n a s p or oz oite c halle n ge m o del.
C o or di n ati n g a ut h or
, Scie ntific Writer ( X P E P har ma & 
Scie nce f or G S K Bi ol o gicals)
C o ntri b uti n g a ut h ors

, Cli nical Researc h & 
De vel o p me nt Lea d

, Statisticia n

, Lea d Statisticia n

 (I n Ve nti v f or G S K Bi ol o gicals), 
St u d y  Deli ver y Ma na ger

, Safet y re prese ntati ve

, Re g ulat or y Affairs 
re prese ntati ve

, O versi g ht Data Ma na ger

, Cli nical Trial S u p pl y Ma na ger

, Cli nical Rea d-o ut Tea m Lea d

, Gl o bal Pate nt re prese ntati ve

, Cli nical a n d E pi de mi ol o g y 
Pr oject Lea d
G S K Bi ol o gic als’ Pr ot oc ol D S v 1 5. 0
© 2 0 1 8 Gl a x o S mit h Kli ne gr o u p of c o m p a nies or its lice ns or.
 
C O N FI D E N TI A L
2 0 9 0 0 3 ( M A L A RI A- 1 0 2 B S T: 0 9 2)
Pr ot o c ol Fi n al V er si o n 2
1 9 2 8 9 c a a 4 a 6 6 7 5 9 c 3 7 d 7 c 5 a 4 2 c a 2f d 6 a 5 5 9 1 7f 5 6
1
2 6- S E P- 2 0 1 8
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
2
Protocol Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
209003 (MALARIA-102 BST:092)
IND number
17337
Date of Protocol
Final Version 2: 26 September 2018
Detailed Title
A Phase IIa, open-label, non-randomized, controlled, 
mono-center study to evaluate the efficacy, 
immunogenicity and safety of a fractional (Fx) 
booster dose of GlaxoSmithKline Biologicals’ 
malaria candidate vaccine RTS,S/AS01E when given 
to healthy adults subjects previously receiving 
various primary dose schedules in a sporozoite 
challenge model.
Sponsor signatory
François Roman,
Clinical and Epidemiology Project Lead,
Diseases of the Developing World project
Signature
Date
CONFIDENTIAL
20903 (MALARIA-102 BST:092)
Protocol Final Version 2
19289ca4a6759c37d7c5a42ca2fd6a5917f56
2
26-SEP-2018
 - ----------------Checksum----------------!Ver.!Created On -  - 
19289caa4a66759c37d7c5a42ca2fd6a55917f56 2.0 10/4/2018 11:30:06 AM -  - 
---------------------------------------------------------------------------- - 
For internal use only

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
3
Protocol Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol
amendments or protocol administrative changes, with the terms of the clinical trial
agreement and with any other study conduct procedures and/or study conduct
documents provided by GSK Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all
applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about
the GSK Biologicals’ study vaccine and other study-related duties and functions as
described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required
by local regulations, obtain the laboratory’s current certification or Quality
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or
elsewhere without the approval of GSK Biologicals and the express written informed
consent of the subject and/or the subject’s legally acceptable representative.

To perform no other biological assays on the clinical samples except those described
in the protocol or its amendment(s).

To co-operate with a representative of GSK Biologicals in the monitoring process of
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to
obtain and supply, as necessary, details about the investigator’s ownership interest in
the sponsor or the investigational vaccine, and more generally about his/her financial
ties with the sponsor. GSK Biologicals will use and disclose the information solely
for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding
ownership interest and financial ties (including those of my spouse and dependent
children).

Agree to promptly update this information if any relevant changes occur during the
course of the study and for one year following completion of the study.

Agree that GSK Biologicals may disclose any information it has about such
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other
documents required by regulatory agencies for this study.
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
3
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
4
eTrack study number and 
Abbreviated Title
209003 (MALARIA-102 BST:092)
IND number
17337
Date of Protocol
Final Version 2: 26 September 2018
Detailed Title
A Phase IIa, open-label, non-randomized, controlled, 
mono-center study to evaluate the efficacy, 
immunogenicity and safety of a fractional (Fx) 
booster dose of GlaxoSmithKline Biologicals’ 
malaria candidate vaccine RTS,S/AS01E when given 
to healthy adults subjects previously receiving 
various primary dose schedules in a sporozoite 
challenge model.
Investigator name
Signature
Date
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
4
26-SEP-2018
 - ----------------Checksum----------------!Ver.!Created On -  - 
19289caa4a66759c37d7c5a42ca2fd6a55917f56 2.0 10/4/2018 11:30:06 AM -  - 
---------------------------------------------------------------------------- - 
For internal use only

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
5
Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89,
1330, Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event (SAE)
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 9.4.2.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
5
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
6
SYNOPSIS
Detailed Title
A Phase IIa, open-label, non-randomized, controlled, mono-
center study to evaluate the efficacy, immunogenicity and
safety of a fractional (Fx) booster dose of GlaxoSmithKline 
Biologicals’ malaria candidate vaccine RTS,S/AS01E when 
given to healthy adults subjects previously receiving various 
primary dose schedules in a sporozoite challenge model.
Indication
Primary immunization against malaria disease caused by 
Plasmodium falciparum (P. falciparum).
Rationale for the 
study and study 
design

Rationale for the study
This follow-up study (MALARIA-102) to the MALARIA-092
study will be conducted at the Walter Reed Army Institute of 
Research (WRAIR) and is designed to evaluate the waning 
efficacy with the fractional schedules and to confirm if 
protection can be extended with an additional Fx dose.
In this booster study, vaccinated subjects from the 
MALARIA-092 study [previously protected or unprotected 
following controlled human malaria infection (CHMI)] will 
receive a booster and undergo a second CHMI three to four 
weeks after vaccination.

Rationale for the study design
The MALARIA-092 study was designed to evaluate varying 
vaccination schedules, a Fx dose and the use of the pediatric 
formulation, RTS,S/AS01E, in the adult CHMI model. The
current study will assess if a Fx dose booster will maintain 
protection in those previously protected and convert 
previously unprotected individuals to protected status.
Given the positive efficacy derived in MALARIA-092 study 
in the group that received RTS,S/AS01E (PedFx), a decision 
has been taken to boost subjects only with a Fx dose from the 
RTS,S/AS01E formulation (0.1 mL). This will facilitate 
deployment in Africa where the same dosage and formulation 
will be used across all age groups. Interim analysis from the 
MALARIA-092 CHMI study showed that vaccine efficacy 
(VE) with the RTS,S/AS01B (comparator group) or 
RTS,S/AS01E were comparable [51% (95% CI: 19%, 70%; p-
value = 0.0010) and 60% (95% CI: 30%, 77%; p-value = 
0.0001), respectively]. Thus for this MALARIA-102 study, 
subjects will receive a booster dose with a Fx dose of a 
RTS,S/AS01E vaccine.
This study will be sponsored by GSK Biologicals and funded 
by PATH.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
6
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
7
Objectives
Primary

To assess vaccine efficacy against the occurrence of P. 
falciparum parasitemia (defined by a positive blood slide):

In subjects who were protected following challenge 
in the MALARIA-092 study and who receive a Fx 
booster dose versus infectivity controls.

In subjects who were not protected following 
challenge in the MALARIA-092 study and who 
receive a Fx booster dose versus infectivity controls.
Secondary
Efficacy

To assess the time-to-onset of P. falciparum parasitemia 
(defined by a positive blood slide):

In subjects who were protected following challenge 
in the MALARIA-092 study and who receive a Fx
booster dose versus the infectivity controls.

In subjects who were not protected following 
challenge in the MALARIA-092 study and who 
receive a Fx booster dose versus the infectivity 
controls.
Immunogenicity

To evaluate anti-circumsporozoite protein (CS) repeat 
region antibody response at specified timepoints.

To evaluate anti-hepatitis B antigen (HBs) Igtot antibody 
response at specified timepoints.
Safety

To assess the reactogenicity (solicited adverse events 
[AEs]) and safety (unsolicited AEs, AEs of specific 
interest and serious adverse events [SAEs]).
Tertiary
Efficacy

To assess vaccine efficacy against the occurrence of P. 
falciparum parasitemia (defined by a positive blood slide):

In subjects who were protected versus subjects who 
were not protected following challenge in the 
MALARIA-092 study and who receive a Fx booster 
dose.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
7
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
8

To assess the time-to-onset of P. falciparum parasitemia 
(defined by a positive blood slide):

In subjects who were protected versus subjects who 
were not protected following challenge in the 
MALARIA-092 study and who receive a Fx booster 
dose.

To assess the occurrence of P. falciparum parasitemia, 
defined by a positive PCR.

To assess the time-to-onset of P. falciparum parasitemia, 
defined by a positive PCR.
Immunogenicity

To evaluate the anti-CS repeat region IgG avidity index at 
specified timepoints.

To evaluate the anti-full length CS protein IgG 
concentrations and anti-C terminal portion of the protein 
(C-term) IgG concentrations at specified timepoints.

To evaluate the 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.
Study design

Experimental design: Phase IIA, open-label, non-
randomized, controlled, mono-centric, single-country 
study with two parallel groups (protected and non-
protected) and one infectivity control group.

Duration of the study: Approximately seven months for 
subjects from the MALARIA-092 study (excluding 
screening) and approximately one month for infectivity 
control subjects (excluding screening).

Epoch 001: Screening period for subjects from the 
MALARIA-092 study (Day -90 to Day -1).

Epoch 002: Vaccination starting at Visit 1 (Day 1) 
and ending at Visit 3 (Day 22).

Epoch 003: Screening period for infectivity control 
subjects (Day -68 to Day 21).

Epoch 004: Challenge starting at Visit 3 (Day 22) 
and ending at Visit 23 (Day 190) or Visit 22 
(Day 50) for the infectivity control group.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
8
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
9

Primary completion Date (PCD): Visit 23 (Day 190).

End of Study (EoS): Last testing results released of 
samples collected at Visit 23 (Day 190).

Study groups: Refer to Synopsis Table 1 and Synopsis 
Table 2.
Synopsis Table 1
Study groups and epochs foreseen in the study
Study 
groups
Approximate 
number of 
subjects*
Age
(Min - Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
P-Fx
20
18-55 years**
x
x
x
NP-Fx
20
18-55 years**
x
x
x
InfectivityCtrl
6-24***
18-55 years
x
x
P-Fx = Pooled subjects from the MALARIA-092 study vaccinated with RTS,S/AS01 (different doses/formulations) and 
protected following the first challenge who will receive a Fx booster dose of RTS,S/AS01E
NP-Fx = Pooled subjects from the MALARIA-092 study vaccinated with RTS,S/AS01 (different doses/formulations) and 
not protected following the first challenge who will receive a Fx booster dose of RTS,S/AS01E
InfectivityCtrl = Subjects who will not receive any vaccination but will undergo sporozoite challenge
*The actual number of subjects will be known after screening. A minimum of 20 subjects per group (P-Fx and NP-Fx) is 
anticipated
**Age at the time of enrollment in the primary study (MALARIA-092)
***Up to 24 subjects, or 4-6 per day, depending on the expected number of days of challenge
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine/Product 
name
Volume to be 
administered
Study groups
P-Fx
NP-Fx
InfectivityCtrl
RTS,S/AS01E
RTS,S
0.1 mL
x
x
-
AS01E
x
x
-

Control: Non-interventional control. For the challenge, 
this will be the InfectivityCtrl group.

Vaccination schedule: All previously vaccinated and 
challenged subjects in MALARIA-092 study will receive 
one Fx dose of RTS,S/AS01E at Visit 1 (Day 1).

Treatment allocation: Non-randomized.

Blinding: Open (refer to Synopsis Table 3).
Synopsis Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
Open
Epoch 002
Open
Epoch 003
Open
Epoch 004
Open
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
9
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
10

Sampling schedule:
For subjects from the P-Fx and NP-Fx groups:

Blood samples for assessment of anti-CS and anti-HBs 
immune response and for serum repository will be 
collected at screening, Day 1*, on the day of challenge 
(Day 22), 28 days post-challenge (Day 50) and at study 
end (Day 190).

Blood samples for peripheral blood mononuclear cells 
(PBMCs) and plasma repository will be collected at 
screening, Day 1*, 7 days post-booster (Day 8), on the 
day of challenge (Day 22), 28 days post-challenge 
(Day 50) and at study end (Day 190).
*Before vaccine administration. These samples might 
not be drawn if Visit 1 occurs less than one week after 
screening, at the discretion of the investigator.
For all subjects:

Blood samples for the evaluation of biochemistry 
(alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], creatinine) and hematology 
(hemoglobin, leukocytes [white blood cells; WBC], 
platelets) parameters will be collected at screening, 
Day 1*, 7 days post-booster* (Day 8), Day 22, the day 
of first parasitemia and 28 days post-challenge 
(Day 50). 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 or clarification of subject 
eligibility.
*Not applicable for the infectivity controls.

Blood sample for assessment of parasitemia (blood 
smear and PCR) will be collected daily for 14 days 
(from Day 27 [Visit 4] to Day 40 [Visit 17]) and then 
every two days for nine days (Day 42 [Visit 18], Day 
44 [Visit 19], Day 46 [Visit 20], Day 48 [Visit 21] and 
Day 50 [Visit 22]). Exceptionally this can occur within 
1 or 3 days if the subject cannot make the visit or for 
schedule conflicts. For subjects who develop malaria, 
blood smear and PCR may be discontinued once the 
subject has three consecutive negative smears 
(separated by more than 12 hours) following the initial 
treatment.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
10
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
11

Blood samples for testing of HIV, hepatitis C virus 
(HCV) and hepatitis B surface antigen (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, at Day 1* and on the day of 
challenge (Day 22).
*Before vaccine administration. Not applicable for the 
infectivity controls.

Type of study: extension of other protocol(s) (MALARIA-
092).

Data collection: electronic Case Report Form (eCRF).
Case definition
The following will be used as case definition of P. falciparum
infection: Asexual blood stage P. falciparum parasite density 
> 0 detected by blood slide reading.
Number of subjects
The target is to enroll all subjects who were vaccinated and 
have undergone challenge in MALARIA-092 study and who are 
willing to take part in this MALARIA-102 booster study. A 
minimum of 40 subjects (20/group) are expected to be enrolled 
in this study. However, there may be more or fewer subjects
who consent to join the study. In addition, up to 24 subjects in 
the infectivity control group will be newly enrolled.
Endpoints
Primary

Occurrence of P. falciparum parasitemia (defined by a 
positive blood slide) following sporozoite challenge (in all 
study groups versus infectivity controls).
Secondary
Efficacy

Time-to-onset of P. falciparum parasitemia (defined by a 
positive blood slide) following sporozoite challenge.
Immunogenicity

Anti-CS repeat region antibody concentrations at screening, 
Day 1, prior to challenge (Day 22), 28 days post-challenge 
(Day 50) and at study end (Day 190).

Anti-HBs Igtot antibody concentrations at screening,
Day 1, prior to challenge (Day 22), 28 days post-challenge 
(Day 50) and at study end (Day 190).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
11
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
12
Safety

Occurrence of solicited local and general AEs within 7 
days after vaccination (day of vaccination and 6 subsequent 
days) in the booster vaccination groups.

Occurrence of unsolicited AEs within 21 days after 
vaccination (day of vaccination and 20 subsequent days), 
according to the Medical Dictionary for Regulatory 
Activities (MedDRA) classification, in the booster 
vaccination groups.

Occurrence of AEs within 29 days after challenge (day of 
challenge and 28 subsequent days), according to the 
MedDRA classification, in all study groups.

Occurrence of AEs of specific interest (potential immune-
mediated diseases [pIMDs] and meningitis) from Day 1 up 
to study conclusion (Day 190), according to the MedDRA 
classification, in all study groups.

Occurrence of SAEs (all, fatal, related to investigational 
vaccine) during the whole study period (from screening up 
to study conclusion [Day 190]), according to the MedDRA 
classification, in all study groups.

Occurrence of abnormal laboratory values at screening, 
Day 1, Day 8, Day 22, the day of first parasitemia and 28 
days post-challenge (Day 50) for the booster vaccination 
groups; and at screening, Day 22, the day of first 
parasitemia and 28 days post-challenge (Day 50) for the 
infectivity control subjects.
Tertiary
Efficacy

Occurrence of P. falciparum parasitemia (defined by a 
positive blood slide) following sporozoite challenge 
(between study groups).

Time-to-onset of P. falciparum parasitemia (defined by a 
positive blood slide) following sporozoite challenge 
(between study groups).

Occurrence of P. falciparum parasitemia (defined by a 
positive PCR) following sporozoite challenge (between 
study groups).

Time-to-onset of P. falciparum parasitemia (defined by a 
positive PCR) following sporozoite challenge (between 
study groups).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
12
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
13
Immunogenicity

Anti-CS repeat region IgG avidity index at Day 1, prior to 
challenge (Day 22), 28 days post-challenge (Day 50) and at 
study end (Day 190).

Anti-full length CS protein IgG concentrations and anti-C-
term IgG concentrations at Day 1, prior to challenge 
(Day 22), 28 days post-challenge (Day 50) and at study end 
(Day 190).

