Reactogenicity, Safety and Immunogenicity Study of GlaxoSmithKline (GSK) Biologicals' Investigational Supra-seasonal Universal Influenza Vaccines - Inactivated (SUIVs) (GSK3816302A) in Healthy Adults
Phase: PHASE1
Conditions: Influenza, Human
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’Institut, 89
1330 Rixensart, Belgium
Primary study vaccine and 
number
!
GlaxoSmithKline (GSK) Biologicals’
investigational Supra-seasonal Universal
Influenza Vaccine (SUIV) - inactivated
(GSK3816302A)
Other study 
vaccines/products
!
GSK Biologicals’ quadrivalent split virion
influenza vaccine Fluarix Quadrivalent
!
Phosphate Buffered Saline (PBS)
eTrack study number and 
Abbreviated Title
207543 (FLU D-SUIV-ADJ-001)
EudraCT number
2017-001584-20
Investigational New Drug 
(IND) number
17602
Date of protocol
Final Version 1: 15 May 2017
Date of protocol amendment Amendment 1 Final: 24 October 2017
Amendment 2 Final: 16 March 2018
Amendment 3 Final: 07 December 2018
Amendment 4 Final: 11 July 2019
Title
Reactogenicity, safety and immunogenicity study of 
GlaxoSmithKline (GSK) Biologicals’ investigational 
supra-seasonal universal influenza vaccines -
inactivated (SUIVs) (GSK3816302A) in healthy 
adults.
Detailed Title
A Phase I/II, randomized, controlled, observer-blind, 
multi-center study to assess the reactogenicity, safety 
and immunogenicity of three GlaxoSmithKline (GSK) 
Biologicals’ investigational supra-seasonal universal 
influenza vaccines (SUIVs) (unadjuvanted or 
adjuvanted with AS03 or AS01) administered as a 1 or 
2-dose priming schedule followed by a booster dose 12
months post-primary vaccination in 18 to 39 year-old
healthy subjects.
Coordinating author
(Amended: 11 July 2019)
!
 Scientific Writer (Modis
Life Sciences for GSK Biologicals)
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PPD

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eTrack study number and 
Abbreviated Title
207543 (FLU D-SUIV-ADJ-001)
EudraCT number
2017-001584-20
Investigational New Drug 
(IND) number
17602
Detailed Title
A Phase I/II, randomized, controlled, observer-blind, 
multi-center study to assess the reactogenicity, safety 
and immunogenicity of three GlaxoSmithKline (GSK) 
Biologicals’ investigational supra-seasonal universal 
influenza vaccines (SUIVs) (unadjuvanted or 
adjuvanted with AS03 or AS01) administered as a 1 or 
2-dose priming schedule followed by a booster dose 12
months post-primary vaccination in 18 to 39 year-old
healthy subjects.
Contributing authors
(Amended: 11 July 2019)
!
, 
, 
,
Clinical Research & Development Leads
!
, 
, Lead
Statisticians
!
, Expert Statistician
!
, Stat Manager
!
, 
, Study
Delivery Leads
!
, 
, Clinical Trial
Supply Managers
!
, Clinical Read-out Team Lead
!
, Safety representative
!
, Oversight Data Manager
!
, 
, Global
Regulatory Affairs representatives
!
, 
, Global Patent
representatives
!
, 
, Pre-clinical
representatives
!
, 
, Clinical and
Epidemiology Project Leads
GSK Biologicals’ Protocol DS v 15.0
© 2017–2019 GlaxoSmithKline group of companies or its licensor.
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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PPD

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Protocol Amendment 4 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
207543 (FLU D-SUIV-ADJ-001)
EudraCT number
2017-001584-20
IND number
17602
Date of protocol amendment
Amendment 4 Final: 11 July 2019
Detailed Title
A Phase I/II, randomized, controlled, observer-blind, 
multi-center study to assess the reactogenicity, safety 
and immunogenicity of three GlaxoSmithKline 
(GSK) Biologicals’ investigational supra-seasonal 
universal influenza vaccines (SUIVs) (unadjuvanted 
or adjuvanted with AS03 or AS01) administered as a 
1 or 2-dose priming schedule followed by a booster 
dose 12 months post-primary vaccination in 18 to 39 
year-old healthy subjects.
Sponsor signatory
Frank Struyf
Clinical and Epidemiology Project Lead,
Supra-seasonal Influenza Vaccine
Signature
Date
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Protocol Amendment 4 Rationale
Amendment number:
Amendment 4
Rationale/background for changes:
Following review of the Day 85 interim analysis and the additional interim analysis 
performed on available immunogenicity data from Phase I subjects who had completed 
their Visit 10 (Month 14 + 28 days), the Sponsor made the decision not to pursue the 
clinical development of the investigational supra-seasonal influenza vaccine. Based on 
these interim analyses results, some assays will not be performed or developed as 
initially planned, either because limited or no response is expected to be observed, or 
because the assay results are no longer relevant in light of the decision not to pursue 
the development of the investigational supra-seasonal influenza vaccine based on the 
chimeric hemagglutinin technology.
The changes are as follows:

The cell-mediated immune response will not be assessed at Month 14 and later
timepoints. The blood sampling for cell-mediated immunity at Visit 12 (Month 26)
has been removed.

The hemagglutination inhibition assay (HI) will not be performed on the
inactivated influenza quadrivalent vaccine H1N1 component, cH11/1N1,
cH6/1N5, H5N8 and H1N1 swine flu strains. For cH5/1N1 and cH8/1N1 the HI
assay will only be performed until Visit 6 (Day 85).

The micro-neutralisation (MN) assay will only be performed for cH6/1N5 and
H1N1 until Visit 6 (Day 85). MN assay will not be performed for H5N8.

The anti-group 2 hemagglutinin (HA) stalk response by ELISA will not be
performed.

The immune response in terms of anti-neuraminidase antibodies will not be
assessed.

The passive transfer experiment in mice will not be performed for the Month 14
and Month 26 timepoints. The blood collection at Month 26 for passive transfer
has been removed.

The anti-H9 full length HA ELISA will not be performed.

Anti-stalk antibody functionality will not be further investigated, except for the
antibody-dependent cell-mediated cytotoxicity until the interim analysis at Day 85.

Occurrence of RT-PCR-confirmed influenza cases endpoint was removed.
In case samples have already been taken but not tested yet, they will be stored for 
future research.
In addition, the list of contributing authors has been updated.
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Protocol Amendment 4 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 GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all
applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about
the GSK Biologicals’ study vaccines/products 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 vaccines/products, and more generally about
his/her financial ties with the sponsor. GSK Biologicals will use and disclose the
information solely for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding
ownership interest and financial ties (including those of my spouse and dependent
children).

Agree to promptly update this information if any relevant changes occur during the
course of the study and for one year following completion of the study.

Agree that GSK Biologicals may disclose any information it has about such
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other
documents required by regulatory agencies for this study.
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eTrack study number and 
Abbreviated Title
207543 (FLU D-SUIV-ADJ-001)
EudraCT number
2017-001584-20
IND number
17602
Date of protocol amendment
Amendment 4 Final: 11 July 2019
Detailed Title
A Phase I/II, randomized, controlled, observer-
blind, multi-center study to assess the 
reactogenicity, safety and immunogenicity of three 
GlaxoSmithKline (GSK) Biologicals’ 
investigational supra-seasonal universal influenza 
vaccines (SUIVs) (unadjuvanted or adjuvanted with 
AS03 or AS01) administered as a 1 or 2-dose
priming schedule followed by a booster dose 12 
months post-primary vaccination in 18 to 39 year-
old healthy subjects.
Investigator name
Signature
Date
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut, 89
1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 8.4.2.
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SYNOPSIS
Detailed Title
A Phase I/II, randomized, controlled, observer-blind, multi-
center study to assess the reactogenicity, safety and 
immunogenicity of three GlaxoSmithKline (GSK) 
Biologicals’ investigational supra-seasonal universal influenza 
vaccines (SUIVs) (unadjuvanted or adjuvanted with AS03 or 
AS01) administered as a 1 or 2-dose priming schedule 
followed by a booster dose 12 months post-primary 
vaccination in 18 to 39 year-old healthy subjects.
Indication
Active immunization for the prevention of disease caused by 
influenza virus.
Rationale for the 
study and study 
design

Rationale for the study
Current seasonal influenza vaccines show good efficacy when 
they are well-matched with the circulating virus strains. 
However, influenza viruses constantly change their surface 
glycoproteins that are the targets of most immune responses, 
allowing them to escape pre-existing immunity, a process 
called antigenic drift. Therefore, seasonal influenza vaccines 
have to be reformulated and re-administered on an annual 
basis. In addition, novel viruses can appear at irregular 
intervals and cause influenza virus pandemics that can claim 
millions of lives.
Influenza A hemagglutinins (HAs) are phylogenetically 
divided into influenza A group 1 (H1, H2, H5, H6, H8, H9, 
H11, H12, H13, H16, H17 and H18) and influenza A group 2
(H3, H4, H7, H10, H14, and H15) based on sequence 
similarities. Protection from influenza viruses is usually 
correlated with antibodies that bind to the membrane distal 
head domain of the HA molecule, thereby blocking the virus 
from attaching to host cell receptors. However, the head 
domain has high plasticity and is the main site of antigenic 
drift.
The membrane proximal stalk domain of the HA is more 
conserved than the head domain and antibodies that target this 
domain have been shown to broadly neutralize influenza 
viruses across several subtypes. The stalk domain is immuno-
subdominant compared to the head domain and is therefore 
usually not targeted by the immune system following 
exposure to influenza virus vaccines [Krammer, 2016].
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The proposed approach of the GlaxoSmithKline (GSK) supra-
seasonal universal influenza vaccine (SUIV) is to circumvent 
the immunodominance of the head domain by sequential 
exposure of the immune system to chimeric HAs (cHAs) that 
pair the globular head region of an exotic (for example, avian) 
HA with the HA stalk of a currently circulating seasonal 
influenza virus. The purpose of this approach is to boost pre-
existing cross-reactive memory responses to the HA stalk 
without further boosting strain-specific responses against the 
head region of HA. This approach has previously provided 
good protection in mice [Goff, 2013a; Krammer, 2014a; 
Nachbagauer, 2016] and ferrets [Krammer, 2014b]. The use 
of adjuvants enhanced the induction of stalk-reactive 
antibodies in mice [Krammer, 2014a; Goff, 2013b]. Although 
the final formulation of SUIV is planned to be a trivalent 
vaccine containing three inactivated split virion cHA 
components (i.e. one from influenza A group 1 (H1), one 
from influenza A group 2 (H3) and one from influenza B), the 
Company will first assess monovalent SUIVs, each containing 
one inactivated split virion cHA antigen from influenza A 
group 1. It is expected that achieving the optimal immune 
response will require improvement of the immunogenic 
properties of the chimeric HAs. This will be assessed in this 
clinical study by comparing two adjuvanted formulations (i.e. 
a formulation adjuvanted with AS03 and a formulation 
adjuvanted with AS01) with the immunogenicity of a non-
adjuvanted formulation. These adjuvants were taken into 
consideration for inclusion in the investigational SUIVs as 
they are the most commonly used adjuvant systems in other 
GSK Biologicals’ vaccines (such as in the pandemic influenza 
vaccine, Pandemrix, which is adjuvanted with AS03A; and the 
malaria vaccine, Mosquirix, which is adjuvanted with AS01E).
An informative study performed by Nachbagauer et al.,
[Nachbagauer, 2014] demonstrated that human sera from 
subjects who had received an inactivated H5N1 vaccine were 
able to protect mice against challenge with an influenza virus 
expressing an unmatched HA head, but a similar HA stalk. 
This study supports the concept of a chimeric HA universal 
influenza vaccine based on re-focusing the immune response 
to the conserved stalk domain by sequential exposure to HAs 
with divergent globular head domains, but conserved stalk 
domains. It has also been demonstrated in mice that a 
chimeric HA-based vaccination regimen induced higher stalk 
antibody titers than the seasonal influenza vaccine.
 
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The stalk antibody responses were long lasting, cross-reactive 
to distantly related HAs and provided protection in vivo in a 
serum passive transfer / challenge model, which further 
support the development of a universal influenza virus 
vaccine candidate built on the chimeric HA technology 
platform [Nachbagauer, 2016].

Rationale for the study design
Approximately 470 subjects 18-39 years of age will be 
equally randomized in 10 different treatment groups to receive 
2 or 3 doses of a monovalent influenza A group 1
investigational SUIV or to receive an annual quadrivalent 
inactivated seasonal influenza vaccine. Each SUIV contains a 
split inactivated influenza virus expressing a chimeric HA 
with the same stalk domain (H1 stalk) at each dose, but a 
different exotic influenza A group 1 head. The antigen dose of 
15 g in each vaccine in this study is based on the standard 
antigen dose for inactivated seasonal influenza vaccines.
Although it is assumed that a minimum of two priming doses 
followed by at least one booster dose may be required to 
induce long-term protection, the use of the adjuvant could 
significantly improve the anti-stalk immune response and 
induce adequate response with only one dose, especially in 
adults that have been previously exposed to the conserved HA 
stalk domain by natural exposure or vaccination. In a recent 
study it has been shown that, in an adult population, anti-stalk 
antibodies are present at high titers pre-vaccination and that 
they are boosted after a single dose of Pandemrix (AS03-
adjuvanted pandemic H1N1) [Tete, 2016]. In this study, it was 
also demonstrated that these H1 HA stalk-specific antibodies 
had neutralizing activity and they were detected already at 
baseline (i.e. prior to vaccination). Vaccination resulted in a 
significant increase in HA stalk-specific neutralizing 
antibodies in the absence of hemagglutination inhibition (HI) 
activity. It was also shown that the avidity of the anti-H1 stalk 
response was 3-fold greater relative to the avidity of the anti-
HA head response to Pandemrix. Knowing that the H1N1pdm 
virus contained a novel HA head domain that was different 
from the pre-pandemic seasonal H1 virus, this paper provides 
rationale for testing, in adults who are likely to be already 
“primed”, a single SUIV dose, followed by a booster dose 14 
months later with a SUIV containing a different HA construct.
 
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Therefore, the vaccine regimen in the SUIV groups will 
consist of sequential primary intramuscular immunization 
with one dose (Day 1) or 2 doses (Day 1 and Day 57) 
followed by a booster dose at Month 14 of a vaccine 
containing split inactivated influenza virus expressing a 
chimeric HA with at each dose the same stalk domain (H1 
stalk) but a different exotic head. The SUIV vaccine will be 
adjuvanted with AS03A or AS01E or non-adjuvanted. The 
interval of two months between the two priming doses was 
selected to ensure optimal priming in a setting where the 
vaccine can be administered the whole year round without 
time pressure for completion of vaccination in contrast with a 
seasonal or pandemic influenza vaccination setting. The 
booster dose at Month 14 is anticipated to be necessary to 
obtain an adequate and persisting anti-stalk antibody response. 
In the control group, subjects will be administered one dose of 
Fluarix Quadrivalent inactivated influenza vaccine (IIV4) on 
Day 1 and then re-vaccinated at Month 14 with the next year’s 
formulation.
The main purpose of this study will be to assess the safety and 
the reactogenicity of each SUIV compared to IIV4. This study 
will also evaluate the adjuvant effect of AS03A and AS01E on 
the immune response when compared to the non-adjuvanted 
formulation. In addition, the immune response after 1 priming 
dose and after 2 priming doses will be evaluated, as well as 
the immune response after a booster dose given 14 or 12 
months after a one dose priming schedule or a 2-dose priming 
schedule, respectively. Since the vaccine sequence of the 
priming dose and the booster dose in the one dose-priming 
schedule groups varies, the effect of the chimeric HA vaccine 
sequence on the humoral immune response will also be 
assessed. Finally, the cell-mediated immune response and the 
protective effect in vivo of the anti-stalk antibodies will be 
explored. Passive surveillance will be put in place in order to 
capture the occurrence of influenza-like illnesses during the 
entire study period. (Amended: 11 July 2019)
Objectives
Primary

To assess the reactogenicity and safety of each vaccine 
dose throughout the entire study period, in all study 
groups.

To describe the anti-H1 stalk humoral immune response 
28 days after each priming dose (1 or 2 dose(s)) in all 
study groups.
 
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Secondary

To evaluate the adjuvant effect of AS03 and AS01 on the 
humoral immune response after 1 and 2 priming dose(s) 
of investigational SUIVs when compared to the non-
adjuvanted formulations.

To describe the persistence of the anti-H1 stalk humoral 
immune response after each priming dose (1 or 2 dose(s)) 
in all study groups up to Month 14.

To describe the humoral immune response after a booster 
dose at Month 14.

To describe the breadth of the humoral immune response 
after each vaccination in all study groups.

To describe the effect of the chimeric HA vaccination-
sequence on the humoral immune response.
Tertiary (Amended: 11 July 2019)

To explore the cell-mediated immune responses (B-cells 
and T-cells).

To explore the immune response against the HA head of 
cH5/1N1 and cH8/1N1 strain by hemagglutination 
inhibition (HI) assay.

To explore the protective effect of the stalk-reactive 
antibodies induced by vaccination in a passive transfer 
challenge experiment in mice.

To develop assays for evaluation/characterization of the 
humoral and cellular immune responses to the 
investigational vaccines.

To explore anti-stalk antibody functionality, e.g., 
antibody-dependent cell-mediated cytotoxicity (ADCC).
 
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Study design

Experimental design: Phase I/II, observer-blind, 
randomized, controlled, multi-centric study with 
10 parallel groups.

Duration of the study:

Epoch 001: Screening (Day -28 to -2) – only for 
Phase I subjects (refer to the Enrolment section
below).

Epoch 002: Primary starting at Visit 1 (Day 1) and 
ending at Visit 7 (Month 8).

Epoch 003: Booster starting at Visit 8 (Month 14) 
and ending at Visit 12 (Month 26).

Primary Completion Date (PCD): Visit 12 (Month 26).

End of Study (EoS): Last testing results released of 
samples collected at Visit 12 (Month 26).

Study groups: The study groups and epochs foreseen in 
this study are provided in Synopsis Table 1.
Synopsis Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects
Age (Min - Max)
Epochs
Epoch 002
Epoch 003
cH8/P/cH5-AS03
47
18 years – 39 years
x
x
cH5/P/cH8-AS03
47
18 years – 39 years
x
x
cH8/5/11-AS03
47
18 years – 39 years
x
x
cH8/P/cH5-AS01
47
18 years – 39 years
x
x
cH5/P/cH8-AS01
47
18 years – 39 years
x
x
cH8/5/11-AS01
47
18 years – 39 years
x
x
cH8/P/cH5
47
18 years – 39 years
x
x
cH5/P/cH8
47
18 years – 39 years
x
x
cH8/5/11
47
18 years – 39 years
x
x
IIV4
47
18 years – 39 years
x
x
 
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Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/Product 
name
Study groups
cH8/P/cH5-
AS03
cH5/P/cH8-
AS03
cH8/5/11-
AS03
cH8/P/cH5-
AS01
cH5/P/cH8-
AS01
cH8/5/11-
AS01
cH8/P/cH5
cH5/P/cH8
cH8/5/11
IIV4
cH8/1N1+AS03A-
like*
cH8/1N1
x
x
x
AS03
x
x
x
PBS
x
x
x
cH5/1N1+AS03A-
like*
cH5/1N1
x
x
x
AS03
x
x
x
PBS
x
x
x
cH11/1N1+AS03A-
like*
cH11/1N1
x
AS03
x
PBS
x
cH8/1N1+AS01E-
like#
cH8/1N1
x
x
x
AS01B
x
x
x
PBS
x
x
x
cH5/1N1+AS01E-
like#
cH5/1N1
x
x
x
AS01B
x
x
x
PBS
x
x
x
cH11/1N1+AS01E-
like#
cH11/1N1
x
AS01B
x
PBS
x
cH8/1N1
cH8/1N1
x
x
x
PBS
x
x
x
cH5/1N1
cH5/1N1
x
x
x
PBS
x
x
x
cH11/1N1
cH11/1N1
x
PBS
x
Fluarix 
Quadrivalent
FLU D-QIV
x
PBS
PBS
x
x
x
x
x
x
x
*AS03A-like is obtained by dilution of AS03 with PBS
# AS01E-like is obtained by dilution of AS01B with PBS
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
Control: active control (Fluarix Quadrivalent).

Vaccination schedule:

Two primary doses at Visit 1 (Day 1) and Visit 4 
(Day 57).

A booster dose at Visit 8 (Month 14).
Phase I subjects will be vaccinated one at the time, at 
least 60 minutes apart, with a maximum of 10 subjects a 
day. This is applicable for Dose 1 (Day 1), Dose 2 
(Day 57) and booster dose (Month 14). Dose 2 can only 
be provided to Phase I subjects upon favorable outcome 
of the 7-day post-Dose 1 safety data review by the IDMC 
of at least 60 Phase I subjects.

Treatment allocation: randomized (1:1:1:1:1:1:1:1:1:1 
ratio) using GSK Biologicals’ Randomization System on 
Internet (SBIR).

Blinding: see Synopsis Table 3.
Synopsis Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
Not applicable
Epoch 002
Observer-blind
Epoch 003
Observer-blind

Sampling schedule: (Amended: 11 July 2019)

Blood samples for safety assessment will be drawn 
from all subjects at all visits: Screening*, Days 1, 8, 
29, 57, 64, 85, Month 8, Month 14, Month 14 + 7 
days, Month 14 + 28 days, Month 20 and Month 26.
*Only for subjects enrolled in Phase I (refer to 
the Enrolment section below).

Blood samples for serology testing will be drawn 
from all subjects at Days 1 (Visit 1), 29 (Visit 3), 85
(Visit 6), Month 8 (Visit 7), Month 14 (Visit 8), 
Month 14 + 28 days (Visit 10), Month 20 (Visit 11) 
and Month 26 (Visit 12).

Blood samples for passive transfer experiment in 
animals will be drawn from all subjects at Days 1 
(Visit 1), 85 (Visit 6), Month 14 (Visit 8)*.
 
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
Blood samples for cell-mediated immunity (CMI) 
assessment will be drawn from a sub-cohort of 225
subjects at Days 1 (Visit 1), 8 (Visit 2), 29 (Visit 3), 
64 (Visit 5), 85 (Visit 6), Month 14 (Visit 8)*, Month 
14 + 7 days (Visit 9)*, and Month 14 + 28 days (Visit 
10)*. The sub-cohort will consist of the first Phase II 
subjects enrolled in pre-specified centers.

During the entire study period, nasal and throat swabs 
will be collected as soon as possible (preferably 
within 24 hours, but not later than 7 days) after the 
onset of an influenza-like illness (ILI) to test for 
influenza and/or other respiratory pathogens by RT-
PCR if deemed necessary, or stored for future 
research.
*Note that samples already collected for these
timepoints by the time of Protocol Amendment 4 
implementation at site will not be tested and will 
be stored, unless deemed necessary based on 
medical review of the cases.

ILI surveillance: ILI is defined as at least one of these 
systemic symptoms:

Temperature (oral) 37.8°C/98.6°F and/or,

Myalgia (widespread muscle ache);
AND at least one of these respiratory symptoms:

Cough and/or,

Sore throat.
Passive surveillance will be carried out from Visit 1 (after 
Dose 1) until the end of the study (Visit 12). Subjects will 
be instructed to contact the investigator/study staff as soon 
as they experience ILI symptoms.

Type of study: self-contained.

Data collection: electronic Case Report Form (eCRF).

Safety monitoring: an Independent Data Monitoring 
Committee (IDMC) consisting of clinical experts and a 
biostatistician, independent from the Sponsor, will review 
unblinded safety data (including laboratory assessment) at 
a regular frequency to monitor the safety of the subjects 
throughout the study.
 
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
Enrolment: the study will follow a staggered enrolment 
with 2 steps; the first being Phase I (N = 80) and the 
second being Phase II (N = 390):

Phase I: During the Phase I enrolment, subjects will 
be vaccinated one at a time, at least 60 minutes apart, 
with a maximum of 10 subjects per day until 80 
subjects are enrolled (i.e. to obtain treatment groups 
of at least 8 subjects/per group). If no safety issue is 
identified by the IDMC upon review of the 7-day 
post-dose 1 safety data (Days 1-7) of all Phase I 
subjects (N = 80), Phase II enrolment will be 
allowed to start.

Phase II: Subjects will be enrolled and vaccinated 
without limitation on the number of vaccinees per day 
or time between consecutive subjects.
Number of subjects
A total of 470 subjects (47 per group) are planned to be 
enrolled in this study, in order to have 430 evaluable subjects
for the primary immunogenicity endpoints.
Endpoints
Primary
Reactogenicity and safety

Occurrence of solicited local and general AEs after each 
vaccination:

Occurrence of solicited local AEs during a 7-day 
follow-up period (i.e. on the day of vaccination and 6 
subsequent days) after each vaccine dose, in all 
vaccine groups.

Occurrence of solicited general AEs during a 7-day 
follow-up period (i.e. on the day of vaccination and 6 
subsequent days) after each vaccine dose, in all 
vaccine groups.

Occurrence of unsolicited AEs after each vaccination:

Occurrence of unsolicited AEs during a 28-day 
follow-up period (i.e. on the day of vaccination and 
27 subsequent days) after each vaccine dose, in all 
vaccine groups.
 
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
Occurrence of hematological and biochemical laboratory 
abnormalities after each vaccination:

Any hematological (red blood cells, white blood cells 
and differential count, platelets count and hemoglobin 
level) or biochemical (alanine aminotransferase, 
aspartate aminotransferase, creatinine, blood urea 
nitrogen [BUN] and BUN-to-creatinine ratio) 
laboratory abnormality at each visit subsequent to 
Day 1, in all vaccine groups.

Occurrence of MAEs, pIMDs and SAEs:

Occurrence of MAEs, pIMDs and SAEs throughout 
the entire study period, in all vaccine groups.
Immunogenicity
Anti-H1 stalk immune response measured by ELISA and by 
MN assay 28 days after each priming dose:

Levels of anti-H1 stalk antibody titers by ELISA and by 
MN assay.
The following aggregate variables will be calculated for 
the above parameters with 95% confidence interval (CI):

Seropositivity rates and geometric mean titers 
(GMTs) at Days 1, 29 and 85.

Percentage of subjects with a 4-fold increase from 
Day 1 to Days 29 and 85.

Percentage of subjects with a 10-fold increase from 
Day 1 to Days 29 and 85.

Mean geometric increase (MGI) from Day 1 to Days 
29 and 85.
Secondary (Amended: 11 July 2019)
Immunogenicity
Adjuvant effect on the anti-stalk immune response in terms of:

GMT ratio for anti-stalk ELISA titer SUIV+AS03 or 
AS01/SUIV non-adjuvanted, 28 days post vaccination (i.e. 
at Day 29 to evaluate the adjuvant effect post-dose 1 and 
at Day 85 to evaluate the adjuvant effect post-dose 2).
 
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Anti-H1 stalk immune response measured by ELISA and by 
MN assay:

Levels of anti-H1 stalk antibody titers by ELISA post-
each vaccination.
The following aggregate variables will be calculated for 
the above parameters with 95% CI:

Seropositivity rates and GMTs at Days 1, 29, 85, 
Month 8, Month 14, Month 14 + 28 days, Month 20 
and Month 26.

Percentage of subjects with a 4-fold increase in 
antibody titers by ELISA from Day 1 to each 
subsequent timepoint listed above.

Percentage of subjects with a 10-fold increase in 
antibody titers by ELISA from Day 1 to each 
subsequent timepoint listed above.

MGI in antibody titers by ELISA from Day 1 to each 
subsequent timepoint listed above.

Levels of anti-H1 stalk antibody titers by MN assay.
The following aggregate variables will be calculated for 
the above parameters with 95% CI:

Seropositivity rates and GMTs at Days 1, 29 and 85.

Percentage of subjects with a 4-fold increase in 
antibody titers by MN assay from Day 1 to each 
subsequent timepoint listed above.

Percentage of subjects with a 10-fold increase in 
antibody titers by MN assay from Day 1 to each 
subsequent timepoint listed above.

MGI in antibody titers by MN assay from Day 1 to 
each subsequent timepoint listed above.
Breadth of the immune response:

Levels of anti-H2 and anti-H18 antibody titers by ELISA.
The following aggregate variables will be calculated for 
the above parameters with 95% CI:

Anti-H2 and anti-H18 seropositivity rates and GMTs 
at Days 1, 29, 85, Month 8, Month 14, Month 14 + 28 
days, Month 20 and Month 26.
 
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
Percentage of subjects with a 4-fold increase in 
anti-H2 and anti-H18 antibody titers from Day 1 to 
each subsequent timepoint listed above.

Percentage of subjects with a 10-fold increase in 
anti-H2 and anti-H18 antibody titers from Day 1 to 
each subsequent timepoint listed above.

MGI in anti-H2 and anti-H18 antibody titers from 
Day 1 to each subsequent timepoint listed above.

Levels of antibody titers by MN assay for H1N1 swine 
influenza and IIV4 H1N1 vaccine strains.
The following aggregate variables will be calculated for
the above parameters with 95% CI:

Seropositivity rates and GMTs at Days 1, 29 and 85.

Percentage of subjects with a 4-fold increase in 
antibody titers from Day 1 to each subsequent 
timepoint listed above.

Percentage of subjects with a 10-fold increase in 
antibody titers from Day 1 to each subsequent 
timepoint listed above.

MGI in antibody titers from Day 1 to each subsequent 
timepoint listed above.
Tertiary (Amended: 11 July 2019)

Evaluation of CMI parameters in terms of frequencies of:

Antigen-specific CD4+/CD8+ T-cells identified as 
producing at least two markers among CD40L, IL-2, 
TNF-and IFN-upon in vitro stimulation at Days 1, 
29 and 85.

B-memory cells reactive with the challenge antigen(s) 
at Days 1, 8, 29, 64 and 85.

Plasmablasts reactive with the challenge antigens at 
Days 1, 8 and 64.
 
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
Levels of HI antibody to chimeric vaccine strains cH5/1N1 
and cH8/1N1:
The following aggregate variables will be calculated with 
95% CI:

Seropositivity rates and GMTs at Days 1, 29 and 85.

Seroprotection rate (SPR) at each timepoint listed 
above.

Seroconversion rate (SCR) at Days 29 and 85.

MGI from Day 1 to each subsequent timepoint listed 
above.

Assessment of the in vivo protective effect of the anti-stalk 
antibodies when transferring Day 1 and Day 85 pooled 
serum from all evaluable subjects of each vaccine groups to 
mice that will be subsequently challenged with cH6/1N5*
or with H1N1 contained in the IIV4, using the following 
endpoints [refer to APPENDIX D]:

Survival over 14 days post-challenge (day of 
death/euthanasia for weight loss > 25% baseline body 
weight) in groups of 35 mice**/serum pool/vaccine 
group/timepoint.

Weight loss (change from baseline over 14 days post-
challenge) in groups of 35 mice**/serum pool/vaccine 
group/timepoint.

Lung virus titer in TCID50/mg (log10 fold change [Day 
1 minus Day 85]), within challenge group.

Pre- and post-transfer titer of human IgG to cH6/1N5*
by ELISA or HI.

Pre- and post-transfer titer of human IgG to H1N1 by 
ELISA or HI.

