An Observer-blind Study to Rank Different Formulations of GSK Biologicals' Investigational RSV Vaccine (GSK3003891A) Administered to Healthy Women
Phase: PHASE2
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline

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PPD 
PPD 
PPD 
PPD 
PPD 
21-AUG-2017 
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PPD 
PPD 
 
 
 
Primary Study 
vaccine(s)/product(s) and 
number(s) 
Other Study 
vaccine(s)/product(s) 
eTrack study number and 
Abbreviated Title 
 
Investigational New Drug 
(IND) number 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l’institut 89, 
1330 Rixensart, Belgium 
 
GlaxoSmithKline (GSK) Biologicals’ investigational 
respiratory syncytial virus (RSV) vaccine 
(GSK3003891A) 
Placebo 
 
204812 (RSV F-021) 
 
15487 
 
EudraCT number 
2016-001135-12 
Date of protocol 
Final Version 3 16 August 2016 
Date of protocol 
amendment 
Amendment 1 Final 21 August 2017 
Title 
An observer-blind study to rank different formulations 
of GSK Biologicals’ investigational RSV vaccine 
(GSK3003891A) administered to healthy women. 
Detailed Title 
A Phase II, randomised, observer-blind, controlled, 
multi-country study to rank different formulations of 
GSK Biologicals’ investigational RSV vaccine 
(GSK3003891A), based on immunogenicity, 
reactogenicity and safety, when administered to 
healthy women, aged 18 - 45 years. 
Co-ordinating author(s) 
(Amended 31 July 2017) 
Contributing authors 
 
• 
(XPE Pharma & Science for GSK 
Biologicals) 
• 
, Senior Science Writer 
• 
and 
, Clinical 
& Epidemiology Project Lead 
(Amended 31 July 2017) 
• 
PPD 
, 
, and PPD 
, Clinical Research & Development Leads 
• 
, Lead Statistician 
• 
, Project Statistician 

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PPD 
PPD 
PPD 
PPD 
eTrack study number and 
Abbreviated Title 
 
Investigational New Drug 
(IND) number 
204812 (RSV F-021) 
 
15487 
 
EudraCT number 
2016-001135-12 
Detailed Title 
A Phase II, randomised, observer-blind, controlled, 
multi-country study to rank different formulations of 
GSK Biologicals’ investigational RSV vaccine 
(GSK3003891A), based on immunogenicity, 
reactogenicity and safety, when administered to 
healthy women, aged 18 - 45 years. 
• 
PPD , , and 
, Study Delivery 
Leads 
• 
PPD 
(Aixial for GSK Biologicals) and 
(CVO-Europe for GSK 
Biologicals), Vaccine Supply Coordinator 
• 
, Clinical Read-Out Team Leader 
GSK Biologicals’ Protocol DS v 14.1.1 
© 2016-2017 the GSK group of companies or its licensor. Unauthorised copying or use of this 
information is prohibited. 

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Protocol Amendment 1 Sponsor Signatory Approval 
 
eTrack study number and 
Abbreviated Title 
204812 (RSV F-021) 
 
IND number 
15487 
EudraCT number 
2016-001135-12 
 
Date of protocol amendment 
Amendment 1 Final 21 August 2017 
 
Detailed Title 
A Phase II, randomised, observer-blind, controlled, 
multi-country study to rank different formulations of 
GSK Biologicals’ investigational RSV vaccine 
(GSK3003891A), based on immunogenicity, 
reactogenicity and safety, when administered to 
healthy women, aged 18 - 45 years. 
 
Sponsor signatory 
Alexander Schmidt 
  Clinical & Epidemiology Project Lead 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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Protocol Amendment 1 Rationale 
 
 
 
Amendment 1 
Amendment number: 
Rationale/background for changes: 
The following minor changes and clarifications have been made 
• The kit used for multiplex respiratory viral panel testing has been changed. 
• Changes to study personnel have been included on the protocol cover page. 