Anti-full length CS protein and anti-C-term IgG avidity at 
Day 1, prior to challenge (Day 22), 28 days post-challenge 
(Day 50) and at study end (Day 190).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
13
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
14
TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................5
SYNOPSIS......................................................................................................................6
LIST OF ABBREVIATIONS...........................................................................................22
GLOSSARY OF TERMS ...............................................................................................24
TRADEMARKS .............................................................................................................28
1.
INTRODUCTION....................................................................................................29
1.1.
Background ................................................................................................29
1.2.
Rationale for the study and study design ....................................................30
1.2.1.
Rationale for the study.................................................................30
1.2.2.
Rationale for the study design......................................................31
1.3.
Benefit : Risk assessment...........................................................................31
1.3.1.
Risk assessment..........................................................................31
1.3.2.
Benefit assessment .....................................................................33
1.3.3.
Overall benefit:risk conclusion .....................................................33
2.
OBJECTIVES.........................................................................................................34
2.1.
Primary objective ........................................................................................34
2.2.
Secondary objectives..................................................................................34
2.3.
Tertiary objectives.......................................................................................35
3.
STUDY DESIGN OVERVIEW ................................................................................36
4.
CASE DEFINITION ................................................................................................39
5.
STUDY COHORT...................................................................................................39
5.1.
Number of subjects/centres ........................................................................39
5.2.
Inclusion criteria for enrollment ...................................................................41
5.3.
Exclusion criteria for enrollment..................................................................42
6.
CONDUCT OF THE STUDY ..................................................................................44
6.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................44
6.2.
Subject identification and randomisation.....................................................45
6.2.1.
Subject identification....................................................................45
6.2.2.
Randomization of treatment.........................................................45
Randomization of supplies..........................................45
Treatment allocation to the subject.............................45
6.2.2.2.1.
Study group and treatment 
number allocation ...................................45
6.3.
Method of blinding ......................................................................................46
6.4.
General study aspects ................................................................................46
6.4.1.
Mosquito challenge......................................................................46
Contraindications to malaria challenge .......................46
Parasite and mosquito strains ....................................47
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
14
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
15
Infection of human subjects........................................47
Determining parasitemia.............................................47
Management of infected human subjects ...................47
Malaria treatment .......................................................49
6.5.
Outline of study procedures ........................................................................51
6.6.
Detailed description of study procedures ....................................................55
6.6.1.
Informed consent.........................................................................55
6.6.2.
Check inclusion and exclusion criteria .........................................55
6.6.3.
Check screening laboratory results..............................................55
6.6.4.
Collect demographic data ............................................................56
6.6.5.
Medical history.............................................................................56
6.6.6.
Physical examination ...................................................................56
6.6.7.
Urine pregnancy test....................................................................56
6.6.8.
Check contraindications to vaccination ........................................56
6.6.9.
Assess pre-vaccination body temperature ...................................57
6.6.10.
Study group and treatment number allocation..............................57
6.6.11.
Study vaccine administration .......................................................57
6.6.12.
Check contraindications to challenge...........................................57
6.6.13.
Sporozoite challenge ...................................................................57
6.6.14.
Distribution of emergency notification card...................................57
6.6.15.
Sampling......................................................................................58
6.6.16.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................59
6.6.17.
Recording of AEs, SAEs, pregnancies and pIMDs.......................59
6.6.18.
Study conclusion..........................................................................59
6.7.
Biological sample handling and analysis.....................................................60
6.7.1.
Use of specified study materials ..................................................60
6.7.2.
Biological samples.......................................................................61
6.7.3.
Laboratory assays .......................................................................62
6.7.4.
Biological samples evaluation......................................................64
Immunological read-outs ............................................64
Hematology/Blood chemistry......................................64
Parasitemia ................................................................65
6.7.5.
Immunological correlates of protection.........................................65
7.
STUDY VACCINE AND ADMINISTRATION...........................................................66
7.1.
Description of study vaccine .......................................................................66
7.2.
Storage and handling of study vaccine .......................................................66
7.3.
Dosage and administration of study vaccine...............................................67
7.4.
Replacement of unusable vaccine ..............................................................67
7.5.
Contraindications to vaccination .................................................................67
7.6.
Concomitant medications/products and concomitant vaccinations..............68
7.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................68
7.6.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from Per-Protocol analyses ...........68
7.7.
Intercurrent medical conditions that may lead to elimination of a 
subject from Per-Protocol analyses.............................................................69
8.
HEALTH ECONOMICS ..........................................................................................69
9.
SAFETY.................................................................................................................70
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
15
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
16
9.1.
Safety definitions ........................................................................................70
9.1.1.
Definition of an adverse event......................................................70
9.1.2.
Definition of a serious adverse event ...........................................71
9.1.3.
Solicited adverse events..............................................................72
Solicited local (injection-site) adverse events..............72
Solicited general adverse events................................72
9.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................72
9.1.5.
Adverse events of specific interest...............................................73
Potential immune-mediated diseases .........................73
Meningitis...................................................................75
9.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................75
9.2.1.
Pregnancy ...................................................................................75
9.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................76
9.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................76
9.3.2.
Post-study adverse events and serious adverse events...............77
9.3.3.
Evaluation of adverse events and serious adverse events...........77
Active questioning to detect adverse events 
and serious adverse events........................................77
Assessment of adverse events...................................78
9.3.3.2.1.
Assessment of intensity..........................78
9.3.3.2.2.
Assessment of causality .........................81
Assessment of outcomes............................................82
9.4.
Reporting of serious adverse events, pregnancies and other events ..........83
9.4.1.
Prompt reporting of serious adverse events, pregnancies 
and other events to GSK Biologicals............................................83
9.4.2.
Contact information for reporting serious adverse events, 
pregnancies and pIMDs...............................................................83
9.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................84
Back-up system in case the electronic 
reporting system does not work..................................84
9.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals ...................................................................................84
9.4.5.
Reporting of AEs of specific interest to GSK Biologicals ..............84
9.4.6.
Updating of SAE, pregnancy and AE of specific interest 
information after removal of write access to the subject’s 
eCRF...........................................................................................85
9.4.7.
Regulatory reporting requirements for serious adverse 
events..........................................................................................85
9.5.
Follow-up of adverse events, serious adverse events and 
pregnancies................................................................................................85
9.5.1.
Follow-up of adverse events and serious adverse events............85
Follow-up during the study..........................................85
Follow-up after the subject is discharged from 
the study.....................................................................86
9.5.2.
Follow-up of pregnancies.............................................................86
9.6.
Treatment of adverse events ......................................................................86
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
16
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
17
9.7.
Subject card................................................................................................87
10. SUBJECT COMPLETION AND WITHDRAWAL.....................................................88
10.1.
Subject completion .....................................................................................88
10.2.
Subject withdrawal......................................................................................88
10.2.1.
Subject withdrawal from the study ...............................................88
10.3.
Screen and baseline failures.......................................................................89
11. STATISTICAL METHODS......................................................................................89
11.1.
Primary endpoint.........................................................................................89
11.2.
Secondary endpoints ..................................................................................89
11.3.
Tertiary endpoints.......................................................................................90
11.4.
Determination of sample size......................................................................90
11.5.
Cohorts for Analyses ..................................................................................91
11.5.1.
Enrolled Set.................................................................................91
11.5.2.
Intent-to-treat set .........................................................................91
11.5.3.
Per-protocol set for analysis of immunogenicity and 
efficacy ........................................................................................91
11.5.4.
Adapted Per-Protocol Set for analysis of efficacy.........................91
11.6.
Derived and transformed data.....................................................................92
11.7.
Analysis of demographics...........................................................................93
11.8.
Analysis of exposure...................................................................................93
11.9.
Analysis of efficacy .....................................................................................94
11.10. Analysis of immunogenicity.........................................................................95
11.11. Analysis of safety........................................................................................95
11.12. Interpretation of analyses............................................................................96
11.13. Conduct of analyses ...................................................................................97
11.13.1. Sequence of analyses..................................................................97
11.13.2. Statistical considerations for interim analyses..............................97
12. ADMINISTRATIVE MATTERS ...............................................................................98
12.1.
Electronic Case Report Form instructions...................................................98
12.2.
Study Monitoring by GSK Biologicals..........................................................98
12.3.
Record retention .........................................................................................99
12.4.
Quality assurance.......................................................................................99
12.5.
Posting of information on publicly available clinical trial registers and 
publication policy ......................................................................................100
12.6.
Provision of study results to investigators .................................................100
12.7.
Data Sharing.............................................................................................100
13. COUNTRY SPECIFIC REQUIREMENTS.............................................................100
14. REFERENCES.....................................................................................................101
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
17
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
18
LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................37
Table 2
Study groups and treatment foreseen in the study .................................37
Table 3
Blinding of study epochs ........................................................................38
Table 4
Study procedures for the P-Fx and NP-Fx groups..................................51
Table 5
Study procedures for the InfectivityCtrl group.........................................53
Table 6
Intervals between study visits for the P-Fx and NP-Fx groups................55
Table 7
Intervals between study visits for the infectivity control group.................55
Table 8
Biological samples .................................................................................61
Table 9
Assays for humoral immunity (antibody determination) ..........................62
Table 10
Assessment of P. falciparum parasitemia...............................................63
Table 11
Hematology, biochemistry and screening tests ......................................63
Table 12
Immunological read-outs........................................................................64
Table 13
Hematology/biochemistry read-outs .......................................................64
Table 14
Parasitemia read-outs ............................................................................65
Table 15
Study vaccine.........................................................................................66
Table 16
Dosage and administration.....................................................................67
Table 17
Solicited local adverse events ................................................................72
Table 18
Solicited general adverse events............................................................72
Table 19
List of potential immune-mediated diseases...........................................73
Table 20
Reporting periods for collecting safety information .................................77
Table 21
Intensity scales for solicited symptoms...................................................78
Table 22
Toxicity grading scales for blood testing.................................................80
Table 23
Timeframes for submitting serious adverse event, pregnancy and
other events reports to GSK Biologicals .................................................83
Table 24
GSK Biologicals’ laboratories ...............................................................104
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
18
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
19
Table 25
Outsourced laboratories.......................................................................104
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
19
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
20
LIST OF FIGURES
PAGE
Figure 1
Study design overview ...........................................................................36
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
20
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
21
LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .....................................................................102
APPENDIX B CLINICAL LABORATORIES ................................................................104
APPENDIX C NHANES I CARDIOVASCULAR RISK CRITERIA................................105
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
21
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
22
LIST OF ABBREVIATIONS
AE:
Adverse Event
ALT:
Alanine Aminotransferase
AS01E:
GSK’s proprietary Adjuvant System containing MPL, QS-21 (25 µg 
MPL and 25 µg QS-21) and liposome
AST:
Aspartate Aminotransferase
-HCG:
Beta-Human Chorionic Gonadotropin
CHMI:
Controlled Human Malaria Infection
CI:
Confidence Interval
CLIA:
Chemiluminescence Enzyme Immunoassay
CS:
Circumsporozoite protein of Plasmodium falciparum
eCRF:
electronic Case Report Form
ELISA:
Enzyme-Linked Immunosorbent Assay
EoS:
End of Study
ES:
Exposed Set
eTDF:
Electronic Temperature excursion Decision Form
FDA:
Food and Drug Administration, United States of America
Fx:
Fractional
GCP:
Good Clinical Practice
GSK:
GlaxoSmithKline
GMC:
Geometric Mean Concentration
HBsAg:
Hepatitis B surface antigen
HCV:
Hepatitis C Virus
HIV:
Human Immunodeficiency Virus
ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
22
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
23
IEC:
Independent Ethics Committee
IgG:
Immunoglobulin G
IMP:
Investigational Medicinal Product
IRB:
Institutional Review Board
MedDRA:
Medical Dictionary for Regulatory Activities
MPL:
3-O-desacyl-4’-monophosphoryl lipid A (produced by GSK)
NHANES I:
National Health And Nutrition Examination Survey I
P. falciparum:
Plasmodium falciparum
PBMC:
Peripheral blood mononuclear cells
PCD:
Primary Completion Date
PCR:
Polymerase Chain Reaction
pIMD:
Potential Immune-Mediated Disease
PPS:
Per-Protocol Set
QS-21:
Quillaja saponaria Molina, fraction 21 (Licensed by GSK from 
Antigenics Inc., a wholly owned subsidiary of Agenus Inc., a 
Delaware, USA corporation)
RCC:
Reverse Cumulative Curve
SAE:
Serious Adverse Event
SBIR:
Randomization System on Internet
SD:
Standard Deviation
SDV:
Source Document Verification
SPM:
Study Procedures Manual
VE:
Vaccine Efficacy
WBC:
White Blood Cell
WRAIR:
Walter Reed Army Institute of Research
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
23
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
24
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,

Combined estrogen and progesterone oral 
contraceptives,

Injectable progestogen,

Implants of etenogestrel or levonorgestrel,

Contraceptive 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), and/or 
progesterone alone oral contraceptive.
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, or for 
subjects who are and will continue to be abstinent from 
penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.
Adverse event (AE):
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product.
An AE can therefore be any 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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
24
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
25
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 enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria.
End of Study (EoS):
(Synonym of End of Trial)
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of 
the last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
8 months after Last Subject Last Visit.
Epoch:
An epoch is a set of consecutive timepoints or a single 
timepoint from a single protocol. Epochs are defined to 
support a main purpose which is either to draw 
conclusions on subject participation or to draw a 
complete conclusion to define or precise the targeted 
label of the product. Supporting means that data collected 
at the timepoints included in an epoch must be sufficient 
to fulfil the purpose of the epoch.
Typical examples of epochs are screening, primary 
vaccinations, boosters, 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 Per-Protocol analysis (see Sections 7.6.2
and 11.5 for details on criteria for evaluability).
Immunological correlate 
of protection:
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
25
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
26
Investigational vaccine:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient being 
tested 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 
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 all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated.
Randomization:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
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:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
26
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
27
Study vaccine/product:
Any investigational vaccine/product being tested and/or 
any authorized use of a vaccine/product/placebo as a 
reference or administered concomitantly, in a clinical trial 
that evaluates the use of an investigational 
vaccine/product.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine or as a control.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
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.
Treatment number:
A number identifying a treatment to a subject, according 
to treatment allocation.
Unsolicited adverse 
event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited AE.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
27
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
28
TRADEMARKS
The following trademarks are used in the present protocol.
Note: In the body of the protocol (including the synopsis), the names of the 
vaccines/products and/or medications will be written without the superscript symbol ™ 
or ® and in italics.
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
Malarone
Atovaquone and proguanil hydrochloride
Trademarks not owned by the 
GlaxoSmithKline group of companies
Generic description
Imodium (Johnson & Johnson Limited)
Loperamide
Coartem (Novartis Pharmaceuticals UK Ltd.)
Artemether/lumefantrine
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
28
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
29
1.
INTRODUCTION
1.1.
Background
GlaxoSmithKline (GSK) Biologicals in partnership with PATH is developing a 
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, in
collaboration with PATH, continued to investigate ways to further improve vaccine 
efficacy levels. Higher vaccine efficacy levels may lead to improved malaria control and 
contribute to the malaria elimination goal set as a long-term target by the global health 
community [Malaria Vaccine Technology Roadmap, 2013].
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. A previous controlled 
human malaria infection (CHMI) study in malaria-naïve adults (MALARIA-071) where a 
0, 1, 7-month schedule, with a fractional (Fx) dose delivered as the third immunization 
(Fx017M) was evaluated showed high efficacy in the Fx017M group compared to 
standard doses given at 0, 1, 2-months (012M group). 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). While all volunteers in the 
infectivity control group developed parasitemia after CHMI, 26 of 30 subjects in the 
Fx017M group (VE = 86.7% [95% CI; 66.8, 94.6]; p-value < 0.0001 by the Fisher exact 
test) and 10 of 16 subjects in the 012M group (VE = 62.5% [95% CI: 29.4, 80.1]; p-value 
= 0.0009) were protected. In the follow-up phase of the study, subjects who were 
protected in the initial challenge were randomized to receive a Fx 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 ten subjects who were initially protected and received a Fx
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 Fx dose [Regules, 2016].
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
29
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
30
The MALARIA-092 CHMI in healthy malaria-naïve subjects aged 18-55 years was 
designed to evaluate the efficacy, immunogenicity and safety of various dose schedules 
and formulations of GSK Biologicals’ candidate malaria vaccines. The study, conducted 
at the Walter Reed Army Institute of Research (WRAIR), aimed to evaluate: (a) the role 
of a Fx second and third dose, (b) a two-dose schedule where the second dose is 
fractional, (c) the use of the pediatric formulation to vaccinate adults, when a pediatric 
dose is delivered to adults, (d) 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), and (e) the impact of varying 
dosing schedules on immune effectors and immune correlates of protection. Group 
AduFx receiving RTS,S/AS01B full dose at Month 0 and Month 1 + RTS,S/AS01B
fractional (Fx) dose (1/5th dose) at Month 7.
The groups evaluated were:

Group 2PedFx receiving double dose of RTS,S/AS01E at Month 0 and Month 1 + 
double dose of RTS,S/AS01E Fx dose (1/5th dose) at Month 7.