Pre- and post-transfer titer of human IgG to 
recombinant HA protein by ELISA.
*Or an alternative challenge virus with similar attributes but more fit 
for purpose.
**If sufficient serum volumes are not available, and depending on the 
challenge virus pathogenicity, the number of mice can be reduced to as 
low as 10 mice per timepoint and virus challenge.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................30
GLOSSARY OF TERMS ...............................................................................................33
TRADEMARKS .............................................................................................................38
1.
INTRODUCTION....................................................................................................39
1.1.
Background ................................................................................................39
1.2.
Rationale for the study and study design ....................................................39
1.2.1.
Rationale for the study.................................................................39
1.2.2.
Rationale for the study design......................................................41
1.3.
Benefit : Risk Assessment ..........................................................................42
1.3.1.
Risk Assessment .........................................................................42
1.3.2.
Benefit Assessment.....................................................................45
1.3.3.
Overall Benefit:Risk Conclusion...................................................45
2.
OBJECTIVES.........................................................................................................46
2.1.
Primary objectives ......................................................................................46
2.2.
Secondary objectives..................................................................................46
2.3.
Tertiary objectives (Amended: 11 July 2019) ..............................................46
3.
STUDY DESIGN OVERVIEW ................................................................................47
4.
STUDY COHORT...................................................................................................52
4.1.
Number of subjects/centers ........................................................................52
4.2.
Inclusion criteria for enrolment....................................................................53
4.3.
Exclusion criteria for enrolment...................................................................54
5.
CONDUCT OF THE STUDY ..................................................................................56
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................56
5.2.
Subject identification and randomization.....................................................57
5.2.1.
Subject identification....................................................................57
5.2.2.
Randomization of treatment.........................................................57
5.2.2.1.
Randomization of supplies..........................................57
5.2.2.2.
Treatment allocation to the subject.............................57
5.2.2.2.1.
Study group and treatment 
number allocation ...................................57
5.2.2.2.2.
Treatment number allocation for 
subsequent doses ..................................58
5.3.
Method of blinding ......................................................................................58
5.4.
General study aspects ................................................................................59
5.4.1.
Independent data monitoring committee ......................................59
5.4.2.
Influenza-like illness surveillance .................................................59
5.5.
Outline of study procedures ........................................................................60
 
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5.6.
Detailed description of study procedures ....................................................66
5.6.1.
Informed consent.........................................................................66
5.6.2.
Check inclusion and exclusion criteria .........................................66
5.6.3.
Collect demographic data ............................................................66
5.6.4.
Medical history.............................................................................66
5.6.5.
History of influenza vaccination....................................................67
5.6.6.
Physical examination ...................................................................67
5.6.7.
Pregnancy test.............................................................................67
5.6.8.
Check contraindications, warnings and precautions to 
vaccination...................................................................................67
5.6.9.
Assess pre-vaccination body temperature ...................................68
5.6.10.
Measure/record height and weight...............................................68
5.6.11.
Study group and treatment number allocation..............................68
5.6.12.
Sampling......................................................................................68
5.6.12.1.
Blood sampling for safety and immune 
response assessments...............................................68
5.6.12.2.
Nasal and throat sampling..........................................69
5.6.13.
Study vaccines/products administration .......................................69
5.6.14.
Surveillance for influenza-like illness and documentation 
of signs and symptoms ................................................................69
5.6.15.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................70
5.6.16.
Recording of AEs, MAEs, SAEs, pregnancies and pIMDs ...........70
5.6.17.
Study conclusion..........................................................................70
5.7.
Biological sample handling and analysis.....................................................71
5.7.1.
Use of specified study materials ..................................................72
5.7.2.
Biological samples.......................................................................72
5.7.3.
Laboratory assays .......................................................................72
5.7.4.
Biological samples evaluation......................................................78
5.7.4.1.
Immunological read-outs ............................................78
5.7.4.2.
Hematology/Blood Chemistry .....................................79
5.7.4.3.
Molecular biology .......................................................79
5.7.5.
Immunological correlates of protection.........................................80
6.
STUDY VACCINES/PRODUCTS AND ADMINISTRATION ...................................80
6.1.
Description of study vaccines/products.......................................................80
6.2.
Storage and handling of study vaccines/products .......................................83
6.3.
Dosage and administration of study vaccines/products...............................83
6.4.
Replacement of unusable vaccine/product doses .......................................85
6.5.
Contraindications to subsequent vaccination ..............................................86
6.6.
Warnings and precautions ..........................................................................86
6.7.
Concomitant medications/products and concomitant vaccinations..............87
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................87
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses............87
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from Per-Protocol analyses.............................................................88
7.
HEALTH ECONOMICS ..........................................................................................88
8.
SAFETY.................................................................................................................89
 
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8.1.
Safety definitions ........................................................................................89
8.1.1.
Definition of an adverse event......................................................89
8.1.2.
Definition of a serious adverse event ...........................................90
8.1.3.
Solicited adverse events..............................................................91
8.1.3.1.
Solicited local (injection-site) adverse events..............91
8.1.3.2.
Solicited general adverse events................................91
8.1.4.
Unsolicited adverse events ..........................................................92
8.1.5.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................92
8.1.6.
Adverse events of specific interest...............................................92
8.1.6.1.
Potential immune-mediated diseases .........................92
8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................94
8.2.1.
Pregnancy ...................................................................................94
8.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................95
8.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................95
8.3.2.
Post-study adverse events and serious adverse events...............98
8.3.3.
Evaluation of adverse events and serious adverse events...........98
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................98
8.3.3.2.
Assessment of adverse events...................................98
8.3.3.2.1.
Assessment of intensity..........................98
8.3.3.2.2.
Assessment of causality .......................100
8.3.3.3.
Assessment of outcomes..........................................101
8.3.3.4.
Medically attended events ........................................101
8.4.
Reporting of serious adverse events, pregnancies, and other events .......102
8.4.1.
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals..........................................102
8.4.2.
Contact information for reporting serious adverse events, 
pregnancies and pIMDs.............................................................102
8.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals .................................................................................103
8.4.3.1.
Back-up system in case the electronic 
reporting system does not work................................103
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals .................................................................................103
8.4.5.
Reporting of pIMDs to GSK Biologicals......................................104
8.4.6.
Updating of SAE, pregnancy, and pIMD information after 
removal of write access to the subject’s eCRF...........................104
8.4.7.
Regulatory reporting requirements for serious adverse 
events........................................................................................104
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies..............................................................................................105
8.5.1.
Follow-up of adverse events and serious adverse events..........105
8.5.1.1.
Follow-up during the study........................................105
8.5.1.2.
Follow-up after the subject is discharged from 
the study...................................................................105
8.5.2.
Follow-up of pregnancies...........................................................106
8.6.
Treatment of adverse events ....................................................................106
 
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8.7.
Subject card..............................................................................................106
8.8.
Holding rules and safety monitoring..........................................................106
8.8.1.
Holding rules..............................................................................107
8.8.2.
Safety monitoring.......................................................................109
9.
SUBJECT COMPLETION AND WITHDRAWAL...................................................110
9.1.
Subject completion ...................................................................................110
9.2.
Subject withdrawal....................................................................................110
9.2.1.
Subject withdrawal from the study .............................................110
9.2.2.
Subject withdrawal from study vaccines/products ......................111
9.3.
Extension study ........................................................................................111
9.4.
Screening failures.....................................................................................111
10. STATISTICAL METHODS....................................................................................112
10.1.
Primary endpoints.....................................................................................112
10.2.
Secondary endpoints (Amended: 11 July 2019)........................................113
10.3.
Tertiary endpoints (Amended: 11 July 2019).............................................114
10.4.
Determination of sample size....................................................................115
10.4.1.
Descriptive objectives ................................................................115
10.4.2.
Confirmatory objective ...............................................................117
10.5.
Analysis sets.............................................................................................118
10.5.1.
Exposed set...............................................................................118
10.5.2.
Per-Protocol set for analysis of immunogenicity.........................118
10.6.
Derived and transformed data...................................................................119
10.7.
Analysis of demographics.........................................................................119
10.8.
Analysis of safety......................................................................................120
10.9.
Analysis of immunogenicity.......................................................................121
10.9.1.
Within group assessment...........................................................121
10.9.1.1.
Humoral immunogenicity assessment ......................121
10.9.1.2.
CMI assessment.......................................................121
10.9.2.
Between group assessment.......................................................121
10.9.2.1.
ANCOVA modelling..................................................121
10.9.2.2.
Descriptive assessment............................................122
10.10. Interpretation of analyses..........................................................................123
10.11. Conduct of analyses .................................................................................123
10.11.1. Sequence of analyses................................................................123
10.11.2. Statistical considerations for interim analyses............................123
11. ADMINISTRATIVE MATTERS .............................................................................124
11.1.
electronic Case Report Form instructions .................................................124
11.2.
Study Monitoring by GSK Biologicals........................................................124
11.3.
Record retention .......................................................................................125
11.4.
Quality assurance.....................................................................................125
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ......................................................................................126
11.6.
Provision of study results to investigators .................................................126
11.7.
Data Sharing.............................................................................................126
12. COUNTRY SPECIFIC REQUIREMENTS.............................................................126
13. REFERENCES.....................................................................................................127
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................49
Table 2
Study groups and treatment foreseen in the study .................................50
Table 3
Blinding of study epochs ........................................................................51
Table 4
Sub-cohort (Amended: 11 July 2019).....................................................53
Table 5
List of study procedures for Phase I subjects (Amended: 11 July 
2019)......................................................................................................60
Table 6
List of study procedures for Phase II subjects (Amended: 11 July 
2019)......................................................................................................63
Table 7
Intervals between study visits.................................................................66
Table 8
Biological samples (Amended: 11 July 2019).........................................72
Table 9
Humoral immunity (Amended: 11 July 2019)..........................................74
Table 10
Cell-mediated immunity..........................................................................75
Table 11
Hematology/biochemistry.......................................................................76
Table 12
Molecular Biology (PCR tests)................................................................77
Table 13
Immunological read-outs for humoral immunity and cell-mediated 
immunity (Amended: 11 July 2019) ........................................................78
Table 14
Read-outs for hematology/blood chemistry ............................................79
Table 15
Read-outs for molecular biology tests (Amended: 11 July 2019)............79
Table 16
Study vaccines/products ........................................................................81
Table 17
Dosage and administration.....................................................................85
Table 18
Solicited local adverse events ................................................................91
Table 19
Solicited general adverse events............................................................91
Table 20
List of potential immune-mediated diseases...........................................93
Table 21
Reporting periods for collecting safety information .................................97
Table 22
Intensity scales for solicited symptoms...................................................99
Table 23
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals ...............................................102
 
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Table 24
Study holding rules...............................................................................108
Table 25
True proportions associated with a 90% probability to observe a 
certain number of adverse events within a group (45 subjects) ............115
Table 26
Two-sided exact 95% confidence intervals for the true adverse 
event rate at different possible observed adverse event rates (45 
subjects) ..............................................................................................116
Table 27
Two-sided exact 95% confidence intervals for the true 
immunological response rate at different possible observed 
response rates (43 evaluable subjects)................................................116
Table 28
Factorial study design: repartition of the subjects according to the 
nature of the priming sequence and to the type of adjuvant 
system .................................................................................................117
Table 29
Detectable fold increase in GMTs with 80% power (N/group = 
129, 2-sided alpha = 0.10, 1-way ANOVA power analysis)...................117
Table 30
Power to show a difference in means using a 1.5 superiority 
margin (N/pooled group = 129, 2-sided alpha = 0.055375)...................118
Table 31
GSK Biologicals’ laboratories ...............................................................133
Table 32
Outsourced laboratories.......................................................................133
Table 33
FDA toxicity grading scales for hematology/biochemistry 
parameters...........................................................................................136
 
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LIST OF FIGURES
PAGE
Figure 1
Study design overview ...........................................................................47
Figure 2
Probability of successfully completing the study in function of 
adverse events incidence rates............................................................109
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .....................................................................129
APPENDIX B CLINICAL LABORATORIES ................................................................133
APPENDIX C FDA GUIDANCE FOR INDUSTRY: TOXICITY GRADING 
SCALE FOR HEALTHY ADULT AND ADOLESCENT 
VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE 
CLINICAL TRIALS (SEPTEMBER 2007) .............................................134
APPENDIX D SERUM PASSIVE TRANSFER/VIRUS CHALLENGE 
EXPERIMENT IN BALB/C MICE FROM ADULT SUBJECTS 
INVOLVED IN THE FLU D-SUIV-ADJ-001 STUDY COHORT..............138
APPENDIX E AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................141
 
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LIST OF ABBREVIATIONS
AE:
Adverse Event
ALT:
Alanine aminotransferase
ANOVA:
Analysis of Variance
AS01:
Adjuvant System 01
AS03:
Adjuvant System 03
AST:
Aspartate aminotransferase
BUN:
Blood Urea Nitrogen
CD4/8/40L:
Cluster of Differentiation 4/8/40 Ligand
cHA:
Chimeric Hemagglutinin
CI:
Confidence Interval
CLS:
Clinical Laboratory Sciences
CMI:
Cell-Mediated Immunity
DIL:
Dilution
eCRF:
electronic Case Report Form
EDD:
Estimated Date of Delivery
EGA:
Estimated Gestational Age
ELISA:
Enzyme-linked immunosorbent assay
EoS:
End of Study
ES:
Exposed Set
eTDF:
electronic Temperature excursion Decision Form
EU/mL:
ELISA units per milliliter
FCB:
Flow Cytometry B-cells
FDA:
Food and Drug Administration, United States
GCP:
Good Clinical Practice
 
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GMT:
Geometric Mean Titer
GSK:
GlaxoSmithKline
HA:
Hemagglutinin
HI:
Hemagglutination Inhibition
IB:
Investigator’s Brochure
ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
ICS:
Intracellular Cytokine Staining
IDMC:
Independent Data Monitoring Committee
IEC:
Independent Ethics Committee
IFN-:
Interferon-gamma
IgG:
Immunoglobulin G
IIV4:
Quadrivalent inactivated influenza vaccine
IL-2:
Interleukin-2
ILI:
Influenza-Like Illness
IM:
Intramuscular
IMP:
Investigational Medicinal Product
IND:
Investigational New Drug
IRB:
Institutional Review Board
LMP:
Last Menstrual Period
MAE:
Medically Attended Event
MedDRA:
Medical Dictionary for Regulatory Activities
MGI:
Mean Geometric Increase
MN:
Microneutralization
NA:
Neuraminidase
 
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PBMC:
Peripheral Blood Mononuclear Cell
PBS:
Phosphate Buffered Saline
PCD:
Primary Completion Date
pIMD:
Potential Immune-Mediated Disease
PT:
Preferred Term
RNA:
Ribonucleic Acid
RT-PCR:
Reverse Transcription-Polymerase Chain Reaction
SAE:
Serious Adverse Event
SBIR:
Randomization System on Internet
SCR:
Seroconversion Rate
SD:
Standard Deviation
SDV:
Source Document Verification
SmPC:
Summary of Product Characteristics
SPM:
Study Procedures Manual
SPR:
Seroprotection rate
SUIV:
Supra-seasonal Universal Influenza Vaccine
TBD:
To Be Determined
TNF-:
Tumor Necrosis Factor-alpha
VAERD:
Vaccine-Associated Enhanced Respiratory Disease
 
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GLOSSARY OF TERMS
Adequate contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example:

Abstinence from penile-vaginal intercourse, when 
this is their preferred and usual lifestyle,

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:
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered 
related to the medicinal product.
An adverse event (AE) can therefore be any unfavorable
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal 
product. For marketed medicinal products, this also 
 
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includes failure to produce expected benefits (i.e. lack of 
efficacy), abuse or misuse.
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
trial, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a serious adverse 
event. In an observer-blind study, the subject and the site 
and sponsor personnel involved in the clinical evaluation 
of the subjects are blinded while other study personnel 
may be aware of the treatment assignment (see Section 
5.3 for details on observer-blinded studies).
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
End of Study (EoS):
(Synonym of End of Trial)
For studies 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 6.7.2
and 10.5 for details on criteria for evaluability).
 
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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.
Influenza-like illness 
(ILI):
ILI is defined as at least one of these systemic 
symptoms:

Temperature (oral) 37.8°C/98.6°F and/or,

Myalgia (widespread muscle ache);
AND at least one of these respiratory symptoms:

Cough and/or,

Sore throat.
Investigational 
vaccine/product:
(Synonym of 
Investigational Medicinal 
Product [IMP])
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.
Mean Geometric 
Increase:
Geometric mean of the fold increase in serum HI titers 
post-vaccination compared to Day 1.
Medically attended event:
An event for which the subject received medical 
attention defined as hospitalization, an emergency room 
visit or a visit to or from medical personnel (medical 
doctor) for any reason.
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 
 
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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.
Protocol amendment:
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: “A written description 
of (a) change(s) to or formal clarification of a protocol”. 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of 
subjects, scope of the investigation, study design, or 
scientific integrity of the study.
Randomization:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Self-contained study:
Study with objectives not linked to the data of another 
study.
Seroconversion rate:
The percentage of vaccinees with either a pre-
vaccination HI titer < 1:10 and a post-vaccination HI 
titer 1:40 or a pre-vaccination HI titer 1:10 and at 
least 4-fold increase in post-vaccination HI titer.
Seroprotection rate:
The percentage of vaccinees with serum HI titer 1:40; 
usually accepted as indicating protection in at least 50% 
of the vaccinees.
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.
Study vaccine/product:
Any investigational vaccine/product being tested and/or 
any authorized use of a vaccine/product/placebo as a 
 
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reference or administered concomitantly, in a clinical 
trial that evaluates the use of an investigational 
vaccine/product.
Sub-cohort:
A group of subjects for whom specific study procedures 
are planned as compared to other subjects or a group of 
subjects who share a common characteristic (e.g. ages, 
vaccination schedule,…) at the time of enrolment.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient 
of the vaccine(s)/product(s) or as a control.
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.
 
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TRADEMARKS
The following trademarks are used in the present protocol.
Note: In the body of the protocol (including the synopsis), the names of the 
vaccines/products will be written without the superscript symbol ™ or ® and in italics.
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
*Arepanrix
GSK’s licensed H1N1 AS03-adjuvanted 
pandemic vaccine
Fluarix
Seasonal influenza vaccine
Mosquirix
Malaria vaccine
**Pandemrix
GSK’s licensed H1N1 AS03-adjuvanted 
pandemic vaccine
*Arepanrix (H1N1) license expired in the European Union in December 2010
**Pandemrix (H1N1) license expired in the European Union in August 2015.
 
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1.
INTRODUCTION
1.1.
Background
Influenza viruses are enveloped negative-sense RNA viruses with a segmented genome 
belonging to the Orthomyxoviridae family. They are classified on the basis of their core 
proteins into three distinct types, A, B, and C. Influenza A and B viruses are primarily 
responsible for human disease, with type A being the most pathogenic. The main 
antigenic determinants of influenza A and B viruses are two surface glycoproteins: 
neuraminidase (NA) and hemagglutinin (HA), both capable of eliciting immune response 
in human beings [Cox, 1998].
Influenza viruses are a serious public health problem, and cause variable but often high 
rates of seasonal disease in the human population, with consequent significant morbidity 
and mortality. Uncomplicated influenza disease is characterized by the abrupt onset of 
constitutional and respiratory symptoms which usually resolve within a week. However, 
in vulnerable populations such as the elderly and children, influenza can aggravate 
existing medical conditions and potentially lead to life-threatening complications. During 
seasonal epidemics, 5-15% of the population is typically infected, resulting in 3-5 million 
cases of severe illness and a quarter to half a million excess deaths worldwide annually.
Most deaths associated with influenza in industrialized countries occur among people age 
65 years or older [WHO, 2016], although infection is most common in children [O'Brien, 
2004; Izurieta, 2000].
Annual influenza vaccination is currently the most effective means of controlling 
influenza and preventing its complications and mortality [WHO, 2016].
Please refer to the current Investigator’s Brochure (IB) for information regarding the pre-
clinical and epidemiological information for the investigational supra-seasonal universal 
influenza vaccines (SUIVs) and the adjuvants.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
Current seasonal influenza vaccines show good efficacy when they are well-matched 
with the circulating virus strains. However, influenza viruses constantly change their 
surface glycoproteins that are the targets of most immune responses, allowing them to 
escape pre-existing immunity, a process called antigenic drift. Therefore, seasonal 
influenza vaccines have to be reformulated and re-administered on an annual basis. In 
addition, novel viruses can appear at irregular intervals and cause influenza virus 
pandemics that can claim millions of lives.
 
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Influenza A HAs are phylogenetically divided into influenza A group 1 (H1, H2, H5, H6, 
H8, H9, H11, H12, H13, H16, H17 and H18) and influenza A group 2 (H3, H4, H7, H10, 
H14, and H15) based on sequence similarities. Protection from influenza viruses is 
usually correlated with antibodies that bind to the membrane distal head domain of the 
HA molecule, thereby blocking the virus from attaching to host cell receptors. However, 
the head domain has high plasticity and is the main site of antigenic drift.
The membrane proximal stalk domain of the HA is more conserved than the head domain 
and antibodies that target this domain have been shown to broadly neutralize influenza 
viruses across several subtypes. The stalk domain is immuno-subdominant compared to 
the head domain and is therefore usually not targeted by the immune system following 
exposure to influenza virus vaccines [Krammer, 2016].
The proposed approach of the GlaxoSmithKline (GSK) Biological’s investigational 
SUIV is to circumvent the immunodominance of the head domain by sequential exposure 
of the immune system to chimeric HAs (cHAs) that pair the globular head region of an 
exotic (for example, avian) HA with the HA stalk of a currently circulating seasonal 
influenza virus. The purpose of this approach is to boost pre-existing cross-reactive 
memory responses to the HA stalk without further boosting strain-specific responses 
against the head region of HA. This approach has previously provided good protection in 
mice [Goff, 2013a; Krammer, 2014a; Nachbagauer, 2016] and ferrets [Krammer, 2014b]. 
The use of adjuvants enhanced the induction of stalk-reactive antibodies in mice
[Krammer, 2014a; Goff, 2013b]. Although the final formulation of SUIV is planned to be 
a trivalent vaccine containing three inactivated split virion cHA components (i.e. one 
from influenza A group 1 (H1), one from influenza A group 2 (H3) and one from 
influenza B), the Company will first assess monovalent SUIVs, each containing one 
inactivated split virion cHA antigen from influenza A group 1. It is expected that 
achieving the optimal immune response will require improvement of the immunogenic 
properties of the chimeric HAs. This will be assessed in this clinical study by comparing 
two adjuvanted formulations (i.e. a formulation adjuvanted with AS03 and a formulation 
adjuvanted with AS01) with the immunogenicity of a non-adjuvanted formulation. These 
adjuvants were taken into consideration for inclusion in the investigational SUIVs as they 
are the most commonly used adjuvant systems in other GSK Biologicals’ vaccines (such 
as in the pandemic influenza vaccine, Pandemrix, which is adjuvanted with AS03A; and 
the malaria vaccine, Mosquirix, which is adjuvanted with AS01E).
An informative study performed by Nachbagauer et al., [Nachbagauer, 2014] 
demonstrated that human sera from subjects who had received an inactivated H5N1 
vaccine were able to protect mice against challenge with an influenza virus expressing an 
unmatched HA head, but a similar HA stalk. This study supports the concept of a 
chimeric HA universal influenza vaccine based on re-focusing the immune response to 
the conserved stalk domain by sequential exposure to HAs with divergent globular head 
domains, but conserved stalk domains. It has also been demonstrated in mice that a 
chimeric HA-based vaccination regimen induced higher stalk antibody titers than the 
seasonal influenza vaccine. The stalk antibody responses were long lasting, cross-reactive 
to distantly related HAs and provided protection in vivo in a serum passive transfer /
challenge model, which further support the development of a universal influenza virus
vaccine candidate built on the chimeric HA technology platform [Nachbagauer, 2016].
 
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1.2.2.
Rationale for the study design
Approximately 470 subjects 18-39 years of age will be equally randomized in 10 
different treatment groups to receive 2 or 3 doses of a monovalent influenza A group 1 
investigational SUIV or to receive an annual quadrivalent inactivated seasonal influenza 
vaccine. Each SUIV contains a split inactivated influenza virus expressing a chimeric HA 
with the same stalk domain (H1 stalk) at each dose, but a different exotic influenza A 
group 1 head. The antigen dose of 15 g in each vaccine in this study is based on the 
standard antigen dose for inactivated seasonal influenza vaccines.
Although it is assumed that a minimum of two priming doses followed by at least one 
booster dose may be required to induce long-term protection, the use of the adjuvant 
could significantly improve the anti-stalk immune response and induce adequate response
with only one dose, especially in adults that have been previously exposed to the 
conserved HA stalk domain by natural exposure or vaccination. In a recent study, it has 
been shown that, in an adult population, anti-stalk antibodies are present at high titers 
pre-vaccination and that they are boosted after a single dose of Pandemrix (AS03-
adjuvanted pandemic H1N1) [Tete, 2016]. In this study, it was also demonstrated that 
these H1 HA stalk-specific antibodies had neutralizing activity and they were detected 
already at baseline (i.e. prior to vaccination). Vaccination resulted in a significant 
increase in HA stalk-specific neutralizing antibodies in the absence of hemagglutination 
inhibition (HI) activity. It was also shown that the avidity of the anti-H1 stalk response 
was 3-fold greater relative to the avidity of the anti-HA head response to Pandemrix. 
Knowing that the H1N1pdm virus contained a novel HA head domain that was different 
from the pre-pandemic seasonal H1 virus, this paper provides rationale for testing, in 
adults who are likely to be already “primed”, a single SUIV dose, followed by a booster 
dose 14 months later with a SUIV containing a different HA construct.
Therefore, the vaccine regimen in the SUIV groups will consist of sequential primary 
intramuscular immunization with one dose (Day 1) or 2 doses (Day 1 and Day 57) 
followed by a booster dose at Month 14 of a vaccine containing split inactivated
influenza virus expressing a chimeric HA with at each dose the same stalk domain (H1 
stalk) but a different exotic head. The SUIV vaccine will be adjuvanted with AS03A or 
AS01E or non-adjuvanted. The interval of two months between the two priming doses 
was selected to ensure optimal priming in a setting where the vaccine can be administered 
the whole year round without time pressure for completion of vaccination in contrast with 
a seasonal or pandemic influenza vaccination setting. The booster dose at Month 14 is 
anticipated to be necessary to obtain an adequate and persisting anti-stalk antibody 
response. In the control group, subjects will be administered one dose of Fluarix 
Quadrivalent inactivated influenza vaccine (IIV4) on Day 1 and then re-vaccinated at 
Month 14 with the next year’s formulation.
 
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The main purpose of this study will be to assess the safety and the reactogenicity of each 
SUIV compared to IIV4. This study will also evaluate the adjuvant effect of AS03A and 
AS01E on the immune response when compared to the non-adjuvanted formulation. In 
addition, the immune response after 1 priming dose and after 2 priming doses will be 
evaluated, as well as the immune response after a booster dose given 14 or 12 months 
after a one dose priming schedule or a 2-dose priming schedule, respectively. Since the 
vaccine sequence of the priming dose and the booster dose in the one dose-priming 
schedule groups varies, the effect of the chimeric HA vaccine sequence on the humoral
immune response will also be assessed. Finally, the cell-mediated immune response and 
the protective effect in vivo of the anti-stalk antibodies will be explored. Passive 
surveillance will be put in place in order to capture the occurrence of influenza-like 
illnesses during the entire study period. (Amended: 11 July 2019)
1.3.
Benefit : Risk Assessment
Please refer to the current IB for the summary of potential risks and benefits of the 
investigational SUIVs and the Adjuvant Systems AS03 and AS01.
Please refer to the Prescribing Information for information regarding the summary 
potential risks and benefits of Fluarix Quadrivalent.
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: adjuvanted SUIV
Theoretical risk of 
acquiring a 
vaccine-induced 
autoimmune 
disease after 
vaccination
Theoretical safety concerns have 
arisen from studies in which 
adjuvants have induced 
autoimmune diseases in various 
animal models and from literature 
reports that diverse compounds 
with “adjuvant” activity could be 
associated with autoimmunity 
[Perricone, 2013].
Close monitoring of potential 
immune-mediated diseases (pIMDs) 
in clinical development programs 
using adjuvants systems. The 
potential risk of events of possible 
autoimmune etiology to occur is 
mentioned in the Informed Consent 
Form (ICF).
Subjects with a history or with a 
current diagnosis of an auto-immune 
disease will be excluded from this 
study.
 
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Important 
Potential/
Identified Risk
Data/Rationale for Risk
Mitigation Strategy
Influenza vaccines: Fluarix Quadrivalent and SUIVs
Anaphylaxis
Anaphylaxis reactions have been 
reported in people who had 
influenza vaccination. People 
allergic to any ingredients in Fluarix 
Quadrivalent or SUIV vaccines 
could have an allergic reaction to 
the vaccine. The viruses for the 
vaccine are grown in eggs; 
therefore, people allergic to eggs 
could have an allergic reaction to 
Fluarix Quadrivalent or SUIVs.
The investigators are advised of 
possible anaphylaxis following Fluarix 
Quadrivalent or SUIVs administration 
by information included in product 
label or IB.
As with all injectable vaccines, 
appropriate medical treatment and 
supervision should always be readily 
available in case of an anaphylactic 
event following the administration of 
the vaccine. Subjects will be closely 
monitored for at least 60 minutes 
(Phase I subjects) or 30 minutes 
(Phase II subjects) after vaccination. 
Subjects with history of any reaction 
or hypersensitivity likely to be 
exacerbated by any component of the 
vaccine, or anaphylaxis following the 
administration of influenza vaccine(s) 
will be excluded from the study.
Narcolepsy
Epidemiological data developed by 
organizations not associated with 
GSK suggest an increased risk of 
narcolepsy following vaccination 
with Pandemrix H1N1 in children 
and adolescents. Due to the 
methodological limitations of the 
studies, which are retrospective 
observational studies, further 
research is needed to determine 
whether the observed risk is related 
to the vaccine, environmental 
effects, genetic factors, other 
factors or a combination of factors. 
Arepanrix, another AS03-
adjuvanted vaccine produced in 
Quebec, Canada, with a slightly 
different H1N1 viral antigen 
manufacturing process, has not 
been associated with an increased 
risk of narcolepsy comparable to 
Pandemrix [Montplaisir, 2014].
Close monitoring of pIMDs in clinical 
development programs using 
adjuvants systems. The potential risk 
of events of possible autoimmune 
etiology to occur (like narcolepsy) is 
mentioned in the ICF.
Subjects with a history or with a 
current auto-immune disease will be 
excluded from this study.
 
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Important 
Potential/
Identified Risk
Data/Rationale for Risk
Mitigation Strategy
GSK considers narcolepsy to be a 
clear signal that requires further 
investigation, and continues to 
support both epidemiological and 
mechanistic studies.
No such risk has been identified in 
clinical trials of AS03-adjuvanted 
vaccines against other pandemic 
influenza antigens.
Study Procedures
Injection site 
hemorrhage in 
individuals with 
thrombocytopenia 
or any other 
coagulation 
disorder
Injection site hemorrhage may 
occur at the injection site in 
populations at increased risk of 
hemorrhage, such as those with 
thrombocytopenia or 
acquired/hereditary coagulation 
disorders.
The investigators are advised of 
possible injection site hemorrhage in 
individuals with thrombocytopenia or 
any coagulation disorder following 
study vaccine administration by 
information included in product labels 
or IB based on the following 
language in the company Core 
Safety Information: “As with other 
vaccines administered 
intramuscularly, all study vaccines 
should be given with caution to 
individuals with thrombocytopenia or 
any coagulation disorder since 
bleeding may occur following an 
intramuscular administration to these 
subjects.”
Syncope 
(fainting)
Syncope (fainting) can occur 
following or even before any 
vaccination as a psychogenic 
response to needle injection.
Vaccination will be done by a trained 
professional and procedures will be 
put in place to avoid injury from 
fainting.
Risk from blood 
sampling
Blood sampling-associated risk of 
discomfort, syncope, dizziness, 
infection at the site after or during 
venipuncture.
Blood samples will be obtained by a 
trained professional and medical 
assistance will be available.
The potential risk of feeling faint, or 
experiencing mild local pain, bruising, 
irritation or redness at the site where 
blood was taken, will be mentioned in 
the ICF. The amount of blood to be 
taken for sampling will not be harmful 
to the subject’s health.
 