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Protocol/Protocol Amendment 1 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’ investigational vaccines and other study-related 
duties and functions as described in the protocol. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if 
required by local regulations, obtain the laboratory’s current certification or 
Quality Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained onsite 
or elsewhere without the approval of GSK Biologicals and the express written 
informed consent of the subject and/or the subject’s legally acceptable 
representative. 
• 
To perform no other biological assays on the clinical samples except those 
described in the protocol or its amendment(s). 
• 
To co-operate with a representative of GSK Biologicals in the monitoring 
process of the study and in resolution of queries about the data. 
• 
That I have been informed that certain regulatory authorities require the 
sponsor to obtain and supply, as necessary, details about the investigator’s 
ownership interest in the sponsor or the investigational vaccine, and more 
generally about his/her financial ties with the sponsor. GSK Biologicals will use 
and disclose the information solely for the purpose of complying with regulatory 
requirements. 
 
Hence I: 
 
• 
Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and 
dependent children). 
• 
Agree to promptly update this information if any relevant changes occur during 
the course of the study and for one year following completion of the study. 
• 
Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities. 
• 
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 

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eTrack study number and 
Abbreviated Title 
204812 (RSV F-021) 
 
IND number 
15487 
EudraCT number 
2016-001135-12 
Date of protocol amendment 
Amendment 1 Final 21 August 2017 
Detailed Title 
A Phase II, randomised, observer-blind, controlled, 
multi-country study to rank different formulations of 
GSK Biologicals’ investigational RSV vaccine 
(GSK3003891A), based on immunogenicity, 
reactogenicity and safety, when administered to 
healthy women, aged 18 - 45 years. 
Investigator name 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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1. Sponsor 
Sponsor Information 
 
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. 
 
5. GSK Biologicals’ Central Safety Physician On-Call Contact information for 
Emergency Unblinding 
 
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to 
protocol Section 8.8. 

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SYNOPSIS 
Detailed Title 
A Phase II, randomised, observer-blind, controlled, multi- 
country study to rank different formulations of GSK 
Biologicals’ investigational RSV vaccine (GSK3003891A), 
based on immunogenicity, reactogenicity and safety, when 
administered to healthy women, aged 18 - 45 years. 
 
Indication 
Active immunisation of pregnant women during the third 
trimester of pregnancy to prevent respiratory syncytial virus 
(RSV) (subtypes A and B)-associated severe lower respiratory 
tract infection (LRTI) in infants by transfer of maternal 
antibodies. 
 
Rationale for the 
study and study 
design 
• 
Rationale for the study 
The safety/reactogenicity and immunogenicity of 6 different 
formulations of the PreF-based investigational RSV vaccine 
(10, 30 and 60 µg of PreF antigen, non-adjuvanted or 
adjuvanted with aluminium [500 µg]) have been evaluated in 
a Phase I study in healthy men, aged 18-44 years (study RSV 
F-001; NCT01905215). No safety signal associated with the 
investigational RSV vaccines was identified which would 
preclude further clinical development. Based on data from that 
Phase I study, the safety/reactogenicity and immunogenicity 
of 30 μg of non-adjuvanted PreF and 60 μg of non-adjuvanted 
and aluminium-adjuvanted PreF formulations are currently 
being evaluated further in non-pregnant women aged 18-45 
years (study RSV F-020; NCT02360475). 
 
The RSV F-020 study is still ongoing but 
safety/reactogenicity and immunogenicity data up to 90 days 
post vaccination are already available for all subjects. Based 
on these results, the non-adjuvanted 30 µg and 60 µg PreF 
formulations were selected for further evaluation in the 
current RSV F-021 study. In addition, the RSV F-021 study 
will also evaluate a formulation containing 120µg of PreF 
antigen. This will allow evaluation of a wider antigen dose 
range to determine if there is a dose response relationship in 
terms of antibody response at the higher dose range that was 
not present at the lower range. 
 