Group PedFx receiving RTS,S/AS01E full dose at Month 0 and Month 1 + 
RTS,S/AS01E Fx dose (1/5th dose) at Month 7.

Group Adu2Fx receiving RTS,S/AS01B full dose at Month 0 + RTS,S/AS01B Fx 
dose (1/5th dose) at Month 1 and Month 7.

Group Adu1Fx receiving RTS,S/AS01B full dose at Month 0 + RTS,S/AS01B Fx 
dose (1/5th dose) at Month 7.
Please refer to the current Investigator’s Brochure for information regarding the pre-
clinical and clinical studies of RTS,S/AS01.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
This follow-up study (MALARIA-102) to the MALARIA-092 study will be conducted at 
WRAIR and is designed to evaluate the waning efficacy with the fractional schedules and 
to confirm if protection can be extended with an additional Fx dose.
In this booster study, vaccinated subjects from the MALARIA-092 study (previously
protected or unprotected following CHMI) will receive a booster and undergo a second 
CHMI three to four weeks after vaccination.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
30
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
31
1.2.2.
Rationale for the study design
The MALARIA-092 study was designed to evaluate varying vaccination schedules, a Fx 
dose and the use of the pediatric formulation, RTS,S/AS01E, in the adult CHMI model. 
The current study will assess if a Fx dose booster will maintain protection in those 
previously protected and convert previously unprotected individuals to protected status.
Given the positive efficacy derived in MALARIA-092 study in the group that received 
RTS,S/AS01E (PedFx), a decision has been taken to boost subjects only with a Fx dose 
from the RTS,S/AS01E formulation (0.1 mL). This will facilitate deployment in Africa 
where the same dosage and formulation will be used across all age groups. Interim
analysis from the MALARIA-092 CHMI study showed that vaccine efficacy (VE) with 
the RTS,S/AS01B (comparator group) or RTS,S/AS01E were comparable [51% (95% CI: 
19%, 70%; p-value = 0.0010) and 60% (95% CI: 30%, 77%; p-value = 0.0001), 
respectively]. Thus for this MALARIA-102 study, subjects will receive a booster dose 
with a Fx dose of a RTS,S/AS01E vaccine.
This study will be sponsored by GSK Biologicals and funded by PATH.
1.3.
Benefit : Risk assessment
Please refer to the current Investigator’s Brochure for 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
Mitigation Strategy
Investigational vaccine: RTS,S/AS01
Important potential risk: 
Meningitis
In the large Phase III study,
MALARIA-055 PRI, an 
imbalance of meningitis cases 
of any etiology (i.e., including 
cases with confirmed etiology 
and cases with no etiology
found), with no cluster in time-
to-onset, has been observed in
children 5-17 months of age at 
first dose. Meningitis has not 
been a safety concern in RTS,S 
studies in adults.
Subjects will be instructed on 
the need to attend the clinic if 
they are unwell. A high level of 
medical supervision is in place 
to detect and treat meningitis if 
it occurs.
Meningitis is an adverse event 
(AE) of specific interest (see 
Section 9.1.5). Clinical details 
of each case will be captured 
through the expedited AE 
report and in a specific eCRF 
screen.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
31
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
32
Important 
Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
Important potential risk: 
Hypersensitivity
(including anaphylaxis)
As with other vaccines, 
hypersensitivity and 
anaphylaxis to one or several 
components of the vaccine can 
rarely occur.
One case of erythema multiform 
and two cases of 
bronchospasm within 30 days 
following RTS,S/AS01 
vaccination were reported as 
hypersensitivity reactions in 
past pediatric studies.
No case of anaphylaxis has 
been reported following 
RTS,S/AS01 vaccination to 
date.
Subjects will be observed 
closely for at least 30 minutes 
following administration of the 
vaccine with appropriate 
medical treatment readily 
available in case of 
anaphylaxis.
History of anaphylaxis post-
vaccination and history of any 
reaction or hypersensitivity 
likely to be exacerbated by 
any component of the vaccine 
are exclusion criteria in this 
study (see Section 5.3). 
Previous anaphylactic reaction 
to a vaccine is a 
contraindication to further 
experimental vaccinations in 
this study (see Section 7.5).
Important potential risk: 
potential immune-
mediated disease
(pIMD)
pIMD is a theoretical concern 
with adjuvanted vaccines as no 
evidence of auto-immune 
disease caused by RTS,S/AS01 
has been observed.
Subjects will be informed of 
this theoretical risk and the 
need to attend the clinic if they 
are unwell. pIMD is an AE of 
specific interest (see Section
9.1.5). The occurrence of 
pIMD cases will be described.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
32
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
33
Important 
Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Pain when taking blood 
samples
When taking the blood samples, 
the subject may feel faint; or 
experience mild pain, bruising, 
irritation or redness.
Subjects will be advised to 
inform or call the study doctor 
immediately if they have any 
side effects that they perceive 
as serious.
Risks associated with 
malaria challenge
The risks associated with the 
sporozoite challenge include 
local inflammatory reactions or 
potential allergic reactions to 
mosquito bites as well as the 
development of malaria infection. 
Transient abnormalities, such as 
fever, headache, mild anemia, 
leukopenia, splenomegaly, 
hepatic tenderness and fatigue, 
are expected consequences of 
malaria. The complications of
malaria which can lead to kidney, 
liver or brain damage, and death, 
are seen during naturally 
acquired malaria when diagnosis 
and treatment are delayed and 
high levels of parasitemia
develop.
Anti-malaria treatment will be
administered to malaria 
infected subjects. Under the 
carefully controlled conditions 
of this study, the chance of 
serious illness or death from 
malaria infection is very small.
1.3.2.
Benefit assessment
No direct benefit is foreseen from study participation. Indirect benefits may be possible 
since subjects will be screened for 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 are considered acceptable and the 
potential risks associated with malaria challenges are minimized by the carefully 
controlled condition of this study.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
33
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
34
2.
OBJECTIVES
2.1.
Primary objective

To assess vaccine efficacy against the occurrence of P. falciparum parasitemia 
(defined by a positive blood slide):

In subjects who were protected following challenge in the MALARIA-092 study 
and who receive a Fx booster dose versus infectivity controls.

In subjects who were not protected following challenge in the MALARIA-092 
study and who receive a Fx booster dose versus infectivity controls.
Refer to Section 11.1 for the definition of the primary endpoint.
2.2.
Secondary objectives
Efficacy

To assess the time-to-onset of P. falciparum parasitemia (defined by a positive blood 
slide):

In subjects who were protected following challenge in the MALARIA-092 study 
and who receive a Fx booster dose versus the infectivity controls.

In subjects who were not protected following challenge in the MALARIA-092 
study and who receive a Fx booster dose versus the infectivity controls.
Immunogenicity

To evaluate anti-circumsporozoite protein (CS) repeat region antibody response at 
specified timepoints.

To evaluate anti-hepatitis B antigen (HBs) Igtot antibody response at specified 
timepoints.
Safety

To assess the reactogenicity (solicited adverse events [AEs]) and safety (unsolicited 
AEs, AEs of specific interest and serious adverse events [SAEs]).
Refer to Section 11.2 for the definition of the secondary endpoints.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
34
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
35
2.3.
Tertiary objectives
Efficacy

To assess vaccine efficacy against the occurrence of P. falciparum parasitemia 
(defined by a positive blood slide):

In subjects who were protected versus subjects who were not protected 
following challenge in the MALARIA-092 study and who receive a Fx booster 
dose.

To assess the time-to-onset of P. falciparum parasitemia (defined by a positive blood 
slide):

In subjects who were protected versus subjects who were not protected 
following challenge in the MALARIA-092 study and who receive a Fx booster 
dose.

To assess the occurrence of P. falciparum parasitemia, defined by a positive PCR.

To assess the time-to-onset of P. falciparum parasitemia, defined by a positive PCR.
Immunogenicity

To evaluate the anti-CS repeat region IgG avidity index at specified timepoints.

To evaluate the anti-full length CS protein IgG concentrations and anti-C terminal 
portion of the protein (C-term) IgG concentrations at specified timepoints.

To evaluate the 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 11.3 for the definition of the tertiary endpoints and to section 11.13.1 for 
the reporting of tertiary endpoint results.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
35
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
36
3.
STUDY DESIGN OVERVIEW
Figure 1
Study design overview
SCR = screening; V = visit; D = day; M = month; BS = blood sampling
*Screening visit applicable for the groups from the MALARIA-092 study receiving the fractional booster dose
**Screening visit applicable for subjects in the infectivity control group
***Blood sample for biochemistry and hematology parameters will be collected the day of first parasitemia and blood 
sample for assessment of parasitemia (blood smear and PCR) will be collected daily for 14 days (from Day 27 [Visit 4]
to Day 40 [Visit 17]) and then every two days for nine days (Day 42 [Visit 18], Day 44 [Visit 19], Day 46 [Visit 20], Day 
48 [Visit 21] and Day 50 [Visit 22]). Exceptionally this can occur within 1 or 3 days if the subject cannot make the visit 
or for schedule conflicts.
Protocol waivers or exemptions are not allowed unless necessary for the management 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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
36
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
37

Experimental design: Phase IIA, open-label, non-randomized, controlled, mono-
centric, single-country study with two parallel groups (protected and non-protected) 
and one infectivity control group.

Duration of the study: Approximately seven months for subjects from the 
MALARIA-092 study (excluding screening) and approximately one month for 
infectivity control subjects (excluding screening).

Epoch 001: Screening period for subjects from the MALARIA-092 study 
(Day -90 to Day -1).

Epoch 002: Vaccination starting at Visit 1 (Day 1) and ending at Visit 3 
(Day 22).

Epoch 003: Screening period for infectivity control subjects (Day -68 to 
Day 21).

Epoch 004: Challenge starting at Visit 3 (Day 22) and ending at Visit 23 
(Day 190) or Visit 22 (Day 50) for the infectivity control group.

Primary Completion Date (PCD): Visit 23 (Day 190).
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last testing results released of samples collected at Visit 23 
(Day 190).
Refer to glossary of terms for the definition of EoS.

Study groups: Refer to Table 1 and Table 2.
Table 1
Study groups and epochs foreseen in the study
Study 
groups
Approximate 
number of 
subjects*
Age
(min - max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
P-Fx
20
18-55 years**
x
x
x
NP-Fx
20
18-55 years**
x
x
x
InfectivityCtrl
6-24***
18-55 years
x
x
P-Fx = Pooled subjects from the MALARIA-092 study vaccinated with RTS,S/AS01 (different doses/formulations) and 
protected following the first challenge who will receive a Fx booster dose of RTS,S/AS01E
NP-Fx = Pooled subjects from the MALARIA-092 study vaccinated with RTS,S/AS01 (different doses/formulations) and 
not protected following the first challenge who will receive a Fx booster dose of RTS,S/AS01E
InfectivityCtrl = Subjects who will not receive any vaccination but will undergo sporozoite challenge
*The actual number of subjects will be known after screening. A minimum of 20 subjects per group (P-Fx and NP-Fx) is 
anticipated
**Age at the time of enrollment in the primary study (MALARIA-092)
***Up to 24 subjects, or 4-6 per day, depending on the expected number of days of challenge
Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine/Product 
name
Volume to be 
administered
Study groups
P-Fx
NP-Fx
InfectivityCtrl
RTS,S/AS01E
RTS,S
0.1 mL
x
x
-
AS01E
x
x
-
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
37
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
38

Control: Non-interventional control. For the challenge, this will be the 
InfectivityCtrl group.

Vaccination schedule: All previously vaccinated and challenged subjects in 
MALARIA-092 study will receive one Fx dose of RTS,S/AS01E at Visit 1 (Day 1).

Treatment allocation: Non-randomized.

Blinding: Open (refer to Table 3).
Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
Open
Epoch 002
Open
Epoch 003
Open
Epoch 004
Open

Sampling schedule:
For subjects from the P-Fx and NP-Fx groups:

Blood samples for assessment of anti-CS and anti-HBs immune response and for 
serum repository will be collected at screening, Day 1*, on the day of challenge 
(Day 22), 28 days post-challenge (Day 50) and at study end (Day 190).

Blood samples for peripheral blood mononuclear cells (PBMCs) and plasma 
repository will be collected at screening, Day 1*, 7 days post-booster (Day 8),
on the day of challenge (Day 22), 28 days post-challenge (Day 50) and at study 
end (Day 190).
*Before vaccine administration. These samples might not be drawn if Visit 1 
occurs less than one week after screening, at the discretion of the investigator.
For all subjects:

Blood samples for the evaluation of biochemistry (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], creatinine) and hematology 
(hemoglobin, leukocytes [white blood cells; WBC], platelets) parameters will be 
collected at screening, Day 1*, 7 days post-booster* (Day 8), Day 22, the day of 
first parasitemia and 28 days post-challenge (Day 50). 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 or clarification of subject eligibility.
*Not applicable for the infectivity controls.

Blood sample for assessment of parasitemia (blood smear and PCR) will be 
collected daily for 14 days (from Day 27 [Visit 4] to Day 40 [Visit 17]) and then 
every two days for nine days (Day 42 [Visit 18], Day 44 [Visit 19], Day 46
[Visit 20], Day 48 [Visit 21] and Day 50 [Visit 22]). Exceptionally this can 
occur within 1 or 3 days if the subject cannot make the visit or for schedule 
conflicts. For subjects who develop malaria, blood smear and PCR may be 
discontinued once the subject has three consecutive negative smears (separated 
by more than 12 hours) following the initial treatment.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
38
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
39

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, at Day 1* and on the day of 
challenge (Day 22).
*Before vaccine administration. Not applicable for the infectivity controls.

Type of study: extension of other protocol(s) (MALARIA-092).

Data collection: electronic Case Report Form (eCRF).
4.
CASE DEFINITION
The following will be used as case definition of P. falciparum infection:

Asexual blood stage P. falciparum parasite density > 0 detected by blood slide 
reading.
5.
STUDY COHORT
5.1.
Number of subjects/centres
Subjects who were vaccinated (different formulations/schedules at 18-55 years of age at 
the time of first vaccination) and challenged in the MALARIA-092 study will be enrolled 
and allocated to the groups as follows:

P-Fx group*: Subjects who were protected following the first challenge and who 
will receive a Fx booster dose of RTS,S/AS01E 12 months after completion of the 
vaccination course in the MALARIA-092 study.

NP-Fx group*: Subjects who were not protected following the first challenge and 
who will receive a Fx booster dose of RTS,S/AS01E 12 months after completion of 
the vaccination course in the MALARIA-092 study.
*The actual number of subjects in these groups will be determined by subjects from the 
MALARIA-092 study who agree to participate in this booster study and fulfil the 
eligibility criteria for each of the groups. A minimum of 20 subjects per group (P-Fx and 
NP-Fx) is anticipated.
In addition, the following group will be enrolled for this study:

InfectivityCtrl group: Subjects who will be newly enrolled in the MALARIA-102 
study and will only undergo sporozoite challenge.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
39
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
40
Refer to the table below for a description of the MALARIA-092 study vaccination
groups:
Study 
groups
Vaccination schedule
Age 
(Min/Max)
AduFx
RTS,S/AS01B full dose at M0, M1 + RTS,S/AS01B Fx dose (1/5th) at M7
18 - 55 years
2PedFx
RTS,S/AS01E double dose at M0, M1 + double dose RTS,S/AS01E Fx dose (1/5th) at M7 18 - 55 years
PedFx
RTS,S/AS01E full dose at M0, M1 + RTS,S/AS01E Fx dose (1/5th) at M7
18 - 55 years
Adu2Fx
RTS,S/AS01B full dose at M0 + RTS,S/AS01B Fx dose (1/5th) at M1, M7
18 - 55 years
Adu1Fx
RTS,S/AS01B full dose at M0 + RTS,S/AS01B Fx dose (1/5th) at M7
18 - 55 years 
M = month
The target is to enroll all subjects who were vaccinated and have undergone challenge in 
MALARIA-092 study and who are willing to take part in this MALARIA-102 booster 
study. A minimum of 40 subjects (20/group) who were vaccinated in the MALARIA-092 
study are expected to be enrolled in this study. However there may be more or fewer 
subjects who consent to join the study. In addition, up to 24 subjects in the infectivity
control group will be newly enrolled. Refer to Section 11.4 for a detailed description of 
the criteria used in the determination of sample size.
Overview of the recruitment plan
On or about the last study visit of the MALARIA-092 study, participants will be asked 
about their willingness to be contacted to take part in a booster study, which will also be 
conducted at WRAIR. The investigator and his team will explain the rationale for 
MALARIA-102 and explain in general terms what the study entails. Only subjects who 
have completed all vaccinations and the primary challenge will be eligible for screening 
for the MALARIA-102 study. Such subjects who are interested in continuing on to 
participation in the MALARIA-102 study will be contacted and scheduled for a screening 
visit during the approved study recruitment window. Screened subjects who fulfill all 
inclusion criteria (and none of the exclusion criteria) for the study will be considered 
eligible to participate in the study.
For the infectivity control group, subjects will be recruited and screened in order to 
provide approximately 6 control subjects for each malaria challenge day required for the 
trial (the number of which will depend on the final number of experimental subjects). Up 
to 24 subjects may eventually be enrolled (defined as undergoing malaria challenge) as
infectivity controls.
To be deemed eligible to participate, control subjects must fulfill all inclusion criteria 
(and none of the exclusion criteria) for the study. For the 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 disease or parasitemia) 
within the last five years (inclusive).
WRAIR has an established process whereby an IRB-approved generic screening protocol 
is used to screen potential subjects managed by the WRAIR Clinical Trials Center. If 
subjects from this pre-screened group agree to be infectivity controls in the MALARIA-
102 study, the required biochemistry, hematology, HIV, HCV and HBsAg and ECG test 
results can be rolled over to the study provided they occur within the screening period, at 
the discretion of the Principal Investigator.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
40
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
41
5.2.
Inclusion criteria for enrollment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity, regulatory acceptability of the study 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:
Only for subjects from the MALARIA-092 study:

Subjects vaccinated and having undergone sporozoite challenge during the primary 
study (MALARIA-092).
For all subjects:

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 performing any study-
specific procedure.