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Vaccine-associated enhanced respiratory disease (VAERD) has been described in 
influenza-naïve pigs vaccinated with inactivated H1 influenza vaccine and subsequently 
challenged with an antigenically mismatched H1 virus [Vincent, 2008; Gauger, 2011]. 
Although VAERD is a reproducible observation under well-controlled laboratory 
conditions with pigs, it has never been observed in natural conditions or in other 
laboratory animal model used to study influenza viruses (i.e. mice and ferrets). VAERD 
has not been described with GSK Biologicals’ AS03-adjuvanted H5N1-pandemic 
vaccination. The latter is a relevant surrogate for the SUIV candidate since it elicits a 
robust immune response to the H1 HA stalk domain without inducing a strong serum 
neutralizing antibody response to A/H1N1pdm09 virus. Although VAERD is not 
considered as a potential safety risk in the current study, surveillance will be performed 
to capture all influenza like illnesses for the duration of the study.
In addition, all cases of respiratory illness, as any safety data, will be closely monitored 
by the Independent Data Monitoring Committee (IDMC). The theoretical risk of VAERD 
will be stated in the ICF.
1.3.2.
Benefit Assessment
Benefits considerations for the subjects include:

Contribution to the process of developing a universal influenza vaccine that would 
potentially provide protection against all influenza A and B strains.

Gaining information about their general health status through the medical 
evaluations/assessments associated with this study (i.e. physical examination, blood 
testing [hematology and biochemistry data]).

Subjects may have the benefit of being protected against seasonal influenza A and B 
if they are enrolled in the IIV4 group.

Subjects receiving one of the investigational monovalent influenza A group 1 SUIVs 
may potentially have the benefit of being protected against influenza A group 1 
viruses (e.g. H1, H5, H9 …). However, the efficacy of the investigational SUIVs has 
not yet been assessed.
1.3.3.
Overall Benefit:Risk Conclusion
It has been demonstrated in mice that the chimeric HA-based vaccination regimen with 
investigational SUIVs similar as the ones used in this study induced higher stalk antibody 
titers than the seasonal influenza vaccine. The stalk antibody responses were long lasting, 
cross-reactive to distantly related HAs and provided protection in vivo in a serum passive 
transfer challenge mouse model [Nachbagauer, 2016]. The investigational SUIVs are 
currently in a very early stage of clinical development and no vaccine efficacy has been 
demonstrated in humans. Taking into account the measures taken to minimize risk to
subjects participating in this study, the potential risks identified in association with the 
SUIVs are justified by the potential benefits linked to the development of the SUIV.
 
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2.
OBJECTIVES
2.1.
Primary objectives

To assess the reactogenicity and safety of each vaccine dose throughout the entire 
study period, in all study groups.

To describe the anti-H1 stalk humoral immune response 28 days after each priming 
dose (1 or 2 dose(s)) in all study groups.
Refer to Section 10.1 for the definition of the primary endpoints.
2.2.
Secondary objectives

To evaluate the adjuvant effect of AS03 and AS01 on the humoral immune response 
after 1 and 2 priming dose(s) of investigational SUIVs when compared to the non-
adjuvanted formulations.

To describe the persistence of the anti-H1 stalk humoral immune response after each 
priming dose (1 or 2 dose(s)) in all study groups up to Month 14.

To describe the humoral immune response after a booster dose at Month 14.

To describe the breadth of the humoral immune response after each vaccination in all 
study groups.

To describe the effect of the chimeric HA vaccination-sequence on the humoral
immune response.
Refer to Section 10.2 for the definition of the secondary endpoints.
2.3.
Tertiary objectives (Amended: 11 July 2019)

To explore the cell-mediated immune responses (B-cells and T-cells).

To explore the immune response against the HA head of cH5/1N1 and cH8/1N1 
strain by hemagglutination inhibition (HI) assay.

To explore the protective effect of the stalk-reactive antibodies induced by 
vaccination in a passive transfer challenge experiment in mice.

To develop assays for evaluation/characterization of the humoral and cellular 
immune responses to the investigational vaccines.

To explore anti-stalk antibody functionality, e.g., antibody-dependent cell-mediated 
cytotoxicity (ADCC).
Refer to Section 10.3 for the definition of the tertiary endpoints.
 
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3.
STUDY DESIGN OVERVIEW
Figure 1
Study design overview
*If a subject presents signs and symptoms of influenza-like illness (ILI) (see Section 5.4.2), nasal and throat swabs will be collected as soon as possible (preferably within 24 hours, but 
not later than 7 days) after the onset of an ILI to test for influenza and/or other respiratory pathogens by RT-PCR if deemed necessary or for storage. (Amended: 11 July 2019)
**IDMC reviews will be performed throughout the study (refer to Section 8.8).
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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 5.5), are essential 
and required for study conduct.

Experimental design: Phase I/II, observer-blind, randomized, controlled, multi-
centric study with 10 parallel groups.

Duration of the study:

Epoch 001: Screening (Day -28 to -2) – only for Phase I subjects (refer to the 
Enrolment section).

Epoch 002: Primary starting at Visit 1 (Day 1) and ending at Visit 7 (Month 8).

Epoch 003: Booster starting at Visit 8 (Month 14) and ending at Visit 12 
(Month 26).

Primary Completion Date (PCD): Visit 12 (Month 26).
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last testing results released of samples collected at Visit 12 
(Month 26).
Refer to glossary of terms for the definition of EoS.

Study groups:

cH8/P/cH5-AS03 group: subjects receiving one dose of cH8/1N1+AS03 at 
Day 1, one dose of PBS at Day 57 and one booster dose of cH5/1N1+AS03 at 
Month 14.

cH5/P/cH8-AS03 group: subjects receiving one dose of cH5/1N1+AS03 at 
Day 1, one dose of PBS at Day 57 and one booster dose of cH8/1N1+AS03 at 
Month 14.

cH8/5/11-AS03 group: subjects receiving one dose of cH8/1N1+AS03 at Day 1, 
one dose cH5/1N1+AS03 at Day 57 and one booster dose of cH11/1N1+AS03 at 
Month 14.

cH8/P/cH5-AS01 group: subjects receiving one dose of cH8/1N1+AS01 at 
Day 1, one dose of PBS at Day 57 and one booster dose of cH5/1N1+AS01 at 
Month 14.

cH5/P/cH8-AS01 group: subjects receiving one dose of cH5/1N1+AS01 at 
Day 1, one dose of PBS at Day 57 and one booster dose of cH8/1N1+AS01 at 
Month 14.

cH8/5/11-AS01 group: subjects receiving one dose of cH8/1N1+AS01 at Day 1, 
one dose cH5/1N1+AS01 at Day 57 and one booster dose of cH11/1N1+AS01 at 
Month 14.

cH8/P/cH5 group: subjects receiving one dose of cH8/1N1 at Day 1, one dose 
of PBS at Day 57 and one booster dose of cH5/1N1 at Month 14.
 
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
cH5/P/cH8 group: subjects receiving one dose of cH5/1N1 at Day 1, one dose 
of PBS at Day 57 and one booster dose of cH8/1N1 at Month 14.

cH8/5/11 group: subjects receiving one dose of cH8/1N1 at Day 1, one dose 
cH5/1N1 at Day 57 and one booster dose of cH11/1N1 at Month 14.

IIV4 group: subjects receiving one dose of Fluarix Quadrivalent at Day 1, one 
dose of PBS at Day 57 and one dose of Fluarix Quadrivalent at Month 14.
Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects
Age (Min - Max)
Epochs
Epoch 002
Epoch 003
cH8/P/cH5-AS03
47
18 years – 39 years
x
x
cH5/P/cH8-AS03
47
18 years – 39 years
x
x
cH8/5/11-AS03
47
18 years – 39 years
x
x
cH8/P/cH5-AS01
47
18 years – 39 years
x
x
cH5/P/cH8-AS01
47
18 years – 39 years
x
x
cH8/5/11-AS01
47
18 years – 39 years
x
x
cH8/P/cH5
47
18 years – 39 years
x
x
cH5/P/cH8
47
18 years – 39 years
x
x
cH8/5/11
47
18 years – 39 years
x
x
IIV4
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18 years – 39 years
x
x
 
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Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/Product 
name
Study groups
cH8/P/cH5-
AS03
cH5/P/cH8-
AS03
cH8/5/11-
AS03
cH8/P/cH5-
AS01
cH5/P/cH8-
AS01
cH8/5/11-
AS01
cH8/P/cH5
cH5/P/cH8
cH8/5/11
IIV4
cH8/1N1+AS03A-
like*
cH8/1N1
x
x
x
AS03
x
x
x
PBS
x
x
x
cH5/1N1+AS03A-
like*
cH5/1N1
x
x
x
AS03
x
x
x
PBS
x
x
x
cH11/1N1+AS03A-
like*
cH11/1N1
x
AS03
x
PBS
x
cH8/1N1+AS01E-
like#
cH8/1N1
x
x
x
AS01B
x
x
x
PBS
x
x
x
cH5/1N1+AS01E-
like#
cH5/1N1
x
x
x
AS01B
x
x
x
PBS
x
x
x
cH11/1N1+AS01E-
like#
cH11/1N1
x
AS01B
x
PBS
x
cH8/1N1
cH8/1N1
x
x
x
PBS
x
x
x
cH5/1N1
cH5/1N1
x
x
x
PBS
x
x
x
cH11/1N1
cH11/1N1
x
PBS
x
Fluarix 
Quadrivalent
FLU D-QIV
x
PBS
PBS
x
x
x
x
x
x
x
*AS03A-like is obtained by dilution of AS03 with PBS
#AS01E-like is obtained by dilution of AS01B with PBS
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
Control: active control (Fluarix Quadrivalent).

Vaccination schedule:

Two primary doses at Visit 1 (Day 1) and Visit 4 (Day 57).

A booster dose at Visit 8 (Month 14).
Phase I subjects will be vaccinated one at the time, at least 60 minutes apart, with a 
maximum of 10 subjects a day. This is applicable for Dose 1 (Day 1), Dose 2 (Day 
57) and booster dose (Month 14). Dose 2 can only be provided to Phase I subjects 
upon favorable outcome of the 7-day post-Dose 1 safety data review by the IDMC of 
at least 60 Phase I subjects.

Treatment allocation: randomized (1:1:1:1:1:1:1:1:1:1 ratio) using GSK 
Biologicals’ Randomization System on Internet (SBIR).

Blinding:
Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
Not applicable
Epoch 002
Observer-blind
Epoch 003
Observer-blind

Sampling schedule: (Amended: 11 July 2019)

Blood samples for safety assessment will be drawn from all subjects at all visits: 
Screening*, Days 1, 8, 29, 57, 64, 85, Month 8, Month 14, Month 14 + 7 days, 
Month 14 + 28 days, Month 20 and Month 26.
*Only for subjects enrolled in Phase I (refer to the Enrolment section).

Blood samples for serology testing will be drawn from all subjects at Days 1 
(Visit 1), 29 (Visit 3), 85 (Visit 6), Month 8 (Visit 7), Month 14 (Visit 8), Month 
14 + 28 days (Visit 10), Month 20 (Visit 11) and Month 26 (Visit 12).

Blood samples for passive transfer experiment in animals will be drawn from all 
subjects at Days 1 (Visit 1), 85 (Visit 6), Month 14 (Visit 8)*.

Blood samples for cell-mediated immunity (CMI) assessment will be drawn 
from a sub-cohort of 225 subjects at Days 1 (Visit 1), 8 (Visit 2), 29 (Visit 3), 
64 (Visit 5), 85 (Visit 6), Month 14 (Visit 8)*, Month 14 + 7 days (Visit 9)* and
Month 14 + 28 days (Visit 10)*. The sub-cohort will consist of the first Phase II 
subjects enrolled in pre-specified centers.

During the entire study period, nasal and throat swabs will be collected as soon 
as possible (preferably within 24 hours, but not later than 7 days) after the onset 
of an influenza-like illness (ILI) to test for influenza and/or other respiratory 
pathogens by RT-PCR if deemed necessary, or stored for future research (see
Section 5.4.2).
*Note that samples already collected for these timepoints by the time of 
Protocol Amendment 4 implementation at site will not be tested and will be 
stored, unless deemed necessary based on medical review of the cases.
 
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
ILI surveillance: ILI is defined as at least one of these systemic symptoms:

Temperature (oral) 37.8°C/98.6°F and/or,

Myalgia (widespread muscle ache);
AND at least one of these respiratory symptoms:

Cough and/or,

Sore throat.
Passive surveillance will be carried out from Visit 1 (after Dose 1) until the end of 
the study (Visit 12). Subjects will be instructed to contact the investigator/study staff 
as soon as they experience ILI symptoms.

Type of study: self-contained.

Data collection: electronic Case Report Form (eCRF).

Safety monitoring: an IDMC consisting of clinical experts and a biostatistician, 
independent from the Sponsor, will review unblinded safety data (including 
laboratory assessment) at a regular frequency to monitor the safety of the subjects 
throughout the study. Refer to Section 8.8 for detailed description of holding rules 
and safety monitoring.

Enrolment: the study will follow a staggered enrolment with 2 steps; the first being 
Phase I (N = 80) and the second being Phase II (N = 390):

Phase I: During the Phase I enrolment, subjects will be vaccinated one at a time, 
at least 60 minutes apart, with a maximum of 10 subjects/day until 80 subjects 
are enrolled (i.e. to obtain treatment groups of at least 8 subjects/group). If no 
safety issue is identified by the IDMC upon review of the 7-day post-dose 1 
safety data (Days 1-7) of all Phase I subjects (N = 80), Phase II enrolment will 
be allowed to start.

Phase II: Subjects will be enrolled and vaccinated without limitation on the 
number of vaccinees per day or time between consecutive subjects.
4.
STUDY COHORT
4.1.
Number of subjects/centers
This study will be conducted in multiple centers. A total of 470 subjects (47/group) are 
planned to be enrolled in this study, in order to have 430 evaluable subjects for the 
primary immunogenicity endpoints. Refer to Section 10.4 for a detailed description of the 
criteria used in the determination of sample size.
 
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Table 4
Sub-cohort (Amended: 11 July 2019)
Sub-cohort name
Description
Estimated number of subjects
Cell-mediated immunity 
(CMI) testing
Additional blood sample (40 mL) to be taken at 
Visits 1, 2, 3, 5, 6, 8, 9 and 10 for CMI testing. This 
will be done at pre-specified sites with adequate 
material for such sampling procedure.
Approximately 225
The sub-cohort will consist of the 
first Phase II subjects enrolled in 
pre-specified sites.
4.2.
Inclusion criteria for enrolment
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:

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, contact the site in case of ILI).
Please refer to the glossary of terms for the definition of ILI.

Written informed consent obtained from the subject prior to performing any study 
specific procedure.

A male or female between, and including, 18 and 39 years of age at the time of the 
first vaccination.

Healthy subjects without acute or chronic, clinically significant pulmonary, 
cardiovascular, hepatic or renal functional abnormality, as established by medical 
history and clinical examination before first vaccination and laboratory screening 
tests (the latter being only applicable for subjects enrolled in Phase I).

Subjects with no history of influenza vaccination within 6 months prior to first study 
vaccination and who are willing to forego any influenza vaccination during the entire
study 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 first vaccination, and

Has a negative pregnancy test on the day of vaccination, and

Has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series (last vaccination at 
Month 14).
Please refer to the glossary of terms for the definition of adequate contraception.
 
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4.3.
Exclusion criteria for enrolment
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:

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccines during the period starting 30 days before the first dose of study 
vaccines (Day -29 to Day 1), or planned use during the study period.

Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 6 
months prior to the first vaccine dose. For corticosteroids, this will mean prednisone 
20 mg/day, or equivalent. Topical steroids are allowed.

Administration of long-acting immune-modifying drugs (e.g. infliximab, rituximab) 
within 6 months before first vaccination (Visit 1), or planned administration any time
during the study period.

Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first dose (Visit 1) up to the blood 
sampling at Day 85 (Visit 6) and in the period starting 30 days before booster 
vaccination at Month 14 (Visit 8) up to the blood sample at Month 14 + 28 days 
(Visit 10).

Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device).

Previous vaccination against influenza within the 6 months preceding the first 
vaccination at Visit 1 or planned use of such vaccines during the study period.

History of vaccination with a (pre)pandemic influenza vaccine other than an 
H1N1pdm09 vaccine or history of laboratory-confirmed influenza infection other 
than seasonal or other than H1N1pdm09 influenza.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

History of or current autoimmune disease.

Subjects diagnosed with excessive daytime sleepiness (unintended sleep episodes 
during the day present almost daily for at least one month) or narcolepsy; or history 
of narcolepsy in a subject’s parent or sibling.

History of Guillain-Barré syndrome.
 
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
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines (including egg proteins); a history of anaphylactic-type 
reaction to consumption of eggs; or a history of severe adverse reaction to a previous 
influenza vaccine.

Hypersensitivity to latex.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 38.0°C / 100.4°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 may be enrolled at the discretion of the investigator.

For subjects with acute disease and/or fever at the time of enrolment, Visit 1 
may be re-scheduled within the allowed time-window.

Administration of immunoglobulins and/or any blood products during the period 
starting 3 months before the first dose of study vaccines or planned administration 
during the study period.

Blood donation within 30 days before the first study blood sampling or planned 
blood donation within 30 days before and up to 30 days after any study blood 
sampling.

Pregnant or lactating female.

History of chronic alcohol consumption and/or drug abuse as deemed by the 
investigator to render the potential subject unable/unlikely to provide accurate safety 
reports.

Female planning to become pregnant or planning to discontinue contraceptive 
precautions.

Any condition that puts the subject at risk for serious influenza-related 
complications, as identified by the Advisory Committee on Immunization Practices 
[Grohskopf, 2017] (note that only criteria applicable for the study population are 
listed below):

Chronic pulmonary (including asthma), cardiovascular (except isolated 
hypertension), renal, hepatic, neurologic, hematologic or metabolic disorders 
(including diabetes mellitus);

Persons who are immunocompromised due to any cause (including 
immunosuppression caused by medications or by HIV infection);

Adolescents (through 18 years) who are receiving aspirin- or salicylate-
containing medications and who might be at risk for experiencing Reye 
syndrome after influenza virus infection;

Residents of nursing homes and other long-term care facilities;

American Indians/Alaska Natives; and

Persons who are extremely obese (Body Mass Index 40).
 
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Additional criterion applicable for Phase I subjects:

Hematological and/or biochemical parameters (complete blood cell count [red blood 
cells, white blood cells], white blood cells differential count [lymphocytes, 
neutrophils and eosinophils], platelets count or hemoglobin level, creatinine or blood 
urea nitrogen) outside the laboratory normal ranges, unless the laboratory 
abnormalities are considered not clinically significant by the investigator.

Liver enzymes (alanine aminotransferase [ALT] or aspartate aminotransferase 
[AST]) outside of the normal laboratory ranges.
5.
CONDUCT OF THE STUDY
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the International Conference on 
Harmonization (ICH) Guideline for 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 informed consent must be obtained from each 
subject, as appropriate, prior to participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.
 
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The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
5.2.
Subject identification and randomization
5.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study center.
5.2.2.
Randomization of treatment
5.2.2.1.
Randomization of supplies
The randomization of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centers/warehouse(s).
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centers in this multi-center study and to thus reduce the overall 
study recruitment period, an over-randomization of supplies will be prepared.
5.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
5.2.2.2.1.
Study group and treatment number allocation
The target will be to enroll 470 eligible subjects who will be randomly assigned to 10
study groups in a (1:1:1:1:1:1:1:1:1:1) ratio (47 subjects in each group).
Allocation of the subject to a study group at the investigator site will be performed using 
SBIR. The randomization algorithm will use a minimization procedure accounting for 
center, sex, age (18-30 years vs. 31-39 years) and history of influenza vaccination since 
the 2014/2015 season (yes vs. no). Minimization factors will have equal weight in the 
minimization algorithm.
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the site staff in charge of the vaccine/product administration will 
access SBIR. Upon providing the subject identification number, the randomization
system will determine the study group and will provide the treatment number to be used 
for the first dose.
 
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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 SPM for specific 
instructions.
5.2.2.2.2.
Treatment number allocation for subsequent doses
For each dose subsequent to the first dose, the study staff in charge of the vaccine/product
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
5.3.
Method of blinding
Data will be collected in an observer-blind manner. By observer-blind, it is meant that 
during the course of the study, the vaccines/products recipient and those responsible for 
the evaluation of any study endpoint (e.g. safety, reactogenicity) will all be unaware of 
which vaccine/product was administered. To do so, vaccine/product preparation and 
administration will be done by authorized medical personnel who will not participate in 
any of the study clinical evaluation assays.
The site staff will work in an observer-blind manner during the entire study. As the 
vaccines appearance and preparation are different, two teams of study personnel will be 
set up:

A team of unblinded personnel (responsible for the reception, preparation and 
administration of the vaccines).

A team of blinded personnel (responsible for the clinical safety evaluation of the 
subjects).
Please refer to the SPM for more information on vaccine preparation and administration 
while maintaining the blind.
An analysis of data collected up to Day 85 and Month 14 + 28 days will be done on as 
cleaned as possible data up to Visit 6 and Visit 10, respectively (refer to Section 10.11.1
for more information). At Day 85 analysis, the GSK statistician will be unblinded (i.e.
will have access to the individual subject treatment assignment). The remaining GSK 
study personnel will stay blinded (i.e. will not have access to the individual subject 
treatment assignment) until study end. It is possible however, due to the limited sample 
size, that unblinding occurs for a few subjects having a specific adverse event (AE) or 
serious adverse event (SAE) (e.g. an AE/SAE occurring only in a single group). 
Therefore anyone having access to the analysis of Day 85 could become unblinded 
regarding those specific cases.
 
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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.
5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects.
5.4.1.
Independent data monitoring committee
An IDMC will be established by GSK Biologicals for the purpose of monitoring the 
study and to provide independent, non-binding advice on safety and ethics. The IDMC 
will provide recommendations about stopping, continuing or modifying the trial. Refer to 
Section 8.8 for a description of the holding rules and safety monitoring put in place for 
this study.
5.4.2.
Influenza-like illness surveillance
ILI is defined as at least one of these systemic symptoms:

Temperature (oral) 37.8°C/98.6°F and/or,

Myalgia (widespread muscle ache);
AND at least one of these respiratory symptoms:

Cough and/or,

Sore throat.
All ILIs will be reported as unsolicited AEs or SAEs, as applicable.
Passive surveillance will be carried out from Visit 1 (after Dose 1) until the end of the 
study (Visit 12). All study participants will be instructed to contact the investigator/study 
staff in case they experience signs symptoms of ILI as defined above.
The investigator/study staff will schedule a visit for the collection of nasal and throat 
swab specimens preferably within 24 hours (but not later than 7 days) after the onset of 
the ILI. Refer to the SPM for a detailed description of the procedures.
 
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5.5.
Outline of study procedures
The list of study procedures is presented in Table 5 for Phase I subjects and in Table 6 for Phase II subjects.
Table 5
List of study procedures for Phase I subjects (Amended: 11 July 2019)
Epoch
Screening
Primary
Booster
In case of 
ILI**
Type of contact
Screening 
Visit*
Visit 1 Visit 2 Visit 3 Visit 4
Visit 5
Visit 6
Visit 7 Visit 8
Visit 9
Visit 10 Visit 11 Visit 12
Timepoints
Pre-Day 1
Day 1
Day 8
Day 29 Day 57 Day 64 Day 85
M8
M14
M14+7D M14+28D
M20
M26
Sampling timepoints
Screening
PRE
PId7
PId28
PId56
PIId7
PIId28
M8
M14
PIIId7
PIIId28
M20
M26
Informed consent
●
Check inclusion/exclusion criteria
●
O
Collect demographic data
●
Medical history
O
●
History of influenza vaccination within previous 3 
seasons (2014/2015, 2015/2016, 2016/2017)
●
Physical examination
●
●
O
O
O
O
O
O
O
O
O
O
O
Pregnancy test §
●
●
●
●
Check contraindications and warnings and 
precautions to vaccination
O
O
O
Pre-vaccination body temperature
●
●
●
Measure/record height and weight
●
Vaccine
Study group and treatment number allocation
O
Treatment number allocation for subsequent 
doses
O
O
Recording of administered treatment number
●
●
●
Vaccine administration
●†
●†
●†
60 minutes post-vaccination observation
O
O
O
Laboratory assays
Blood sampling for antibody determination
(~12 mL)
●
●
●
●
●
●
●
●
Blood sampling for hematology/biochemical 
analysis (~5.5 mL)
●
●‡
●
●
●
●
●
●
●
●
●
●
●
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Epoch
Screening
Primary
Booster
In case of 
ILI**
Type of contact
Screening 
Visit*
Visit 1 Visit 2 Visit 3 Visit 4
Visit 5
Visit 6
Visit 7 Visit 8
Visit 9
Visit 10 Visit 11 Visit 12
Timepoints
Pre-Day 1
Day 1
Day 8
Day 29 Day 57 Day 64 Day 85
M8
M14
M14+7D M14+28D
M20
M26
Sampling timepoints
Screening
PRE
PId7
PId28
PId56
PIId7
PIId28
M8
M14
PIIId7
PIIId28
M20
M26
Blood sampling for passive transfer (~2.5 mL)
●
●
●
Nasal and throat swab sampling
●
ILI surveillance
Surveillance for ILI
O
O
O
O
O
O
O
O
O
O
O
O
Documentation of symptoms and signs of ILI
●
●
●
●
●
●
●
●
●
●
●
●
●
Safety assessments
Record any concomitant 
medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
●
●
●
●
Distribution of diary cards 1
O
O
O
O
O
O
O
O
Recording of solicited AEs within 7 days post-
vaccination
●
●
●
●
●
●
Recording of unsolicited AEs within 28 days 
post-vaccination
●
●
●
●
●
●
●
●
●
Recording of ILIs as unsolicited AEs/SAE, as 
applicable
●
●
●
●
●
●
●
●
●
●
●
●
●
Return of diary cards
O
O
O
O
O
O
O
O
O
O
O
O
Diary card transcription by investigator
●
●
●
●
●
●
●
●
●
●
●
●
Recording of AEs and SAEs leading to 
withdrawal from the study
●
●
●
●
●
●
●
●
●
●
●
●
●
Recording of SAEs, MAEs, pIMDs and 
pregnancies
●
●
●
●
●
●
●
●
●
●
●
●
●
Recording of SAEs related to study participation, 
or to a concurrent GSK medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Screening conclusion
●
Study conclusion
●
Note: the double-line border following Day 85 and Month 14 + 28 days indicates the analyses which will be performed on all data (i.e. data that are as clean as possible) obtained up to 
Day 85 and Month 14 + 28 days, respectively.
D = day; M = month (= 28 days); PRE = pre-vaccination; PI = post-dose 1; PII = post-dose 2; PIII = post-dose 3 (booster)
AE = adverse events, ILI = influenza-like illness; SAE = serious adverse event; MAE = medically attended event; pIMD = potential immune-mediated disease
● is used to indicate a study procedure that requires documentation in the individual eCRF
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○ is used to indicate a study procedure that does not require documentation in the individual eCRF
* Screening evaluations may be completed 2 to 28 days before Day 1. Site staff should allow sufficient time between the Screening and Visit 1 to receive and review screening safety 
laboratory test results. If a delay occurs such that the interval between Screening and the Visit 1 vaccination exceeds 28 days, a re-screening visit should be scheduled before Visit 1 
during which blood sample collection for safety laboratory assessment must be repeated; an interim medical history and physical examination must be obtained and inclusion / 
exclusion criteria must be re-reviewed. Only data from the re-screening visit, if it occurs, will be recorded in the eCRF and taken into consideration.
** This visit is only applicable following passive surveillance contacts for subjects with ILI (see Section 5.4.2).
§ Only for females subjects of childbearing potential. An urine pregnancy test will be performed. A serum pregnancy test instead of a urine pregnancy test should only be considered if 
required by local or ethics committee regulations. If a serum pregnancy test instead of a urine pregnancy test is required by country, local or ethics committee regulations, a blood 
sample will be collected from women of childbearing potential at these visits and will be used for the test as per local guidance. The results must be obtained and be confirmed negative 
before vaccination.
† Blood samples must be taken before vaccine administration
‡ Blood sample for hematology/biochemical assessment will not be drawn at Visit 1 if this visit occurs less than one week after the screening visit
1 Diary cards will allow the collection of solicited and unsolicited symptoms, concomitant medications/vaccinations, MAEs and episode(s) of ILI. Refer to the SPM for more details on 
the usage of the diary cards.
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Table 6
List of study procedures for Phase II subjects (Amended: 11 July 2019)
Epoch
Primary
Booster
In case 
of ILI *
Type of contact
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12
Timepoints
Day 1
Day 8
Day 29
Day 57
Day 64
Day 85
M8
M14
M14+7D M14+28D
M20
M26
Sampling timepoints
PRE
PId7
PId28
PId56
PIId7
PIId28
M8
M14
PIIId7
PIIId28
M20
M26
Informed consent
●
Check inclusion/exclusion criteria
●
Collect demographic data
●
Medical history
●
History of influenza vaccination within 
previous 3 seasons (2014/2015, 2015/2016, 
2016/2017)
●
Physical examination
●
O
O
O
O
O
O
O
O
O
O
O
Pregnancy test §
●
●
●
Check contraindications and warnings and 
precautions to vaccination
O
O
O
Pre-vaccination body temperature
●
●
●
Measure/record height and weight
●
Vaccine
Study group and treatment number allocation
O
Treatment number allocation for subsequent 
doses
O
O
Recording of administered treatment number
●
●
●
Vaccine administration
●†
●†
●†
30 minutes post-vaccination observation
O
O
O
Laboratory assays
Blood sampling for antibody determination
(~12 mL)
●
●
●
●
●
●
●
●
Blood sampling for CMI response (~40 mL)#
●
●
●
●
●
●
●
●
Blood sampling for hematology/biochemical 
analysis (~5.5 mL)
●
●
●
●
●
●
●
●
●
●
●
●
Blood sampling for passive transfer (~2.5 mL)
●
●
●
Nasal and throat swab sampling
●
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Epoch
Primary
Booster
In case 
of ILI *
Type of contact
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12
Timepoints
Day 1
Day 8
Day 29
Day 57
Day 64
Day 85
M8
M14
M14+7D M14+28D
M20
M26
Sampling timepoints
PRE
PId7
PId28
PId56
PIId7
PIId28
M8
M14
PIIId7
PIIId28
M20
M26
ILI surveillance
Surveillance for ILI
O
O
O
O
O
O
O
O
O
O
O
O
Documentation of symptoms and signs of ILI
●
●
●
●
●
●
●
●
●
●
●
●
●
Safety assessments
Record any concomitant 
medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
●
●
●
●
●
●
●
●
Distribution of diary cards 1
O
O
O
O
O
O
O
O
Recording of solicited AEs within 7 days post-
vaccination
●
●
●
●
●
●
Recording of unsolicited AEs within 28 days 
post-vaccination
●
●
●
●
●
●
●
●
●
Recording of ILIs as unsolicited AEs/SAE, as 
applicable
●
●
●
●
●
●
●
●
●
●
●
●
●
Return of diary cards
O
O
O
O
O
O
O
O
O
O
O
O
Diary card transcription by investigator
●
●
●
●
●
●
●
●
●
●
●
●
Recording of AEs and SAEs leading to 
withdrawal from the study
●
●
●
●
●
●
●
●
●
●
●
●
●
Recording of SAEs, MAEs, pIMDs and 
pregnancies
●
●
●
●
●
●
●
●
●
●
●
●
●
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
●
Study conclusion
●
Note: the double-line border following Day 85 and Month 14 + 28 days indicates the analyses which will be performed on all data (i.e. data that are as clean as possible) obtained up to 
Day 85 and Month 14 + 28 days, respectively.
D = day; M = month (= 28 days); PRE = pre-vaccination; PI = post-dose 1; PII = post-dose 2; PIII = post-dose 3 (booster)
CMI = cell-mediated immunity; AE = adverse events, ILI = influenza-like illness; SAE = serious adverse event; MAE = medically attended event; pIMD = potential immune-mediated 
disease
● is used to indicate a study procedure that requires documentation in the individual eCRF
○ is used to indicate a study procedure that does not require documentation in the individual eCRF
* This visit is only applicable following passive surveillance contacts for subjects with ILI (see Section 5.4.2).
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§ Only for females subjects of childbearing potential. An urine pregnancy test will be performed. A serum pregnancy test instead of a urine pregnancy test should only be considered if
required by local or ethics committee regulations. If a serum pregnancy test instead of a urine pregnancy test is required by country, local or ethics committee regulations, a blood 
sample will be collected from women of childbearing potential at these visits and will be used for the test as per local guidance. The results must be obtained and be confirmed negative 
before vaccination.
† Blood samples must be taken before vaccine administration
# Only for subjects included in the CMI sub-cohort
1 Diary cards will allow the collection of solicited and unsolicited symptoms, concomitant medications/vaccinations, MAEs and episode(s) of ILI. Refer to the SPM for more details on 
the usage of the diary cards.
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Whenever possible, the investigator should arrange study visits within the interval 
described in Table 7.
Table 7
Intervals between study visits
Interval
Optimal length of interval
Allowed interval**
Screening to Visit 1*
2-28 days
Visit 1 Visit 2
7 days
7-9 days
Visit 1 Visit 3
28 days
28-38 days
Visit 1 Visit 4
56 days
56-66 days
Visit 4 Visit 5
7 days
7-9 days
Visit 4 Visit 6
28 days
28-38 days
Visit 4 Visit 7
168 days
168-196 days
Visit 4 Visit 8
336 days
336-364 days
Visit 8 Visit 9
7 days
7-9 days
Visit 8 Visit 10
28 days
28-38 days
Visit 8 Visit 11
168 days
168-196 days
Visit 8 Visit 12
336 days
336-364 days
*Only applicable for Phase I subjects. Screening evaluations may be completed 2 to 28 days before Day 1. Site staff 
should allow sufficient time between the screening and Day 1 visits to receive and review screening safety laboratory 
test results. If a delay occurs such that the interval between screening and the Day 1 vaccination exceeds 28 days, a 
re-screening visit should be scheduled before Visit 1.
**Visits out of the allowed interval can lead to elimination from the Per-Protocol set for immunogenicity analysis.
5.6.
Detailed description of study procedures
5.6.1.
Informed consent
The signed/witnessed informed consent of the subject must be obtained before study 
participation. Refer to Section 5.1 for the requirements on how to obtain informed 
consent.
5.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment.
5.6.3.
Collect demographic data
Record demographic data such as date of birth (only month and year), sex, race (ethnicity 
and geographic ancestry) in the subject’s eCRF.
5.6.4.
Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF.
 