The purpose of this study is to rank the different vaccine 
formulations based on safety/reactogenicity and 
immunogenicity data. The formulations eliciting strong 
immune responses while maintaining an acceptable safety 
profile will be considered for further evaluation, including in 
studies vaccinating pregnant women. 

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• 
Rationale for the study design 
Healthy, non-pregnant women aged 18 - 45 years will be 
enrolled in this study: 
• 
Women aged 18 - 45 years are selected to match the 
vaccine’s target population, i.e. pregnant women, as 
closely as possible (gender, age). 
• 
Non-pregnant women are selected to avoid unnecessarily 
exposing a vulnerable population (pregnant women and 
the foetuses/children) to a higher dose of the vaccine that 
has not previously been studied in non-pregnant women. 
• 
Rationale for the use of placebo 
The placebo group is included as a control for both the 
safety/reactogenicity and immunogenicity assessments. 
 
Objectives 
Primary 
 
• 
To rank different formulations of the investigational RSV 
vaccine based on safety/reactogenicity and 
immunogenicity data up to 1 month post-vaccination 
(Day 30). 
 
Secondary 
 
• 
To evaluate the reactogenicity and safety of a single 
intramuscular dose of the RSV investigational vaccines 
up to study conclusion. 
• 
To evaluate the immunogenicity of a single intramuscular 
dose of the RSV investigational vaccines up to 90 days 
after vaccination (Day 90). 
• 
To further assess the safety of the investigational RSV 
vaccines by evaluating whether a single dose of the 
vaccines induces antibodies against the residual host cell 
protein neogenin (NEO) up to 1 month post-vaccination 
(Day 30) 
 
• 
To estimate the incidence of medically attended RSV- 
associated RTIs up to study conclusion. 
Tertiary 
 
• 
If deemed necessary, to further characterise the immune 
response of a single intramuscular dose of the RSV 
investigational vaccines. 

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Study design 
• 
Experimental design: Phase II, observer-blind, 
randomised, controlled, multi-country, study with four 
parallel groups. 
• 
Duration of the study: the intended duration of the study 
will be approximately 1 year from Visit 1 to study 
conclusion (Day 360). 
 
Epoch 001: Primary starting at Visit 1 (Day 0) and 
ending at Visit 5 (Day 90). 
 
Epoch 002 : Follow-up phase starting one day after 
Day 90 and ending at Day 360 contact. 
• 
Primary completion Date (PCD):Visit 3 (Day 30). 
• 
End of Study (EoS): Last testing results released of 
samples collected at Visit 5 (i.e. last testing results 
released for the assays related to the primary and 
secondary endpoints). 
• 
Study groups: 
Synopsis Table 1 
Study groups and epochs foreseen in the study 
 
Study groups 
Number of 
subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
Epoch 002 
30 PreF 
~100 
18 - 45 years 
x 
x 
60 PreF 
~100 
18 - 45 years 
x 
x 
120 PreF 
~100 
18 - 45 years 
x 
x 
Control 
~100 
18 - 45 years 
x 
x 
Synopsis Table 2 
Study groups and treatment foreseen in the study 
 
Treatment name 
Vaccine/ 
Product name 
Study Groups 
30 PreF 
60 PreF 
120 PreF 
Control 
30 µg PreF 
PreF-30 
NaCl 
X 
60 µg PreF 
PreF-60 
NaCl 
X 
120 µg PreF 
PreF-120 
NaCl 
X 
Placebo 
Formulation 
buffer S9b 
X 
 
• 
Control: placebo control 
• 
Vaccination schedule: One intramuscular vaccination at 
Day 0. 
• 
Treatment allocation: Subjects will be randomised using 
a centralised randomisation system on internet (SBIR) at 
Day 0. The randomisation algorithm will use a 
minimisation procedure accounting for age (18 - 32 years 
or 33 - 45 years) and centre. 