Healthy subjects as established by medical history and clinical examination before 
entering into the study.

Available to participate for the duration of the study (approximately seven months 
for all subjects from MALARIA-092 and one month for the infectivity control 
subjects; excluding the screening period).

Female subjects of non-childbearing potential may be enrolled in the study.

Non-childbearing potential is defined as pre-menarche, current bilateral tubal 
ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause.
Please refer to the glossary of terms for 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 Day 1, and has agreed 
to continue adequate contraception during the entire treatment period and for 
two months after malaria challenge (only for subjects from the MALARIA-092 
study).

Has practiced adequate contraception for 30 days prior to malaria challenge, and 
has agreed to continue adequate contraception up to two months after malaria 
challenge (only for the infectivity control subjects).

Has a negative pregnancy test at enrollment.
Please refer to the glossary of terms for the definition of adequate contraception.
For the infectivity control subjects:

Male or female subjects between, and including, 18 and 55 years of age.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
41
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
42
5.3.
Exclusion criteria for enrollment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity, regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:
For all subjects except the infectivity control subjects:

Any medical condition that in the judgment of the investigator would make
intramuscular injection unsafe.

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine.

History of anaphylaxis post-vaccination.
For all subjects:

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before Day 1 (Day -29 to Day 1) 
(for P-Fx and NP-Fx groups)/before the malaria challenge (for infectivity control 
subjects), or planned use during the study period.

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 Day 1 (for P-Fx and NP-Fx groups) or malaria challenge (for 
infectivity control subjects). For corticosteroids, this will mean prednisone 
20 mg/day, 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 anti-malarial effects (e.g., tetracyclines for 
dermatologic patients, sulfa for recurrent urinary tract infections, etc.).

Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period within seven days of Day 1 (for P-Fx and NP-Fx groups) or 
the malaria challenge (for infectivity control subjects).

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 HIV, HBsAg or HCV.

Planned travel to malaria endemic areas during the study period.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
42
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
43

History of any reaction or hypersensitivity that would prevent the subject from 
utilizing all of the following: chloroquine, atovaquone/proguanil, 
artemether/lumefantrine.

Current use of medications known to cause drug reactions that would prevent the 
subject from utilizing any of the following: chloroquine, atovaquone/proguanil, 
artemether/lumefantrine.

History of severe reactions to mosquito bites.

Acute disease and/or fever at the time of enrollment.

Fever is defined as temperature 37.5°C/99.5°F for oral, axillary or tympanic 
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.

Hepatomegaly, right upper quadrant abdominal pain or tenderness.

Any abnormal (clinically significant) baseline laboratory screening tests: ALT, AST, 
creatinine, hemoglobin, platelet count, total WBC, out of normal range.

Personal history of auto-immune disease.

Administration of immunoglobulins and/or any blood products during the period 
starting three months before Day 1 (for P-Fx and NP-Fx groups)/the malaria 
challenge (for infectivity control subjects), or planned administration during the 
study period.

Pregnant or lactating female.

Female planning to become pregnant or planning to discontinue contraceptive 
precautions.

History of chronic alcohol consumption and/or drug abuse.

History of blood donation within 56 days preceding enrollment.

Any other significant finding that in the opinion of the investigator would increase 
the risk of having an adverse outcome from participating in this study.

Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by physical examination or laboratory 
screening tests.

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 20-
35 years old [see APPENDIX 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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
43
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
44
Only for infectivity control subjects:

Previous vaccination against malaria.

History of splenectomy.

Family history of congenital or hereditary immunodeficiency.

Major congenital defects.

Serious chronic illness.

History of any neurological disorders or seizures (except for a single episode of 
simple febrile seizure in childhood).

Diagnosed with malaria within the last 5 years (inclusive).
6.
CONDUCT OF THE STUDY
6.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the International Conference on 
Harmonization (ICH) Guideline for Good Clinical Practice (GCP), all applicable subject 
privacy requirements and the guiding principles of the Declaration of Helsinki.
GSK will obtain favorable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favorable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written or witnessed/thumb printed informed consent must be obtained 
from each subject prior to participation in the study.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
44
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
45
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol and any other necessary 
documentation) by the IRB/IEC.
6.2.
Subject identification and randomisation
6.2.1.
Subject identification
Subject identification numbers will be the same as the ones assigned in the primary study 
MALARIA-092, with the exception that the identifying protocol number will be changed 
to reflect the new study, as applicable. New identification numbers will be generated for 
infectivity controls.
6.2.2.
Randomization of treatment
Randomization of supplies
The list of treatment numbers for the supplies is generated at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS) (Cary, NC, USA) by GSK Biologicals.
Treatment allocation to the subject
The treatment numbers will be allocated by dose. The allocation will be sequential in the 
order in which the subjects are vaccinated.
6.2.2.2.1.
Study group and treatment number allocation
The target is to enroll all subjects who were vaccinated and have undergone challenge in 
the MALARIA-092 study and who are willing to take part in this MALARIA-102 
booster study. A minimum of 40 subjects (20/vaccine group) are expected to be enrolled
in this study. However there may be more or fewer subjects who consent to join the 
study.
Subjects from the MALARIA-092 study will not be randomized but the treatment 
allocation will be done via a randomization system on internet (SBIR) to allow 
monitoring of vaccine storage and expiry dates.
Subjects from the infectivity control group will not be randomized and will not appear in 
SBIR; they will simply be registered in the eCRF database.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
45
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
46
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the study staff in charge of the vaccine administration will 
access SBIR. Upon providing the subject identification number, the randomisation
system will provide the treatment number to be used for the 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.
6.3.
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.
6.4.1.
Mosquito challenge
Subjects from the two vaccine groups (P-Fx and NP-Fx) 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 three weeks after vaccination (Day 22 [Visit 3]).
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.
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.
A subject with a minor illness but who does not have fever during the pre-challenge 
assessment may be challenged at the discretion of the investigator. If the subject is 
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
46
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
47
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 6 and 
Table 7, 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.
Parasite and mosquito strains
The 3D7 clone of P. falciparum is 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 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 Anopheles stephensi.
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 insectary of 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 
challenge model. Routinely, transient local allergic reactions (itching, rash) typical of 
mosquito bites occur at sites of the bites.
Determining parasitemia
Post-challenge, parasitemia will be determined by microscopy of Giemsa-stained thick 
blood films (smear) and PCR. 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.
Management of infected human subjects
The pre-patent period (period between infection with a parasite and the demonstration of 
the parasite in the body) for P. falciparum in man normally averages 9-12 days. In 
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
47
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
48
previous studies, the pre-patent period in controls varied from 7-18 days. The shortest 
reported pre-patent period in man is 5 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 the fifth day after their challenge (Day 27 [Visit 4]), subjects will be seen
and evaluated daily by a study investigator and blood will be drawn for blood smears and 
PCR 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. Additional PCR 
tests may also be performed at investigator discretion, but may not necessarily be run in 
real time.
Beginning on the ninth day post-challenge (Day 31 [Visit 8]), a group of hotel rooms in 
the local area of WRAIR will be reserved for malaria-challenged subjects. 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.
During the hotel phase, all challenged subjects will be assessed on a daily basis in an 
identical manner. An evaluation will be done ideally each morning (headache, muscle 
aches, etc.) and blood will be drawn for smear and PCR. There may be the rare occasion 
where subject assessment is done later in the day but every effort must be made for the 
assessment to be done in the morning. All challenged subjects will be instructed to check 
in with clinical staff by telephone call or texting or in-person each afternoon or evening 
during the hotel stay until they are positive for malaria. A member of the WRAIR staff 
will contact him/her and if they are not available during the time of contact. A telephone 
script will be used to guide the site staff during these contacts. 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 and PCR, 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 
nights (between Day 31 [Visit 8] to Day 40 [Visit 17], inclusive). 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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
48
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
49
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 and PCR every two days up 
to 28 days post-challenge (Days 42 [Visit 18], 44 [Visit 19], 46 [Visit 20], 48 [Visit 21] 
and 50 [Visit 22]). Exceptionally this can occur within 1 or 3 days if the subject cannot 
make the visit or for schedule conflicts. 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 42, 44, 46 and 48 (20, 22, 24 and 26 days post-challenge), but will be 
required to come to the clinic center at Day 50 (28 days post-challenge [Visit 22]). 
Telephone contact (spoken or written) 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 42, 44, 46 and 48 which fall upon a weekend.
Malaria treatment
During the evaluation of protective efficacy, as soon as a malaria infection is documented 
with a positive blood smear 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 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 (once a day for 
three consecutive days) or artemether/lumefantrine (Coartem) standard oral dosage of 
80 mg/480 mg (initial dose, additional dose 8 hours later, and then twice daily for the 
following two days) can be used to treat subjects.
The malaria strain used for challenge (P. falciparum strain 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 and loperamide (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 (once a day for three consecutive days), 
or artemether/lumefantrine (Coartem) standard oral dosage of 80 mg/480 mg (initial 
dose, additional dose 8 hours later, and then twice daily for the following two days).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
49
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
50
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 in secure 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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
50
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
51
6.5.
Outline of study procedures
Table 4
Study procedures for the P-Fx and NP-Fx groups
Epoch
Epoch 001
Epoch 002
Epoch 004
Equivalent timepoints based on MALARIA-092 study
M19
M20
M21
M26
Type of contact
(Visit #)
SCR #1
Visit 1
Visit 2
Visit 3
Visit 4 to 
Visit 21
Visit Par*
Visit 22
Visit 23
Timepoints
Day -90 to 
-1
Day 1
Day 8
Day 22
Day 27 to 
Day 48
Day 50
Day 190
Sampling timepoints
SCR1
Vacc
Post-vacc
DoC
Post-challenge
Informed consent
●
Check inclusion/exclusion criteria a
●
O
Check screening laboratory results b
●
Collect demographic data
●
Medical history
●
Physical examination
●
O #
O #
O #
O #
O #
O #
O #
Urine pregnancy test
●
●
●
Check contraindications to vaccination c
O
Pre-vaccination body temperature
●
Treatment number allocation
O
Recording of administered treatment number
●
Vaccine administration
●
Check contraindications to challenge c
O
Sporozoite challenge
●
Distribution of emergency notification card
O
Blood sampling for HIV, HCV and HBsAg (17 mL)
●
Blood sampling for assessment of parasitemia (blood smear) (~2 mL)
●**
●
Blood sampling for assessment of parasitemia (PCR) (~2 mL)
●**
●
Blood sampling for antibody determination (20 mL)
●
●e
●
●
●
Blood sampling for PBMCs and plasma repository (40 mL)
●
●e
●
●
●
●
Blood sampling for hematology/biochemical analysis (~7.5 mL) d
●
●
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
Distribution of diary cards
O
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
51
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
52
Epoch
Epoch 001
Epoch 002
Epoch 004
Equivalent timepoints based on MALARIA-092 study
M19
M20
M21
M26
Type of contact
(Visit #)
SCR #1
Visit 1
Visit 2
Visit 3
Visit 4 to 
Visit 21
Visit Par*
Visit 22
Visit 23
Timepoints
Day -90 to 
-1
Day 1
Day 8
Day 22
Day 27 to 
Day 48
Day 50
Day 190
Sampling timepoints
SCR1
Vacc
Post-vacc
DoC
Post-challenge
Return of diary cards
Of
Og
Diary card transcription by investigator
●
●
Recording of solicited AEs within 7 days post-vaccination
●
●
Recording of unsolicited AEs within 21 days post-vaccination
●
●
Recording of AEs post-challenge
●
●
●
●
Recording of SAEs and pregnancies
●
●
●
●
●
●
●
Recording of pIMDs and meningitis
●
●
●
●
●
●
●
Recording of SAEs related to study participation, or to a concurrent GSK 
medication/vaccine
●
●
●
●
●
●
●
●
Study conclusion
●
M = month; SCR #1 = screening for subjects from the MALARIA-092 study; Vacc = vaccination; DoC = day of challenge; HIV = human immunodeficiency virus; HCV = hepatitis C 
virus, HBsAg = hepatitis B surface antigen; PBMCs = peripheral blood mononuclear cells; AEs = adverse events; SAEs = serious adverse events; pIMDs = potential immune-
mediated diseases
Visit 5 = Day 28 / Visit 6 = Day 29 / Visit 7 = Day 30 / Visit 8 = Day 31 / Visit 9 = Day 32 / Visit 10 = Day 33 / Visit 11 = Day 34 / Visit 12 = Day 35 / Visit 13 = Day 36 / Visit 14 = 
Day 37 / Visit 15 = Day 38 / Visit 16 = Day 39 / Visit 17 = Day 40 / Visit 18 = Day 42 / Visit 19 = Day 44 / Visit 20 = Day 46
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
#History-directed physical examination
*A blood sample for biochemistry and hematology parameters will be collected the day of first parasitemia (between Visit 4 [Day 27] and Visit 21 [Day 48]).
**A blood sample for assessment of parasitemia (blood smear and PCR) will be collected daily for 14 days (from Day 27 [Visit 4] to Day 40 [Visit 17]) and then every two days for 9 
days (Day 42 [Visit 18], Day 44 [Visit 19], Day 46 [Visit 20], Day 48 [Visit 21] and Day 50 [Visit 22]). Exceptionally this can occur within 1 or 3 days if the subject cannot make the visit or 
for schedule conflicts. For subjects who develop malaria (positive blood smear), blood smear and PCR may be discontinued once the subject has three consecutive negative smears 
(separated by more than 12 hours) following initial treatment.
a Including a check of NHANES-I criteria and electrocardiogram [see APPENDIX C].
b The screening laboratory results (HIV, HCV, HBsAg, ALT, AST, creatinine, hemoglobin, leukocytes [WBC], platelets, and urine -HCG) must be checked during the screening 
activities and before vaccination.
c There is no specific section in the eCRF to record the contraindications. The absolute contraindications to administration of study vaccine or challenge have to be recorded in the AE 
or SAE section of the eCRF.
d Blood sampling for hematology and biochemistry analysis includes ALT, AST, creatinine, hemoglobin, leukocytes (WBC), and platelets.
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
52
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
53
e Blood sample might not be drawn at Visit 1 if this visit occurs less than one week after the screening visit, at the discretion of the investigator
f Return of diary cards for the collection of solicited AEs
g Return of diary cards for the collection of unsolicited AEs
Table 5
Study procedures for the InfectivityCtrl group
Epoch
Epoch 003
Epoch 004
Equivalent timepoints based on MALARIA-092 study
M20
M21
Type of contact
(Visit #)
SCR #2
Visit 3
Visit 4 to 
Visit 21
Visit Par*
Visit 22
Timepoints
Day -68 to 21
Day 22
Day 27 to 
Day 48
Day 50
Sampling timepoints
SCR2
DoC
Post-challenge
Informed consent
●
Check inclusion/exclusion criteria a
●
O
Check screening laboratory results b
●
Collect demographic data
●
Medical history
●
Physical examination
●
O#
O#
O#
O#
Urine pregnancy test
●
●
Check contraindications to challenge c
O
Sporozoite challenge
●
Distribution of emergency notification card
O
Blood sampling for HIV, HCV and HBsAg (17 mL)
●
Blood sampling for assessment of parasitemia (blood smear) (2 mL)
●**
●
Blood sampling for assessment of parasitemia (PCR) (~2 mL)
●**
●
Blood sampling for hematology/biochemical analysis (7.5 mL) d
●
●
●
●
Record any concomitant medications/vaccinations
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
Recording of AEs post-challenge
●
●
●
●
Recording of SAEs and pregnancies
●
●
●
●
Recording of SAEs related to study participation, or to a concurrent GSK medication/vaccine
●
●
●
●
●
Study conclusion
●
SCR #2 = screening for infectivity control subjects; DoC = Day of challenge; HIV = human immunodeficiency virus; HCV = hepatitis C virus, HBsAg = hepatitis B surface antigen; AEs
= adverse events; SAEs = serious adverse events
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
53
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
54
Visit 5 = Day 28 / Visit 6 = Day 29 / Visit 7 = Day 30 / Visit 8 = Day 31 / Visit 9 = Day 32 / Visit 10 = Day 33 / Visit 11 = Day 34 / Visit 12 = Day 35 / Visit 13 = Day 36 / Visit 14 = 
Day 37 / Visit 15 = Day 38 / Visit 16 = Day 39 / Visit 17 = Day 40 / Visit 18 = Day 42 / Visit 19 = Day 44 / Visit 20 = Day 46
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
#History-directed physical examination
*A blood sample for biochemistry and hematology parameters will be collected the day of first parasitemia (between Visit 4 [Day 27] and Visit 21 [Day 48]).
**A blood sample for assessment of parasitemia (blood smear and PCR) will be collected daily for 14 days (from Day 27 [Visit 4] to Day 40 [Visit 17]) and then every two days for 9 
days (Day 42 [Visit 18], Day 44 [Visit 19], Day 46 [Visit 20], Day 48 [Visit 21] and Day 50 [Visit 22]). Exceptionally this can occur within 1 or 3 days if the subject cannot make the visit or 
for schedule conflicts. For subjects who develop malaria (positive blood smear), blood smear and PCR may be discontinued once the subject has three consecutive negative smears 
(separated by more than 12 hours) following initial treatment.
a Including a check of NHANES-I criteria and electrocardiogram [see APPENDIX C].
b The screening laboratory results (HIV, HCV, HBsAg, ALT, AST, creatinine, hemoglobin, leukocytes [WBC], platelets, and urine -HCG) must be checked during the screening 
activities.
c There is no specific section in the eCRF to record the contraindications. The absolute contraindications to administration of study vaccine or challenge have to be recorded in the AE 
or SAE section of the eCRF.
d Blood sampling for hematology and biochemistry analysis includes ALT, AST, creatinine, hemoglobin, leukocytes (WBC), and platelets.
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
54
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
55
Whenever possible, the investigator should arrange study visits within the interval 
described in Table 6 and Table 7
Table 6
Intervals between study visits for the P-Fx and NP-Fx groups
Interval
Optimal length of interval*
Allowed interval**
Screening #1 Visit 1
1 to 90 days
-
Visit 1 Visit 2
7 days
6-8 days
Visit 1 Visit 3 (challenge)
21 days
21-28 days
Visit 3 Visit 22
28 days
21-35 days
Visit 22 Visit 23
140 days
126-154 days
*Whenever possible the investigator should arrange study visits within this interval.
**Subjects may not be eligible for inclusion in the Per-Protocol Set (PPS) for analysis of immunogenicity and efficacy if 
they make the study visit outside this interval.
Table 7
Intervals between study visits for the infectivity control group
Interval
Optimal length of interval*
Allowed interval**
Screening #2 Visit 3 (challenge)
1 to 90 days
-
Visit 3 Visit 22
28 days
21-35 days
*Whenever possible the investigator should arrange study visits within this interval.
**Subjects may not be eligible for inclusion in the PPS for analysis of immunogenicity and efficacy if they make the 
study visit outside this interval.
6.6.
Detailed description of study procedures
6.6.1.
Informed consent
The signed informed consent of the subject must be obtained before study participation. 
Refer to Section 6.1 for the requirements on how to obtain informed consent.
6.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 5.2 and 5.3 before 
enrollment and prior to Day 1 (for P-Fx and NP-Fx groups)/to the malaria challenge (for 
infectivity control group).
The check of inclusion and exclusion criteria will include an electrocardiogram and the 
check of NHANES I criteria (see APPENDIX C).
6.6.3.
Check screening laboratory results
Check the results of the 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.
WRAIR has an established process whereby an IRB-approved generic screening protocol 
is used to screen potential subjects managed by the WRAIR Clinical Trials Center. For 
infectivity controls, please refer to Section 5.1 (overview of the recruitment plan) for 
further information.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
55
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
56
6.6.4.
Collect demographic data
Record demographic data such as date of birth, sex, race and ethnicity 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 Day 1 (for P-Fx and NP-Fx groups)/to the malaria challenge (for 
infectivity control group) in the eCRF.
6.6.6.
Physical examination
Perform a physical examination of the subject, including assessment of oral 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 (screening) will be 
performed only if the subject indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the investigator or delegate.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
6.6.7.
Urine pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test at screening 
and at Day 1 (prior to any study vaccine administration). The study vaccine may only be 
administered if the pregnancy test is negative.
Note: Pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit.
All female subjects are also to have a urine pregnancy test prior to the sporozoite 
challenge. The sporozoite challenge may only be performed if the pregnancy test is 
negative.
6.6.8.
Check contraindications to vaccination
Contraindications to vaccination must be checked at the beginning of the vaccination 
visit. Refer to Sections 7.5 for more details.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
56
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
57
6.6.9.
Assess pre-vaccination body temperature
The oral body temperature of each subject needs to be measured prior to the study 
vaccine administration. If the subject has fever (fever is defined as temperature 
37.5°C/99.5°F regardless the location of measurement) on the day of vaccination, the 
vaccination visit will be rescheduled within the allowed interval for this visit (Table 6).
6.6.10.
Study group and treatment number allocation
Treatment number allocation will be performed as described in Section 6.2.2. The 
number of each administered treatment must be recorded in the eCRF.
6.6.11.
Study vaccine administration