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5.6.5.
History of influenza vaccination
Any history of influenza vaccination in the past three seasons (2014/2015; 2015/2016 and 
2016/2017) will be recorded. Self-reporting by the subject is acceptable (medical records
are not required).
5.6.6.
Physical examination
Perform a physical examination of the subject, including assessment of oral body 
temperature and resting vital signs: systolic/diastolic blood pressure, heart rate and 
respiratory rate after at least 10 minutes of rest, pulmonary auscultation. Collected 
information needs to be recorded in the eCRF.
Any findings from the(se) physical examination(s) need to be recorded in the subject’s 
medical record, in the medical history screen of the eCRF or reported as an AE or SAE, 
as applicable, if they meet the protocol definition of AE or SAE (see Sections 8.1.1 and 
8.1.2).
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled within the allowed 
interval for that visit (see Table 7).
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
5.6.7.
Pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The test result is to be recorded in the eCRF. The study 
vaccines/products may only be administered if the pregnancy test is negative.
A serum pregnancy test instead of a urine pregnancy test should only be considered if 
required by country, local or ethics committee regulations. If a serum pregnancy test 
instead of a urine pregnancy test is required by country, local or ethics committee 
regulations, a blood sample will be collected from women of childbearing potential at the 
vaccination visits and will be used for the test as per local guidance.
Note: Pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit.
5.6.8.
Check contraindications, warnings and precautions to 
vaccination
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 6.5 and 6.6 for more details.
 
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5.6.9.
Assess pre-vaccination body temperature
The oral body temperature of each subjects needs to be measured prior to any study 
vaccines/products administration. If the subject has fever (fever is defined as temperature 
38.0°C/100.4°F) on the day of vaccination, the vaccination visit will be rescheduled 
within the allowed interval for that visit (see Table 7).
5.6.10.
Measure/record height and weight
Measure and record the height and weight of the subjects in the eCRF.
5.6.11.
Study group and treatment number allocation
Study group and treatment number allocation will be performed as described in Section 
5.2.2. The number of each administered treatment must be recorded in the eCRF.
5.6.12.
Sampling
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
5.6.12.1.
Blood sampling for safety and immune response assessments
Blood samples will be taken during certain study visits as specified in Section 5.5 List of 
Study Procedures:

A volume of approximately 12 mL of whole blood should be drawn from all subjects 
for each analysis of humoral immune response at each pre-defined timepoint. After 
centrifugation, serum samples should be kept at –20°C/ –4°F or below until 
shipment. Refer to the SPM for more details on sample storage conditions.

A volume of approximately 40 mL of whole blood should be drawn from all subjects 
included in the CMI sub-cohort for analysis of CMI response at each pre-defined 
timepoint. The blood should be stored at the investigator’s site at room temperature 
and it must not be centrifuged. Samples will be shipped at room temperature (20 to 
25°C/68 to 77°F) to the designated laboratory for cell separation to be performed 
within 24 hours. Refer to the SPM for more details on sample storage conditions.

A volume of approximately 5.5 mL of whole blood should be drawn from all 
subjects for each hematology and biochemistry analysis at each pre-defined 
timepoint. Blood will be collected in 2 tubes (2 mL for hematology and 3.5 mL for 
biochemistry) or in one tube, but then will be separated in 2 aliquots. The aliquot for 
biochemistry analysis will be centrifuged. 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.

A volume of approximately 2.5 mL of whole blood should be drawn from all 
subjects for the passive transfer testing at each pre-defined timepoint. After 
 
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centrifugation, serum samples should be kept at –20°C/ –4°F or below until 
shipment. Refer to the SPM for more details on sample storage conditions.
5.6.12.2.
Nasal and throat sampling
Cells and secretions from the nasopharynx will be collected using sterile nasal and throat 
swabs any time during the study if a subject presents with an ILI. Samples should be kept 
at –70°C/–94°F or below until shipment. Refer to the SPM for more details on sample 
storage conditions.
5.6.13.
Study vaccines/products administration

After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccines/products will be administered intramuscularly (IM) in the deltoid of the 
non-dominant arm (refer to Section 6.3 for detailed description of the 
vaccines/products administration procedure). If the investigator or delegate 
determines that the subject’s health on the day of administration temporarily 
precludes vaccines/products administration, the visit will be rescheduled within the 
allowed interval for this visit (refer to Table 7).

The subjects will be observed closely for at least 60 minutes (Phase I subjects) or 30 
minutes (Phase II subjects) following the administration of the vaccines/products, 
with appropriate medical treatment readily available in case of anaphylaxis.
5.6.14.
Surveillance for influenza-like illness and documentation of signs 
and symptoms
Subjects will be instructed to contact the investigator/study staff as soon as they 
experience ILI signs or symptoms from Visit 1 (after Dose 1) until the end of the study 
(Visit 12) (see Section 5.4.2). The subjects will be requested to come to the study site to 
collect nasal and throat swabs as soon as possible after the onset of the ILI symptoms 
(preferably within 24 hours and not later than 7 days after the onset of an ILI). In case the 
subject has no possibility to come, a study staff member will visit the subject to collect 
nasal and throat swabs. All samples will be obtained, if possible, before 
antimicrobial/influenza antiviral therapy is started. However, if microbial/antiviral 
therapy has started, the swab will be collected and the therapy will be recorded on the ILI 
diary cards. The most suitable time for collecting the swabs is in the morning before a 
meal. If the sample cannot be collected in the morning, the subject should be instructed 
not to take any meal at least one hour before sampling.
The ILI date of onset, the ILI signs and symptoms and the date of swab specimen 
collection will be collected in the eCRF. In addition, all cases of ILI have to be recorded 
as unsolicited AE or SAE in the eCRF.
An ILI not reported to the study team within 7 days following the onset of ILI will be 
considered and recorded in the CRF as a miscase. For these miscases, no swabs will be 
collected.
 
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5.6.15.
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 6.7.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.8.
5.6.16.
Recording of AEs, MAEs, SAEs, pregnancies and pIMDs

Refer to Section 8.3 for procedures for the investigator to record AEs, medically 
attended events (MAEs), SAEs, pregnancies and potential immune-mediated 
diseases (pIMDs). Refer to Section 8.4 for guidelines and how to report SAE, 
pregnancy and pIMD 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.

At each visit (except Visits 2, 5 and 9), diary cards will be provided to the subject to 
record AEs, MAE(s) and episode(s) of ILI. The subject will be instructed to measure 
and record the body temperature (preferably measured orally), 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 27 days)
occurring after vaccination. In addition, MAE(s) and episode(s) of ILI occurring 
during the entire study period will be collected. 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 at each 
visit.

Any unreturned diary cards will be sought from the subject through telephone call(s) 
or any other convenient procedure.

The investigator and/or delegate will transcribe the collected information into the 
eCRF in English.
5.6.17.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness.

complete the Study Conclusion screen in the eCRF.
 
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5.7.
Biological sample handling and analysis
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be asked to give a specific consent
to allow GSK or a contracted partner to use the samples for future research. Future 
research will be subject to the laws and regulations in the respective countries and 
will only be performed once an independent Ethics Committee or Review Board has 
approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject.
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).
If additional testing is performed, the marker priority ranking given in Section 5.7.4 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.
 
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5.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the per-protocol analysis (see Section 10.5 for the definition 
of analysis sets). 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.
5.7.2.
Biological samples
Table 8
Biological samples (Amended: 11 July 2019)
Sample type
Quantity
Unit
Timepoint
Sub-cohort name**
Blood
Approximately 20
mL
Visits 1, 6, 8
All subjects
Approximately 5.5*
mL
Visits 2, 4, 5, 9
Approximately 17.5
mL
Visits 3, 7, 10, 11, 12
Blood
Approximately 40
mL
Visits 1, 2, 3, 5, 6, 8, 9, 10
In addition for the 
CMI sub-cohort
Nasal and 
throat swabs
Not defined
-
Within 24 hours (but not later than 
7 days) after the onset of the ILI
All subjects
*Note that an additional blood sample (5.5 mL) will be drawn at Screening visit for Phase I subjects.
**Refer to Table 4 for sub-cohort description.
Note that if a serum pregnancy test instead of a urine pregnancy test is required, a blood 
sample (2 mL) will be collected from women of child-bearing potential at screening 
(Phase I subjects), Visits 1, 4 and 8, and will be used for the test as per local guidance.
5.7.3.
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.
Humoral immune responses
Serological assays (quantification of antibodies by ELISA, microneutralization [MN] and 
hemagglutination inhibition [HI] assays) will be performed at GSK Biologicals’ 
laboratory or in a laboratory designated by GSK Biologicals using standardized 
procedures (Table 9).
Cell-mediated immunity
T-cell, B-memory cell and plasmablast responses will be evaluated at GSK Biologicals’
laboratory or in a laboratory designated by GSK Biologicals using standardized
procedures (Table 10).
 
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Hematology and biochemistry
Hematology and biochemistry assays for safety assessment will be performed in a central 
laboratory (Table 11).
Molecular biology (PCR tests) (Amended: 11 July 2019)
At the onset of an ILI episode (refer to Section 5.4.2 for the ILI definition), nasal and 
throat swab specimens will be taken according the procedure described in the SPM. Nasal 
and throat swab specimens will be tested by RT-PCR for influenza and/or other 
respiratory virus infections at GSK Biologicals’ central laboratory or in a laboratory 
designated by GSK Biologicals, if deemed necessary, or will be stored for future 
research (Table 12).
Passive transfer experiment
The passive transfer experiment in mice will be conducted at GSK Biologicals’ 
laboratory or in a laboratory designated and validated by GSK Biologicals using 
standardized procedures. Refer to APPENDIX D for more details.
 
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Table 9
Humoral immunity (Amended: 11 July 2019)
System
Component (Strain or Antigen Description)
Method
Kit/Manufacturer
Unit
Cut-off
Laboratory*
ELISAs
Serum
cH6/1 HA = Recombinant antigen based on 
A/mallard/Sweden/81/2002 (H6N1) head domain 
with stalk domain from HA of H1N1 virus 
A/California/04/09
Anti-H1 HA stalk ELISA
In-house assay
ELISA units 
per mL 
(EU/mL)
66
GSK Biologicals’ 
laboratory** or 
laboratory designated 
by GSK Biologicals
H2 HA full length = Recombinant antigen based on 
A/Japan/305/1957 (H2N2) HA
Anti-H2 HA full length ELISA
22
H18 HA full length = Recombinant antigen based 
on A/flat-faced bat/Peru/033/2010 (H18N11) HA
Anti-H18 HA full length ELISA
43
Microneutralization (MN) assays
Serum
cH6/1N5 virus:
HA head: A/mallard/Sweden/81/2002 (H6N1)
HA stalk: A/California/04/2009 (H1N1)
N5: A/mallard/Sweden/86/2003 (H12N5)
Anti-H1 HA stalk MN Assay
In-house assay
1/DIL (IC50)
20
GSK Biologicals’ 
laboratory** or 
laboratory designated 
by GSK Biologicals
H1N1 swine influenza virus:
A/Swine/Jiangsu/40/2011 (H1N1)
Anti-heterosubtypic HA Group 1 
virus MN Assay
20
IIV4 H1N1 strains$
Anti-heterosubtypic HA Group 1 
virus MN Assay
20
Hemagglutination Inhibition (HI) assay
Serum
Chimeric vaccine strains:
cH5/1N1 and cH8/1N1
HI assay
In-house assay
1/DIL
10
GSK Biologicals’ 
laboratory** or 
laboratory designated 
by GSK Biologicals
TBD = to be determined; DIL = dilution
*Refer to APPENDIX B for the laboratory addresses.
**GSK Biologicals laboratory refers to Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; Dresden, Germany
$ IIV4 H1N1 strains will depend on the World Health Organization recommendation for the 2017/2018 season (Dose 1 at Day 1) and the 2018/2019 season (booster dose at Month 14).
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Table 10
Cell-mediated immunity
System
Component
Challenge
Method
Unit
Laboratory*
PBMCs
T-cells stained with probes for various 
activation markers (such as IL-2, TNF-
, IFN-, CD40-L)
None, H1 (A/California/04/2009) 
stalk peptide pool
T-cell response by ICS 
assay
Frequencies of CD4+/CD8+ T-cells 
expressing activation 
markers/million CD4+/CD8+ T-cells
GSK Biologicals**
PBMCs
B-cells reactive to “challenge” 
antigens
None, H1 stalk domain (cHA 6/1)
B-memory cells by 
ELISPOT
Frequencies of antigen-specific 
memory B-cells/million memory B-
cells
GSK Biologicals**
PBMCs
Plasmablasts detected using cH6/1 
biotinylated probe
H1 stalk domain (cHA 6/1)
Plasmablast detection to 
HA by flow cytometry
Frequencies of antigen-specific 
plasmablasts/million PBMCs
GSK Biologicals**
PBMC = Peripheral blood mononuclear cells; IL-2 = interleukin-2; TNF-= Tumor Necrosis Factor-alpha; IFN-= interferon-gamma; CD40-L = Cluster of Differentiation 40-Ligand; 
ICS = intracellular cytokine staining
*Refer to APPENDIX B for the laboratory addresses.
**GSK Biologicals laboratory refers to CLS in Rixensart, Belgium; Wavre, Belgium
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Table 11
Hematology/biochemistry
System
Discipline
Component
Method
Scale**
Laboratory
Whole 
blood
Hematology
Leukocytes (white blood cells)
As per central 
laboratory 
procedure
Quantitative
Central 
laboratory***
Neutrophils*
Lymphocytes*
Basophils*
Monocytes*
Eosinophils*
Hemoglobin
Platelets
Erythrocytes (red blood cells)
Serum
Biochemistry
Alanine aminotransferase (ALT)
As per central 
laboratory 
procedure
Quantitative
Aspartate aminotransferase (AST)
Creatinine1
Urea nitrogen1
*For white blood cell differential count.
**Grading of laboratory parameters will be based on the Food and Drug Administration (FDA) Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
(refer to APPENDIX C).
***Refer to APPENDIX B for the laboratory addresses
1 The Blood Urea Nitrogen (BUN)-to-creatinine ratio is to be calculated.
Note that hematology and biochemistry data will be transferred from the central 
laboratory performing the testing into the clinical database as soon as possible to ensure 
that all necessary information are available for IDMC reviews. In addition results will be 
communicated as soon as possible to the investigators via lab reports, hard copies, faxes
or emails.
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.
Further characterization of the vaccine-induced immune responses may include 
assessment of HLA-DRB10401 and HLA-A201 alleles expression to evaluate the 
presence of H1 stalk specific CD4+ and CD8+ T-cells using tetramer technology.
 
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Table 12
Molecular Biology (PCR tests)
Component
Kit/ 
Manufacturer
Method
Unit
Laboratory
Nasal swab samples
Influenza A virus (Flu A)
Influenza B virus (Flu B)
In-house
RT-PCR
Qualitative assay 
(positive/negative)
GSK Biologicals* 
or designated 
laboratory
Human Influenza A virus subtype H1 (Flu A-H1)
Human Influenza A virus subtype H3 (Flu A-H3)
In-house
RT-PCR
Qualitative assay 
(positive/negative)
RSV A virus (RSV A)
RSV B virus (RSV B)
In-house
Qualitative
RT-PCR
Copies/mL or 
pos/neg
Human adenovirus (AdV)
Human metapneumovirus (MPV)
Human enterovirus (HEV)
Human parainfluenza virus 1 (PIV1)
Human parainfluenza virus 2 (PIV2)
Human parainfluenza virus 3 (PIV3)
Human parainfluenza virus 4 (PIV4)
Human bocavirus (HBoV)
Human rhinovirus (HRV)
Human coronavirus 229E (CoV 229E)
Human coronavirus NL63 (CoV NL63)
Human coronavirus OC43 (CoV OC43)
Allplex
Respiratory 
Panel or 
equivalent’
Multiplex real-
time PCR
Qualitative assay 
(positive/negative)
Pos/neg = positive/negative
*GSK Biologicals laboratory refers to the CLS in Rixensart, Belgium; Wavre, Belgium.
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
 
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5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
Table 13
Immunological read-outs for humoral immunity and cell-mediated 
immunity (Amended: 11 July 2019)
Blood sampling timepoint
Sub-
cohort
Name
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
Humoral immunity
Visit 1 (Day 1)
Visit 3 (Day 29)
Visit 6 (Day 85)
Visit 7 (Month 8)
Visit 8 (Month 14)
Visit 10 (Month 14 + 28 days)
Visit 11 (Month 20)
Visit 12 (Month 26)
PRE
PId28
PIId28
M8
M14
PIIId28
M20
M26
All
subjects
∃470
Anti-H1 HA stalk ELISA
Anti-H2 HA full length ELISA
Anti-H18 HA full length ELISA
Visit 1 (Day 1)
Visit 3 (Day 29)
Visit 6 (Day 85)
PRE
PId28
PIId28
All
subjects
∃470
Anti-H1 HA stalk MN assay
Anti-heterosubtypic HA Group 1 
virus MN assay (H1N1 swine)
Anti-heterosubtypic HA Group 1 
virus MN assay (IIV4 H1N1 strains)
HI with cH5/1N1 and cH8/1N1 
virus
Cell-mediated immunity
Visit 1 (Day 1)
Visit 3 (Day 29)
Visit 6 (Day 85)
PRE
PId28
PIId28
CMI sub-
cohort*
∃225
T-cell response by ICS assay
Visit 1 (Day 1)
Visit 2 (Day 8)
Visit 3 (Day 29)
Visit 5 (Day 64)
Visit 6 (Day 85)
PRE
PId7
PId28
PIId7
PIId28
CMI sub-
cohort*
∃225
B memory cells by ELISPOT
Visit 1 (Day 1)
Visit 2 (Day 8)
Visit 5 (Day 64))
PRE
PId7
PIId7
CMI sub-
cohort*
∃225
Plasmablast detection to HA by 
flow cytometry
PRE = pre-vaccination; PI = post-dose 1; PII = post-dose 2; PIII = post-dose 3 (booster); D = day; M = month; ELISA = 
enzyme-linked immunosorbent assay; MN = microneutralization; ICS = intracellular cytokine staining
*CMI sub-cohort comprising ∃50% of the enrolled Phase II subjects.
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 13.
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P
P
D
P
P
D
P
P
DP
P
DP
P
DP
P
DP
P
D
P
P
D
P
P
D
P
P
D

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5.7.4.2.
Hematology/Blood Chemistry
Table 14
Read-outs for hematology/blood chemistry
Blood sampling timepoint
Number of 
subjects
Component
Type of contact 
and timepoint
Sampling 
timepoint
Screening
Screening
All screened 
subjects*
Hematology: leukocytes, neutrophils, lymphocytes, basophils, 
monocytes, eosinophils, hemoglobin, platelets, erythrocytes
Biochemistry: ALT, AST, creatinine**, urea nitrogen**
Visit 1 (Day 1)
Visit 2 (Day 8)
Visit 3 (Day 29)
Visit 4 (Day 57)
Visit 5 (Day 64)
Visit 6 (Day 85)
Visit 7 (Month 8)
Visit 8 (Month 14)
Visit 9 (Month 14 + 
7 days)
Visit 10 (Month 14 
+ 28 days)
Visit 11 (Month 20)
Visit 12 (Month 26)
PRE
PId7
PId28
PId56
PIId7
PIId28
M8
M14
PIIId7
PIIId28
M20
M26
All
Hematology: leukocytes, neutrophils, lymphocytes, basophils, 
monocytes, eosinophils, hemoglobin, platelets, erythrocytes
Biochemistry: ALT, AST, creatinine**, urea nitrogen**
ALT = alanine aminotransferase
AST = aspartate aminotransferase
*Only for Phase I subjects
**The BUN-to-creatinine ratio is to be calculated.
5.7.4.3.
Molecular biology
Table 15
Read-outs for molecular biology tests (Amended: 11 July 2019)
Sampling timepoint
Number of 
subjects
Component
Type of contact and 
timepoint
Sampling timepoint
Assessment visit
Unscheduled
Event-driven
Influenza A virus (Flu A)
Influenza B virus (Flu B)
Human Influenza A virus subtype H1 (Flu A-H1)
Human Influenza A virus subtype H3 (Flu A-H3)
RSV A virus (RSV A)
RSV B virus (RSV B)
Human adenovirus (AdV)
Human metapneumovirus (MPV)
Human enterovirus (HEV)
Human parainfluenza virus 1 (PIV1)
Human parainfluenza virus 2 (PIV2)
Human parainfluenza virus 3 (PIV3)
Human parainfluenza virus 4 (PIV4)
Human bocavirus (HBoV)
Human rhinovirus (HRV)
Human coronavirus 229E (CoV 229E)
Human coronavirus NL63 (CoV NL63)
Human coronavirus OC43 (CoV OC43)
 
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Additional viral/bacterial diagnosis testing on the nasal and throat swabs, such as (but not 
limited to) multiplex PCR and/or high-throughput sequencing, may be done, if deemed 
necessary, provided specific assays become available at GSK Biologicals’ laboratory or a 
laboratory designated by GSK Biologicals.
5.7.5.
Immunological correlates of protection
For the investigational SUIVs, no generally accepted immunological correlate of 
protection has been demonstrated so far for the antigen(s) used in the vaccines.
6.
STUDY VACCINES/PRODUCTS AND ADMINISTRATION
6.1.
Description of study vaccines/products
All candidate vaccines/products to be used have been developed and manufactured by 
GSK Biologicals.
The investigational SUIVs have been developed by the Icahn School of Medicine at
Mount Sinai (New York, United States) in cooperation with GSK Biologicals.
The Quality Control Standards and Requirements for each candidate vaccines/products 
are described in separate Quality Assurance documents (e.g. release protocols, certificate 
of analysis) and the required approvals have been obtained.
The vaccines/products are labelled and packed according to applicable regulatory 
requirements.
 
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Table 16
Study vaccines/products
Treatment name
Vaccine/product
name
Formulation
Presentation
Volume to be 
administered
Number of 
doses
cH5/1N1 + 
AS03A-like
cH5/1N1
HA head,A/Vietnam/1203/2004 (H5N1); HA stalk,A/California/04/2009 (H1N1); 
NA,A/California/04/2009 (H1N1); HA=15µg
Freeze-dried pellet
0.5 mL**
1
AS03
Emulsion containing tocopherol,tocopherol=47.44mg/ml
Whitish to yellowish 
homogenous milky liquid 
emulsion in multi-dose vial
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; MgCl₂=50µg
Liquid in vial
cH8/1N1 + 
AS03A-like
cH8/1N1
HA head,A/mallard/Sweden/24/2002 (H8N4); HA stalk,A/California/04/2009 
(H1N1); NA,A/California/04/2009 (H1N1); HA=15µg
Freeze-dried pellet
0.5 mL**
1
AS03
Emulsion containing tocopherol,tocopherol=47.44mg/ml
Whitish to yellowish 
homogenous milky liquid 
emulsion in multi-dose vial
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; 
MgCl₂=50µg
Liquid in vial
cH11/1N1 + 
AS03A-like
cH11/1N1
HA head,A/Northern Shoveler/ Netherlands/18/1999 (H11N9); HA 
stalk,A/California/04/2009 (H1N1); NA,A/California/04/2009 (H1N1); HA=15µg
Freeze-dried pellet
0.5 mL**
1
AS03
Emulsion containing tocopherol,tocopherol=47.44mg/ml
Whitish to yellowish 
homogenous milky liquid 
emulsion in multi-dose vial
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; 
MgCl₂=50µg
Liquid in vial
cH5/1N1 + 
AS01E-like
cH5/1N1
HA head,A/Vietnam/1203/2004 (H5N1); HA stalk,A/California/04/2009 (H1N1); 
NA,A/California/04/2009 (H1N1); HA=15µg
Freeze-dried pellet
0.5 mL**
1
AS01B
MPL=50µg; QS21=50µg; Liposomes*
Liquid in vial
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; MgCl₂=50µg
Liquid in vial
cH8/1N1 + 
AS01E-like
cH8/1N1
HA head,A/mallard/Sweden/24/2002 (H8N4); HA stalk,A/California/04/2009 
(H1N1); NA,A/California/04/2009 (H1N1); HA=15µg
Freeze-dried pellet
0.5 mL**
1
AS01B
MPL=50µg; QS21=50µg; Liposomes*
Liquid in vial
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; MgCl₂=50µg
Liquid in vial
cH11/1N1 + 
AS01E-like
cH11/1N1
HA head,A/Northern Shoveler/ Netherlands/18/1999 (H11N9); HA 
stalk,A/California/04/2009 (H1N1); NA,A/California/04/2009 (H1N1); HA=15µg
Freeze-dried pellet
0.5 mL**
1
AS01B
MPL=50µg; QS21=50µg; Liposomes*
Liquid in vial
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; MgCl₂=50µg
Liquid in vial
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Treatment name
Vaccine/product
name
Formulation
Presentation
Volume to be 
administered
Number of 
doses
cH5/1N1
cH5/1N1
HA head,A/Vietnam/1203/2004 (H5N1); HA stalk,A/California/04/2009 (H1N1); 
NA,A/California/04/2009 (H1N1); HA=15µg
Freeze-dried pellet
0.5 mL***
1
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; MgCl₂=50µg
Liquid in vial
cH8/1N1
cH8/1N1
HA head,A/mallard/Sweden/24/2002 (H8N4); HA stalk,A/California/04/2009 
(H1N1); NA,A/California/04/2009 (H1N1); HA=15µg
Freeze-dried pellet
0.5 mL***
1
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; MgCl₂=50µg
Liquid in vial
cH11/1N1
cH11/1N1
HA head,A/Northern Shoveler/ Netherlands/18/1999 (H11N9); HA 
stalk,A/California/04/2009 (H1N1); NA,A/California/04/2009 (H1N1); HA=15µg
Freeze-dried pellet
0.5 mL***
1
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; MgCl₂=50µg
Liquid in vial
PBS
PBS
Na₂HPO₄=1.3mg; KH₂PO₄=186µg; NaCl=3.85mg; KCl=100µg; 
MgCl₂=50µg
Liquid in vial
0.5 mL
1
Fluarix 
Quadrivalent
FLU-D-QIV
A/H1N1=15µg; A/H3N2=15µg; B/Yamagata=15µg; B/Victoria=15µg #
Pre-filled syringe
0.5 mL
2
MPL = Monophosphoryl Lipid A
AS03A-like will be obtained by dilution of the AS03 with PBS
AS01E-like will be obtained by dilution of the AS01B with PBS
*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 dilution and reconstitution
***After reconstitution
#The strains will depend on the World Health Organization recommendation for the Northern Hemisphere 2017/2018 season (Dose 1 at Day 1) and the Northern Hemisphere 
2018/2019 season (booster dose at Month 14)
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6.2.
Storage and handling of study vaccines/products
The study vaccines/products must be stored at the respective label storage temperature 
conditions in a safe and locked place. Access to the storage space should be limited to 
authorized study personnel. The storage conditions will be assessed during pre-study 
activities under the responsibility of the Sponsor study contact. The storage temperature 
should be continuously monitored with calibrated (if not validated) temperature 
monitoring device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the 
SPM for more details on storage of the study vaccines/products.
Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 2.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines/products.
6.3.
Dosage and administration of study vaccines/products
Dose preparation is to be performed by an unblinded member of the site staff. Detailed 
instructions for vaccine preparation will be provided separately in the SPM.
For study vaccines adjuvanted with AS03, preparation of the AS03A-like adjuvant 
through dilution of AS03 (presented in multi-dose vials) with the accompanying PBS 
diluent is required prior to mixing with the investigational flu freeze-dried cake for 
reconstitution. After reconstitution, the individual dose of the appropriate study vaccine 
will be withdrawn into a syringe using aseptic technique. The needles used for vial 
withdrawal are to be disposed of and replaced by new needles for intramuscular (IM) 
injection.
For study vaccines adjuvanted with AS01, preparation of the AS01E-like adjuvant 
through dilution of AS01B (presented in single-dose vials) with the accompanying PBS 
diluent is required prior to mixing with the investigational flu freeze-dried cake for 
reconstitution. After reconstitution, the individual dose of the appropriate study vaccine 
will be withdrawn into a syringe using aseptic technique. The needles used for vial 
withdrawal are to be disposed of and replaced by new needles for IM injection.
For non-adjuvanted study vaccines, thorough mixing of two components (accompanying 
PBS diluent and investigational flu freeze-dried cake) is required for reconstitution. The
individual dose of the appropriate study vaccine will be withdrawn into a syringe using 
aseptic technique. The needles used for vial withdrawal are to be disposed of and 
replaced by new needles for IM injection.
 