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• 
Blinding: Observer-blind in Epoch 001 and single-blind 
in Epoch 002. 
Synopsis Table 3 
Blinding of study epochs 
 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
Epoch 002 
single-blind 
 
• 
Sampling schedule: 
 
Blood samples for haematology/biochemistry will be 
collected (~10 mL) from all subjects at Visit 1 (Day 
0), Visit 2 (Day 7) Visit 3 (Day 30), Visit 4 (Day 60) 
and Visit 5 (Day 90). 
 
Blood samples for humoral immune response 
evaluation will be collected (~17 mL) from all 
subjects at Visit 1 (Day 0), Visit 3 (Day 30), Visit 4 
(Day 60) and at Visit 5 (Day 90). 
 
Nasal swabs will be collected from subjects in case 
of a medically attended respiratory tract infection 
from enrolment (Visit 1) until Contact 3. 
• 
Type of study: self-contained 
• 
Data collection: Electronic Case Report Form (eCRF). 
• 
Safety monitoring: When the first 25% of subjects (i.e. 
~100 subjects; ~25 subjects per study group) have been 
vaccinated, enrolment will be paused until completion of 
an unblinded review by a GSK internal Safety Review 
Committee (iSRC). Continuation of study enrolment will 
be conditional to a favourable outcome of the iSRC 
evaluation of all available safety and reactogenicity data 
collected up to at least 7 days post-vaccination (including 
Day 7 haematology and biochemistry parameters). In 
addition, the blinded safety data will be reviewed by GSK 
Biologicals’ Safety Review Team (SRT) on a regular 
basis throughout the study. 
Refer to Section 8.10 for description of safety monitoring. 
 
Number of subjects 
The target is to enrol approximately 400 eligible women 
(~100 per group). 
 
Endpoints 
Primary 
 
• 
Occurrence of AEs from vaccination up to Day 7, for all 
subjects in each investigational RSV vaccine group: 
 
Occurrence of any Grade 2 and Grade 3 general AE 

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(solicited and unsolicited); 
 
Occurrence of Grade 2 and Grade 3 fever; 
 
Occurrence of any vaccine-related SAE. 
• 
Functional antibody titres against RSV at Day 0 and Day 
30, for all subjects in each investigational RSV vaccine 
group. 
 
Neutralising antibody titres against RSV-A 
• 
PCA concentrations at Day 0 and Day 30 for all subjects 
in each investigational RSV vaccine group. 
 
Secondary 
 
• 
Occurrence of AEs from vaccination up to study 
conclusion: 
 
Occurrence of each solicited local and general AE, 
during a 7-day follow-up period after vaccination 
(i.e. the day of vaccination and 6 subsequent days), 
for all subjects in all groups; 
 
Occurrence of any unsolicited AE, during a 30-day 
follow-up period after vaccination (i.e. the day of 
vaccination and 29 subsequent days), for all subjects 
in all groups; 
 
Occurrence of any haematological (haemoglobin 
level, White Blood Cells [WBC], lymphocyte, 
neutrophil, eosinophil and platelet count) and 
biochemical (alanine amino-transferase [ALT], 
aspartate amino-transferase [AST] and creatinine) 
laboratory abnormality at Day 0, Day 7, Day 30, Day 
60 and Day 90 for all subjects in all groups; 
 
Occurrence of any SAE, for all subjects in all groups. 
• 
Functional antibody titres against RSV for all subjects in 
all groups: 
 
Neutralising antibody titres against RSV-A at Day 0, 
Day 30, Day 60 and Day 90; 
 
Neutralising antibody titres against RSV-B at Day 0, 
Day 30, Day 60 and Day 90. 
• 
PCA concentration at Day 0, Day 30, Day 60 and Day 90 
for all subjects in all groups. 
• 
Humoral immune response to the residual host cell 
protein NEO in the investigational RSV vaccine at pre- 
vaccination (Day 0), and 1 month post-vaccination (Day 

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30) for all subjects in all groups. 
 