After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly in the deltoid muscle of the non-
dominant arm (preferably), except, at the discretion of the investigator, if there are
tattoos, rashes, burns or other skin disorders which make the evaluation of AE(s) at 
the injection site impossible (refer to Section 7.3 for detailed description of the 
vaccine administration procedure). If the investigator or delegate determines that the 
subject’s health on the day of administration temporarily precludes vaccine 
administration, the visit will be rescheduled within the allowed interval for this visit 
(refer to Table 6).

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.
6.6.12.
Check contraindications to challenge
Contraindications to sporozoite challenge are to be checked for all subjects at the 
beginning of the challenge visit as described in Section 6.4.1.1.
6.6.13.
Sporozoite challenge
After completing the prerequisite procedures prior to challenge, all subjects will be 
challenged with malaria as outlined in Section 6.4.1.3.
6.6.14.
Distribution of emergency notification card
In addition to the subject card (refer to Section 9.7), upon entry into the challenge phase
of the study, all subjects will be issued an emergency notification card containing the 
subject’s name, details on the exposure to malaria and a 24-hour emergency telephone 
contact numbers for study investigators.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
57
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
58
6.6.15.
Sampling
Blood samples will be taken during certain study visits as specified in Section 6.5 List of 
Study Procedures.
For P-Fx and NP-Fx groups:

Blood sampling for assessment of antibody determination and serum repository
A volume of approximately 20 mL of whole blood (to provide at least 10 mL of 
serum) should be drawn from all subjects for each analysis of humoral immune 
response (anti-CS ELISA, anti-CS avidity, anti-HBs and serum repository) at each 
pre-defined timepoint. After centrifugation, serum samples should be kept at 
–20°C/–4°F or below until shipment. Refer to the SPM for more details on sample 
storage conditions.

Blood sampling for PBMC and plasma repository
A volume of approximately 40 mL of whole blood should be drawn at each pre-
defined timepoint for the purpose of the PBMC and plasma repository. The blood 
should be stored at room temperature until 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.
For all subjects:

Blood sampling for HIV, HCV and HBsAg
A volume of approximately 17 mL of whole blood should be drawn from all 
screened subjects to assess HIV, HCV and HBsAg status.

Blood sampling for assessment of parasitemia (blood smear and PCR)
A volume of approximately 4 mL should be drawn from all subjects at each pre-
defined timepoint for the assessment of parasitemia by blood smear and PCR. For 
subjects who develop malaria (positive blood smear), blood samples for smears and 
PCR may be discontinued once the subject has three consecutive negative smears
(separated by more than 12 hours) following initial treatment.

Blood sampling for hematology and biochemistry analysis
A volume of approximately 7.5 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).
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
58
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
59
6.6.16.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 7.6.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 7.7.
6.6.17.
Recording of AEs, SAEs, pregnancies and pIMDs

Refer to Section 9.3 for procedures for the investigator to record AEs, SAEs, 
pregnancies and AEs of specific interest (pIMDs and meningitis). Refer to Section 
9.4 for guidelines and how to report SAE, pregnancy and AE of specific interest 
reports to GSK Biologicals.

The subjects will be instructed to contact the investigator immediately should they
manifest any signs or symptoms they perceive as serious.
For the P-Fx and NP-Fx groups:

At the vaccination visit, diary cards will be provided to the subject. The subject will 
be instructed to measure and record the oral body temperature and any solicited 
local/general AEs (i.e., on the day of vaccination and during the next 6 days) or any 
unsolicited AEs (i.e., on the day of vaccination and during the next 20 days occurring 
after vaccination. The subject will 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 2 and Visit 3.

Any unreturned diary cards will be sought from the subject through telephone call(s) 
or any other convenient procedure.

The investigator or delegate will transcribe the collected information into the eCRF 
in English.
6.6.18.
Study conclusion
The investigator will:

Review data collected to ensure accuracy and completeness.

Complete the Study Conclusion screen in the eCRF.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
59
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
60
6.7.
Biological sample handling and analysis
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment). Samples will not be labelled with information that directly identifies the 
subject but will be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects will be asked to give a specific consent to allow GSK or a contracted 
partner to use the samples for future research. Future research will be subject to the 
laws and regulations in the United States and will only be performed once an 
independent Ethics Committee or Review Board has approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject.
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).
If additional testing is performed, the marker priority ranking given in Section 6.7.4 may 
be changed.
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
6.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the Per-Protocol analysis (See Section 11.5 for the 
definition of cohorts to be analyzed). The investigator must ensure that his/her personnel 
and the laboratory(ies) under his/her supervision comply with this requirement. However, 
when GSK Biologicals does not provide material for collecting and storing clinical 
samples, appropriate materials from the investigator’s site must be used. Refer to the 
Module on Clinical Trial Supplies in the SPM.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
60
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
61
6.7.2.
Biological samples
Table 8
Biological samples
Sample type
Sample type
Quantity
Timepoint
Study groups
Whole blood
Blood sampling for HIV, HCV and HBsAg
17 mL
Screening #1
P-Fx
NP-Fx
Screening #2
Infectivity control
Blood sampling for assessment of
parasitemia (blood smear and PCR)
4 mL
Visit 4 (Day 27)
Visit 5 (Day 28)
Visit 6 (Day 29)
Visit 7 (Day 30)
Visit 8 (Day 31)
Visit 9 (Day 32)
Visit 10 (Day 33)
Visit 11 (Day 34)
Visit 12 (Day 35)
Visit 13 (Day 36)
Visit 14 (Day 37)
Visit 15 (Day 38)
Visit 16 (Day 39)
Visit 17 (Day 40)
Visit 18 (Day 42)
Visit 19 (Day 44)
Visit 20 (Day 46)
Visit 21 (Day 48)
Visit 22 (Day 50)
All subjects
Blood sampling for antibody determination 
and serum repository
20 mL
Screening #1
Visit 1 (Day 1)**
Visit 3 (Day 22)
Visit 22 (Day 50)
Visit 23 (Day 190)
P-Fx
NP-Fx
Blood sampling for PBMC and plasma 
repository
40 mL
Screening #1
Visit 1 (Day 1)**
Visit 2 (Day 8)
Visit 3 (Day 22)
Visit 22 (Day 50)
Visit 23 (Day 190)
P-Fx
NP-Fx
Blood sampling for hematology and 
biochemistry analysis
7.5 mL
Screening #1
Visit 1 (Day 1)
Visit 2 (Day 8)
P-Fx
NP-Fx
Screening #2
Infectivity control
Visit 3 (Day 22)
Visit 22 (Day 50)
Visit Par*
All subjects
*Biochemistry and hematology parameters will be collected the day of first parasitemia (between Visit 4 [Day 27] and 
Visit 21 [Day 48]).
**Blood sample might not be drawn at Visit 1 if this visit occurs less than one week after the screening visit, at the 
discretion of the investigator
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
61
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
62
6.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis.
Serological assays for the determination of anti-CS antibodies will be performed by 
enzyme-linked immunosorbent assay (ELISA) at laboratories designated by GSK 
Biologicals using standardized and validated procedures.
Serological assays for the determination of anti-HBs antibodies will be performed by 
chemiluminescence enzyme immunoassay (CLIA) at GSK Biologicals’ laboratory using 
standardized and validated procedures.
Table 9
Assays for humoral immunity (antibody determination)
System
Component
Method
Kit/Manufacturer
Unit
Cut-off
Laboratory
Serum
Plasmodium 
falciparum.Circumsporozoite 
Protein.R32LR Ab.IgG
ELISA
In house
EU/mL
1.9
CEVAC
Serum
Plasmodium 
falciparum.Circumsporozoide 
Protein.R32LR Ab.IgG Avidity
ELISA
In house
%
Not 
applicable
CEVAC
Serum
Plasmodium falciparum.anti-C-
Term Circumsporozoide Ab.IgG
ELISA
In house
EPT
100
WRAIR
Serum
Plasmodium falciparum.anti-C-
Term Circumsporozoide Ab.IgG 
avidity
ELISA
In house
Avidity 
Index
Not 
applicable
WRAIR
Serum
Plasmodium 
falciparum.Circumsporozoite Full 
length(N+C-Terminal) 
Recombinant+NANP 
Protein+NVDP Protein Ab.IgG
ELISA
In house
1/DIL
Not 
applicable
WRAIR
Serum
Plasmodium falciparum.anti-full 
length Circumsporozoide Ab.IgG 
avidity
ELISA
In house
Avidity 
Index
Not 
applicable
WRAIR
Serum
Hepatitis B Virus.Surface Ab
(Total Ig)
CLIA
ADVIA Centaur 
anti-HBs2 
(Siemens 
Healthcare)
mIU/mL
6.2
GSK 
Biologicals*
Ab = antibody; Ig = immunoglobulin; ELISA = enzyme-linked immunosorbent assay; CEVAC = Center For 
Vaccinology; EPT = endpoint titer; WRAIR = Walter Reed Army Institute of Research; CLIA = chemiluminescence 
enzyme immunoassay
*GSK Biologicals laboratory refers to Clinical Laboratory Sciences (CLS) In Rixensart, Belgium; Wavre, Belgium.
Other assays on stored serum, PBMCs and plasma samples may be performed to 
investigate the safety and/or vaccine induced anti-malaria and hepatitis B immune 
responses.
The repository laboratory for serum samples will be GSK Biologicals’ clinical 
laboratories and for plasma and PBMC samples will be Precision Bioservices, Inc.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
62
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
63
Assessment of P. falciparum parasitemia will be performed by blood slide microscopy 
reading and real-time PCR at WRAIR, as applicable.
Table 10
Assessment of P. falciparum parasitemia
System
Component
Method
Unit
Laboratory
Whole blood
Plasmodium falciparum parasites*
Blood slide 
microscopy reading
Parasite/L
WRAIR
Whole blood
Plasmodium falciparum parasites*
Real-time PCR
Positive/negative
WRAIR
WRAIR = Walter Reed Army Institute of Research; PCR = polymerase chain reaction
*P. falciparum parasite count includes blood-stage parasites.
Hematology, biochemistry and screening tests (e.g., HIV, leukocytes) will be performed 
by different methods/assays at Quest Diagnostics, Inc., (all except pregnancy testing) and 
at the WRAIR (pregnancy testing).
Table 11
Hematology, biochemistry and screening tests
System
Component
Method
Scale
Laboratory
Serum
HIV-IgG + Ag (SER,GLR)
Immunoassay
Qualitative
Quest Diagnostics, Inc.
Serum
Hepatitis B Virus.Surface Ab
CLIA
Qualitative
Quest Diagnostics, Inc.
Serum
Hepatitis C virus Ab
Immunoassay
Qualitative
Quest Diagnostics, Inc.
Urine
-HCG*
Immunoassay
Qualitative
WRAIR
Whole blood
Hemoglobin
Not applicable
Quantitative
Quest Diagnostics, Inc.
Leukocytes (White Blood 
Cells)
Platelets
Serum
Alanine Aminotransferase
Not applicable
Quantitative
Quest Diagnostics, Inc.
Aspartate Aminotransferase
Creatinine
HIV = human immunodeficiency virus; IgG = immunoglobulin G; Ag = antigen; Ab = antibody; CLIA = 
chemiluminescence enzyme immunoassay; HCV = hepatitis C virus; -HCG = beta-human chorionic gonadotropin; 
WRAIR = Walter Reed Army Institute of Research
*Urinary pregnancy test
Additional exploratory testing on the vaccine and/or on the disease under study may be 
performed within the framework of the study if deemed necessary for accurate 
interpretation of the data or should such assay(s) become available at GSK. These assays 
may not be represented in the objectives/endpoints of the study protocol.
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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
63
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
64
6.7.4.
Biological samples evaluation
Immunological read-outs
Table 12
Immunological read-outs
Blood sampling timepoint
Study 
groups
Number of
subjects
Component
Components 
priority rank
Type of contact 
and timepoint
Sampling 
timepoint
Screening #1
Visit 1 (Day 1)
Visit 3 (Day 22)
Visit 22 (Day 50)
Visit 23 (Day 190)
Screening
Vaccination day
Challenge day
Post-challenge
Post-challenge
P-Fx
NP-Fx
40*
Anti-CS Ab
1
Anti-CS avidity index
2
Anti-C term Ab
3
Anti-C term avidity index
4
HBsAg Ab
5
CS = circumsporozoite; Ab = antibody; HBsAg = hepatitis B surface antigen
*A minimum of 20 subjects per group (P-Fx and NP-Fx) is anticipated
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analyzed according to priority ranking provided in Table 12.
Additional serological assays for the determination of anti-full length CS antibodies titers 
and avidity will be performed by ELISA at WRAIR following the same order as in the 
table above (i.e., determination of antibody titers before avidity).
Hematology/Blood chemistry
Table 13
Hematology/biochemistry read-outs
Blood sampling timepoint
Study groups
Number of
subjects
Component
Type of contact and 
timepoint
Sampling timepoint
Screening #1
SCR#1
P-Fx
NP-Fx
40**
HIV IgG + Ag
HBsAg Ab
HCV Ab
Hemoglobin
Leukocytes (WBC)
Platelets
ALT
AST
Creatinine
Screening #2
SCR#2
Infectivity control
24
Visit 1 (Day 1)
Visit 2 (Day 8)
Vaccination day
Post-vaccination
P-Fx
NP-Fx
40**
Hemoglobin
Leukocytes (WBC)
Platelets
ALT
AST
Creatinine
Visit 3 (Day 22)
Visit 22 (Day 50)
Visit Par*
Post-challenge
Post-challenge
All subjects
64
HIV = human immunodeficiency virus; IgG = immunoglobulin G; Ag = antigen; HBsAg = hepatitis B surface antigen;
Ab = antibody; HCV = hepatitis C virus; WBC = white blood cell; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase
*Biochemistry and hematology parameters will be collected the day of first parasitemia (between Visit 4 [Day 27] and 
Visit 21 [Day 48]).
**A minimum of 20 subjects per group (P-Fx and NP-Fx) is anticipated
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
64
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
65
Parasitemia
Table 14
Parasitemia read-outs
Blood sampling 
timepoint
Study groups
Number of 
subjects
Component
Components 
priority rank
Visit 4 (Day 27)
Visit 5 (Day 28)
Visit 6 (Day 29)
Visit 7 (Day 30)
Visit 9 (Day 32)
Visit 8 (Day 31)
Visit 10 (Day 33)
Visit 11 (Day 34)
Visit 12 (Day 35)
Visit 13 (Day 36)
Visit 14 (Day 37)
Visit 15 (Day 38)
Visit 16 (Day 39)
Visit 17 (Day 40)
Visit 18 (Day 42)
Visit 19 (Day 44)
Visit 20 (Day 46)
Visit 21 (Day 48)
Visit 22 (Day 50)
All subjects
64
Blood smear
1
PCR
2
PCR = polymerase chain reaction
In case of insufficient blood sample volume to perform assays for parasitemia 
assessment, samples will be analyzed according to priority ranking provided in Table 14.
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 
concentrations above 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.
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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
65
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
66
7.
STUDY VACCINE AND ADMINISTRATION
7.1.
Description of study vaccine
The candidate RTS,S/AS01 vaccine to be used has been developed and manufactured by 
GSK Biologicals.
The Quality Control Standards and Requirements for the candidate vaccine are described 
in separate Quality Assurance documents (e.g., release protocols, certificate of analysis) 
and the required approvals have been obtained.
The vaccine is labelled and packed according to applicable regulatory requirements.
Table 15
Study vaccine
Treatment 
name
Vaccine
name
Formulation
Presentation
Volume to be 
administered*
Number of 
doses
RTS,S/AS01E
(1/5th dose)
RTS,S
RTS,S=25µg
Lyophilized pellet 
in a glass vial
0.1 mL
1
AS01E
MPL=25µg; 
QS21=25µg; Liposomes
Liquid solution in 
a glass vial
MPL = Monophosphoryl lipid; QS-21 = Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc., a 
wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation)
*After reconstitution
7.2.
Storage and handling of study vaccine
The study vaccine must be stored at the respective label storage temperature conditions in 
a safe and locked place. Access to the storage space should be limited to authorized study 
personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccine.
Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 0.0°C to +8.0C/+32°F to +46°F (for 
+2°C to +8°C/+36°F to +46°F label storage condition) impacting investigational
medicinal products (IMPs) must be reported in the appropriate (electronic) temperature 
excursion decision form. 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.
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 vaccine.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
66
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
67
7.3.
Dosage and administration of study vaccine
In this study, the commercial presentation of RTS,S/AS01E will be used, i.e., a glass vial 
of lyophilized RTS,S antigen to be reconstituted with a glass vial of AS01E Adjuvant 
System. A full dose of RTS,S/AS01E (0.5 mL) contains 25 g of the RTS,S antigen and 
25 g of each immunostimulant MPL and QS-21.
From the reconstituted vaccine vial, 0.1 mL will be withdrawn to administer a Fx booster 
dose of RTS,S/AS01E.
Table 16
Dosage and administration
Type of contact 
and timepoint
Study group
Treatment name
Volume to be 
administered
Route
Site
Location
Laterality*
Visit 1
(Day 1)
P-Fx
NP-Fx
RTS,S/AS01E
(1/5th dose)
0.1 mL
IM
Deltoid
Non-
Dominant
IM: intramuscular
*The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the non-
dominant arm (e.g., in case of skin alterations due to tattoos, rashes, burns or other skin disorders subject to the 
discretion of the investigator), an injection in the dominant arm may be performed.
7.4.
Replacement of unusable vaccine
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 10% additional vaccine doses will be
supplied to replace those that are unusable.
7.5.
Contraindications to vaccination
The following event constitutes contraindications to administration of RTS,S/AS01E at 
that point in time; if this event occurs 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. The preferred location for 
measuring temperature in this study will be the oral cavity.