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PBS, when given as placebo, is presented in a vial and does not require mixing.
The IIV4 will be delivered in a monodose syringe, ready to use.
All vials of vaccines/products provided in this study are intended for single use only.
All vials of vaccines/products should be kept at room temperature for a few minutes prior 
to reconstitution/preparation. All vaccines/products must be administered within one hour 
after being taken out of the fridge.
All used vials will be retained for monitoring and reconciliation purposes.
All doses must have a volume of 0.5 mL for injection and are to be administered IM into 
the deltoid region of the non-dominant arm. All study vaccines will be administered by 
an unblinded member of the site staff who may also participate in dose preparation, but 
who is barred from participation in any other study functions and may not contribute any 
observations.
The needle for any IM injection should be long enough to reach the muscle mass and 
prevent vaccine from seeping into subcutaneous tissue, but not so long as to involve 
underlying nerves and blood vessels or bone. Vaccinators should be familiar with the 
anatomy of the area into which they are injecting vaccine. Refer to Table 17.
 
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Table 17
Dosage and administration
Type of contact 
and timepoint
Study group
Treatment 
name
Volume to be 
administered
Route
Site
Location
Laterality
Visit 1 (Day 1)
cH5/P/cH8-AS03
cH5/1N1 + 
AS03A-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/P/cH5-AS03
cH8/1N1 + 
AS03A-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/5/11-AS03
cH5/P/cH8-AS01
cH5/1N1 + 
AS01E-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/P/cH5-AS01
cH8/1N1 + 
AS01E-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/5/11-AS01
cH5/P/cH8
cH5/1N1
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/5/11
cH8/1N1
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/P/cH5
IIV4
FLU D-QIV
0.5 mL
IM
Deltoid
Non-Dominant**
Visit 4 (Day 57)
cH8/5/11-AS03
cH5/1N1 + 
AS03A-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/5/11-AS01
cH5/1N1 + 
AS01E-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/5/11
cH5/1N1
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/P/cH5-AS03
PBS
0.5 mL
IM
Deltoid
Non-Dominant**
cH5/P/cH8-AS03
cH8/P/cH5-AS01
cH5/P/cH8-AS01
cH8/P/cH5
cH5/P/cH8
IIV4
Visit 8 (Month 14)
cH8/P/cH5-AS03
cH5/1N1 + 
AS03A-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH5/P/cH8-AS03
cH8/1N1 + 
AS03A-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/5/11-AS03
cH11/1N1 + 
AS03A-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/P/cH5-AS01
cH5/1N1 + 
AS01E-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH5/P/cH8-AS01
cH8/1N1 + 
AS01E-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/5/11-AS01
cH11/1N1 + 
AS01E-like
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/P/cH5
cH5/1N1
0.5 mL*
IM
Deltoid
Non-Dominant**
cH5/P/cH8
cH8/1N1
0.5 mL*
IM
Deltoid
Non-Dominant**
cH8/5/11
cH11/1N1
0.5 mL*
IM
Deltoid
Non-Dominant**
IIV4
FLU D-QIV
0.5 mL
IM
Deltoid
Non-Dominant**
IM = Intramuscular
*After reconstitution
**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, an injection in the dominant arm may be performed.
6.4.
Replacement of unusable vaccine/product doses
In addition to the vaccine/product doses provided for the planned number of subjects 
(including over-randomization when applicable), at least 5% additional vaccine/product
doses will be supplied to replace those that are unusable.
 
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6.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of 
any study vaccines/products. If any of these events occur during the study, the subject 
must not receive additional doses of vaccines/products but may continue other study 
procedures at the discretion of the investigator (see Section 8.5):

Anaphylaxis following the administration of vaccine(s)/product(s).

Pregnancy (see Section 8.2.1).

Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe.

Occurrence of an SAE judged to be vaccine-related by the investigator.

Occurrence of a new pIMD or the exacerbation of an existing pIMD. Refer to 
Section 8.1.6.1 for the definition of pIMDs.

Discovery of any health condition which, in the investigator’s opinion, places the 
subject at increased risk from receiving further study vaccines dose(s); or discovery 
of a change in the subject’s health status which make him/her unable to comply with 
protocol-mandated safety follow-up.

Hypersensitivity to the active substances or to any of the excipients or to any 
component that may be present as traces.
The following events constitute contraindications to administration of any study 
vaccines/products at that point in time; if any of these events occur at the time scheduled 
for vaccination, the subject may be vaccinated at a later date, within the time window 
specified in the protocol (see Section 5.5), or the subject may be withdrawn at the 
discretion of the investigator (see Section 8.5):

Acute disease and/or fever at the time of vaccination.

Fever is defined as temperature 38.0°C / 100.4°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 all vaccines/products.
6.6.
Warnings and precautions
Refer to the approved product label/package insert of Fluarix Quadrivalent.
 
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6.7.
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.
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF:

All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting on the day of administration of the first dose 
of study vaccines up to study end (Day 1 to Month 26).

Any concomitant vaccination administered during the period starting 30 days before 
the first dose of study vaccines/products and ending at the last study visit (Day -30 to
Month 26).

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring (fever is defined as 
temperature 38.0°C/100.4°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 6.7.2.

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 SAEs 
and pIMD need to be recorded on the expedited Adverse Event report.
6.7.2.
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 10.5 for the analysis sets.

Any investigational or non-registered product (drug or vaccine) other than the study
vaccines/products 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.
 
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
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab, rituximab).

A vaccine not foreseen by the study protocol administered during the period starting 
30 days before the first dose of study vaccines/products (Visit 1) up to the blood 
sampling at Day 85 (Visit 6) and in the period starting 30 days before the booster 
dose at Month 14 (Visit 8) up to the blood sampling at Month 14 + 28 days 
(Visit 10)*.
*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 (SmPC) or Prescribing Information and according to the local 
governmental recommendations and provided a written approval of the Sponsor is 
obtained.

Administration of any influenza vaccine during the study period.

Immunoglobulins and/or any blood products administered during the study period.

Drug and/or alcohol abuse.
6.8.
Intercurrent medical conditions that may lead to elimination 
of a subject from Per-Protocol analyses
At each study visit subsequent to the first vaccination visit, it must be verified if the 
subject has experienced or is experiencing any intercurrent medical condition. If it is the 
case, the condition(s) must be recorded in the eCRF.
Subjects’ data may be eliminated from the Per-Protocol set for immunogenicity if, during 
the study, they incur a condition that has the capability of altering their immune response 
or are confirmed to have an alteration of their initial immune status (i.e. if any confirmed 
or suspected immunosuppressive or immunodeficient condition appears during the study 
period).
7.
HEALTH ECONOMICS
Not applicable.
 
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8.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAE as provided in 
this protocol.
Each subject will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.
8.1.
Safety definitions
8.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any 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:

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 vaccines/products 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
vaccines/products or a concurrent medication (overdose per se should not be 
reported as an AE/SAE).

Signs, symptoms temporally associated with study vaccines/products administration.

Significant failure of expected pharmacological or biological action.

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
Examples of an AE DO NOT include:

Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.
 
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
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF.
8.1.2.
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 fulfills 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.
 
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Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization.
8.1.3.
Solicited adverse events
Solicited AEs (Table 18 and Table 19) occurring during the 7-day follow-up period after 
each vaccination (day of vaccination and 6 subsequent days) will be recorded in the 
appropriate section of the eCRF. The investigator should record in the eCRF any pain 
relief and/or antipyretics taken by the subject to correct the AEs (local and/or general) 
during the 7-day follow-up period after vaccination.
8.1.3.1.
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 18
Solicited local adverse events
Pain at injection site
Redness at injection site
Swelling at injection site
8.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 19
Solicited general adverse events
Fatigue
Fever
Gastrointestinal symptoms †
Headache
Myalgia
Shivering
Arthralgia
†Gastrointestinal symptoms include nausea, vomiting, diarrhea and/or abdominal pain.
Note: Subjects will be instructed to measure and record the oral body temperature 
(preferred route) in the evening. Should additional temperature measurements be
performed at other times of day, subjects will be instructed to record the highest
temperature in the diary card.
 
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8.1.4.
Unsolicited adverse events
Unsolicited AEs occurring during the 28-day follow-up period (day of vaccination and 27 
subsequent days) after each vaccination will be recorded in the appropriate section of the 
eCRF.
8.1.5.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry,
hematology, urinalysis) or other abnormal assessments (e.g. physical examination 
findings) 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 8.1.1 and 
8.1.2). The grading of laboratory parameters will be based on the Food and Drug 
Administration (FDA) Guidance for Industry “Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (refer to 
APPENDIX C). 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.
In case of clinically significant grade 3 and above abnormal laboratory findings that 
cannot be reasonably explained (e.g. due to a pre-existing or current medical condition), 
the investigator will be recommended to recall the subject in a timely manner (preferably 
within 7 days after investigator’s awareness/assessment of the abnormal findings) for a 
repeat test to confirm the result.
The investigator will exercise his/her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
8.1.6.
Adverse events of specific interest
8.1.6.1.
Potential immune-mediated diseases
AEs of specific interest for safety monitoring include pIMDs, a subset of AEs that 
include autoimmune diseases and other inflammatory and/or neurologic disorders of 
interest which may or may not have an autoimmune etiology. AEs that need to be 
recorded and reported as pIMDs include those listed in Table 20.
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.
Once a pIMD is diagnosed (serious or non-serious) in a subject, the investigator (or 
designate) must complete, date and sign the electronic Expedited Adverse Events Report.
 
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Table 20
List of potential immune-mediated diseases
Neuro-inflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve disorders, including 
paralyses/paresis (e.g. Bell’s palsy) 

Optic neuritis

Multiple sclerosis

Transverse myelitis

Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants

Acute disseminated 
encephalomyelitis, including site 
specific variants (e.g. non-infectious 
encephalitis, encephalomyelitis, 
myelitis, myeloradiculoneuritis)

Myasthenia gravis, including Lambert-
Eaton myasthenic syndrome

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)
Vasculitides
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 
thrombocytop
enia

Antiphospholi
pid syndrome

Pernicious 
anemia

Autoimmune 
aplastic 
anemia

Autoimmune 
neutropenia 

Autoimmune 
pancytopenia

Autoimmune glomerulonephritis,
including:

IgA nephropathy

Glomerulonephritis rapidly 
progressive

Membranous 
glomerulonephritis

Membrano-proliferative 
glomerulonephritis

Mesangio-proliferative 
glomerulonephritis

Tubulo-intestinal 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

Good pasture syndrome

Raynaud’s phenomenon
 
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Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune 
hepatitis

Primary biliary 
cirrhosis

Primary sclerosing 
cholangitis

Autoimmune 
cholangitis

Inflammatory Bowel disease, including:

Crohn’s disease

Ulcerative colitis

Microscopic colitis

Ulcerative proctitis

Celiac disease

Autoimmune pancreatitis

Autoimmune thyroiditis 
(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.
8.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
8.2.1.
Pregnancy
Female subjects who are pregnant or lactating at the time of vaccination must not receive 
additional doses of study vaccines/products but may continue other study procedures at 
the discretion of the investigator.
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE.
Note: The pregnancy itself should always be recorded on the electronic pregnancy report.
The following should always be considered as SAE and will be reported as described in 
Sections 8.4.1 and 8.4.3:

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.
 
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
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 vaccines/products will be 
reported to GSK Biologicals as described in Section 8.4.3. 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.
8.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
8.3.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs starting within 28 days following administration of each dose of study 
vaccines/products (vaccination day and 27 subsequent days) must be recorded into the 
appropriate section of the eCRF, irrespective of intensity or whether or not they are 
considered vaccination-related.
All cases of ILI (refer to Section 5.4.2 for the ILI definition) starting after Dose 1 
administration (Day 1) up to the study conclusion (Month 26) must be recorded into the 
appropriate sections of the eCRF (specific screen for recording of ILI and AE/SAE 
screen, as applicable), irrespective of intensity, or whether or not they are considered 
vaccination-related, or whether or not they are associated with a medically attended visit.
The time period for collecting and recording MAEs/SAEs will begin at the first receipt of 
study vaccines/products and will end 12 months following administration of the last dose 
of study vaccines/products for each subject (Day 1 to Month 26). See Section 8.4 for 
instructions on reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccines/product.
In addition to the above-mentioned reporting requirements and in order to fulfill
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study.
 
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The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccines/products and will end 12 months following administration of the last dose 
of study vaccines/products. See section 8.4 for instructions on reporting of pregnancies.
The time period for collecting and recording of pIMDs will begin at the first receipt of 
study vaccines/products and will end 12 months following administration of the last dose 
of study vaccines/products. See section 8.4 for instructions on reporting of pIMDs.
An overview of the protocol-required reporting periods for AEs, SAEs, MAEs, pIMDs 
and pregnancies is given in Table 21.
 
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Table 21
Reporting periods for collecting safety information
Event
Screen.
Visit*
Visit 1
Visit 4
Visit 8
Study 
Conclusion
Day 1
7 days 
post-vacc
28 days 
post-vacc
Day 57
7 days 
post-vacc
28 days 
post-vacc
Month 14
7 days 
post-vacc
28 days 
post-vacc
Month 26
Solicited local and general AEs
Unsolicited AEs
ILIs
AEs/SAEs leading to 
withdrawal from the study
SAEs
MAEs
SAEs related to study 
participation or concurrent GSK 
medication/vaccine**
Pregnancies
pIMDs
Vacc = vaccination
*Only applicable for Phase I subjects
**To be collected as of consent obtained (e.g. at Screening visit for Phase I subjects and at Visit 1 for Phase II subjects)
Screen. = screening; AEs = adverse events; ILIs = influenza-like illnesses; SAEs = serious adverse events; MAEs = medically attended events; pIMDs = potential immune-mediated
diseases
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8.3.2.
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 21. 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 vaccines/products, the investigator will promptly 
notify the Study Contact for Reporting SAEs.
8.3.3.
Evaluation of adverse events and serious adverse events
8.3.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject should be asked a non-leading 
question such as:
‘Have you felt different in any way since receiving the vaccines/products or since the 
previous visit?’
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in 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.
8.3.3.2.
Assessment of adverse events
8.3.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
 
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Table 22
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
Arthralgia
0
Normal
1
Easily tolerated
2
Interferes with normal activity
3
That prevents normal activity
Myalgia
0
Normal
1
Easily tolerated
2
Interferes with normal activity
3
That prevents normal activity
Shivering
0
Normal
1
Easily tolerated
2
Interferes with normal activity
3
That prevents normal activity
*Fever is defined as temperature 38.0°C / 100.4°F. The preferred location for measuring temperature in this study 
will be the oral cavity.
The maximum intensity of local injection site redness/swelling/fever will be scored at 
GSK Biologicals as follows:
Redness/swelling
0:
20 mm
1:
> 20 - 50 mm
2:
> 50 - 100 mm
3:
> 100 mm
Temperature > 39°C/102.2°F will be considered as grade 3 fever.
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
 
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The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities. In 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 8.1.2.
Note that the grading of laboratory parameters will be based on the FDA Guidance for 
Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials” (refer to Section 8.1.5 and APPENDIX C).
8.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between study vaccines/products 
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 vaccines/products will be considered and investigated. The investigator will also 
consult the IB and/or SmPC and/or Prescribing Information for marketed products to 
determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
 
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All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question: Is there a reasonable possibility that the AE may have been caused 
by the study vaccine/product?
YES
:
There is a reasonable possibility that the study vaccines/products
contributed to the AE. 
NO
:
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccines/products. There are other, more likely 
causes and administration of the study vaccines/products is not suspected to 
have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccines/products, if applicable.

Erroneous administration.

Other cause (specify).
8.3.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
8.3.3.4.
Medically attended events
For each solicited and unsolicited symptom the subject experiences, the subject will be 
asked if he/she received medical attention defined as hospitalization, or an otherwise 
unscheduled visit to or from medical personnel for any reason, including emergency 
room visits. This information will be recorded in the eCRF.
 
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8.4.
Reporting of serious adverse events, pregnancies, and 
other events
8.4.1.
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 23, once the investigator determines that 
the event meets the protocol definition of a SAE.
Pregnancies that occur in the time period defined in Section 8.3 will be reported promptly 
to GSK within the timeframes described in Table 23, once the investigator becomes 
aware of the pregnancy.
pIMDs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 23, once the investigator determines that 
the event meets the protocol definition of a pIMD.
Table 23
Timeframes for submitting serious adverse event, pregnancy and
other events reports to GSK Biologicals
Type of Event
Initial reports
Follow-up of relevant information on a 
previous report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours* ‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited 
Adverse Events Report
Pregnancies
2 weeks*
electronic pregnancy report
2 weeks*
electronic pregnancy report
pIMDs
24 hours** ‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited 
Adverse Events Report
*Timeframe allowed after receipt or awareness of the information.
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD.
‡ The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD.
8.4.2.
Contact information for reporting serious adverse events,
pregnancies and pIMDs
Study Contact for Reporting SAEs, pIMDs and pregnancies
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs, pIMDs and pregnancies
24/24 hour and 7/7 day availability
GSK Biologicals Clinical Safety & Pharmacovigilance
US sites only: Fax:
Canadian sites only: Fax:
Outside US & Canada sites: Fax:
 or 
Email address:

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PPD
PPD
PPD
PPD
PPD

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8.4.3.
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.
8.4.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events 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.
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report.
 
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8.4.5.
Reporting of pIMDs to GSK Biologicals
Once a pIMD 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 information regarding a pIMD, 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 pIMD causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the pIMD.
Refer to Section 8.4.3.1 for back-up system in case the electronic reporting system does 
not work.
8.4.6.
Updating of SAE, pregnancy, and pIMD information after removal 
of write access to the subject’s eCRF
When additional SAE, pregnancy or pIMD information is received after removal of the 
write access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 23.
8.4.7.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.4.1. 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 vaccines/products and unexpected. The 
purpose of the report is to fulfill specific regulatory and GCP requirements, regarding the 
product under investigation.
 
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8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies
8.5.1.
Follow-up of adverse events and serious adverse events
8.5.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 23).
All MAEs, AEs and pIMDs (serious or non-serious) documented at a previous 
visit/contact and designated as not recovered/not resolved or recovering/resolving will be 
reviewed at subsequent visits/contacts until the 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 the last vaccination.
8.5.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

With MAEs, SAEs, pIMDs (serious or non-serious), or subjects withdrawn from the 
study as a result of an AE, until the event has resolved, subsided, stabilized, 
disappeared, or until the event is otherwise explained, or the subject is lost to follow-
up.

With other non-serious AEs, until the event is otherwise explained or they are 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.
 
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8.5.2.
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 
doesn’t need to be longer than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
8.6.
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/pIMD
should be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to 
Section 6.7).
8.7.
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.
8.8.
Holding rules and safety monitoring
Study holding rules (see Section 8.8.1) and safety monitoring (see Section 8.8.2) have 
been defined.
The investigator is not permitted to administer Dose 2 of the study vaccine to the subjects 
enrolled in the Phase I until receipt of the favorable outcome of the IDMC safety 
evaluation based on safety data collected up to 7 days post-Dose 1 in at least 60 Phase I 
subjects.
Vaccination in Phase II subjects can only start after receipt of the favorable outcome of 
the IDMC safety evaluation based on safety data collected up to 7 days post-Dose 1 in all
Phase I subjects (N = 80) (refer to Enrolment design).
During the entire study period, there will be regular IDMC reviews (monthly during the 
vaccination phases and every 6 months during the safety follow-up phases).
 
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Dose 3 (booster) can only be administered to Phase II subjects upon favorable outcome of 
the 7-day post-Dose 3 safety data review of Phase I subjects by the IDMC.
In addition, if any safety concern is identified by the investigator (i.e. meeting of holding 
rules 1a-1d see Table 24or any other safety concern), he/she should inform GSK
Biologicals immediately, and vaccination may be put on hold as a consequence.
If any safety concern is identified in other study(ies) in which the investigational SUIV is 
used, GSK Biologicals might also request to put the vaccination in this study on hold 
during the period needed to perform the assessment of safety data of the other study(ies).
8.8.1.
Holding rules
Study holding rules which will be applied during the safety evaluation are defined below.
If a holding rule 1a through 1d is observed by the investigator, it will be reported 
promptly to GSK within 24 hours. Meeting the other holding rules will be determined by 
IDMC review of safety data at regular intervals.
These holding rules have been written under the assumption that safety data of all 
subjects will be available. Therefore, the investigator will be requested to record safety 
data meeting the criteria of holding rules in the eCRF within 24 hours after reception of 
the data to ensure that all necessary information are available for IDMC reviews. If the 
data from all subjects are not available, the holding rules will be assessed on a pro-rata 
basis.
Upon meeting of any holding rules, further vaccination will be immediately put on hold 
pending safety review and consultation with the GSK Biologicals’ Vaccine Safety 
Monitoring Board (VSMB), as appropriate.
GSK Biologicals’ decision on whether to suspend, modify, or continue the conduct of the 
study on all groups or on selected groups will be communicated to the investigators, to 
CBER, and to the IRBs/IECs.
In case of a safety concern, the final responsibility to recommend whether or not the trial 
should be stopped permanently rests with the sponsor, after having considered all the 
safety information available. If the trial is stopped, a letter indicating the reasons for 
stopping the study will be sent to the IRBs/IECs via the investigator(s), and to CBER via 
GSK Biologicals.
 
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Table 24
Study holding rules
Holding 
rules
Event
Number/
percentage
of subjects
1a
Death or any life-threatening SAE.
1
1b
Any SAE that cannot reasonably be attributed to a cause other than vaccination
1
1c
Any withdrawal from the study or withdrawal from study vaccine(s)/product(s) (by 
investigator or subject request) following a grade 3 AE that cannot reasonably be 
attributed to a cause other than vaccination.
1
1d
Any local or general solicited AE leading to hospitalization, or fever > 40°C
(104°F) (oral route) that cannot reasonably be attributed to a cause other than 
vaccination, or necrosis at the injection site, within the 7-day (Days 1-7) post-
vaccination period.
1
2a
Any grade 3 solicited local AE lasting 48h or more in an investigational group, 
within the 7-day (Days 1-7) post-vaccination period.
30% (and 
2 subjects 
in one group)
2b
Any grade 3 solicited general AE lasting 48h or more in an investigational group, 
that cannot reasonably be attributed to a cause other than vaccination, within the 7-
day (Days 1-7) post-vaccination period.
20% (and 
2 subjects 
in one group)
2c
Any grade 3 unsolicited AE in an investigational group, that cannot reasonably be 
attributed to a cause other than vaccination, within the 28-day (Days 1-28) post-
vaccination period
OR
Any grade 3 abnormality in pre-specified hematological or biochemical laboratory 
parameters* in an investigational group, that cannot reasonably be attributed to a 
cause other than vaccination, within the 7 days post-vaccination.
20% (and 
2 subjects 
in one group)
*Grading of laboratory parameters will be based on the FDA Guidance for Industry “Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (refer to APPENDIX C).
Figure 2 gives the probability of not meeting each holding rule 1 and 2 for 45 subjects in 
an investigational group. This evaluation was performed for the sample size of the initial 
protocol (i.e. 450 subjects, 45/group) and it was not repeated at the time of the protocol 
amendment 1 because of the small difference in the number of subjects per group (now 
470 subjects in total, 47/group).
Each holding rule 1a-d has 80% chance of not being met for an event with a true 
incidence rate below 1.0% and has less than 5% of chance of not being met for an event 
with a true incidence rate above 7%.
Holding rule 2a has more than 90% chance of not being met for an event with a true 
incidence rate below 20% and has less than 52% of chance of not being met for an event 
with a true incidence rate above 30%.
Holding rules 2b and 2c have more than 90% chance of not being met for an event with a 
true incidence rate below 10% and has less than 45% of chance of not being met for an 
event with a true incidence rate above 20%.
 
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Figure 2
Probability of successfully completing the study in function of 
adverse events incidence rates
8.8.2.
Safety monitoring
An IDMC will be established by GSK Biologicals for the purpose of monitoring the 
study and to provide independent, non-binding advice on safety and ethics. The IDMC 
will provide recommendations about stopping, holding, continuing or modifying the trial. 
During the whole study period, there will be regular IDMC reviews (monthly during the 
vaccination phases and every 6 months during the safety follow-up phases. The frequency 
of these reviews may be adapted upon IDMC recommendation if deemed necessary).
During the Phase I enrolment, subjects will be vaccinated one at a time, at least 60 
minutes apart, with a maximum of 10 subjects per day until 80 subjects are enrolled (i.e. 
to obtain treatment groups of at least 8 subjects/group):

If no safety issue is identified upon review of the 7 days post-Dose 1 safety data 
(Days 1-7) of at least 60 Phase I subjects, Dose 2 will be administered to Phase I 
subjects.

If no safety issue is identified upon review of the 7-day post-Dose 1 safety data 
(Days 1-7) of all Phase I subjects (N = 80), Phase II enrolment will start.
Phase I subjects will be vaccinated one at the time, at least 60 minutes apart, with a 
maximum of 10 subjects a day. This is applicable for Dose 1 (Day 1), Dose 2 (Day 57) 
and Dose 3 (booster) (Month 14) of the Phase I subjects.
Phase II subjects will be enrolled and vaccinated without limitation on the number of 
vaccinees per day or time between consecutive subjects.
 
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The frequency of IDMC sessions and other operational details are described in the IDMC 
charter. In case of a serious safety issue during the study, GSK Biologicals will inform 
the IDMC as well as fulfil its regulatory obligation expeditiously.
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who returns for the concluding visit foreseen in the protocol (Visit 12) is
considered to have completed the study.
9.2.
Subject withdrawal
Withdrawals will not be replaced.
9.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit 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:

Serious adverse event.

Unsolicited non-serious adverse event.

Solicited adverse event

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).
 
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*In case a subject is withdrawn from the study because 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 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 8.5.1.2).
9.2.2.
Subject withdrawal from study vaccines/products
A ‘withdrawal’ from the study vaccines/products refers to any subject who does not 
receive the complete treatment, i.e. when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the study vaccines/products may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol.
Information relative to premature discontinuation of the study vaccines/products will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination/treatment was made by 
the subject himself/herself, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Unsolicited non-serious adverse event.

Solicited adverse event

Not willing to be vaccinated

Other (specify).
9.3.
Extension study
During the study conclusion visit, the investigator will ask each subject if they are 
interested to participate in a long-term study. If a subject is not interested in participating 
in the long-term study, the reason for refusal will be documented in the subject’s eCRF.
9.4.
Screening failures
Only applicable for Phase I subjects: Screening and baseline failures are defined as 
subjects who withdraw or are withdrawn from the study after giving informed consent, 
but before receiving the study vaccine at Day 1. Data reported to the eCRF for these 
subjects will be limited to:

ICF information,

Demographic data,

Inclusion/exclusion criteria,
 
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
Blood sampling for hematology/biochemistry (if performed).

Screening conclusion and study conclusion data.
Medical history, physical examination, height, weight and vital signs data, and history of 
previous influenza vaccination do not need to be reported to the eCRF.
10.
STATISTICAL METHODS
10.1.
Primary endpoints
Reactogenicity and safety

Occurrence of solicited local and general AEs after each vaccination:

Occurrence of solicited local AEs during a 7-day follow-up period (i.e. on the 
day of vaccination and 6 subsequent days) after each vaccine dose, in all vaccine 
groups.

Occurrence of solicited general AEs during a 7-day follow-up period (i.e. on the 
day of vaccination and 6 subsequent days) after each vaccine dose, in all vaccine 
groups.

Occurrence of unsolicited AEs after each vaccination:

Occurrence of unsolicited AEs during a 28-day follow-up period (i.e. on the day 
of vaccination and 27 subsequent days) after each vaccine dose, in all vaccine 
groups.

Occurrence of hematological and biochemical laboratory abnormalities after each 
vaccination:

Any hematological (red blood cells, white blood cells and differential count, 
platelets count and hemoglobin level) or biochemical (alanine aminotransferase, 
aspartate aminotransferase, creatinine, blood urea nitrogen [BUN] and BUN-to-
creatinine ratio) laboratory abnormality at each visit subsequent to Day 1, in all 
vaccine groups.

Occurrence of MAEs, pIMDs and SAEs:

Occurrence of MAEs, pIMDs and SAEs throughout the entire study period, in 
all vaccine groups.
Immunogenicity
Anti-H1 stalk immune response measured by ELISA and by MN assay 28 days after each 
priming dose:

Levels of anti-H1 stalk antibody titers by ELISA and by MN assay.
The following aggregate variables will be calculated for the above parameters with 
95% confidence interval (CI):

Seropositivity rates and geometric mean titers (GMTs) at Days 1, 29 and 85.
 
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
Percentage of subjects with a 4-fold increase from Day 1 to Days 29 and 85.

Percentage of subjects with a 10-fold increase from Day 1 to Days 29 and 85.

Mean geometric increase (MGI) from Day 1 to Days 29 and 85.
10.2.
Secondary endpoints (Amended: 11 July 2019)
Immunogenicity
Adjuvant effect on the anti-stalk immune response in terms of:

GMT ratio for anti-stalk ELISA titer SUIV+AS03 or AS01/SUIV non-adjuvanted, 
28 days post vaccination (i.e. at Day 29 to evaluate the adjuvant effect post-dose 1 
and at Day 85 to evaluate the adjuvant effect post-dose 2).
Anti-H1 stalk immune response measured by ELISA and by MN assay:

Levels of anti-H1 stalk antibody titers by ELISA post-each vaccination.
The following aggregate variables will be calculated for the above parameters with 
95% CI:

Seropositivity rates and GMTs at Days 1, 29, 85, Month 8, Month 14, Month 14 
+ 28 days, Month 20 and Month 26.

Percentage of subjects with a 4-fold increase in antibody titers by ELISA from 
Day 1 to each subsequent timepoint listed above.

Percentage of subjects with a 10-fold increase in antibody titers by ELISA 
from Day 1 to each subsequent timepoint listed above.

MGI in antibody titers by ELISA from Day 1 to each subsequent timepoint 
listed above.

Levels of anti-H1 stalk antibody titers by MN assay.
The following aggregate variables will be calculated for the above parameters with 
95% CI:

Seropositivity rates and GMTs at Days 1, 29 and 85.

Percentage of subjects with a 4-fold increase in antibody titers by MN assay 
from Day 1 to each subsequent timepoint listed above.

Percentage of subjects with a 10-fold increase in antibody titers by MN assay 
from Day 1 to each subsequent timepoint listed above.

MGI in antibody titers by MN assay from Day 1 to each subsequent timepoint 
listed above.
Breadth of the immune response:

Levels of anti-H2 and anti-H18 antibody titers by ELISA.
The following aggregate variables will be calculated for the above parameters with 
95% CI:
 
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
Anti-H2 and anti-H18 seropositivity rates and GMTs at Days 1, 29, 85, Month 8, 
Month 14, Month 14 + 28 days, Month 20 and Month 26.

Percentage of subjects with a 4-fold increase in anti-H2 and anti-H18 antibody 
titers from Day 1 to each subsequent timepoint listed above.

Percentage of subjects with a 10-fold increase in anti-H2 and anti-H18 
antibody titers from Day 1 to each subsequent timepoint listed above.

MGI in anti-H2 and anti-H18 antibody titers from Day 1 to each subsequent 
timepoint listed above.

Levels of antibody titers by MN assay for H1N1 swine influenza and IIV4 H1N1 
vaccine strains.
The following aggregate variables will be calculated for the above parameters with 
95% CI:

Seropositivity rates and GMTs at Days 1, 29 and 85.

Percentage of subjects with a 4-fold increase in antibody titers from Day 1 to 
each subsequent timepoint listed above.

Percentage of subjects with a 10-fold increase in antibody titers from Day 1 to 
each subsequent timepoint listed above.

MGI in antibody titers from Day 1 to each subsequent timepoint listed above.
10.3.
Tertiary endpoints (Amended: 11 July 2019)

Evaluation of CMI parameters in terms of frequencies of:

Antigen-specific CD4+/CD8+ T-cells identified as producing at least two 
markers among CD40L, IL-2, TNF-and IFN-upon in vitro stimulation at 
Days 1, 29 and 85.