Neutralising antibody titres against NEO 
• 
Occurrence of medically attended RSV-associated RTIs 
up to study conclusion. 
Tertiary 
 
See section 5.7.3 for additional testing proposed to further 
characterise the immune response to the investigational RSV 
vaccine. 

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TABLE OF CONTENTS 
 
PAGE 
 
SPONSOR INFORMATION ............................................................................................ 7 
SYNOPSIS ...................................................................................................................... 8 
LIST OF ABBREVIATIONS ........................................................................................... 22 
GLOSSARY OF TERMS ............................................................................................... 25 
TRADEMARKS ............................................................................................................. 30 
1. 
INTRODUCTION .................................................................................................... 31 
1.1. 
Background ................................................................................................ 31 
1.1.1. 
Disease burden ............................................................................ 31 
1.1.2. 
Current management of RSV disease in infants ........................... 31 
1.1.3. 
RSV vaccination strategies .......................................................... 32 
1.1.3.1. 
GSK Biologicals’ investigational RSV vaccine ............. 32 
1.1.3.2. 
Other RSV investigational vaccines ............................ 33 
1.1.4. 
GSK Biologicals’ investigational RSV vaccine composition .......... 33 
1.2. 
Rationale for the study and study design .................................................... 34 
1.2.1. 
Rationale for the study ................................................................. 34 
1.2.2. 
Rationale for the study design ...................................................... 35 
1.2.3. 
Rationale for the use of placebo ................................................... 35 
1.2.4. 
Safety considerations ................................................................... 35 
1.2.5. 
Study blinding .............................................................................. 37 
1.3. 
Benefit : Risk Assessment .......................................................................... 37 
1.3.1. 
Risk Assessment ......................................................................... 37 
1.3.2. 
Benefit Assessment ..................................................................... 39 
1.3.3. 
Overall Benefit:Risk Conclusion ................................................... 39 
2. 
OBJECTIVES ......................................................................................................... 40 
2.1. 
Primary objective ........................................................................................ 40 
2.2. 
Secondary objectives .................................................................................. 40 
2.3. 
Tertiary objective ........................................................................................ 40 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 41 
4. 
STUDY COHORT ................................................................................................... 43 
4.1. 
Number of subjects/centres ........................................................................ 43 
4.2. 
Inclusion criteria for enrolment .................................................................... 43 
4.3. 
Exclusion criteria for enrolment ................................................................... 44 
5. 
CONDUCT OF THE STUDY .................................................................................. 46 
5.1. 
Regulatory and ethical considerations, including the informed 
consent process .......................................................................................... 46 
5.2. 
Subject identification and randomisation of treatment ................................. 47 
5.2.1. 
Subject identification .................................................................... 47 
5.2.2. 
Randomisation of treatment ......................................................... 47 
5.2.2.1. 
Randomisation of supplies .......................................... 47 