Subjects with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever can be administered the vaccine.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
67
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
68
7.6.
Concomitant medications/products and concomitant 
vaccinations
At each study visit, the investigator or delegate should question the subject about any 
medications/products taken and vaccinations received 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 during the period within seven days following Day 1 (Day 1 to Day 8)
and during the entire sporozoite challenge (Day 22 to Day 50).

Any concomitant vaccination administered in the period starting seven days before 
Day 1 and ending at the last study visit (Day -7 to Day 190).

Prophylactic medication (i.e., medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination) (for P-Fx and NP-Fx 
groups).
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 regardless the location of measurement). The preferred 
location for measuring temperature in this study will be the oral cavity.

Any concomitant medications/products/vaccines listed in Section 7.6.2.

Any concomitant medications/products/vaccines relevant to a SAE/pIMD to be 
reported as per protocol or administered at any time during the study period for the 
treatment of a SAE/pIMD. In addition, concomitant medications relevant to SAE(s)
and pIMD(s) 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 Per-Protocol 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 
Per-Protocol analysis. See Section 11.5 for cohorts to be analyzed:

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period.

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e., more than 14 days in total) during the study period. For corticosteroids, this will 
mean prednisone 20 mg/day, or equivalent. Inhaled and topical steroids are 
allowed.

Long-acting immune-modifying drugs administered at any time during the study 
period (e.g., infliximab).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
68
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
69

A vaccine not foreseen by the study protocol administered during the period starting 
seven days before dose and ending seven days after the dose of vaccine
administration*.
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.,
a pandemic) is organized by the public health authorities, outside the routine 
immunization program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Summary of Product 
Characteristics or Prescribing Information and according to the local governmental 
recommendations and provided a written approval of the Sponsor is obtained.
Although vaccination with routine recommended national vaccination such as with 
the influenza or pneumococcal vaccines will not lead to elimination, every effort 
should be made to have the vaccinations occurring either more than seven days 
before vaccination or more than seven days after vaccination.

Immunoglobulins and/or any blood products administered during the study period.

Drugs known to have anti-Plasmodium properties, used during the challenge period 
before identification of parasitemia.
7.7.
Intercurrent medical conditions that may lead to elimination 
of a subject from Per-Protocol analyses
For vaccinated subjects, at each study visit subsequent to the vaccination visit, it must be 
verified if the subject has experienced or is experiencing any intercurrent medical 
condition. If it is the case, the condition(s) must be recorded in the eCRF.
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 Per-Protocol set (PPS) for analysis of 
immunogenicity and efficacy if, 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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
69
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
70
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 they/the 
subject manifest any signs or symptoms they perceive as serious.
9.1.
Safety definitions
9.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Examples of an AE include:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study vaccine administration even 
though they may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
vaccine or a concurrent medication (overdose per se should not be reported as an 
AE/SAE).

Signs, symptoms temporally associated with study vaccine administration.

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e., invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 9.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
70
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
71
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 
study vaccination. These events will be recorded in the medical history section of the 
eCRF.
9.1.2.
Definition of a serious adverse event 
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalization or prolongation of existing hospitalization,
Note: In general, hospitalization signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalization are also considered AEs. If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity, OR
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza like illness, and accidental trauma (e.g., sprained ankle) 
which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
e.
Is a congenital anomaly/birth defect in the offspring of a study subject.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
71
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
72
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization.
9.1.3.
Solicited adverse events
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 17
Solicited local adverse events
Pain at injection site
Redness at injection site
Swelling at injection site
Solicited general adverse events
The following general AEs will be solicited:
Table 18
Solicited general adverse events
Fatigue
Fever
Gastrointestinal symptoms*
Headache
*Gastrointestinal symptoms include nausea, vomiting, diarrhea and/or abdominal pain.
Note: It is recommended that subjects measure and record the oral body temperature in 
the evening. Should temperature (including additional) measurements be performed at
other times of day, subjects will be instructed to record the highest temperature in the 
diary card.
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 Sections 9.1.1 and 9.1.2). Clinically significant abnormal laboratory 
findings or other abnormal assessments that are present at baseline and significantly 
worsen following the start of the study will also be reported as AEs or SAEs.
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
72
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
73
9.1.5.
Adverse events of specific interest
Potential immune-mediated diseases
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 aetiology. AEs that need to be recorded and 
reported as pIMDs include those listed in Table 19.
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e., pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.
Table 19
List of potential immune-mediated diseases
Neuro-inflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve neuropathy, 
including paralysis and paresis 
(e.g., Bell’s palsy).

Optic neuritis.

Multiple sclerosis.

Transverse myelitis.

Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other variants.

Acute disseminated 
encephalomyelitis, including 
site specific variants, e.g., non-
infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis.

Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome.

Demyelinating peripheral 
neuropathies including:
-
Chronic inflammatory 
demyelinating 
polyneuropathy,
-
Multifocal motor 
neuropathy,
-
Polyneuropathies 
associated with 
monoclonal gammopathy.

Narcolepsy.

Systemic lupus erythematosus 
and associated conditions.

Systemic scleroderma
(systemic sclerosis), including:
-
Diffuse scleroderma,
-
CREST syndrome.

Idiopathic inflammatory 
myopathies, including:
-
Dermatomyositis,
-
Polymyositis.

Anti-synthetase syndrome.

Rheumatoid arthritis and 
associated conditions including:
-
Juvenile idiopathic 
arthritis,
-
Still’s disease.

Polymyalgia rheumatica.

Spondyloarthropathies, 
including:
-
Ankylosing spondylitis,
-
Reactive arthritis (Reiter's 
syndrome),
-
Undifferentiated 
spondyloarthritis,
-
Psoriatic arthritis,
-
Enteropathic arthritis.

Relapsing polychondritis.

Mixed Connective Tissue 
disorder.

Gout.

Psoriasis.

Vitiligo.

Erythema nodosum.

Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis).

Lichen planus.

Sweet’s syndrome.

Localized scleroderma 
(Morphoea).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
73
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
74
Vasculitis
Blood disorders
Others

Large vessels vasculitis 
including:
-
Giant Cell Arteritis 
(Temporal Arteritis),
-
Takayasu's Arteritis.

Medium sized and/or small 
vessels vasculitis including:
-
Polyarteritis nodosa,
-
Kawasaki's disease,
-
Microscopic Polyangiitis,
-
Wegener's Granulomatosis 
(granulomatosis with 
polyangiitis),
-
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis or eosinophilic 
granulomatosis with 
polyangiitis),
-
Buerger’s disease 
(thromboangiitis obliterans),
-
Necrotizing vasculitis 
(cutaneous or systemic),
-
Anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type 
unspecified),
-
Henoch-Schonlein purpura 
(IgA vasculitis),
-
Behcet's syndrome,
-
Leukocytoclastic vasculitis.

Autoimmune hemolytic 
anemia.

Autoimmune 
thrombocytopenia.

Antiphospholipid syndrome.

Pernicious anemia.

Autoimmune aplastic anemia.

Autoimmune neutropenia.

Autoimmune pancytopenia.

Autoimmune 
glomerulonephritis 
including:
-
IgA nephropathy,
-
Glomerulonephritis 
rapidly progressive,
-
Membranous 
glomerulonephritis,
-
Membrano-
proliferative 
glomerulonephritis,
-
Mesangioproliferative 
glomerulonephritis,
-
Tubulointerstitial 
nephritis and uveitis 
syndrome.

Ocular autoimmune 
diseases including:
-
Autoimmune uveitis,
-
Autoimmune retinitis.

Autoimmune myocarditis.

Sarcoidosis.

Stevens-Johnson 
syndrome.

Sjögren’s syndrome.

Alopecia areata.

Idiopathic pulmonary 
fibrosis.

Goodpasture syndrome.

Raynaud’s phenomenon.
Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune hepatitis.

Primary biliary cirrhosis.

Primary sclerosing cholangitis.

Autoimmune cholangitis.

Inflammatory Bowel disease, 
including:
-
Crohn’s disease,
-
Ulcerative colitis,
-
Microscopic colitis,
-
Ulcerative proctitis.

Celiac disease.

Autoimmune pancreatitis.

Autoimmune thyroiditis 
(Hashimoto thyroiditis).

Grave's or Basedow’s 
disease.

Diabetes mellitus type I.

Addison’s disease.

Polyglandular 
autoimmune syndrome.