B-memory cells reactive with the challenge antigen(s) at Days 1, 8, 29, 64 and
85.

Plasmablasts reactive with the challenge antigens at Days 1, 8 and 64.

Levels of HI antibody to chimeric vaccine strains cH5/1N1 and cH8/1N1:
The following aggregate variables will be calculated with 95% CI:

Seropositivity rates and GMTs at Days 1, 29 and 85.

Seroprotection rate (SPR) at each timepoint listed above.

Seroconversion rate (SCR) at Days 29 and 85.

MGI from Day 1 to each subsequent timepoint listed above.

Assessment of the in vivo protective effect of the anti-stalk antibodies when 
transferring Day 1 and Day 85 pooled serum from all evaluable subjects of each 
vaccine groups to mice that will be subsequently challenged with cH6/1N5* or with 
H1N1 contained in the IIV4, using the following endpoints [refer to APPENDIX D]:
 
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
Survival over 14 days post-challenge (day of death/euthanasia for weight loss 
> 25% baseline body weight) in groups of 35 mice**/serum pool/vaccine 
group/timepoint.

Weight loss (change from baseline over 14 days post-challenge) in groups of 35
mice**/serum pool/vaccine group/timepoint.

Lung virus titer in TCID50/mg (log10 fold change [Day 1 minus Day 85]), within 
challenge group.

Pre- and post-transfer titer of human IgG to cH6/1N5* by ELISA or HI.

Pre- and post-transfer titer of human IgG to H1N1 by ELISA or HI.

Pre- and post-transfer titer of human IgG to recombinant HA protein by ELISA.
*Or an alternative challenge virus with similar attributes but more fit for purpose.
**If sufficient serum volumes are not available, and depending on the challenge virus pathogenicity, 
the number of mice can be reduced to as low as 10 mice per timepoint and virus challenge.
10.4.
Determination of sample size
10.4.1.
Descriptive objectives
The primary objectives of the study are to assess the reactogenicity and safety of each 
vaccine dose throughout the study and to describe the anti-H1 stalk immune response 28 
days after each priming dose.
At the time of the protocol amendment 1, it was decided to increase the sample size from 
450 to 470 subjects to take into account a larger rate of non-evaluable subjects than 
anticipated. The power computations from the initial protocol relative to safety endpoints 
were not modified because of the small sample size increase (about 2 subjects per group, 
from 45 to 47). The immunogenicity endpoints evaluation will be done primarily on the 
Per-Protocol set, which is not deemed to increase (about 43 subjects per group).
Table 25 shows the true proportions associated with a 90% probability to observe an 
event in 45 subjects (e.g. SAE, pIMD).
Table 25
True proportions associated with a 90% probability to observe a 
certain number of adverse events within a group (45 subjects)
True 
proportion
Number of adverse events observed 
with > 90% probability
0.049
> 0
0.083
> 1
0.114
> 2
0.142
> 3
Table 26 illustrates the 95% CIs for different possible numbers of AEs within each group.
 
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Table 26
Two-sided exact 95% confidence intervals for the true adverse event 
rate at different possible observed adverse event rates (45 subjects)
Observed number of 
adverse events
Observed adverse 
event proportion
95% exact confidence interval
Lower limit
Upper limit
0
0.000
0.000
0.079
1
0.022
0.001
0.118
2
0.044
0.005
0.152
3
0.067
0.014
0.183
4
0.089
0.025
0.212
5
0.111
0.037
0.241
10
0.222
0.112
0.371
20
0.444
0.296
0.600
30
0.667
0.511
0.800
Table 27 presents the 95% CIs for different possible rates of immunological response 
within each group. A rate of unevaluable subjects of 2/45 (4%) has initially been 
considered for the immune response post-primary vaccination. As from protocol 
amendment 1, a rate of non-evaluable subjects of 4/47 (9%) has been considered for the 
immune response post-primary vaccination.
Table 27
Two-sided exact 95% confidence intervals for the true 
immunological response rate at different possible observed 
response rates (43 evaluable subjects)
Observed number of 
responses
Observed response 
proportion
95% exact confidence interval
Lower limit
Upper limit
25
0.581
0.421
0.730
30
0.698
0.539
0.828
35
0.814
0.667
0.916
40
0.930
0.809
0.985
*Response rate can be either seropositivity rate, percentages of subjects with a 4-fold increase or percentages of 
subjects with a 10-fold increase
The advantage of adding an adjuvant and the preference for a specific priming 
sequence/number of priming doses will be assessed by making use of the factorial nature 
of the trial design, which is summarized in Table 28. The anti-H1 stalk antibody titers by 
ELISA will primarily be modelled. The standard deviation (SD) used for the calculation 
cannot be obtained at the present stage due to unavailability of the final assay under 
development at Néomed. As a consequence, the assumed SD of log10 titers was derived 
from study FLU-CC-SUIV-001 (e-track number 201598). In that study, anti-H1 HA stalk 
ELISA antibody titers were obtained using the existing anti-stalk ELISA [Pica, 2012],
and the observed SD of log10 titers was 0.43 (Day 42). SDs of 0.45 and 0.50 were thus 
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Table 28
Factorial study design: repartition of the subjects according to the 
nature of the priming sequence and to the type of adjuvant system
N evaluable 
subjects
1 priming dose 
(cH8/1N1)
1 priming dose 
(cH5/1N1)
2 priming doses 
(cH8/1N1 and 
cH5/1N1)
Total
AS01
43 subjects
43 subjects
43 subjects
129 subjects
AS03
43 subjects
43 subjects
43 subjects
129 subjects
No adjuvant
43 subjects
43 subjects
43 subjects
129 subjects
Total
129 subjects
129 subjects
129 subjects
387 subjects
Using a 1-way Analysis of Variance (ANOVA) power analysis in PASS 12.0.10, 
considering 3 pooled groups of size n = 129 subjects, 2-sided alpha = 0.10, SD of log10
(titers) = 0.45 to 0.50, and a scenario with a maximum difference in GMTs of 2-fold
(repartition type 1-1-2 or 1-2-2), we obtain the SD of group means associated with 80% 
power to detect differences among the means versus the alternative of equal means. This 
value is then converted in fold increase according to the scenario. The values are 
presented in Table 29.
Table 29
Detectable fold increase in GMTs with 80% power (N/group = 129, 2-
sided alpha = 0.10, 1-way ANOVA power analysis)
10.4.2.
Confirmatory objective
The most important secondary objective in the study is to establish whether an adjuvant 
system is needed. This evaluation will primarily be based on levels of anti-H1 stalk titers 
by ELISA at Day 29 and Day 85 (i.e. 28 days post-last vaccination). Power calculations 
were conducted for the detection of differences in GMTs between each of the 3 pooled 
groups of 129 subjects (AS01, AS03, no adjuvant) considering a margin of superiority of 
1.5 fold. The 2-sided significance level (alpha) of each test is 0.0554; it corresponds to a 
critical value from a 2-sided Dunnett test (accounting for the comparison of AS01 to non 
adjuvanted and AS03 to non-adjuvanted) of 1.922 (2-sided alpha = 0.10, DF = 384 (129 
subjects/pooled group), 3 pooled groups).
Table 30 provides the power associated with different true GMT ratio values using PASS 
12.0.2 Two-Sample T-Test (Superiority by a Margin) Power Analysis. Again, SDs of 
log10 (titers) of 0.45 and 0.50 were considered. With a standard deviation of 0.45, the
power reaches 80% if the actual difference is 2.14 fold or greater. Similarly, with a SD of 
0.50, the power reaches 80% if the actual difference is 2.23 fold or greater.
SD of log10 (titers)
SD of group Means
Detectable Fold increase
0.45
0.064
1.36
0.50
0.071
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Table 30
Power to show a difference in means using a 1.5 superiority margin 
(N/pooled group = 129, 2-sided alpha = 0.055375)
Actual difference in 
means (fold-difference)
SD of log10 (titers)
Power
2.00
0.45
0.620
2.00
0.50
0.533
2.14
0.45
0.800
2.14
0.50
0.714
2.23
0.45
0.875
2.23
0.50
0.800
2.50
0.45
0.979
2.50
0.50
0.949
3.00
0.45
0.999
3.00
0.50
0.998
The success criterion for this objective can be defined as follows: the use of the adjuvant 
(AS01 or AS03) will be considered justified if the lower limit of the 94.46% CI of the 
GMT ratio (adjuvanted vs non-adjuvanted) is > 1.50.
10.5.
Analysis sets
10.5.1.
Exposed set
The Exposed Set (ES) will include all subjects with at least one vaccine administration 
documented:

A safety analysis based on the ES will include all vaccinated subjects.

An immunogenicity analysis based on the ES will include all vaccinated subjects for 
whom immunogenicity results are available.
The ES analyses will be performed per treatment actually administered.
10.5.2.
Per-Protocol set for analysis of immunogenicity
The Per-Protocol set will be adapted by timepoint to include all eligible subjects’ data up 
to the time of important protocol deviation, namely:

Dose of study vaccine not according to protocol procedures and to their random 
assignment.

Randomisation code broken.

Non-compliance with the procedures and intervals defined in the protocol (refer to
Table 7).

Intake of concomitant medication/product/vaccination leading to elimination from 
the Per-Protocol analysis.

Occurrence of medical condition leading to elimination from the Per-Protocol 
analysis (refer to Section 6.7.2).
 
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10.6.
Derived and transformed data

The cut-off value is defined by the laboratory before the analysis and is described in 
Section 5.7.3. A seronegative subject is a subject whose titre is below the cut-off 
value. A seropositive subject is a subject whose titre is greater than or equal to the 
cut-off value.

The GMTs calculations are performed by taking the anti-log of the mean of the log 
titre transformations. Antibody titres below the cut-off of the assay will be given an 
arbitrary value of half the cut-off for the purpose of GMT calculation.

The MGI is defined as the geometric mean of the fold increase in serum HI titres
post-vaccination compared to Day 1.

All CIs are 95% CIs. The 95% CIs for GMT are obtained within each group 
separately. The 95% CI for the mean of log-transformed titre is first obtained 
assuming that log-transformed titres are normally distributed with unknown variance. 
The 95% CI for the GMT is then obtained by exponential-transformation of the 95% 
CI for the mean of log-transformed titre.

Handling of missing data: for a given subject and a given immunogenicity 
measurement, missing or non-evaluable measurements will not be replaced. 
Therefore, analysis will exclude subjects with missing or non-evaluable 
measurements.

Reactogenicity and safety

For the analysis of solicited symptom, missing or non-evaluable measurements 
will not be replaced. Therefore the analysis of the solicited symptoms based on 
the ES will include only subjects/doses with documented safety data (i.e. 
symptom screen completed). 

For the analysis of unsolicited AEs/MAEs/ILIs/SAEs/concomitant medication,
all vaccinated subjects will be considered and subjects who did not report an 
event will be considered as subjects without an event.
10.7.
Analysis of demographics
Demographic characteristics (center, age at study vaccination in years, gender, ethnicity, 
geographic ancestry, history of influenza vaccination since the 2014/2015 season) and 
withdrawal status will be summarized by group in the ES, using descriptive statistics:

Frequency tables will be generated for categorical variable such as center.

Mean, median, standard deviation will be provided for continuous data such as age.
 
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10.8.
Analysis of safety
The analysis will be performed on the ES.
All analyses will be descriptive. Data will be presented by dose, overall/dose and 
overall/subject. Outputs will be presented by study group. Analyses will be repeated 
pooling groups according to the adjuvant (AS01, AS03, no adjuvant).

The percentage of subjects with at least one local AE (solicited and unsolicited), with 
at least one general AE (solicited and unsolicited) and with any AE during the 
solicited follow-up period will be tabulated with exact 95% CI. The same 
calculations will be performed for AEs rated as grade 3.

The percentage of subjects reporting each individual solicited local and general AE 
during the solicited follow-up period will be tabulated with exact 95% CI. The same 
tabulation will be performed for grade 3 AEs and for AEs with relationship to 
vaccination.

The verbatim reports of unsolicited AEs will be reviewed by a physician and the 
signs and AEs will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA). The percentage of subjects with at least one report of 
unsolicited AE classified by the MedDRA and reported up to 28 days after 
vaccination will be tabulated with exact 95% CI. The same tabulation will be 
performed for grade 3 unsolicited AEs and for unsolicited AEs with a relationship to 
vaccination.

The percentage of subjects with MAE(s) will be summarized by group with exact 
95% CI.

The percentage of subjects with episode(s) of ILI will be summarized by group with 
exact 95% CI. (Amended: 11 July 2019)

At each hematology/biochemistry sampling timepoint, by study group, individual 
hematological and biochemical values will be presented as number of subjects out of 
range (above and below normal range) and tabulated by toxicity grading (refer to
APPENDIX C). In addition, changes from baseline (median/interquartile range) will
be presented.

SAEs and pIMDs will be described in detail. Withdrawals due to (S)AEs will also be 
summarized.
 
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10.9.
Analysis of immunogenicity
The analysis of immunogenicity will be performed primarily on the Per-Protocol set. If 
5% or more of the vaccinated subjects are eliminated from the Per-Protocol set at one 
timepoint, a second analysis will be performed on the ES.
10.9.1.
Within group assessment
10.9.1.1.
Humoral immunogenicity assessment
For each study group, at each timepoint at which the tests are done and results are 
available, for each humoral immunity parameter, the following analyses will be 
performed:

Seropositivity rates and GMTs, with exact 95% CI.

MGI from Day 1, with 95% CI.

Percentage of subjects with at least 4-fold increase from Day 1, with exact 95% CI.

Percentage of subjects with at least 10-fold increase from Day 1, with exact 95% CI.

Distribution of antibody titers using reverse cumulative distribution curves.
The correlation between anti-H1 HA stalk ELISA and anti-H1 HA stalk MN assay results 
will be explored.
10.9.1.2.
CMI assessment
For each study group, at Days 1, 8, 29, 64 and 85, the frequency of specific CD4+/CD8+ 
T-cells, B-memory cells and plasmablasts will be summarised using descriptive statistics.
(Amended: 11 July 2019)
10.9.2.
Between group assessment
10.9.2.1.
ANCOVA modelling
The anti H1 HA stalk ELISA titers will be modelled using an ANCOVA model. Twenty-
eight days post priming/post booster log10 (titers) will be modelled as a function of the 
adjuvant (AS01, AS03, no adjuvant) and of the priming sequence (cH8/1N1, cH5/1N1, 
cH8/1N1 and cH5/1N1), including the pre-vaccination titer as covariate. The primary 
analysis will not include any interaction term.
For the parameter related to the priming sequence, in absence of a reference group, the 
overall test of difference (to reject the null hypothesis of no difference) will be done at 
significance level 0.10. If the test is statistically significant at level 0.10, the different 
pairwise comparisons will be performed at the same alpha level.
 
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For the parameter related to the adjuvant, the pairwise comparisons to the non-adjuvant 
reference group (AS01 vs no adjuvant and AS03 vs no adjuvant) are planned to be 
performed without preamble. Therefore, a Dunnett test will be used for the pairwise 
comparisons.
10.9.2.2.
Descriptive assessment
GMT ratios and their 2-sided 95% CI will be computed after fitting an ANCOVA model 
on the log10 transformation of ELISA/MN titers, including vaccine group as fixed effect 
and the pre-vaccination titer as covariate.
Differences in percentage of subjects with a fold increase from baseline and their 95% 
CIs will be calculated.
The assessment timepoints will be described in the Statistical Analysis Plan, but generally 
speaking, the 4 weeks post-dose results will be compared.
The following group ratios/differences will be provided:

Evaluation of the proof of principle:

cH8/5/11-AS03 vs IIV4.

cH8/5/11-AS01 vs IIV4.

cH8/5/11 vs IIV4.

Evaluation of the number of priming doses:

cH8/5/11-AS03 vs cH8/P/cH5-AS03.

cH8/5/11-AS01 vs cH8/P/cH5-AS01.

cH8/5/11 vs cH8/P/cH5

Assessment of the adjuvant systems:

cH8/5/11-AS03 vs cH8/5/11-AS01.

cH8/P/cH5-AS03 vs cH8/P/cH5-AS01.

cH5/P/cH8-AS03 vs cH5/P/cH8-AS01.

Description of the priming sequence:

cH8/P/cH5-AS03 vs cH5/P/cH8-AS03.

cH8/P/cH5-AS01 vs cH5/P/cH8-AS01.
Additional ratios/differences might be considered if deemed necessary at the time 
analysis.
 
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10.10.
Interpretation of analyses
Comparative analyses will be descriptive with the aim to characterise the difference in 
reactogenicity/immunogenicity between groups.
With respect to the secondary objective and decision rule linked to the use of an adjuvant, 
the interpretation will be done according to the CI for the GMT ratios (pooled AS01 vs 
pooled non-adjuvanted and pooled AS03 vs pooled non-adjuvanted). The use of the 
adjuvant (AS01 or AS03) will be considered justified if the lower limit of the 94.46% CI 
of the GMT ratio (adjuvanted vs non-adjuvanted) is > 1.50.
10.11.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final Study Report.
10.11.1.
Sequence of analyses
All interim analyses will be conducted on data as clean as possible. The final analysis 
will be performed on fully clean data.
Excluding the IDMC monitoring analyses, the analyses will be performed in a stepwise 
manner:

Interim analyses will be performed when safety, reactogenicity and immunogenicity 
(including at least H1 anti-stalk ELISA) data from all subjects are available up to 
Day 85 and up to Month 14 + 28 days*. The GSK statistician/statistical analyst will 
be unblinded for these analyses (i.e. will have access to the individual subject 
treatment assignment). The remaining GSK study personnel will remain blinded (see 
Section 5.3).
*Note that for this timepoint, an additional interim analysis will be performed on all 
available immunogenicity data when Phase I subjects eligible for booster vaccination 
have completed their Visit 10 according to the allowed interval.

A final analysis of all data will be performed when all data up to study conclusion 
are available. This analysis will be reported in an integrated Study Report and made 
available to the investigators.
If the data for tertiary endpoints become available at a later stage, (an) additional 
analysis/analyses will be performed. These data will be documented in annex(es) to the 
Study Report and will be made available to the investigators at that time.
10.11.2.
Statistical considerations for interim analyses
No statistical adjustment will be made for the interim analyses, which are intended to 
provide final outputs related to the different endpoints and timepoints in a phased 
manner.
 
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11.
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. 
11.1.
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.
11.2.
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.
 
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The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the 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.
11.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period 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.
11.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
 
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11.5.
Posting of information on publicly available clinical trial 
registers and publication policy
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post PCD and to have secondary endpoint 
disclosed at latest 12 months after the Last Subject Last Visit 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.
11.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
11.7.
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.
12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
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13.
REFERENCES
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
Cox NJ, Fukuda K. Influenza. Infect.Dis.Clin.North Am. 1998;12:27-38.
Crotty S, Aubert RD, Glidewell J, Ahmed R. Tracking human antigen-specific memory B 
cells: a sensitive and generalized ELISPOT system. J Immunol Methods. 2004 Mar; 286 
(1-2): 111-22.
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
Gauger PC, Vincent AL, Loving CL, Lager KM, Janke BH, Kehrli ME Jr, Roth JA. 
Enhanced pneumonia and disease in pigs vaccinated with an inactivated human-like (δ-
cluster) H1N2 vaccine and challenged with pandemic 2009 H1N1 influenza virus. 
Vaccine. 2011 Mar 24; 29 (15): 2712-9.
Goff PH, Krammer F, Hai R, Seibert CW, Margine I, García-Sastre A, Palese P. 
Induction of cross-reactive antibodies to novel H7N9 influenza virus by recombinant 
Newcastle disease virus expressing a North American lineage H7 subtype hemagglutinin. 
J Virol. 2013a Jul; 87 (14): 8235-40.
Goff PH, Eggink D, Seibert CW, Hai R, Martínez-Gil L, Krammer F, Palese P. Adjuvants 
and immunization strategies to induce influenza virus hemagglutinin stalk antibodies. 
PLoS One. 2013b Nov 6; 8 (11): e79194.
Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal 
Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization 
Practices - United States, 2017–18 Influenza Season. MMWR Recomm Rep 2017; 66 
(No. RR-2): 1-20.
Izurieta HS, Thompson WW, Kramarz P, Shay DK, Davis RL, DeStefano F, Black S, 
Shinefield H, Fukuda K. Influenza and the rates of hospitalization for respiratory disease 
among infants and young children. NEJM. 2000;342(4):232-9.
Krammer F, Margine I, Hai R, Flood A, Hirsh A, Tsvetnitsky V, Chen D, Palese P. H3 
stalk-based chimeric hemagglutinin influenza virus constructs protect mice from H7N9 
challenge. J Virol. 2014a Feb; 88 (4): 2340-3.
Krammer F, Hai R, Yondola M, Tan GS, Leyva-Grado VH, Ryder AB, Miller MS, Rose 
JK, Palese P, García-Sastre A, Albrecht RA. Assessment of influenza virus 
hemagglutinin stalk-based immunity in ferrets. J Virol. 2014b Mar; 88 (6): 3432-42.
 
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Krammer F. Novel universal influenza virus vaccine approaches. Curr Opin Virol. 2016 
Apr; 17: 95-103.
Montplaisir J, Petit D, Quinn MJ, Ouakki M, Deceuninck G, Desautels A, Mignot E, De 
Wals P. Risk of narcolepsy associated with inactivated adjuvanted (AS03) A/H1N1 
(2009) pandemic influenza vaccine in Quebec. PLoS One. 2014 Sep 29; 9 (9): e108489. 
doi: 10.1371/journal.pone.0108489.
Nachbagauer R, Wohlbold TJ, Hirsh A, Hai R, Sjursen H, Palese P, Cox RJ, Krammer F. 
Induction of broadly reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in 
humans. J Virol. 2014 Nov; 88 (22): 13260-8.
Nachbagauer R, Kinzler D, Choi A, Hirsh A, Beaulieu E, Lecrenier N, Innis BL, Palese 
P, Mallett CP, Krammer F. A chimeric haemagglutinin-based influenza split virion 
vaccine adjuvanted with AS03 induces protective stalk-reactive antibodies in mice. 
Nature Partner Journals (NPJ) Vaccines, Article number: 16015 (2016) 
doi:10.1038/npjvaccines.2016.15
O'Brien MA, Uyeki TM, Shay DK, Thompson WW, Kleinman K, McAdam A, Yu XJ, 
Platt R, Lieu TA. Incidence of outpatient visits and hospitalizations related to influenza in 
infants and young children. Pediatrics. 2004; 113: 585-93.
Perricone C, Colafrancesco S, Mazor RD, Soriano A, Agmon-Levin N, Shoenfeld Y. 
Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the 
pathogenic, clinical and diagnostic aspects. J Autoimmun. 2013 Dec; 47:1-16.
Pica N, Hai R, Krammer F, Wang TT, Maamary J, Eggink D, Tan GS, Krause JC, Moran 
T, Stein CR et al.: Hemagglutinin stalk antibodies elicited by the 2009 pandemic 
influenza virus as a mechanism for the extinction of seasonal H1N1 viruses. Proc Natl 
Acad Sci USA 2012, 109: 2573-2578.
Tete S.M., Krammer F., Lartey S., et al. Dissecting the hemagglutinin head and stalk-
specific IgG antibody response in healthcare workers following pandemic H1N1 
vaccination. Nature Partner Journals (NPJ) Vaccines, Article number: 16001 (2016) 
doi:10.1038/npjvaccines.2016.1.
Vincent AL, Lager KM, Janke BH, Gramer MR, Richt JA. Failure of protection and 
enhanced pneumonia with a US H1N2 swine influenza virus in pigs vaccinated with an 
inactivated classical swine H1N1 vaccine. Vet Microbiol. 2008 Jan 25; 126 (4): 310-23.
WHO World Health Organization Factsheet Number 211. Influenza November 2016. 
https://www.who.int/mediacentre/factsheets/fs211/en
 
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APPENDIX A
LABORATORY ASSAYS
Anti-stalk ELISA protocol:
The prevalence of anti-stalk antibodies will be measured by ELISA using reagents based 
on HA-group specific chimeric HAs. The chimeric HA consists of an exotic head domain 
on top of a vaccine-antigen stalk domain. For example, the cH6/1 antigen has been 
constructed to measure anti-stalk antibodies against H1. Since humans are naïve to the
H6 head domain, reactivity measured with this substrate indicates reactivity to the H1 
stalk. Chimeric antigens will be developed for the two HA groups (group A1 and group 
A2) and will be used in a classical ELISA. Briefly, the antigen is coated on 96 well 
plates. After blocking, the serum is added and sequentially diluted. After incubation and 
washing steps, a detection antibody is used to distinguish serum antibodies attached to the 
antigen and optical density measurement provides quantitative information about the 
amount of antibodies in the serum. Positive and negative controls are developed in 
addition of an antigen-specific standard.
The breadth of the immune response within the group 1 HA subtypes will be measured
using a full length HA ELISA.
Microneutralization (MN) assay protocol:
The functionality of the stalk-reactive antibodies is evaluated by MN assays developed 
using chimeric viruses. As done for the ELISA, the objective is to avoid interference 
caused by antibodies directed against HA head but also caused by antibodies directed 
against NA; for that purpose we use viruses expressing an HA with an HA group-specific 
stalk and an HA head domain and NA to which humans are naïve. Briefly, measurements 
are conducted on thawed frozen serum samples. Samples are heat inactivated for 30 min 
at 56°C. A standardized amount of virus is mixed with serial dilutions of serum and 
incubated to allow binding of the antibodies to the virus. A cell suspension, containing a 
defined amount of Madin-Darby Canine Kidney (MDCK) cells is then added to the 
mixture of virus and antiserum and incubated at 35°C (2°C). After the incubation 
period, virus replication is visualized (by hemagglutination of red blood cells or OD 
reading) and a neutralization titer is calculated between the highest serum dilution able to 
totally neutralize the virus and one of the next serum dilution where viruses remain 
detectable. Each serum sample is tested once.
Hemagglutination inhibition (HI) assay protocol:
HI antibody titers are determined using the method derived from the WHO Manual on 
Animal Influenza Diagnosis and Surveillance, WHO/CDS/CSR/NCS/2002.5.
Measurements are conducted on thawed frozen serum samples with a standardized and 
comprehensively validated micro-method using 2 hemagglutinating units (2 HAU) of the 
appropriate antigens and a 0.45% fowl erythrocyte suspension. Non-specific serum 
inhibitors are removed by heat treatment and receptor-destroying enzymes.
 
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Starting with an initial dilution of 1:10, a dilution series (by a factor of 2) is prepared up 
to an end dilution of 1:10240. The titration end-point is taken as the highest dilution step 
that shows complete inhibition of hemagglutination. All assays are performed in 
duplicate. The usual cut-off value is 10 1/DIL.
ELISPOT (memory B cell detection assay):
The B-cell ELISPOT allows the quantification of antigen-specific memory B-cells. These 
cells are responsible of long term (humoral) memory and will be the cells recalled during 
an infection subsequent to vaccination. This assay is designed to evaluate the frequency 
(per million memory B-cells) of HA stalk specific memory B-cells from peripheral blood 
samples.
The protocol is adapted from the assay developed by [Crotty, 2004], and involves the 
incubation of PBMC that have been differentiated into antibody secreting cells in nitro-
plates coated with either the antigen of interest (for the detection of antigen-specific 
memory B-cells) or anti-human Ig (for the detection of total memory B-cells). A 
conventional immuno-enzymatic procedure [Crotty, 2004] is applied to detect 
antibody/antigen spots enumerating memory B-cells and the results are expressed as the 
frequencies of antigen-specific memory B-cells within the total memory B-cell 
population.
Flow Cytometry B-cells (FCB) for plasmablasts detection
The FCB assay has been developed to allow detection of HA stalk specific plasmablasts. 
Upon vaccination or natural challenge, these differentiated B-cells are transiently present 
in the periphery (peak at Day 7 post-antigen encounter) and are the cells producing the 
antibodies. The FCB assay has been set up to detect the cells producing the anti-HA stalk 
antibodies that the SUIV is designed to induce.
The PBMC are thawed and immuno-stained for surface markers allowing phenotypic 
identification of the plasmablasts (CD14- / IgD- / CD20- / CD19+ / CD38+). Cells are 
then permeabilized and immune-stained with a specific biotinylated probe (here the 
chimeric HA protein cH6/1) which will bind to the cognate antibodies (here the anti-HA 
stalk antibodies) within the plasmablasts. The probe is then detected with a fluorescently 
labelled streptavidin, and analysis performed by multi-parametric flow cytometry. Results 
are expressed as frequencies of antigen specific plasmablasts per million PBMC.
T-cell detection by Intracellular Cytokine Staining (ICS) assay:
This assay is applied to measure the frequency of antigen-specific T-lymphocytes in 
peripheral blood. CD4+ T-lymphocytes are critical helper cells supporting the 
differentiation of antibody secreting cells (B-cells). CD8+ T-lymphocytes are direct 
effector cells able to kill virus-infected cells.
 
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Blood samples are collected by venipuncture and PBMCs are prepared by centrifugation 
onto a Lymphoprep cushion within 24 hours following collection. PBMC suspensions are 
stored in liquid nitrogen until analysis. To measure T-cell responses elicited by the 
vaccine candidate, samples are thawed and stimulated with relevant antigen (synthetic 
peptides covering the HA stalk domain). Re-stimulated cells are then immunostained for 
surface markers such as CD3, CD4 and CD8 followed by cell permeabilization and 
immunostaining for effector molecules (cytokines/activation marker) such as IL-2, IFN-γ, 
TNF-α and CD40L (additional effector molecules could also be explored). Analysis is 
performed by multiparametric flow cytometry, and the results are expressed as 
frequencies of CD4+ (or CD8+) T-cells producing various combinations of the 
cytokine/activation markers assessed per million CD4+ (or CD8+) T-cells.
RT-qPCR assay for influenza detection:
Viral RNAs extracted from the clinical sample are amplified and detected using Flu-A 
and Flu-B specific primers and probes (designed in the Matrix gene). Viral Load values 
are quantified and the sample is considered positive when the measured Viral Load is 
equal to or above the assay cut-off. Several controls are included throughout the process, 
both at the extraction and RT-PCR steps to monitor the extraction and RT-PCR 
efficiencies and any potential contamination that may occur during each run.
RT-PCR assay for influenza A/H1N1 and A/H3N2 typing:
A RT-PCR allowing the identification of Flu-A/H1N1 and Flu-A/H3N2 is performed on 
the nucleic acids generated for Flu-A and Flu-B detection. Specific primers designed in 
the HA gene of Flu-A/H1N1 and Flu-A/H3N2 are used to perform the discrimination. In 
addition, Flu-A/H1N1 and Flu-A/H3N2 RT-PCR positive controls corresponding to the 
RNA from reference strains are evaluated in parallel with the samples. No template 
controls are also used to monitor any potential contamination during each RT-PCR run.
RT-qPCR assay for RSV detection:
Viral RNAs extracted from the clinical sample are amplified and detected using RSV-A 
and RSV-B specific primers and probes designed in the N gene encoding the 
nucleocapsid protein. Viral load values are quantified and the sample is considered 
positive when the measured viral load is equal to or above the assay cut-off. Several 
controls are included throughout the process, both at the extraction and RT-PCR steps to 
monitor the extraction and RT-PCR efficiencies and any potential contamination that may 
occur during each run.
 