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5.2.2.2. 
Treatment allocation to the subject ............................. 47 
5.2.2.2.1.       
Study group and treatment 
number allocation ................................... 47 
5.3. 
Method of blinding....................................................................................... 48 
5.4. 
General study aspects ................................................................................ 48 
5.5. 
Outline of study procedures ........................................................................ 49 
5.6. 
Detailed description of study procedures ..................................................... 52 
5.6.1. 
Informed consent ......................................................................... 52 
5.6.2. 
Check inclusion and exclusion criteria .......................................... 52 
5.6.3. 
Collect demographic data ............................................................ 52 
5.6.4. 
Medical history ............................................................................. 52 
5.6.5. 
Physical examination ................................................................... 53 
5.6.6. 
Pregnancy test ............................................................................. 53 
5.6.7. 
Check contraindications, warnings  and  precautions  to 
vaccination ................................................................................... 53 
5.6.8. 
Assess pre-vaccination body temperature .................................... 53 
5.6.9. 
Study group and treatment number allocation .............................. 54 
5.6.10. 
Blood sampling ............................................................................ 54 
5.6.11. 
Collection of nasal swab samples ................................................ 54 
5.6.12. 
Study Vaccine administration ....................................................... 54 
5.6.13. 
30 minutes post-vaccination observation ...................................... 55 
5.6.14. 
Distribution of Subject Card .......................................................... 55 
5.6.15. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ..................................................... 55 
5.6.16. 
Recording of AEs, SAEs and pregnancies ................................... 55 
5.6.17. 
Extension/Booster study .............................................................. 56 
5.6.18. 
D180, D270 and D360 Contacts .................................................. 56 
5.6.19. 
Study conclusion .......................................................................... 56 
5.7. 
Biological sample handling and analysis ..................................................... 57 
5.7.1. 
Use of specified study materials ................................................... 57 
5.7.2. 
Biological samples ....................................................................... 58 
5.7.3. 
Laboratory assays........................................................................ 58 
5.7.4. 
Biological samples evaluation ...................................................... 61 
5.7.4.1. 
Haematology/Blood Chemistry ................................... 61 
5.7.4.2. 
Immunological read-out .............................................. 62 
5.7.4.3. 
Molecular biology ........................................................ 62 
5.7.5. 
Immunological correlates of protection ......................................... 63 
6. 
STUDY VACCINES ADMINISTRATION ................................................................. 63 
6.1. 
Description of study vaccines ...................................................................... 63 
6.2. 
Storage and handling of study vaccines ...................................................... 63 
6.3. 
Dosage and administration of study vaccines.............................................. 64 
6.4. 
Replacement of unusable vaccine doses .................................................... 64 
6.5. 
Contraindications to vaccination .................................................................. 65 
6.6. 
Concomitant medications/products and concomitant vaccinations .............. 65 
6.6.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 65 
6.6.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses ........................ 66 
6.7. 
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses ......................................................................... 66 

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7. 
HEALTH ECONOMICS .......................................................................................... 66 
8. 
SAFETY ................................................................................................................. 67 
8.1. 
Safety definitions ........................................................................................ 67 
8.1.1. 
Definition of an adverse event ...................................................... 67 
8.1.2. 
Definition of a serious adverse event ........................................... 68 
8.1.3. 
Solicited adverse events .............................................................. 69 
8.1.3.1. 
Solicited local (injection-site) adverse events .............. 69 
8.1.3.2. 
Solicited general adverse events ................................ 69 
8.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 69 
8.1.5. 
Medically Attended Respiratory Tract Infections ........................... 70 
8.2. 
Events or outcomes not qualifying as adverse events or serious 
adverse events (pregnancy) ........................................................................ 70 
8.3. 
Detecting and recording adverse events, serious adverse events 
and pregnancies ......................................................................................... 71 
8.3.1. 
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies ..................................... 71 
8.3.2. 
Post-Study adverse events and serious adverse events .............. 72 
8.3.3. 
Evaluation of adverse events and serious adverse events ........... 73 
8.3.3.1. 
Active questioning to detect adverse events 
and serious adverse events ........................................ 73 
8.3.3.2. 
Assessment of adverse events ................................... 74 
8.3.3.2.1.       ..................................................... Asse
ssment of intensity .................................. 74 
8.3.3.2.2.       ..................................................... Asse
ssment of causality ................................. 75 
8.3.3.3. 
Assessment of outcomes ............................................ 76 
8.3.3.4. 
Medically attended visits ............................................. 76 
8.4. 
Reporting of serious adverse events, pregnancies, and other events .......... 77 
8.4.1. 
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals ............................................ 77 
8.4.2. 
Contact information for reporting serious adverse events 
and pregnancies .......................................................................... 77 
8.4.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................... 77 
8.4.3.1. 
Back-up system in case the electronic reporting 
system does not work ................................................. 78 
8.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals ................................................................................... 78 
8.4.5. 
Updating of SAE and pregnancy information after removal 
of write access to the subject’s eCRF .......................................... 78 
8.4.6. 
Regulatory   reporting   requirements   for   serious   adverse 
events .......................................................................................... 78 
8.5. 
Follow-up  of  adverse  events,   serious   adverse   events   and 
pregnancies ................................................................................................ 79 
8.5.1. 
Follow-up of adverse events and serious adverse events ............ 79 
8.5.1.1. 
Follow-up during the study .......................................... 79 
8.5.1.2. 
Follow-up after the subject is discharged from 
the study ..................................................................... 79 
8.5.2. 
Follow-up of pregnancies ............................................................. 80 
8.6. 
Treatment of adverse events ....................................................................... 80 
8.7. 
Unblinding ................................................................................................... 80 