Autoimmune 
hypophysitis.
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the 
final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely.
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
74
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
75
Meningitis
For the further evaluation of the safety signal of meningitis in the investigational vaccine 
groups, all cases of meningitis occurring during the study will be reported as a SAE.
9.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
9.2.1.
Pregnancy
Female subjects who become pregnant after the vaccination will not receive the 
sporozoite challenge may continue the study for safety follow-up only, 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 an electronic pregnancy report.
The following should always be considered as SAE and will be reported as described in 
Sections 9.4.1 and 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 fetus after 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 fetus is 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 study vaccine will 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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
75
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
76
9.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
9.3.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
Only for the P-Fx and NP-Fx groups:
All AEs starting within 21 days following administration of the dose of study vaccine
(Day 1 to Day 21) must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related.
SAEs that are related to the study vaccine will be collected and recorded from the time of 
the receipt of study vaccine until the subject is discharged from the study.
For all subjects:
The time period for collecting and recording AEs post-challenge will begin at the first 
day of challenge (Day 22) up to 29 days post-challenge (Day 50).
The time period for collecting and recording AEs of specific interest (pIMDs and 
meningitis) will begin at Day 1 (for P-Fx and NP-Fx groups)/the first day of sporozoite 
challenge (Day 22) (for infectivity control group) and will end at the last study visit (Day 
190 for the P-Fx and NP-Fx groups/Day 50 for the infectivity control group). See Section 
9.4 for instructions on reporting of pIMDs.
The time period for collecting and recording SAEs will begin at Day 1 (for P-Fx and NP-
Fx groups)/the first day of sporozoite challenge (Day 22) (for infectivity control group) 
and will end at the last study visit (Day 190 for the P-Fx and NP-Fx groups/Day 50 for
the infectivity control group) for each subject. See Section 9.4 for instructions on 
reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from
Day 1 (for P-Fx and NP-Fx groups)/the first day of sporozoite challenge (Day 22) (for 
infectivity control group).
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e.,
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study (screening) until she/he is discharged 
from the study.
The time period for collecting and recording pregnancies will begin at Day 1 (for P-Fx 
and NP-Fx groups)/the first day of sporozoite challenge (Day 22) (for infectivity control 
group) and will end at the last study visit (Day 190 for the P-Fx and NP-Fx 
groups/Day 50 for the infectivity control group). See Section 9.4 for instructions on 
reporting of pregnancies.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
76
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
77
An overview of the protocol-required reporting periods for AEs, SAEs and pregnancies is 
given in Table 20.
Table 20
Reporting periods for collecting safety information
Event
Study 
Conclusion**
SCR*
V1
V3
V7
V22
V23
D1
D7
D21
D22
D30
D50
D190
Solicited local and 
general AEs post-
vaccination
Unsolicited AEs post-
vaccination
AEs post-challenge
SAEs (all, fatal, 
related)
Pregnancies
AEs of specific 
interest#
SAEs related to study 
participation or concurrent 
GSK medication/vaccine
SCR = screening; D = Day; V = Visit
*I.e., consent obtained.
**Visit applicable for all groups except for the infectivity control subjects (note that Day 50 is the study end for infectivity 
controls)
#pIMDs and meningitis
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 in Table 20. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study vaccine, the investigator will promptly notify the 
Study Contact for Reporting SAEs.
9.3.3.
Evaluation of adverse events and serious adverse events
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 vaccine or since 
the previous visit?”
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
77
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
78
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms.
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 21
Intensity scales for solicited symptoms
Adverse Event
Intensity 
grade
Parameter
Pain at injection site
0
None
1
Mild: Any pain neither interfering with nor preventing normal every day activities.
2
Moderate: Painful when limb is moved and interferes with every day activities.
3
Severe: Significant pain at rest. Prevents normal every day activities.
Redness at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fever*
Record temperature in °C/°F
Headache
0
Normal
1
Mild: Headache that is easily tolerated
2
Moderate: Headache that interferes with normal activity
3
Severe: Headache that prevents normal activity
Fatigue
0
Normal
1
Mild: Fatigue that is easily tolerated
2
Moderate: Fatigue that interferes with normal activity
3
Severe: Fatigue that prevents normal activity
Gastrointestinal 
symptoms (nausea, 
vomiting, diarrhea and/or 
abdominal pain)
0
Normal
1
Mild: Gastrointestinal symptoms that are easily tolerated
2
Moderate: Gastrointestinal symptoms that interfere with normal activity
3
Severe: Gastrointestinal symptoms that prevent normal activity
*Fever is defined as temperature 37.5°C / 99.5°F. The preferred location for measuring temperature in this study will 
be the oral cavity.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
78
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
79
The maximum intensity of local injection site redness and 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
The maximum intensity of fever will 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)
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
79
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
80
The normal ranges and toxicity grading for laboratory safety parameters used in this 
study are presented in Table 22.
Table 22
Toxicity grading scales for blood testing
Adverse event
Intensity grade
Intensity*
Hemoglobin (males)
Normal range
12.5 g/dL
1
< 12.5 but 11.0 g/dL
2
< 11.0 but 10.0 g/dL
3
< 10.0 g/dL
Hemoglobin (females)
Normal range 
11.5 g/dL
1
< 11.5 but 10.5 g/dL
2
< 10.5 but 9.5 g/dL
3
< 9.5 g/dL
Increase in leukocytes 
Normal range
10 799 cells/mm3
(WBC)
1
10 800 – 15 000 cells/mm3
2
15 001 – 20 000 cells/mm3
3
> 20 001 cells/mm3
Decrease in leukocytes 
Normal range
3200 cells/mm3
(WBC)
1
2500 - 3199 cells/mm3
2
1500 - 2499 cells/mm3
3
< 1500 cells/mm3
Decrease in platelets
Normal
140 000 cells/mm3
1
125 000 – 139 000 cells/mm3
2
100 000 – 124 000 cells/mm3
3
< 100 000 cells/mm3
Alanine aminotransferase 
Normal range
Below ULN (60 U/L for males; 40 U/L for females)
1
1.1 - 2.5 x ULN
2
2.6 – 5 x ULN
3
> 5 x ULN
Aspartate aminotransferase Normal range
Below ULN (40 U/L for males; 35 U/L for females
1
1.1 - 2.5 x ULN
2
2.6 – 5 x ULN
3
> 5 x ULN
Creatinine (males)
Normal range 
1.39 mg/dL
1
1.4 - 1.79 mg/dL
2
1.8 - 2.0 mg/dL
3
> 2.0 mg/dL
Creatinine (females)
Normal range
1.29 mg/dL
1
1.3 – 1.69 mg/dL
2
1.7 – 1.9 mg/dL
3
>1.9 mg/dL
ULN: upper limit of normal range
*Grading scale adapted from [FDA guidance for industry: toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials (September 2007)].
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
80
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
81
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.
9.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between study vaccine and the 
occurrence of each AE/SAE using clinical judgement. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e.,
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine(s)/product(s) cannot be determined the investigator should indicate the 
AE to be related to all products.
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccine will be considered and investigated. The investigator will also consult the 
Investigator’s Brochure to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
81
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
82
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 study vaccine?”
YES:
There is a reasonable possibility that the study vaccine contributed to the AE.
NO:
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine. There are other, more likely causes and 
administration of the study vaccine is not suspected to have contributed to the 
AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 9.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccine, if applicable.

Erroneous administration.

Other cause (specify).
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).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
82
26-SEP-2018

C O N FI D E N TI A L
2 0 9 0 0 3 ( M A L A RI A -1 0 2 B S T: 0 9 2)
Pr ot o c ol Fi n al V er si o n 2
2 6 -S E P -2 0 1 8
8 3
9. 4.
R e p orti n g of s eri o u s a d v er s e e v e nt s, pr e g n a n ci e s a n d ot h er 
e v e nt s
9. 4. 1.
Pr o m pt r e p orti n g of s eri o u s a d v er s e e v e nt s, pr e g n a n ci e s a n d 
ot h er e v e nt s t o G S K Bi ol o gi c al s
S A Es t hat occ ur i n t he ti me peri o d defi ne d i n Secti o n 9. 3 will be re p orte d pr o m ptl y  t o 
G S K wit hi n t he ti mefra mes descri be d i n Ta ble 2 3 , o nce t he i n vesti gat or deter mi nes t hat 
t he e ve nt meets t he pr ot oc ol defi niti o n of a S A E.
Pre g na ncies t hat occ ur i n t he ti me peri o d defi ne d i n Secti o n 9. 3 will be re p orte d pr o m ptl y  
t o G S K wit hi n t he ti mefra mes descri be d i n Ta ble 2 3 , o nce t he i n vesti gat or bec o mes 
a ware of t he pre g na nc y.
A Es of s pecific i nterest ( pI M Ds a n d me ni n gitis) t hat occ ur i n t he ti me peri o d defi ne d i n 
Secti o n 9. 3 will be re p orte d pr o m ptl y  t o G S K wit hi n t he ti mefra mes descri be d i n Ta ble 
2 3 , o nce t he i n vesti gat or deter mi nes t hat t he e ve nt meets t he pr ot oc ol defi niti o n of a A Es 
of s pecific i nterest .
T a bl e 2 3
Ti m efr a m e s f or s u b mitti n g s eri o u s a d v er s e e v e nt, pr e g n a n c y  a n d 
ot h er e v e nt s r e p ort s t o G S K Bi ol o gi c al s
T y p e of E v e nt
I niti al R e p ort s
F oll o w -u p of R el e v a nt I nf or m ati o n o n a 
Pr e vi o u s R e p ort
Ti m efr a m e
D o c u m e nt s
Ti m efr a m e
D o c u m e nt s
S A Es
2 4 h o urs* #
el ectr o nic Ex p e dit e d A dv ers e 
Ev e nts R e p ort
2 4 h o urs*
el ectr o nic Ex p e dit e d A dv ers e 
Ev e nts R e p ort
Pr e g n a nci es
2 w e eks*
el ectr o nic pr e g n a ncy r e p ort
2 w e eks*
el ectr o nic pr e g n a ncy r e p ort
A Es of s p ecific 
i nt er est ( pI M Ds 
a n d m e ni n gitis)
2 4 h o urs** #
el ectr o nic Ex p e dit e d A dv ers e 
Ev e nts R e p ort
2 4 h o urs*
el ectr o nic Ex p e dit e d A dv ers e 
Ev e nts R e p ort
*Ti m efr a m e all o w e d aft er r ec ei pt or a w ar e n ess of t h e i nf or m ati o n.
** Ti m efr a m e all o w e d o nc e t h e i nv esti g at or d et er mi n es t h at t h e ev e nt m e ets t h e pr ot oc ol d efi niti o n of a A E of s p ecific 
i nt er est.
#T h e i nv esti g at or will b e r e q uir e d t o c o nfir m r evi e w of t h e S A E/ A E of s p ecific i nt er est c a us ality by ticki n g t h e ‘r evi e w e d’ 
b ox i n t h e el ectr o nic Ex p e dit e d A dv ers e Ev e nts R e p ort wit hi n 7 2 h o urs of s u b missi o n of t h e S A E/ A E of s p ecific 
i nt er est.
9. 4. 2.
C o nt a ct i nf or m ati o n f or r e p orti n g s eri o u s a d v er s e e v e nt s ,
pr e g n a n ci e s a n d pI M D s
St u d y C o nt act f or Re p orti n g S A Es , pI M Ds a n d pre g n a ncies
Refer t o t he l ocal st u d y c o ntact i nf or mati o n d oc u me nt.
B ac k - u p St u d y C o nt act f or Re p orti n g S A Es, pI M Ds a n d pre g n a ncies
2 4/ 2 4 h o ur a n d 7/ 7 da y  a vaila bilit y:
G S K Bi ol o gic als Cli nic al S afet y & P h ar m ac o vi gil a nce
U S sites o nl y:
Fa x: 
 
C O N FI D E N TI A L
2 0 9 0 0 3 ( M A L A RI A- 1 0 2 B S T: 0 9 2)
Pr ot o c ol Fi n al V er si o n 2
1 9 2 8 9 c a a 4 a 6 6 7 5 9 c 3 7 d 7 c 5 a 4 2 c a 2f d 6 a 5 5 9 1 7f 5 6
8 3
2 6- S E P- 2 0 1 8
P P D

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
84
9.4.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
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.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.
9.4.4.
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
should be estimated by ultrasound examination and recorded in the pregnancy report.
9.4.5.
Reporting of AEs of specific interest to GSK Biologicals
Once a AE of specific interest (pIMD and meningitis) is diagnosed (serious or non-
serious) in a study subject, the investigator (or designate) must complete the information 
in the electronic Expedited Adverse Events Report WITHIN 24 HOURS after he/she 
becomes aware of the diagnosis. The report allows to specify that the event is a pIMD 
and whether it is serious or non-serious. 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 
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
84
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
85
information regarding a AE of specific interest, the report should still be completed 
within 24 hours. Once additional relevant information is received, the report should be 
updated WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the AE of specific 
interest causality by ticking the ‘reviewed’ box in the electronic Expedited Adverse 
Events Report within 72 hours of submission of the AE of specific interest.
Refer to Section 9.4.3.1 for back-up system in case the electronic reporting system does 
not work.
9.4.6.
Updating of SAE, pregnancy and AE of specific interest
information after removal of write access to the subject’s eCRF
When additional SAE, pregnancy or AE of specific interest information is received after
removal of the write access to the subject’s eCRF, new or updated information should be 
recorded on the appropriate paper report, with all changes signed and dated by the 
investigator. The updated report should be faxed to the Study Contact for Reporting 
SAEs (refer to the Sponsor Information) or to GSK Biologicals Clinical Safety and 
Pharmacovigilance department within the designated reporting timeframes specified in
Table 23.
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 safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the study vaccine and unexpected. The purpose of the 
report is to fulfil specific 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
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 23).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
85
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
86
All SAEs and AE of specific interest (pIMDs and meningitis) (serious or non-serious)
documented at a previous visit/contact and designated as not recovered/not resolved or 
recovering/resolving will be reviewed at subsequent visits/contacts until the last visit of 
the subject.
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 
30 days after vaccination/challenge, as applicable.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

With SAEs, AE of specific interest (pIMDs or meningitis) (serious or non-serious), 
or subjects withdrawn from the study as a result of an AE, until the event has 
resolved, subsided, stabilized, disappeared, or until the event is otherwise explained, 
or the subject is lost to follow-up.
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper/electronic 
Expedited Adverse Events Report and/or pregnancy report as applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognized follow-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 Report if applicable. Generally, the follow-up period does
not 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.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of a SAE/AE of 
specific interest (pIMDs and meningitis) should be recorded in Expedited Adverse Event 
Report of the subject’s eCRF (refer to Section 7.6).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
86
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
87
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 during 
the study duration.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
87
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
88
10.
SUBJECT COMPLETION AND WITHDRAWAL
10.1.
Subject completion
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study.
10.2.
Subject withdrawal
Withdrawals will not be replaced.
10.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol.
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subjects who do not return for
scheduled visits or follow-up.
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

SAE.

Unsolicited non-serious AE.

Solicited AE.

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/she has withdrawn consent, the 
investigator will document the reason for withdrawal of consent, if specified by the 
subject, in the eCRF.
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
88
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
89
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).
10.3.
Screen and baseline failures
Screening failures are defined as subjects who are withdrawn from the study after giving 
informed consent, but who do not meet the inclusion criteria. Reason for screening failure 
will be collected.
11.
STATISTICAL METHODS
11.1.
Primary endpoint

Occurrence of P. falciparum parasitemia (defined by a positive blood slide) 
following sporozoite challenge (in all study groups versus infectivity controls).
11.2.
Secondary endpoints
Efficacy

Time-to-onset of P. falciparum parasitemia (defined by a positive blood slide) 
following sporozoite challenge.
Immunogenicity

Anti-CS repeat region antibody concentrations at screening, Day 1, prior to challenge 
(Day 22), 28 days post-challenge (Day 50) and at study end (Day 190).

Anti-HBs Igtot antibody concentrations at screening, Day 1, prior to challenge 
(Day 22), 28 days post-challenge (Day 50) and at study end (Day 190).
Safety

Occurrence of solicited local and general AEs within 7 days after vaccination (day of 
vaccination and 6 subsequent days) in the booster vaccination groups.

Occurrence of unsolicited AEs up to 21 days after vaccination (day of vaccination 
and 20 subsequent days), according to the Medical Dictionary for Regulatory 
Activities (MedDRA) classification, in the booster vaccination groups.

Occurrence of AEs up to 29 days after challenge (day of challenge and 28
subsequent days), according to the MedDRA classification, in all study groups.

Occurrence of AEs of specific interest (potential immune-mediated diseases [pIMDs] 
and meningitis) from Day 1 up to study conclusion (Day 190), according to the 
MedDRA classification, in all study groups.

Occurrence of SAEs (all, fatal, related to investigational vaccine) during the whole 
study period (from screening up to study conclusion [Day 190]), according to the 
MedDRA classification, in all study groups.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
89
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
90

Occurrence of abnormal laboratory values at screening, Day 1, Day 8, Day 22, the 
day of first parasitemia and 28 days post-challenge (Day 50) for the booster 
vaccination groups; and at screening, Day 22, the day of first parasitemia and 28 
days post-challenge (Day 50) for the infectivity control subjects.
11.3.
Tertiary endpoints
Efficacy

Occurrence of P. falciparum parasitemia (defined by a positive blood slide) 
following sporozoite challenge (between study groups).

Time-to-onset of P. falciparum parasitemia (defined by a positive blood slide) 
following sporozoite challenge (between study groups).

Occurrence of P. falciparum parasitemia (defined by a positive PCR) following 
sporozoite challenge (between study groups).

Time-to-onset of P. falciparum parasitemia (defined by a positive PCR) following 
sporozoite challenge (between study groups).
Immunogenicity

Anti-CS repeat region IgG avidity index at Day 1, prior to challenge (Day 22), 28 
days post-challenge (Day 50) and at study end (Day 190).

Anti-full length CS protein IgG concentrations and anti-C-term IgG concentrations at 
Day 1, prior to challenge (Day 22), 28 days post-challenge (Day 50) and at study end 
(Day 190).

Anti-full length CS protein and anti-C-term IgG avidity at Day 1, prior to challenge 
(Day 22), 28 days post-challenge (Day 50) and at study end (Day 190).
11.4.
Determination of sample size
The target enrollment for the MALARIA-092 study was 130 vaccinated subjects 
(26/vaccine group) and up to 30 subjects (or 4-6 per day, depending on the expected 
number of days of challenge) in the infectivity control group. Approximately 20 subjects 
in each group were expected to undergo sporozoite challenge (100 vaccinated subjects 
overall). Based on past experience, an approximate 20% will refuse to participate in the 
booster study and there will be an approximate 20% drop-out rate in vaccinees for the 
booster study. With an assumed vaccine efficacy (VE) of 68% in the primary study, 
there will be a minimum of 20 subjects per group in this MALARIA-102 study. In 
addition, up to 24 infectivity control subjects will be newly enrolled for this study.
Assuming at least 19/20 controls and 6/20 vaccinees become positive (VE of 68%), the 
trial has 99% power to detect statistically significant vaccine efficacy of each of the 
vaccination groups over the infectivity controls (p-value < 0.05).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
90
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
91
The power to detect a statistically significant VE of each of the vaccination groups over 
the infectivity controls (p-value < 0.05) is presented in the table below:
Controls
(N)
Vaccines
(N)
Vaccine 
efficacy
(%)
Protected 
controls
(N)
Protected 
vaccinees
(N)
Power*
(%)
20
20
89
1
18
100
20
20
78
1
16
100
20
20
68
1
14
99.1
20
20
58
1
12
94.6
20
20
47
1
10
81.8
*Two independent proportions power analysis - Test statistic: Fisher exact test
11.5.
Cohorts for Analyses
11.5.1.
Enrolled Set
The Enrolled Set will include all screened subjects who provide informed consent and 
provide demographic and/or other baseline screening measurements, regardless of the 
subject’s randomization and vaccination status in the trial, and receive a subject ID (for 
infectivity control subjects).
11.5.2.
Intent-to-treat set
The Intent-To-Treat Set (ITTS) will include all subjects from the P-Fx and NP-Fx groups 
who received the Fx dose of study vaccine. All challenged infectivity controls will also 
be included and will be presented as a separate study group.
11.5.3.
Per-protocol set for analysis of immunogenicity and efficacy
The Per-Protocol Set (PPS) for analysis of immunogenicity and efficacy will include all 
subjects included in the ITTS who fulfilled all eligibility criteria and received the Fx dose 
according to protocol procedures, did not use any medication, vaccine or blood products 
forbidden by the protocol, did not report any underlying medical condition influencing 
the efficacy response, had available data concerning immunogenicity endpoint measures, 
and underwent P. falciparum challenge. This will include subjects for whom assay results 
are available for antibodies against at least one study vaccine antigen after Day 1.
11.5.4.
Adapted Per-Protocol Set for analysis of efficacy
The Adapted PPS for analysis of efficacy will include all subjects included in the ITTS
who fulfilled all eligibility criteria and received the Fx dose according to protocol 
procedures and underwent P. falciparum challenge.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
91
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
92
11.6.
Derived and transformed data
Immunogenicity:

A subject seropositive for anti-CS antibody will be a subject whose antibody 
concentration will be greater than or equal to the cut-off value (anti-CS 
1.9 EU/mL).