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Multiplex RT-PCR assay for viral pathogen detection:
A qualitative PCR multiplex assay is used for the detection and identification of multiple 
respiratory virus nucleic acids in nasal and throat swabs from individuals suspected of 
respiratory tract infections. The following virus types and subtypes can be identified in 
the assay:

Parainfluenza 1 virus

Parainfluenza 2 virus

Parainfluenza 3 virus

Parainfluenza 4 virus

Human Metapneumovirus

Rhinovirus

Enterovirus

Adenovirus

Coronavirus 229E

Coronavirus OC43

Coronavirus NL63

Human Bocavirus
Following total nucleic acids extraction, viruses are detected by multiplex real-time RT-
PCR assays targeting the above mentioned viruses. A comparative analysis of the 
fluorescence intensities of each target is performed to detect the viruses present in the 
sample. Several controls are included throughout the process, both at the extraction and 
RT-PCR steps to monitor the extraction and RT-PCR efficiencies and any potential 
contamination that may occur during each run.
 
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APPENDIX B
CLINICAL LABORATORIES
Table 31
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
GSK Dresden
GlaxoSmithKline Biologicals
Branch of SmithKline Beecham Pharma 
GmbH & Co. KG
Zirkusstrasse 40, D-01069 Dresden
Germany
Table 32
Outsourced laboratories
Laboratory
Address
Néomed-Labs Inc.
525, Cartier Ouest Laval
Quebec Canada H7V 3S8
NÉOMED-LABS Inc.
Q2 Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355, USA
Q2 Solutions Clinical Trials (UK)
Unit B1, Parkway West Industrial Estate
Cranford Lane – Heston,
Middlesex TW5 9QA
UK
 
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APPENDIX C
FDA GUIDANCE FOR INDUSTRY: TOXICITY 
GRADING SCALE FOR HEALTHY ADULT AND 
ADOLESCENT VOLUNTEERS ENROLLED IN 
PREVENTIVE VACCINE CLINICAL TRIALS 
(SEPTEMBER 2007)
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking 
on this topic. It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public. You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes and regulations. If you want to 
discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify 
the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance.
i.
INTRODUCTION
Preventive vaccines are usually developed to prevent disease in a healthy population. The 
Office of Vaccines Research and Review, Centre for Biologics Evaluation and Research, 
regulates preventive vaccines under authority of section 351 of the Public Health Service 
Act (42 U.S.C. 262), as well as specific sections of the Federal Food, Drug, and Cosmetic 
Act, and reviews investigational new drug applications (INDs) and biologics license 
applications (BLAs). (See, for example, Title 21 Code of Federal Regulations (CFR) 
Parts 312, 600, and 601). Most of the clinical trials of preventive vaccines conducted to 
support INDs and BLAs enroll healthy volunteers in all phases of vaccine testing. The 
enrolment of healthy volunteers warrants a very low tolerance for risk in those clinical 
trials.
This guidance provides you, sponsors, monitors, and investigators of vaccine trials, with 
recommendations on assessing the severity of clinical and laboratory abnormalities in 
healthy adult and adolescent volunteers enrolled in clinical trials. The grading system 
described in the table can also be useful in defining a particular study’s stopping rules 
(e.g. a certain number of AEs, as defined in the table, may call for stopping the study). 
Less extreme observations (e.g. mild) may not require discontinuing the study vaccine 
but can still contribute to evaluating safety by identifying parameters to focus upon in 
subsequent product development. Uniform criteria for categorizing toxicities in healthy 
volunteers can improve comparisons of safety data among groups within the same study 
and also between different studies. We, FDA, recommend using toxicity grading scale 
tables, provided below, as a guideline for selecting the assessment criteria to be used in a 
clinical trial of a preventive vaccine. We recommend incorporation of such appropriate, 
uniform, criteria into the investigational plan, case report forms, and study reports and 
correspondence with FDA, sponsors, monitors, investigators, and IRBs.
This guidance finalizes the draft guidance of the same title dated April 2005 (70 FR 
22664, May 2, 2005).
 
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FDA’s guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements 
are cited. The use of the word should in FDA’s guidances means that something is 
suggested or recommended, but not required.
ii.
BACKGROUND
Standardized toxicity assessment scales have been widely used to evaluate products 
treating specific diseases. For example, the National Cancer Institute’s Common Toxicity 
Criteria Scale and the Division of AIDS’ Toxicity Grading Scale standardize the 
evaluation of adverse events (AEs) among patients with cancer and HIV/AIDS, 
respectively (Refs. 1, 2). The defined toxicity parameters in those scales are designed for 
patients who may already experience mild, moderate, or severe adverse clinical or 
laboratory events due to the disease process, and may not be appropriate for healthy 
volunteers.
In the development of the toxicity grading scales for healthy volunteers, we chose 
parameter limit values based on published information, when such values were available 
(Refs. 1-6). For example, the Brighton Collaboration has developed case definitions and 
guidelines to evaluate some AEs associated with administering vaccines (Ref. 3). In some 
cases, parameter limit values were based on clinical experience and experience reviewing 
vaccine clinical trials that enroll normal healthy subjects.
Toxicity grading scales for laboratory abnormalities should consider the local laboratory 
reference values when the parameter limit values are defined. The characterization of 
laboratory parameters among some populations of healthy adults and adolescents may 
require the exercise of clinical judgment, for example, consideration of the potential for 
ethnic differences in white blood cell (WBC) counts or gender differences in creatine 
phosphokinase (CPK) values.
iii. TOXICITY GRADING SCALE TABLES
AEs in a clinical trial of an investigational vaccine must be recorded and monitored and, 
when appropriate, reported to FDA and others involved in an investigation (sponsors, 
IRBs, and investigators). (See, for example, 21 CFR 312.32, 312.33, 312.50, 312.55, 
312.56, 312.60, 312.62, 312.64, and 312.66). Although the use of a toxicity grading scale 
for AEs would not replace these regulatory requirements, using a scale to categories 
adverse events observed during a clinical trial may assist you in monitoring safety and 
making required reports. Nonetheless, we believe that categorization or grading of data as 
outlined in this document is supplementary to and should not replace full and complete 
data analysis.
 
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These guidelines for toxicity grading scales are primarily intended for healthy adult and 
adolescent volunteers. The parameters in the tables below are not necessarily applicable 
to every clinical trial of healthy volunteers. The parameters monitored should be 
appropriate for the specific study vaccine. For some preventive vaccines under 
development, it may be appropriate to include additional parameters to be monitored 
during a clinical trial or to alter the choice of values in the toxicity table. For example, 
additional parameters might be added based on one or more of the following: safety 
signals observed in pre-clinical toxicology studies, the biological plausibility of the 
occurrence of certain AEs, or previous experience with a similar licensed product.
As discussed above, the tables do not represent a recommendation to monitor all the 
listed parameters in all clinical trials of healthy volunteers, nor do the tables represent all 
possible parameters to be monitored. In addition, these tables do not represent study 
inclusion or exclusion criteria. We recommend that the parameters monitored be 
appropriate for the study vaccine administered to healthy volunteers participating in the 
clinical trial.
a.
Tables for Clinical Abnormalities
Note from the sponsor: The tables in this section of the guidance will not be used in this 
particular study. Instead, the parameters as provided in the study protocol are to be used.
b.
Tables for Laboratory Abnormalities
The laboratory values provided in the tables below serve as guidelines and are dependent 
upon institutional normal parameters. Institutional normal reference ranges should be 
provided to demonstrate that they are appropriate.
Only those parameters that will be assessed as part of the study have been maintained in 
the tables below.
Table 33
FDA toxicity grading scales for hematology/biochemistry 
parameters
Serum*
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)**
Blood Urea Nitrogen – BUN 
mg/dL
23 – 26
27 – 31
> 31
Requires dialysis
Creatinine – mg/dL
1.5 – 1.7
1.8 – 2.0
2.1 – 2.5
> 2.5 or requires 
dialysis
Liver Function Tests –ALT, 
AST increase by factor
1.1 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10 x ULN
> 10 x ULN
ULN = upper limit of the normal range.
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
**The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium value that falls within a 
Grade 3 parameter (125-129 mE/L) should be recorded as a Grade 4 hyponatremia event if the subject had a new 
seizure associated with the low sodium value.
 
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Hematology*
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Hemoglobin (Female) - gm/dL
11.0 – 12.0
9.5 – 10.9
8.0 – 9.4
< 8.0
Hemoglobin (Female) change from 
baseline value - gm/dL
Any decrease –
1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
Hemoglobin (Male) - gm/dL
12.5 – 13.5
10.5 – 12.4
8.5 – 10.4
< 8.5
Hemoglobin (Male) change from 
baseline value - gm/dL
Any decrease –
1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
WBC Increase - cell/mm³
10 800 – 15 000
15 001 – 20 000
20 001 –
25 000
> 25 000
WBC Decrease - cell/mm³
2 500 – 3 500
1 500 – 2 499
1 000 – 1 499
< 1 000
Lymphocytes Decrease - cell/mm³
750 – 1 000
500 – 749
250 – 499
< 250
Neutrophils Decrease - cell/mm³
1 500 – 2 000
1 000 – 1 499
500 – 999
< 500
Eosinophils - cell/mm³
650 – 1 500
1 501 – 5 000
> 5 000
Hyper-eosinophilic
Platelets Decreased - cell/mm³
125 000 –
140 000
100 000 –
124 000
25 000 –
99 000
< 25 000
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
iv. REFERENCES for Appendix C
1.
National Cancer Institute Common Toxicity Criteria, April 30, 1999. 
(http://ctep.cancer.gov/reporting/CTC-3.html)
2.
Division of AIDS Table for Grading Severity of Adult Adverse Experiences; August 
1992. (http://rcc.tech-res-intl.com/tox_tables.htm)
3.
The Brighton Collaboration. Finalized Case Definitions and Guidelines. 
(http://brightoncollaboration.org/internet/en/index/definition___guidelines.html)
4.
HIV Vaccine Trials Network Table for Grading Severity of Adverse Experiences; 
September 18, 2002. (http://rcc.tech-res-intl.com/tox_tables.htm)
5.
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, December 2004. 
(http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/Safety/DAID
SAEGradingTable.pdf) 
6.
Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. 
New England Journal of Medicine. 2004;351:1548-1563.
 
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APPENDIX D
SERUM PASSIVE TRANSFER/VIRUS 
CHALLENGE EXPERIMENT IN BALB/C MICE 
FROM ADULT SUBJECTS INVOLVED IN THE FLU 
D-SUIV-ADJ-001 STUDY COHORT
Objectives (Amended: 11 July 2019)
This study is considered as part of exploratory read-outs in the clinical protocol.
1.
The in vivo protective effect of transferring pooled adult human serum from subjects 
from the FLU D-SUIV-ADJ-001 study cohort to mice and subsequently challenging 
them with chimeric head-stalk HA virus, for example cHx/1Ny virus (Hx = most 
likely H6/1, Ny = most likely N5; to be decided) or circulating H1N1 (most likely 
H1N1 strain contained in the IIV4 control annual vaccines in accordance with WHO 
recommendation) will be assessed in terms of the following endpoints:

1A: Survival over 14 days post-challenge (day of death or euthanasia for weight 
loss > 25% baseline body weight) in groups of 10 to 35 mice/human-
group/timepoint (number of mice = most likely 25, to be decided upon the 
pathogenicity of the challenge virus in mice; the exact sample size will be 
specified in an annex statistical report).

1B: Weight loss (change from baseline over 14 days post-challenge) in groups 
of 10 to 35 mice/human-group/timepoint.

1C: Lung virus titer in TCID50/mg on Day 3 and/or Day 6 post-challenge in
subset of 5 mice for each timepoint. This assessment will be performed at Day 3 
or Day 6 post-challenge, or both, depending on anticipated additional supportive 
pre-clinical data.
Comparisons between FLU D-SUIV-ADJ-001 study groups and/or timepoints 
(Day 1 and Day 85) will be investigated.
2.
The association between pre- or post-transfer human IgG binding antibody titers to 
the challenge viruses and the lung virus titer at Day 3 and/or Day 6 and the post-
challenge outcome will be explored.

2A: Measure of the pre- and post-transfer geometric mean human IgG binding 
antibody specific to cH6/1Nx virus, H1N1 virus or recombinant HA proteins in 
blood collected from mice receiving either one of the serum pools (Day 1 and
Day 85).

2B: Descriptive analyses will be conducted to detect possible associations 
between the antibody titers as measured in 2A and post-challenge endpoints.
a.
Proportion of survival over 14 days post-challenge,
b.
Weight loss,
c.
Geometric mean lung virus titer.
 
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Protocol endpoints (Amended: 11 July 2019):
Objective
Endpoint
1A
Survival over 14 days post-challenge (day of death or euthanasia for weight loss 
>25% baseline body weight) in groups of 10 to 35 mice*/serum pool/timepoint
1B
Weight loss (change from baseline over 14 days post-challenge) in groups of 10 to 
35 mice*/serum pool/timepoint
1C
Lung virus titer in TCID50/mg (log10 fold change (D1 - D85)), within challenge group
2A
Pre- or post-transfer of human IgG binding antibody titers to cH6/1Nx virus by 
ELISA or HI,
Pre- or post-transfer of human IgG binding antibody titers to H1N1 virus by ELISA
or HI
Pre- or post-transfer of human IgG binding antibody titers to recombinant HA 
proteins by ELISA
*If sufficient serum volumes are not available and depending on the challenge virus pathogenicity, the number of mice 
can be reduced to as low as 10 mice per timepoint and virus challenge
Methods
Viruses:
Challenge virus
Surface glycoprotein attributes
Virus-specific 
protection mediated by
cH6/1Nx (or an 
alternative challenge 
virus with similar 
attributes but more fit 
for purpose)

Exotic HA head domain not matched to vaccines strains

HA stalk domain from H1-representative of all group A1 
influenza stalk, matched to vaccine strains

Exotic neuraminidase not matched to vaccine strain
HA stalk antibody 
responses
H1N1 virus (most 
likely strain contained 
in the IIV4 control)

HA head domain, matched to circulating strain

HA stalk domain matched to vaccine strain

Neuraminidase matched to vaccine strain
HA (stalk and head) and 
NA antibody responses
Both viruses will be pre-assessed for mouse lethality in LD50 experiments (in the
presence of control adult human serum pools). The volume and route of inoculation will 
be 0.05 mL intra-nasal/intra-tracheal administered to anesthetized mice.
Human serum pools:
Serum pools will be created using serum samples from all evaluable subjects to constitute
an aliquot of an equal volume across the groups and the timepoints Day 1 and Day 85 
from the FLU D-SUIV-ADJ-001 cohort. (Amended: 11 July 2019)
 
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Passive transfer experimental method:

Twenty to 35 mice per timepoint per virus challenge will be transferred with a 
standard amount of undiluted human pooled serum (volume to be determined, within 
the range 150-250 L). The exact sample size by challenge study will be specified in 
an annex statistical report. Also, most likely all the human group serums will be 
tested but some groups might be excluded depending on the results obtained, as the 
clinical trial progresses and in accordance with the animal ethical 3R’s principles.
Pre-transfer pooled serum human IgG titers against HA proteins or influenza virus 
will be evaluated by ELISA as previously mentioned.

Two hours post serum transfer,  the mice will be sedated and:

Blood will be collected for determination of post-transfer human IgG titers 
against HA proteins or influenza viruses by ELISA.

Then challenged with 10 x LD50 delivered by the IN/IT route.

Mice will be monitored daily for 14 days for weight-loss and will be euthanized if 
they lose > 25% of their initial body weight or if any human endpoints defined in the 
ethical protocol are met.

On Day 3 and/or Day 6 post-infection, 5 mice per timepoint/virus will be euthanized 
to assess viral lung titers. This will occur at Day 3 or Day 6 post-challenge, or both, 
depending on anticipated additional supportive pre-clinical data. Upon results, lung 
histopathology may be performed at selected timepoints on relevant groups.

Weighing of the mice and lungs processing will be performed in an open fashion. 
Viral plaques will be counted by a blinded technician.

Lung suspensions will be made by homogenization in PBS and frozen at -80°C for 
later plaque assay using a standard method.
Statistical analytical plan:
Statistical analysis will be performed to evaluate the improved survival after challenge of 
any vaccine groups (mice receiving human pooled serum from chimeric HA- approach 
groups) compared to control group (mice receiving human pooled serum from IIV4 
group), measured at each timepoint. Additional analysis might be added to the study to 
detect potential association between post-transfer titers and survival, post-transfer titers 
and weight loss or between lung-titers at Day 3 or Day 6 and survival.
The analyses and reporting of those data will be handled by the pre-clinical team 
according to their processes. No data will be incorporated in the clinical study report, but 
presented as an appendix.
Ethical statement:
The study protocol will be ethically reviewed and approved by the appropriate ethical 
committee and the study will be carried out in accordance with national and international 
directives and the GSK Biologicals’ policy on the care, welfare and treatment of animals.
 
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APPENDIX E
AMENDMENTS AND ADMINISTRATIVE CHANGES 
TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R&D
Protocol Amendment 1
eTrack study number and 
Abbreviated Title
207543 (FLU D-SUIV-ADJ-001)
IND number
17602
EudraCT number
2017-001584-20
Amendment number:
Amendment 1
Amendment date:
24 October 2017
Co-ordinating author:
, Scientific Writer (XPE Pharma 
& Science for GSK Biologicals)
Rationale/background for changes:
This protocol is amended for the following reasons:
!
To ensure that only healthy subjects with no risk factors for severe influenza-
related complications can be enrolled, an additional exclusion criterion has been 
added:
#
Any condition that puts the subject at risk for serious influenza-related 
complications, as identified by the Advisory Committee on Immunization 
Practices.
!
To account for an higher rate of non-evaluable subjects, the sample size has been 
increased by 20 subjects.
!
The possibility to use a qualitative assay for the RSV-PCR assay has been added.
!
To add the possibility to assess the lung titers in mice in the passive transfer 
experiment at Day 3 or at Day 6 post-challenge, or both, depending on anticipated 
additional supportive pre-clinical data; and to clarify that the pool of serum will be 
obtained using serum samples from evaluable subjects.
!
To update the list of potential Immune-Mediated Diseases (pIMDs) to be aligned 
with the new version of the Medical Dictionary for Regulatory Activities. In 
addition, gout was added as the monitoring plan for this event (now considered a 
pIMD) became a commitment for the Company.

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!
To clarify that the vaccines/products must be brought to room temperature before 
reconstitution/preparation instead of before use.
!
To correct values in the Table 27 presenting 2-sided exact 95% confidence 
intervals for the true immunological response rate at different possible observed 
response rates.
!
To include the IND number which was assigned after protocol finalization.
In addition, minor corrections/updates have been made and the list of contributing 
authors has been updated.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Cover page
The symbol ™ has been deleted and the trademark has been put in italics:
Other study 
vaccines/products
!
GSK Biologicals’ quadrivalent split virion 
influenza vaccine Fluarix Quadrivalent™
The following change has also been implemented on the Sponsor and Investigator 
Approval pages:
Investigational New Drug 
(IND) number
To be provided 17602
Contributing authors
(continued)
!
[…]
!
, 
, Global Patent 
representatives
!
, 
, Pre-clinical 
representatives
Copyright 2017 the GlaxoSmithKline group of companies or its licensor. All rights reserved. 
Unauthorized copying or use of this information is prohibited.
Glossary of terms
Protocol amendment:
The International Conference on Harmonisation 
(ICH) defines a protocol amendment as: “A written 
description of (a) change(s) to or formal clarification 
of a protocol”. GSK Biologicals further details this to 
include a change to an approved protocol that affects 
the safety of subjects, scope of the investigation, study 
design, or scientific integrity of the study.

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PPD
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PPD

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Trademarks
The symbols ™ have been deleted and the trademarks have been put in italics:
*Arepanrix™
Fluarix™
Mosquirix™
**Pandemrix™
Section 1.2.2 Rationale for the study design (+ in synopsis)
Approximately 450 470 subjects 18-39 years of age will be equally randomized in 10
different treatment groups to receive […]
Section 3
Study design overview (+ in synopsis)
Figure 1: Study design overview
The number of subjects has been updated (at the top of the figure):
Table 1: Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects
Age (Min - Max)
Epochs
Epoch 002
Epoch 003
cH8/P/cH5-AS03
45 47
18 years – 39 years
x
x
cH5/P/cH8-AS03
45 47
18 years – 39 years
x
x
cH8/5/11-AS03
45 47
18 years – 39 years
x
x
cH8/P/cH5-AS01
45 47
18 years – 39 years
x
x
cH5/P/cH8-AS01
45 47
18 years – 39 years
x
x
cH8/5/11-AS01
45 47
18 years – 39 years
x
x
cH8/P/cH5
45 47
18 years – 39 years
x
x
cH5/P/cH8
45 47
18 years – 39 years
x
x
cH8/5/11
45 47
18 years – 39 years
x
x
IIV4
45 47
18 years – 39 years
x
x

Sampling schedule:

[…]

Blood samples for cell-mediated immunity (CMI) assessment will be drawn 
from a sub-cohort of 50% of 225 subjects at Days 1 (Visit 1), […]

Enrolment: the study will follow a staggered enrolment with 2 steps; the first being 
Phase I (N = 80) and the second being Phase II (N = 370 390):
 
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Section 4.1
Number of subjects/centers (+ in synopsis)
This study will be conducted in multiple centers. A total of 450 470 subjects (45
47/group) are planned to be enrolled in this study, in order to have 430 evaluable subjects 
for the primary immunogenicity endpoints. […]
Table 4
Sub-cohort
Sub-cohort name
Description
Estimated number of subjects
Cell-mediated immunity 
(CMI) testing
Additional blood sample (40 mL) to be taken at 
Visits 1, 2, 3, 5, 6, 8, 9, 10 and 12 for CMI testing. 
This will be done at pre-specified sites with 
adequate material for such sampling procedure.
Approximately 225
(50% of the enrolled subjects)
The sub-cohort will consist of the 
first Phase II subjects enrolled in 
pre-specified sites.
Section 4.3
Exclusion criteria for enrolment

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants […], or equivalent. Inhaled and Topical steroids are allowed.

[…]

Any condition that puts the subject at risk for serious influenza-related 
complications, as identified by the Advisory Committee on Immunization Practices 
[Grohskopf, 2017] (note that only criteria applicable for the study population are 
listed below):

Chronic pulmonary (including asthma), cardiovascular (except isolated 
hypertension), renal, hepatic, neurologic, hematologic or metabolic disorders 
(including diabetes mellitus);

Persons who are immunocompromised due to any cause (including 
immunosuppression caused by medications or by HIV infection);

Adolescents (through 18 years) who are receiving aspirin- or salicylate-
containing medications and who might be at risk for experiencing Reye 
syndrome after influenza virus infection;

Residents of nursing homes and other long-term care facilities;

American Indians/Alaska Natives; and

Persons who are extremely obese (Body Mass Index 40).
Section 5.2.2.2.1
Study group and treatment number allocation
The target will be to enroll 450 470 eligible subjects who will be randomly assigned to 
10 study groups in a (1:1:1:1:1:1:1:1:1:1) ratio (45 47 subjects in each group).
 
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Section 5.7.3 Laboratory assay
Table 12
Molecular Biology (PCR tests)
Component
Kit/ Manufacturer
Method
Unit
Laboratory
Nasal swab samples
[…]
[…]
[…]
[…]
GSK Biologicals* 
or designated 
laboratory
RSV A virus (RSV A)
RSV B virus (RSV B)
In-house
Quantitative or 
qualitative RT-PCR
Copies/mL or
pos/neg
Pos/neg = positive/negative
*GSK Biologicals laboratory refers to the CLS in Rixensart, Belgium; Wavre, Belgium.
Section 5.7.4.1
Immunological read-outs
Table 13
Immunological read-outs for humoral immunity and cell-mediated 
immunity
Blood sampling timepoint
Sub-
cohort 
Name
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
Humoral immunity
Visit 1 (Day 1)
[…]
PRE
[…]
All 
subjects
∃450
∃470
Anti-H1 HA stalk ELISA
[…]
[…]
Visit 1 (Day 1)
[…]
PRE
[…]
All 
subjects
∃450
∃470
Anti-H1 HA stalk MN assay
[…]
[…]
Visit 1 (Day 1)
[…]
PRE
[…]
All 
subjects
∃450
∃470
HI with IIV4 H1N1 strain from 
2017/2018 season
Visit 8 (Month 14)
[…]
M14
[…]
All 
subjects
∃450
∃470
HI with IIV4 H1N1 strain from 
2018/2019 season
[…]
[…]
Section 6.3
Dosage and administration of study vaccines/products
[…]
All vials of vaccines/products should be kept at room temperature for at least 15 a few
minutes prior to use reconstitution/preparation. All vaccines/products must be 
administered within one hour of reconstitution/preparation after being taken out of the 
fridge.

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Section 8.1.6.1
Potential immune-mediated diseases
Table 20
List of potential immune-mediated diseases
Neuro-inflammatory disorders
Musculoskeletal disorders
Skin disorders

[…]

Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome 

Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with 
monoclonal gammopathy).

Demyelinating peripheral 
neuropathies including:

Chronic inflammatory 
demyelinating 
polyneuropathy

Multifocal motor neuropathy

Polyneuropathies associated 
with monoclonal 
gammopathy

Narcolepsy

[…]

Systemic scleroderma (systemic 
sclerosis), including:

Diffuse systemic form
scleroderma

CREST syndrome

[…]

Rheumatoid arthritis, and 
associated conditions including:

Juvenile chronic idiopathic
arthritis

Still’s disease

Polymyalgia rheumatica

Spondyloarthritis
Spondyloarthropathies, 
including:

[…]

Psoriatic arthropathy
arthritis

Enteropathic arthritis

[…]

Gout

[…]

Autoimmune bullous 
skin diseases 
(including pemphigus, 
pemphigoid and 
dermatitis 
herpetiformis)

Alopecia areata

[…]
Vasculitides
Blood disorders
Others

Large vessels vasculitis including:

Giant cell arteritis (temporal 
arteritis) such as

Takayasu's arteritisand 
temporal arteritis.

Medium sized and/or small vessels 
vasculitis including:

[…]

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),

[…]

Autoimmune 
hemolytic anemia

[…]

Autoimmune glomerulonephritis, 
including:

[…]

Tubulo-intestinal nephritis 
and uveitis syndrome

Ocular autoimmune diseases, 
including:

Autoimmune uveitis

Autoimmune retinopathy
retinitis

Autoimmune 
myocarditis/cardiomyopathy

[…]

Alopecia areata

[…]
 
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Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune hepatitis

[…]

Inflammatory Bowel disease, 
including:

Crohn’s disease

[…]

Autoimmune thyroiditis (including
Hashimoto thyroiditis)

[…]
Section 8.8.1 Holding rules
[…]
Figure 2 gives the probability of not meeting each holding rule 1 and 2 for the 45 subjects 
in an investigational group. This evaluation was performed for the sample size of the 
initial protocol (i.e. 450 subjects, 45/group) and it was not repeated at the time of the 
protocol amendment 1 because of the small difference in the number of subjects per 
group (now 470 subjects in total, 47/group).
Section 10.3
Tertiary endpoints (+ in synopsis)

Assessment of the in vivo protective effect of the anti-stalk antibodies when 
transferring Day 1, Day 85, Month 14 and Month 26 pooled serum from all 
evaluable subjects of each vaccine groups […]
Section 10.4.1 
Descriptive objectives
[…]
At the time of the protocol amendment 1, it was decided to increase the sample size 
from 450 to 470 subjects to take into account a larger rate of non-evaluable subjects 
than anticipated. The power computations from the initial protocol relative to safety 
endpoints were not modified because of the small sample size increase (about 2 
subjects per group, from 45 to 47). The immunogenicity endpoints evaluation will be 
done primarily on the Per-Protocol set, which is not deemed to increase (about 43 
subjects per group).
[…]
Table 27 presents the 95% CIs for different possible rates of immunological response 
within each group. A rate of unevaluable subjects of 2/45 (4%) has initially been 
considered for the immune response post-primary vaccination. As from protocol 
amendment 1, a rate of non-evaluable subjects of 4/47 (9%) has been considered for 
the immune response post-primary vaccination.
Table 27
Two-sided exact 95% confidence intervals for the true immunological 
response rate at different possible observed response rates (43 evaluable 
subjects)
Observed number of 
responses
Observed response 
proportion
95% exact confidence interval
Lower limit
Upper limit
25
0.581
0.421
0.730
30
0.698
0.547 0.539
0.828
35
0.781 0.814
0.667
0.916
40
0.930
0.809
0.985
*Response rate can be either seropositivity rate, percentages of subjects with a 4-fold increase or percentages of 
subjects with a 10-fold increase
 
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Section 13
References
Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal 
Influenza with Vaccines: Recommendations of the Advisory Committee on 
Immunization Practices - United States, 2017–18 Influenza Season. MMWR Recomm 
Rep 2017; 66 (No. RR-2): 1-20.
Appendix A
Laboratory assays
Anti-stalk ELISA protocol:
The prevalence of anti-stalk antibodies will be measured by ELISA using reagents based 
on HA-group specific chimeric HAs […]. Chimeric antigens will be developed for the 3
two HA groups (group A1, and group A2 and group B) and will be used in a classical 
ELISA […].
Appendix D
Serum passive transfer/virus challenge experiment in BALB/c mice 
from adult subjects involved in the FLU D-SUIV-ADJ-001 study cohort
Objectives
This study is considered as part of exploratory read-outs in the clinical protocol.
1.
The in vivo protective effect of transferring pooled adult human serum […] will be 
assessed in terms of the following endpoints:

[…]

1C: Lung virus titer in pfu/g [log10 fold-change (Day 1 – Day 85), (Day 1 –
Month 14), (Day 1 – Month 26)] on Day 3 and/or Day 6 post-challenge in subset 
of 5 mice for each timepoint. This assessment will be performed at Day 3 or 
Day 6 post-challenge, or both, depending on anticipated additional supportive 
pre-clinical data.
2.
The association between post-transfer ELISA titer of human IgG to the challenge 
viruses (anti-stalk IgG) at Day 3 and/or Day 6 and the post-challenge outcome will 
be explored.

2A: Measure of the post-transfer geometric mean ELISA titer […] upon 
challenge and at Day 3 and/or Day 6 post-transfer.
Methods
Human serum pools:
Serum pools will be created using all residual serum samples from all evaluable subjects
with sufficient volume to furnish to constitute an aliquot of an equal volume across the 
groups and the timepoints Day 1, Day 85, Month 14 and Month 26 from the FLU D-
SUIV-ADJ-001 cohort.
 
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Passive transfer experimental method:

Twenty to 35 mice per timepoint per virus challenge will be transferred […], the 
number of mice can be reduced to as low as 10 mice per timepoint and virus for the 
survival monitoring and 10 5 for the lung virus titer assays.

[…]

On Day 3 and/or Day 6 post-infection, 5 mice per timepoint/virus will be euthanized 
to assess viral lung titers (5 mice per timepoint/virus x 2 harvesting days x 5 
timepoints x 2 virus; 100 mice in total). This will occur at Day 3 or Day 6 post-
challenge, or both, depending on anticipated additional supportive pre-clinical 
data.
 
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GlaxoSmithKline Biologicals SA
Vaccines R&D
Protocol Amendment 2
eTrack study number and 
Abbreviated Title
207543 (FLU D-SUIV-ADJ-001)
IND number
17602
EudraCT number
2017-001584-20
Amendment number:
Amendment 2
Amendment date:
16 March 2018
Coordinating author:
, Scientific Writer (XPE Pharma & 
Science for GSK Biologicals)
Rationale/background for changes:
This protocol is amended for the following reasons:
!
Based on recommendations from the Independent Data Monitoring Committee, 
wording has been added to ensure that subjects with clinically significant grade 3 
and above abnormal laboratory findings that cannot be reasonably explained may
be followed up with a repeat test.
!
To add an hemagglutination inhibition (HI) assay against cH6/1N5, H5N8 and 
H1N1 swine virus (as a tertiary objective/endpoint). These strains are the same as 
those to be tested by micro-neutralization (MN) assay .This will permit the 
measurement of the induction of antibodies reactive against the head domain of the 
antigens.
!
To change the description of the influenza virus strain for the H2 full length 
ELISA testing.
!
The results of the MN assay were removed from the data to be included the 
interim analysis planned at Day 85 due a delay in the availability of this testing.
!
The protocol for the passive transfer/virus challenge experiment has been updated.
In addition, minor corrections/updates have been made and the list of contributing 
authors has been updated.

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Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Cover page
Contributing authors
!
, 
Clinical Research & 
Development Leads
!
, Lead 
Statisticians
!
[…]
!
, Clinical 
and Epidemiology Project Leads
Section 2.3
Tertiary objectives (+ in synopsis)
!
To explore the immune response against the IIV4 H1N1, and the HA head of 
cH5/1N1, cH8/1N1, cH11/1N1, the chimeric cH6/1N5 strain, H5N8 virus strain 
and H1N1 swine virus strain by hemagglutination inhibition (HI) assay.
Section 5.7.3 Laboratory assays
Table 9
Humoral immunity
System
Component (Strain or Antigen Description)
Method
[…]
Cut-off*
Serum
cH6/1 HA = Recombinant antigen based on 
A/mallard/Sweden/81/2002 (H6N1) head domain with 
stalk domain from HA of H1N1 virus A/California/04/09
Anti-H1 HA stalk 
ELISA
[…]
TBD
H2 HA full length = Recombinant antigen based on 
A/mallard/Netherlands/5/1999 (H2N9)
A/Japan/305/1957 (H2N2) HA
Anti- H2 HA full 
length ELISA
[…]
TBD
[…]
[…]
[…]
[…]
Hemagglutination Inhibition (HI) assay
Serum
[…]
HI assay
[…]
[…]
Chimeric cH6/1N5 strain
TBD
H5N8 virus strain
TBD
H1N1 swine virus strains
TBD
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Section 5.7.4.1
Immunological read-outs
Table 13
Immunological read-outs for humoral immunity and cell-mediated 
immunity
Blood sampling timepoint
Sub-
cohort 
Name
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
Humoral immunity
Visit 1 (Day 1)
Visit 3 (Day 29)
Visit 6 (Day 85)
Visit 8 (Month 14)
Visit 10 (Month 14 + 28 days)
Visit 12 (Month 26)
PRE
PId28
PIId28
M14
PIIId28
M26
All 
subjects
∃470
[…]
[…]
HI with cH5/1N1 and cH8/1N1 
virus
HI with cH6/1N5, H5N8 and H1N1
swine virus strains
Visit 1 (Day 1)
Visit 3 (Day 29)
Visit 6 (Day 85)
Visit 8 (Month 14)
PRE
PId28
PIId28
M14
All 
subjects
∃470
HI with IIV4 H1N1 strain from 
2017/2018 season
Visit 8 (Month 14)
Visit 10 (Month 14 + 28 days)
Visit 12 (Month 26)
M14
PIIId28
M26
All 
subjects
∃470
HI with IIV4 H1N1 strain from 
2018/2019 season
HI with cH11/1N1 virus
Section 6.7.2 Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses
!
Administration of any influenza vaccine during the study period.
Section 8.1.5 Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events
[…]
In case of clinically significant grade 3 and above abnormal laboratory findings that 
cannot be reasonably explained (e.g. due to a pre-existing or current medical 
condition), the investigator will be recommended to recall the subject in a timely 
manner (preferably within 7 days after investigator’s awareness/assessment of the 
abnormal findings) for a repeat test to confirm the result.
Section 10.3
Tertiary endpoints (+ in synopsis)
!
Levels of HI antibody to IIV4 H1N1, and chimeric vaccine strains, chimeric 
cH6/1N5 strain, H5N8 virus strain and H1N1 swine virus strain:
The following aggregate variables will be calculated with 95% CI:
#
[…]
!
Assessment of the in vivo protective effect of the anti-stalk antibodies […]:
#
Survival over 14 days post-challenge (day of death/euthanasia for weight loss 
> 25% baseline body weight) in groups of 25 35 mice**/serum pool/vaccine 
group/timepoint.
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P
P
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P
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
Mean Weight loss (change from baseline over 14 days post-challenge) in groups 
of 25 35 mice**/serum pool/vaccine group/timepoint.

Lung virus titer in plaque-forming units (pfu)/µg TCID50/mg (log10 fold change 
[Day 1 minus Day 85, Month 14 and Month 26]), within challenge group.

Pre- and post-transfer titer of human IgG to cH6/1N5* by ELISA or HI.

Pre- and post-transfer titer of human IgG to H1N1 by ELISA or HI.

Pre- and post-transfer titer of human IgG to recombinant HA protein by 
ELISA.

Evaluation of the anti-H9 full length HA response by ELISA pre-and post-
vaccination.
Section 10.11.1
Sequence of analyses
Excluding the IDMC monitoring analyses, the analyses will be performed in a stepwise 
manner:

Interim analyses will be performed when safety, reactogenicity and immunogenicity 
(including at least H1 anti-stalk ELISA and MN) data from all subjects are available 
up to Day 85 and up to Month 14 + 28 days. […]
Appendix D
Serum passive transfer/virus challenge experiment in BALB/c mice 
from adult subjects involved in the FLU D-SUIV-ADJ-001 study cohort
Objectives
This study is considered as part of exploratory read-outs in the clinical protocol.
1.
The in vivo protective effect of transferring pooled adult human serum […] will be 
assessed in terms of the following endpoints:

1A: Survival over 14 days post-challenge (day of death or euthanasia for weight 
loss > 25% baseline body weight) in groups of 10 to 25 35 mice/human-
group/timepoint (number of mice = most likely 25, to be decided upon the 
pathogenicity of the challenge virus in mice; the exact sample size will be 
specified in an annex statistical report).

1B: Mean Weight loss (change from baseline over 14 days post-challenge) in 
groups of 10 to 25 35 mice/human-group/timepoint.

1C: Lung virus titer in pfu/g TCID50/mg [log10 fold-change (Day 1 – Day 85), 
(Day 1 – Month 14), (Day 1 – Month 26)] on Day 3 and/or Day 6 post-challenge 
in subset of 5 mice for each timepoint. […]
Comparisons between FLU D-SUIV-ADJ-001 study groups and/or timepoints 
(Day 1, Day 85, Month 14 and Month 26) will be investigated.
 
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2.
The association between pre- or post-transfer ELISA human IgG binding antibody
titers of human IgG to the challenge viruses (anti-stalk IgG) and the lung virus titer
at Day 3 and/or Day 6 and the post-challenge outcome will be explored.

2A: Measure of the pre- and post-transfer geometric mean ELISA titer of 
human IgG human IgG binding antibody specific to cH6/1Nx virus, and human 
IgG to A/H1N1pdm09 virus or recombinant HA proteins in blood collected 
from mice receiving either one of the serum pools (Day 1, Day 85, Month 14 
and Month 26) upon challenge and at Day 3 and/or Day 6 post-transfer.

2BC: Correlation Descriptive analyses will be conducted to detect possible 
associations between the antibody titers as measured in 2A and post-challenge 
endpoints as listed above.
a.
Proportion of survival over 14 days post-challenge,
b.
Mean Weight loss,
c.
Geometric mean lung virus titer.
Protocol endpoints:
Objective
Endpoint
1A
Primary: Survival over 14 days post-challenge (day of death or euthanasia for 
weight loss >25% baseline body weight) in groups of 10 to 25 35 mice*/serum 
pool/timepoint
1B
Primary: mean Weight loss (change from baseline over 14 days post-challenge) in 
groups of 10 to 25 35 mice*/serum pool/timepoint
1C
Exploratory: Lung virus titer in pfu/g TCID50/mg (log10 fold change (D1 - D85), (D1
- M14) (D1 - M26), within challenge group
2A
Exploratory: Pre- or post-transfer ELISA titer of human IgG binding antibody 
titers to cH6/1Nx virus by ELISA or HI,
Exploratory: Pre- or post-transfer ELISA titer of human IgG binding antibody 
titers to A/H1N1pdm09 virus by ELISA or HI
Pre- or post-transfer of human IgG binding antibody titers to recombinant HA 
proteins by ELISA
*If sufficient serum volumes are not available and depending on the challenge virus pathogenicity, the number of mice 
can be reduced to as low as 10 mice per timepoint and virus challenge
Methods
Viruses:
[…]
Both viruses will be pre-assessed for mouse lethality in LD50 experiments (with and 
without in the presence of control adult human serum pools). The volume and route […]
 
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Passive transfer experimental method:

Twenty to 35 mice per timepoint […] (volume to be determined, within the range 
150-250 L): (35 mice x 2 virus challenges x 4 timepoints = 280 mice in total per 
human group). The exact sample size by challenge study will be specified in an 
annex statistical report. However, depending on the lethality of the virus or if 
sufficient serum volumes are not available, the number of mice can be reduced to as 
low as 10 mice per timepoint and virus for the survival monitoring and 5 for the lung 
virus titer assays. Also, most likely all the human group […] in accordance with the 
animal ethical 3R’s principles. Pre-transfer pooled serum human IgG titers against
HA proteins or influenza virus will be evaluated by ELISA as previously 
mentioned.

Two hours post serum transfer,  the mice will be sedated and:

Blood will be collected for determination of post-transfer human IgG titers 
against HA proteins or influenza viruses by ELISA.

Then challenged with 5 10 x LD50 delivered by the IN/IT route (or a lower dose 
selected to provide a level of weight-loss and lethality using Day 1 serum that 
could be reduced by a 3-10 fold increased level of anti-HA stalk antibodies 
present in post-vaccination serum).

[…]

On Day 3 and/or Day 6 post-infection, 5 mice per timepoint/virus will be euthanized 
to assess viral lung titers (5 mice per timepoint/virus x 2 harvesting days x 5 
timepoints x 2 virus; 100 mice in total). This will occur at Day 3 or Day 6 post-
challenge, or both, depending on anticipated additional supportive pre-clinical data.
Upon results, lung histopathology may be performed at selected timepoints on 
relevant groups.
Statistical analytical plan:
Primary objective is defined as Statistical analysis will be performed to evaluate the
improved survival after challenge of any vaccine groups […], measured at each 
timepoint. Additional exploratory testing analysis might be added to the study, including 
potential correlation to detect potential association between post-transfer titers and 
survival, post-transfer titers and weight loss or correlation between lung-titers at Day 3 
or Day 6 and survival.
The analyses and reporting of those data will be handled by the pre-clinical team 
according to their processes. No data will be incorporated in the clinical study report, 
but presented as an appendix.
Ethical statement:
The study protocol will be ethically reviewed and approved […]the GSK Biologicals’ 
policy on the care, welfare and treatment of animals (the country and animal facilities 
where the study where the study will be carried out remains to be defined at this stage).
 
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Vaccines R&D
Protocol Amendment 3
eTrack study number and 
Abbreviated Title
207543 (FLU D-SUIV-ADJ-001)
IND number
17602
EudraCT number
2017-001584-20
Amendment number:
Amendment 3
Amendment date:
07 December 2018
Coordinating author:
, Scientific Writer (XPE Pharma & 
Science for GSK Biologicals)
Rationale/background for changes:
This protocol is amended for the following reasons:
!
To specify that an additional interim analysis will be performed on available 
immunogenicity data when Phase I subjects eligible for booster vaccination have 
completed their Visit 10 (Month 14 + 28 days timepoint).
!
To clarify that laboratory parameters (hematology and biochemistry) reported as 
clinically significant adverse events have to be graded according the Food and 
Drug Administration Guidance for Industry “Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”.
!
To update the wording of the objective (and corresponding endpoint) related to 
testing of anti-Group 2 HA by ELISA.
!
To add the description of the anti-H9 HA full length ELISA testing.
In addition, the list of contributing authors has been updated.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Cover page
Contributing authors
!
Clinical Research & Development Leads
!
, Clinical Trial 
Supply Managers
!
, Global 
Regulatory Affairs representatives

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Section 2.3
Tertiary objectives (+ in synopsis)
!
To explore the anti-H3 anti-Group 2 HA stalk response (e.g., H3, H4, H10, …) (i.e. 
influenza A group 2).
Section 5.7.3 Laboratory assays
Table 9
Humoral immunity
System
Component (Strain or Antigen 
Description)
Method
Kit/ 
Manufacturer
Unit
Cut-off*
ELISAs
Serum
H18 HA full length = […]
Anti-H18 HA […]
In-house 
assay
ELISA units 
per mL 
(EU/mL)
TBD
H9 HA full length = Recombinant 
antigen based on A/chicken/Hong 
Kong/G9/1997 HA
Anti-H9 HA full 
length ELISA
TBD
N1 NA = […]
Anti-N1 NA ELISA
TBD
Table 12
Molecular Biology (PCR tests)
Component
Kit/ 
Manufacturer
Method
Unit
Laboratory
Nasal swab samples
[…]
[…]
[…]
[…]
GSK Biologicals* 
or designated 
laboratory
Human Influenza A virus subtype H1 (Flu A-H1)
Human Influenza A virus subtype H3 (Flu A-H3)
In-house
RT-PCR
Qualitative assay 
(positive/negative)
RSV A virus (RSV A)
RSV B virus (RSV B)
In-house
Quantitative or
Qualitative RT-
PCR
Copies/mL or
pos/neg
Section 5.7.4.1
Immunological read-outs
Table 13
Immunological read-outs for humoral immunity and cell-mediated 
immunity
Blood sampling timepoint
Sub-
cohort 
Name
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
Humoral immunity
Visit 1 (Day 1)
Visit 3 (Day 29)
[…]
PRE
PId28
[…]
All 
subjects
∃470
Anti-H18 HA full length ELISA
Anti-H9 HA full length ELISA
Visit 1 (Day 1)
Visit 3 (Day 29)
[…]
PRE
PId28
[…]
All 
subjects
∃470
Anti-N1 NA ELISA
HI with cH5/1N1 and cH8/1N1 
virus
HI with cH6/1N5, H5N8 and H1N1 
swine virus strains
Visit 1 (Day 1)
Visit 3 (Day 29)
[…]
PRE
PId28
[…]
All 
subjects
∃470
HI with IIV4 H1N1 strain from 
2017/2018 season
Visit 8 (Month 14)
Visit 10 (Month 14 + 28 days)
Visit 12 (Month 26)
M14
PIIId28
M26
All 
subjects
∃470
HI with IIV4 H1N1 strain from 
2018/2019 season
HI with cH11/1N1 virus
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Section 8.1.5 Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events
In absence of diagnosis, abnormal laboratory findings […] (refer to Sections 8.1.1 and 
8.1.2). The grading of laboratory parameters will be based on the Food and Drug 
Administration (FDA) Guidance for Industry “Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (refer 
to Appendix C). Clinically significant abnormal laboratory findings […]
Section 8.3.3.2.1
Assessment of intensity
[…]
Note that the grading of laboratory parameters will be based on the FDA Guidance for 
Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” (refer to Section 8.1.5 and 
Appendix C).
Section 10.3
Tertiary endpoints

Evaluation of the anti-H3 anti-Group 2 HA stalk response (e.g., H3, H4, H10, …) 
by ELISA and/or MN assay pre-and post-vaccination
Section 10.11.1
Sequence of analyses

Interim analyses will be performed when safety, reactogenicity and immunogenicity 
(including at least H1 anti-stalk ELISA) data from all subjects are available up to 
Day 85 and up to Month 14 + 28 days*. The GSK statistician/statistical analyst […]
*Note that for this timepoint, an additional interim analysis will be performed on 
all available immunogenicity data when Phase I subjects eligible for booster 
vaccination have completed their Visit 10 according to the allowed interval.
 
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Vaccines R&D
Protocol Amendment 4
eTrack study number and 
Abbreviated Title
207543 (FLU D-SUIV-ADJ-001)
IND number
17602
EudraCT number
2017-001584-20
Amendment number:
Amendment 4
Amendment date:
11 July 2019
Coordinating author:
, Scientific Writer (Modis Life 
Sciences for GSK Biologicals)
Rationale/background for changes:
Following review of the Day 85 interim analysis and the additional interim analysis 
performed on available immunogenicity data from Phase I subjects who had completed 
their Visit 10 (Month 14 + 28 days), the Sponsor made the decision not to pursue the 
clinical development of the investigational supra-seasonal influenza vaccine. Based on 
these interim analyses results, some assays will not be performed or developed as 
initially planned, either because limited or no response is expected to be observed, or 
because the assay results are no longer relevant in light of the decision not to pursue 
the development of the investigational supra-seasonal influenza vaccine based on the 
chimeric hemagglutinin technology.
The changes are as follows:
!
The cell-mediated immune response will not be assessed at Month 14 and later 
timepoints. The blood sampling for cell-mediated immunity at Visit 12 (Month 26) 
has been removed.
!
The hemagglutination inhibition assay (HI) will not be performed on the 
inactivated influenza quadrivalent vaccine H1N1 component, cH11/1N1, 
cH6/1N5, H5N8 and H1N1 swine flu strains. For cH5/1N1 and cH8/1N1, the HI 
assay will only be performed until Visit 6 (Day 85).
!
The micro-neutralisation (MN) assay will only be performed for cH6/1N5 and 
H1N1 until Visit 6 (Day 85). MN assay will not be performed for H5N8.
!
The anti-group 2 hemagglutinin (HA) stalk response by ELISA will not be 
performed.
!
The immune response in terms of anti-neuraminidase antibodies will not be 
assessed.

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!
The passive transfer experiment in mice will not be performed for the Month 14 
and Month 26 timepoints. The blood collection at Month 26 for passive transfer 
has been removed.
!
The anti-H9 full length HA ELISA will not be performed.
!
Anti-stalk antibody functionality will not be further investigated, except for the 
antibody-dependent cell-mediated cytotoxicity until the interim analysis at Day 85.
!
Occurrence of RT-PCR-confirmed influenza cases endpoint was removed.
In case samples have already been taken but not tested yet, they will be stored for 
future research.
In addition, the list of contributing authors has been updated.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Cover page
Coordinating author
!
, Scientific Writer (XPE Pharma & 
Science Modis Life Sciences for GSK Biologicals)
Contributing authors
!
, Expert Statistician
!
[…]
!
, Study Delivery Leads
Section 1.2.2 Rationale for the study design (+ in synopsis)
[…] Finally, the cell-mediated immune response after each vaccination and the protective 
effect in vivo of the anti-stalk antibodies will be explored. Passive surveillance will be put 
in place in order to capture the occurrence of RT-PCR-confirmed influenza cases
influenza-like illnesses during the entire study period.
Section 2.3
Tertiary objectives (+ in synopsis)
!
To explore the cell-mediated immune responses (B-cells and T-cells) after each 
vaccination.
!
To explore the immune response against the IIV4 H1N1, the HA head of cH5/1N1 
and cH8/1N1, cH11/1N1, the chimeric cH6/1N5 strain, H5N8 virus strain and H1N1 
swine virus strain by hemagglutination inhibition (HI) assay.
!
To explore the anti-Group 2 HA stalk response (e.g., H3, H4, H10, …).
!
To explore the immune response in terms of anti-NA antibodies after each 
vaccination.
!
To evaluate the occurrence of RT-PCR-confirmed influenza cases during the entire 
study period.
!
[…]
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
To develop and validate assays for evaluation/characterization of the humoral and 
cellular immune responses to the investigational vaccines.

To explore the humoral immune response in term of anti-H9 full length HA serum 
antibodies.

To explore anti-stalk antibody functionality, (e.g., antibody-dependent cell-mediated 
cytotoxicity (ADCC), complement dependent lysis (CDL), antibody dependent 
cellular phagocytosis (ADCP) or glycoform analysis assays).
Section 3
Study design overview (+ in synopsis)
Figure 1
Study design overview
*If a subject presents signs and symptoms of influenza-like illness (ILI) […] to test for influenza and/or other respiratory 
pathogens by RT-PCR if deemed necessary, or for storage.
[…]

Sampling schedule

[…]

Blood samples for passive transfer experiment in animals will be drawn from all 
subjects at […], Month 14 (Visit 8)* and Month 26 (Visit 12).

Blood samples for cell-mediated immunity (CMI) assessment will be drawn 
from a sub-cohort of  225 subjects at […], Month 14 (Visit 8)*, Month 14 + 7 
days (Visit 9)*, and Month 14 + 28 days (Visit 10)* and Month 26 (Visit 12).

During the entire study period, nasal and throat swabs will be collected […] by 
RT-PCR if deemed necessary, or stored for future research.
*Note that samples already collected for these timepoints by the time of 
Protocol Amendment 4 implementation at site will not be tested and will be 
stored, unless deemed necessary based on medical review of the cases.
Section 4.1
Number of subjects/centres
Table 4
Sub-cohort
Sub-cohort name
Description
Estimated number of subjects
Cell-mediated immunity 
(CMI) testing
Additional blood sample (40 mL) to be taken at Visits 
1, 2, 3, 5, 6, 8, 9 and 10 and 12 for CMI testing. […]
Approximately 225
The sub-cohort will consist […].
Section 5.5
Outline of study procedures
Table 5
List of study procedures for Phase I subjects
Epoch
Screening
[…]
Booster
In case of 
ILI**
Type of contact
Screening Visit*
Visit 8
Visit 9
Visit 10
Visit 11 Visit 12
Timepoints
Pre-Day 1
M14
M14+7D M14+28D
M20
M26
Sampling timepoints
Screening
M14
PIIId7
PIIId28
M20
M26
Blood sampling for 
passive transfer (~2.5 mL)
●
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Table 6
List of study procedures for Phase II subjects
Epoch
[…]
Booster
In case of 
ILI**
Type of contact
Visit 8
Visit 9
Visit 10
Visit 11 Visit 12
Timepoints
M14
M14+7D M14+28D
M20
M26
Sampling timepoints
M14
PIIId7
PIIId28
M20
M26
Blood sampling for CMI response (~40 mL)#
●
●
●
-●-
Blood sampling for passive transfer (~2.5 mL)
●
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Section 5.7.2 Biological samples
Table 8
Biological samples
Sample type
Quantity
Unit
Timepoint
Sub-cohort name**
Blood
Approximately 20
mL
Visits 1, 6, 8 and 12
All subjects
Approximately 5.5*
mL
Visits 2, 4, 5, 9
Approximately 17.5
mL
Visits 3, 7, 10, 11, 12
Blood
Approximately 40
mL
Visits 1, 2, 3, 5, 6, 8, 9, 
10 and 12
In addition for the 
CMI sub-cohort
Section 5.7.3 Laboratory assays
Molecular biology (PCR tests)
At the onset of an ILI episode, […]. Each Nasal and throat swab specimens will be tested 
by RT-PCR for influenza and/or other respiratory virus infections […], if deemed 
necessary, or will be stored for future research.
Table 9
Humoral immunity
Component (Strain or Antigen 
Description)
Method
Kit/
Manufacturer
Unit
Cut-off*
ELISAs
cH6/1 HA = […]
Anti-H1 HA stalk ELISA
In-house 
assay
ELISA 
units per 
mL 
(EU/mL)
TBD 66
H2 HA full length = […]
Anti-H2 HA full length ELISA
TBD 22
H18 HA full length = […]
Anti-H18 HA full length ELISA
TBD 43
H9 HA full length = Recombinant antigen 
based on A/chicken/Hong Kong/G9/1997 HA
Anti-H9 HA full length ELISA
TBD
N1 NA = Recombinant antigen based on 
A/California/04/2009 (H1N1) NA
Anti-N1 NA ELISA
TBD
Microneutralization (MN) assays
cH6/1N5 virus:
[…]
Anti-H1 HA stalk MN Assay
In-house 
assay
1/DIL 
(IC50)
TBD
20
H1N1 swine influenza virus:
A/Swine/Jiangsu/40/2011 (H1N1)
Anti-heterosubtypic HA Group 
1 virus MN Assay
TBD
20
IIV4 H1N1 strains$
Anti-heterosubtypic HA Group 
1 virus MN Assay
TBD
20
Hemagglutination Inhibition (HI) assay
IIV4 H1N1 strains$
HI assay
In-house 
assay
1/DIL
TBD
Chimeric vaccine strains:
cH5/1N1 and cH8/1N1 and cH11/1N1
TBD
10
Chimeric cH6/1N5 strain
TBD
H5N8 virus strain
TBD
H1N1 swine virus strains
TBD
[…]
 
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*Cut-off value will be determined following set-up/qualification data.
**Refer to APPENDIX B for the laboratory addresses.
***GSK Biologicals laboratory refers to […]
$ IIV4 H1N1 strains will depend on the World Health Organization recommendation for the 2017/2018 season (Dose 1 
at Day 1) and the 2018/2019 season (booster dose at Month 14).
Section 5.7.4.1
Immunological read-outs
Table 13
Immunological read-outs for humoral immunity and cell-mediated 
immunity
Blood sampling timepoint
Sub-
cohort 
Name
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
Humoral immunity
Visit 1 (Day 1)
Visit 3 (Day 29)
[…]
PRE
PId28
[…]
All
subjects
∃470
[…]
[…]
Anti-H9 HA full length ELISA
Visit 1 (Day 1)
Visit 3 (Day 29)
Visit 6 (Day 85)
Visit 8 (Month 14)
Visit 10 (Month 14 + 28 days)
Visit 12 (Month 26)
PRE
PId28
PIId28
M14
PIIId28
M26
All
subjects
∃470
Anti-H1 HA stalk MN assay
Anti-heterosubtypic HA Group 1 
virus MN assay (H5N8)
Anti-heterosubtypic HA Group 1 
virus MN assay (H1N1 swine)
Anti-heterosubtypic HA Group 1 
virus MN assay (IIV4 H1N1 strains)
Anti-N1 NA ELISA
HI with cH5/1N1 and cH8/1N1 
virus
HI with cH6/1N5, H5N8 and H1N1 
swine virus strains
Visit 1 (Day 1)
Visit 3 (Day 29)
Visit 6 (Day 85)
Visit 8 (Month 14)
PRE
PId28
PIId28
M14
All 
subjects
∃470
HI with IIV4 H1N1 strain from 
2017/2018 season
Visit 8 (Month 14)
Visit 10 (Month 14 + 28 days)
Visit 12 (Month 26)
M14
PIIId28
M26
All 
subjects
∃470
HI with IIV4 H1N1 strain from 
2018/2019 season
HI with cH11/1N1 virus
Cell-mediated immunity
Visit 1 (Day 1)
Visit 3 (Day 29)
Visit 6 (Day 85)
Visit 8 (Month 14)
Visit 10 (Month 14 + 28 days)
Visit 12 (Month 26)
PRE
PId28
PIId28
M14
PIIId28
M26
CMI sub-
cohort*
∃225
T-cell response by ICS assay
Visit 1 (Day 1)
[…]
Visit 8 (Month 14)
Visit 9 (Month 14 + 7 days)
Visit 10 (Month 14 + 28 days)
Visit 12 (Month 26)
PRE
[…]
M14
PIIId7
PIIId28
M26
CMI sub-
cohort*
∃225
B memory cells by ELISPOT
Visit 1 (Day 1)
[…]
Visit 8 (Month 14)
Visit 9 (Month 14 + 7 days)
PRE
[…]
M14
PIIId7
CMI sub-
cohort*
∃225
Plasmablast detection to HA by 
flow cytometry
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Section 5.7.4.3
Molecular biology
Table 15
Read-outs for molecular biology tests
Sampling timepoint
Number of 
subjects
Component
Type of contact and 
timepoint
Sampling timepoint
Assessment visit
Unscheduled
All nasal and 
throat swabs
(Event-driven)
Influenza A virus (Flu A)
Influenza B virus (Flu B)
[…]
Section 10.2
Secondary endpoints (+ in synopsis)
Anti-H1 stalk immune response measured by ELISA and by MN assay after each dose:
[…]

Levels of anti-H1 stalk antibody titers by MN assay post-each vaccination.
The following aggregate variables will be calculated for the above parameters with 
95% CI:

Seropositivity rates and GMTs at Days 1, 29 and 85, Month 14, Month 14 + 28 
days and Month 26.

[…]

Levels of antibody titers by MN assay for H5N8, H1N1 swine influenza and IIV4 
H1N1 vaccine strains.
The following aggregate variables will be calculated for the above parameters with 
95% CI:

Seropositivity rates and GMTs at Days 1, 29 and 85, Month 14, Month 14 + 28 
days and Month 26.
Section 10.3
Tertiary endpoints (+ in synopsis)

Evaluation of CMI parameters in terms of frequencies of:

Antigen-specific CD4+/CD8+ T-cells […] at Days 1, 29 and 85, Month 14, 
Month 14 + 28 days and Month 26.

B-memory cells […] at Days 1, 8, 29, 64 and 85, Month 14, Month 14 + 7 days, 
Month 14 + 28 days and Month 26.

Plasmablasts […] at Days 1, 8 and 64, Month 14, Month 14 + 7 days.

Levels of HI antibody to IIV4 H1N1, chimeric vaccine strains cH5/1N1 and 
cH8/1N1, chimeric cH6/1N5 strain, H5N8 virus strain and H1N1 swine virus strain:
The following aggregate variables will be calculated with 95% CI:

Seropositivity rates and GMTs at Days 1, 29 and 85, Month 14, Month 14 + 28 
days and Month 26.

[…]
 
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
Seroconversion rate (SCR) at Days 29 and 85, Month 14, Month 14 + 28 days 
and Month 26.

Evaluation of the anti-Group 2 HA stalk response (e.g., H3, H4, H10, …) by ELISA 
and/or MN assay pre-and post-vaccination.

Levels of anti-N1 NA antibody by ELISA at Days 1, 29, 85, Month 14, Month 14 + 
28 days and Month 26.

Occurrence of RT-PCR-confirmed influenza cases during the entire study period.

Assessment of the in vivo protective effect of the anti-stalk antibodies when 
transferring Day 1 and Day 85, Month 14 and Month 26 pooled serum […]:

Lung virus titer in TCID50/mg (log10 fold change [Day 1 minus Day 85, Month 
14 and Month 26]), within challenge group.

Evaluation of the anti-H9 full length HA response by ELISA pre-and post-
vaccination.
Section 10.8
Analysis of safety
[…]

The percentage of subjects with episode(s) of ILI (any, RT-PCR-confirmed) will be 
summarized by group with exact 95% CI.
Section 10.9.1.2
CMI assessment
For each study group, at Days 1, 8, 29, 64 and 85 at each timepoint where a blood sample 
result is available from subjects in the CMI sub-cohort, the frequency of specific 
CD4+/CD8+ T-cells, B-memory cells and plasmablasts will be summarised using 
descriptive statistics.
Appendix D
Serum passive transfer/virus challenge experiment in BALB/c mice 
from adult subjects involved in the FLU D-SUIV-ADJ-001 study cohort
Objectives
1.
The in vivo protective effect of transferring pooled adult human serum from subjects 
from the FLU D-SUIV-ADJ-001 study cohort to mice […]:

1C: Lung virus titer in TCID50/mg on Day 3 and/or Day 6 post-challenge […].
Comparisons between FLU D-SUIV-ADJ-001 study groups and/or timepoints 
(Day 1 and Day 85, Month 14 and Month 26) will be investigated.
2.
The association between pre- or post-transfer human IgG binding antibody titers […]

2A: Measure of the pre- and post-transfer geometric mean human IgG binding 
antibody specific to cH6/1Nx virus[…] (Day 1 and Day 85, Month 14 and 
Month 26).
 
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Protocol endpoints:
Objective
Endpoint
[…]
[…]
1C
Lung virus titer in TCID50/mg (log10 fold change (D1 - D85), (D1 - M14) (D1 - M26)),
within challenge group
Human serum pools:
Serum pools will be created using serum samples […] and the timepoints Day 1 and Day 
85, Month 14 and Month 26 from the FLU D-SUIV-ADJ-001 cohort.
 
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207543 (FLU D-SUIV-ADJ-001)
Protocol Amendment 4 Final
1ef2d9809b8439587a0ee23181725e4a0623e2bc
166
11-JUL-2019