Seroprotection rate for anti-HBs antibody is defined as the percentage of subjects 
with antibody concentration greater than or equal to an established cut-off (anti-HBs 
10 mIU/mL).

The percentage of subjects seropositive/seroprotected and associated two-sided 95% 
Clopper-Pearson confidence intervals (CIs) will be computed by vaccine group for 
each available immunogenicity monitoring.

The geometric mean concentrations (GMC) calculations will be performed by taking 
the anti-log of the mean of the log transformations. Antibody concentrations below 
the cut-off of the assay will be given an arbitrary value of half the cut-off of the 
assay for the purpose of GMC calculation.

Handling of missing data:

For a given subject and a given immunogenicity measurement, missing or non-
evaluable measurements will not be replaced. Therefore, an analysis will 
exclude subjects with missing or non-evaluable measurements.
Reactogenicity (P-Fx and NP-Fx groups) and safety (all subjects):

Handling of missing data:

Subjects who missed reporting symptoms (unsolicited or concomitant 
medications) will be treated as subjects without symptoms (unsolicited or 
concomitant medications, respectively). In case of significant non-compliance of 
study procedures for reporting symptoms, the analysis plan will be reassessed to 
ensure more accurate reporting of study data by further analysis.

For a given subject and the analysis of solicited symptoms within 7 days post-
vaccination, missing or non-evaluable measurements will not be replaced. Therefore 
the analysis of the solicited symptoms based on the ITTS will include only 
vaccinated subjects for doses with documented safety data (i.e., symptom screen 
completed). More specifically the following rules will be used:

Subjects who documented the absence of a solicited symptom after the Fx dose 
will be considered not having that symptom after that dose.

Subjects who documented the presence of a solicited symptom after the Fx 
booster dose and fully or partially recorded daily measurement over the solicited 
period will be included in the summaries at the Fx dose and classified according 
to their maximum observed daily recording over the solicited period.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
92
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
93

Subjects who documented the presence of a solicited symptom after the Fx dose 
without having recorded any daily measurement will be assigned to the lowest 
intensity category at that dose (i.e., 37.5°C for fever or grade 1 for other 
symptoms).

Fx dose without symptom sheets documented will be excluded.

For analysis of unsolicited AEs, such as SAEs or AEs by primary MedDRA term, 
and for the analysis of concomitant medications, all subjects, as applicable, will be 
considered.
11.7.
Analysis of demographics
A study flow table (consort) will be generated to present the number of subjects screened, 
randomized, receiving the Fx dose and included in the PPS for analyses of 
immunogenicity and efficacy.
The analysis of demographics will be performed on the ITTS and on the PPS for analysis 
of immunogenicity and efficacy.
Demographic characteristics (age at booster vaccination in years for the vaccinated 
groups and at the time of the screening for the infectivity control group, gender, and race) 
will be summarized by group and overall using descriptive statistics:

Frequency tables will be generated for categorical variables such as race.

Mean, median, standard deviation (SD) and range will be provided for continuous 
data such as age.
Previous study group (i.e., in the MALARIA-092 study) will be tabulated.
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 PPS for analyses of immunogenicity and efficacy will be tabulated.

The number of withdrawn subjects will be tabulated according to the reason for 
withdrawal.
11.8.
Analysis of exposure
The number and percentage of subjects with vaccination will be summarized overall and 
by group for all study groups where a vaccination is part of the study procedure. The 
analysis of exposure will be performed on the ITTS.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
93
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
94
11.9.
Analysis of efficacy
The analysis of efficacy will be performed on the PPS for analysis of immunogenicity 
and efficacy.
Efficacy will be assessed by comparison of P. falciparum parasitemia incidence and 
time-to-onset of P. falciparum parasitemia after sporozoite challenge. The analysis of the 
primary objective will based on blood smears results; additional exploratory analyses will 
be performed based PCR results (tertiary objectives).
Vaccine efficacy (VE) 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. falciparum parasitemia 
incidence after challenge between each one of the study groups (P-Fx and NP-Fx) and the 
infectivity control group.
Kaplan-Meier analysis will be performed on time-to-onset of P. falciparum parasitemia, 
for comparisons between each one of the study groups (P-Fx and NP-Fx) and the 
infectivity control group, using the log-rank statistic.
The same methodology will be applied for the evaluation of the study groups (P-Fx vs. 
NP-Fx) versus each other. If there are sufficient evaluable subjects to draw some 
conclusions, descriptive analyses based on initial group assignment versus control will be 
performed.
All statistical tests will be two-tailed at 5% significance level.
Risk periods
For the analyses of time-to-onset of parasitemia (Kaplan-Meier and log-rank), time-at-
risk will start on first day of challenge. Time-at-risk will be censored on Visit 22 (Day 
50; 28 days post-challenge), drop-out date, start date of anti-malarial treatment or date 
meeting an endpoint, whichever occurs first. Time-at-risk will be calculated as: censor 
date – date challenge + 1.
For the analysis of proportion affected (relative risk), all subjects included in the PPS for 
analysis of immunogenicity and efficacy will be considered at risk of infection and no 
censoring or elimination will be applied for subjects not completing the entire protocol 
defined post-challenge follow-up (Day 50; 28 days post challenge).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
94
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
95
11.10.
Analysis of immunogenicity
The analysis of immunogenicity will be performed on the PPS for analysis of 
immunogenicity and efficacy.
For each group, at each timepoint where a blood sample is collected:

The percentage of subjects with seropositive levels of anti-CS (proportion of subjects 
with anti-CS antibody concentrations 1.9 EU/mL) with 95% CI will be determined 
at specified blood sampling timepoints. Anti-CS antibody concentrations will be 
summarized by GMC. Anti-CS antibody concentrations will be displayed using 
reverse cumulative curves (RCCs). Similar analysis will be performed for the anti-
full length CS protein (proportion of subjects with anti-CS antibody titers 200 
1/DIL) and anti-C-term antibodies (proportion of subjects with anti-CS antibody 
concentrations 100 Endpoint Titer).

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. Anti-HBs antibody concentrations will be summarized by 
GMC. Anti-HBs antibody concentrations will be displayed using RCCs.

Anti-CS, anti-full length CS protein and anti-CS avidity index will be summarized 
by mean, SD, median and quartile and box and whiskers plots will be generated.
11.11.
Analysis of safety
The analysis of safety will be performed on the ITTS.
For the P-Fx and NP-Fx groups:

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 21-day follow-up period after the booster Fx dose will be tabulated with exact
95% CI. 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 each individual solicited general AE (any grade, grade 3, any 
related, grade 3 related, resulting in medically attended visit) during the 7-day 
follow-up period (Days 1-7) after the booster Fx dose will be tabulated for each 
group, with exact 95% CI.

For fever (defined as temperature 37.5°C/99.5°F for oral, axillary or tympanic 
route), the number and percentage of subjects reporting fever by half degree (°C) 
cumulative increments during the first seven days (Days 1-7) after the booster Fx
dose will be tabulated. Similar tabulations will be performed for any fever with a 
causal relationship to vaccination and grade 3 (> 39.0°C) causally related fever. The 
maximum temperature reported over the 7-day follow-up period will be tabulated.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
95
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
96

The percentage of subjects reporting unsolicited AEs within 21 days (Days 1-21)
after the booster Fx dose 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 using concomitant medication (any medication, any 
antipyretic and any prophylactic medication, respectively) during the 7-day follow-
up period after vaccination will be summarized by group.
For all subjects:

The percentage of subjects reporting AEs during 29 days after the sporozoite 
challenge (Day 22-Day 50) 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 AEs of specific interest (meningitis and pIMDs) 
from Day 1 until last study visit (Day 190) (for P-Fx and NP-Fx groups)/from the 
day of challenge until last study visit (Day 50) (for infectivity control group), 
classified by MedDRA preferred term level, will be tabulated with exact 95% CI.

The percentage of subjects reporting SAEs (all, fatal, related) occurring from Day 1 
until last study visit (Day 190) (for P-Fx and NP-Fx groups)/from the day of 
challenge until last study visit (Day 50) (for infectivity control group), classified by 
the MedDRA preferred term level will be tabulated with exact 95% CI.

Subjects reporting pregnancies will be described.

The percentage of subjects reporting an AE or SAE leading to withdrawal from study
from Day 1 until last study visit (Day 190) (for P-Fx and NP-Fx groups)/from the 
day of challenge (for infectivity control group) until last study visit (Day 50), 
classified by MedDRA preferred term level, will be tabulated with exact 95% CI.

The percentage of subjects using concomitant medication during the entire 
sporozoite challenge (Days 22-50) will be summarized by group.

Biochemistry (ALT, AST and creatinine) and hematological (hemoglobin, WBC and 
platelets) laboratory values will be presented by visit according to toxicity grading 
scales and tabulated by group. The normal ranges and toxicity grading for laboratory 
safety parameters used in this study are presented in Table 22.
11.12.
Interpretation of analyses
All analyses performed during this study will be descriptive. The inferential analyses will 
not be considered confirmatory but rather used as an estimation of the probability that an 
effect is true.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
96
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
97
11.13.
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.
11.13.1.
Sequence of analyses
The analyses will be performed stepwise:

An interim analysis will be performed as soon as the results of the challenge phase 
will be available on data as clean as possible, including safety and immunogenicity 
results, if available. This analysis will be descriptive and performed on the Adapted 
PPS for analysis of efficacy. Results will be used to make a decision on future field 
trials.

When all the remaining data up to Day 190 will be available, the main analysis will 
be performed. An integrated clinical study report containing all data will be written 
and made available to the investigators.
If the data for exploratory assessments become available at a later stage, (an) additional 
analysis/analyses will be performed and results will be reported in a publication, if
applicable.
11.13.2.
Statistical considerations for interim analyses
A descriptive analysis to evaluate vaccine efficacy against infection of P. falciparum will 
be performed on the Adapted PPS for analysis of efficacy at the time of the interim 
analysis. Note that the main objective of the study linked to this endpoint will be analysed 
at the end of the study, on the PPS for analysis of immunogenicity and efficacy and can 
output different results.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
97
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
98
12.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled.
12.1.
Electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction 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 other items, the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
98
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
99
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form.
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. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report.
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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
99
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
100
12.5.
Posting of information on publicly available clinical trial 
registers and publication policy
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required timeframe, in compliance
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post-PCD and to have secondary endpoint 
disclosed at latest 12 months after the last subject last visit (LSLV) as described in the 
protocol.
GSK also aims to publish the results of these studies in searchable, peer-reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors.
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.
12.7.
Data Sharing
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non-GSK studies, to investigate further about the study product(s) and other 
product(s), and/or the disease/condition under investigation and related diseases and 
conditions.
13.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
100
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
101
14.
REFERENCES
Ballou WR, Sherwood JA, Neva FA, et al. Safety and efficacy of a recombinant DNA 
Plasmodium falciparum sporozoite vaccine. Lancet 1987; 8545: 1277-1281.
Centers for 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: 25 
April 2018)
Clement F, Dewar V, Van Braeckel E et al. Validation of an enzyme-linked 
immunosorbent assay for the quantification of human IgG directed against the repeat 
region of the circumsporozoite protein of the parasite Plasmodium falciparum. Malar J.
2012; 11:384.
EMA Guideline 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: 25 April 2018)
European Consensus Group on Hepatitis B Immunity. Are booster immunizations needed 
for lifelong hepatitis B immunity? Lancet. 2000; 355 (9203): 561-565.
FDA guidance for industry: toxicity grading scale for healthy adult and adolescent 
volunteers enrolled in preventive vaccine clinical trials (September 2007). 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/Vaccines/UCM091977.pdf (last access: 25 April 2018).
Malaria Vaccine Funders Group. Malaria Vaccine Technology Roadmap. 2013. 
http://www.who.int/immunization/topics/malaria/vaccine_roadmap/TRM_update_nov13.
pdf?ua=1 (last access: 25 April 2018).
Regules JA, Cicatelli SB, Bennett JW, Paolino KM, Twomey PS, et al. Fractional Third 
and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled 
Human Malaria Parasite Infection and Immunogenicity Study. J Infect Dis. 2016 Sep 1;
214 (5): 762-71.
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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
101
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
102
APPENDIX A
LABORATORY ASSAYS
Anti-CS antibody
Antibody concentrations against P. falciparum CS-repeat region will be measured at 
CEVAC by a standard ELISA methodology using plate adsorbed recombinant R32LR 
antigen, as described by. [Clement, 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 1.9 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.
Antibody titers and subclasses against full-length CS and the C-term of CS
Standardized procedures established in the Clinical Immunology Laboratory at WRAIR
to measure IgG antibodies against the full-length recombinant CS protein and the 
recombinant C-term of CS protein will be performed according to Standard Operating 
Procedures (SOPs) from the laboratory. Results are expressed in endpoint titer and the 
cut-off is set at 100.
Antibody IgG1, IgG2, IgG3 and IgG4 subclasses against the full-length recombinant CS 
protein and the recombinant C-term of CS protein will be performed using a Luminex 
assay according to SOPs from the laboratory. Results are expressed in Mean Fluorescent
Intensity and the cut-off is set at 50.
Avidity assays against CS repeat region, CS full length and C-term antigens
The anti-CS repeat region avidity assay uses NH4SCN to demonstrate the avidity of the 
antibodies in the assay, according to Standard Operating Procedures (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 (NH4SCN 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 
concentration under chaotropic reagent/anti-CS repeat region concentration without 
chaotropic reagent) is calculated and reported.
The avidity assay against full length CS protein and C-term uses 4M urea as chaotropic 
reagent and the result is also reported as avidity index % (anti-CSP full length 
concentration under chaotropic reagent/anti-CS protein full length concentration without 
chaotropic reagent and anti-C-term concentration under chaotropic reagent/anti-C-term 
titer without chaotropic reagent, respectively).
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
102
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
103
Blood smear and PCR testing for assessment of P. falciparum parasitemia
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.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
103
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
104
APPENDIX B
CLINICAL LABORATORIES
Table 24
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biological’s Clinical 
Laboratory Sciences, Rixensart
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart – Belgium
GSK Biological’s Clinical 
Laboratory Sciences, Wavre-Nord 
Noir Epine
Avenue Fleming, 20 - B-1300 Wavre - Belgium
Table 25
Outsourced laboratories
Laboratory
Address
CEVAC - University of Gent
De Pintelaan, 185 Gent
Belgium
Division of Malaria Vaccine 
Development - WRAIR
Walter Reed Army Institute of Research
Silver Spring, MD 20910, United States
Precision Bioservices, Inc.
8425 Progress Drive
Frederick, MD 21701, United States
Quest Diagnostics, Inc.
1901 Sulphur Spring Road
Baltimore, MD 21227, United States
Q2 Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355
United States
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
104
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
105
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 (ECG)
12-lead ECG taken?  Y / N
If not, reason___________________________________________________________
Electrocardiogram interpreted by:
__________________________________________________
Electrocardiogram interpretation:
__________________________________________________
Only volunteers with NHANES I low risk criteria as well as non-significant ECG, as 
determined by expert consultant cardiologist, are accepted in the study.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
105
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
106
Table A (for Males)
Note: Subjects aged between 18 and 35 years will be assessed as if they are 35 (the 
minimum age covered by the NHANES criteria/tables). While this process likely over-
estimates (minimally) the cardiac risk of these young subjects, the only associated effect 
would be eliminating a healthy volunteer than including a cardiac risk.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
106
26-SEP-2018

CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
26-SEP-2018
107
Table B (for Females)
Note: Subjects aged between 18 and 35 years will be assessed as if they are 35 (the 
minimum age covered by the NHANES criteria/tables). While this process likely over-
estimates (minimally) the cardiac risk of these young subjects, the only associated effect 
would be eliminating a healthy volunteer than including a cardiac risk.
 
CONFIDENTIAL
209003 (MALARIA-102 BST:092)
Protocol Final Version 2
19289caa4a66759c37d7c5a42ca2fd6a55917f56
107
26-SEP-2018