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8.8. 
Emergency unblinding ................................................................................ 80 
8.9. 
Subject card ................................................................................................ 81 
8.10. Safety monitoring ........................................................................................ 81 
8.10.1. 
Safety review team ...................................................................... 81 
8.10.2. 
Internal safety review committee .................................................. 81 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................... 83 
9.1. 
Subject completion ...................................................................................... 83 
9.2. 
Subject withdrawal ...................................................................................... 83 
9.2.1. 
Subject withdrawal from the study ................................................ 83 
10. STATISTICAL METHODS ...................................................................................... 84 
10.1. Primary endpoints ....................................................................................... 84 
10.2. Secondary endpoints .................................................................................. 84 
10.3. Tertiary endpoints ....................................................................................... 85 
10.4. Determination of sample size ...................................................................... 85 
10.5. Cohorts for Analyses ................................................................................... 86 
10.5.1. 
Total vaccinated cohort ................................................................ 86 
10.5.2. 
According-to-protocol    cohort    for    analysis     of 
immunogenicity ............................................................................ 86 
10.6. Derived and transformed data ..................................................................... 87 
10.7. Analysis of demographics ........................................................................... 88 
10.8. Analysis for ranking RSV formulations ........................................................ 89 
10.9. Analysis of safety ........................................................................................ 89 
10.10. Analysis of immunogenicity ......................................................................... 91 
10.11. Analysis of medically attended RTIs ............................................................ 92 
10.12. Interpretation of analyses ............................................................................ 92 
10.13. Conduct of analyses ................................................................................... 92 
10.13.1. Sequence of analyses .................................................................. 93 
10.13.2. Statistical considerations for interim analyses .............................. 93 
11. ADMINISTRATIVE MATTERS ............................................................................... 93 
11.1. electronic Case Report Form instructions .................................................... 93 
11.2. Study Monitoring by GSK Biologicals .......................................................... 94 
11.3. Record retention ......................................................................................... 95 
11.4. Quality assurance ....................................................................................... 95 
11.5. Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................ 95 
11.6. Provision of study results to investigators .................................................... 96 
12. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 97 
12.1. Requirements for Germany ......................................................................... 97 
12.2. Requirements for France ............................................................................ 97 
13. REFERENCES ..................................................................................................... 102 

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LIST OF TABLES 
 
PAGE 
 
Table 1 
Study groups and epochs foreseen in the study ..................................... 42 
Table 2 
Study groups and treatment foreseen in the study .................................. 42 
Table 3 
Blinding of study epochs ........................................................................ 42 
Table 4 
List of study procedures ......................................................................... 49 
Table 5 
Intervals between study visits ................................................................. 52 
Table 6 
Biological samples ................................................................................. 58 
Table 7 
Haematology/Serum Chemistry .............................................................. 58 
Table 8 
Humoral Immunity (Antibody determination) ........................................... 59 
Table 9 
Molecular biology (PCR tests) ................................................................ 59 
Table 10 
Haematology/Blood Chemistry ............................................................... 61 
Table 11 
Immunological read outs ........................................................................ 62 
Table 12 
Molecular biology tests ........................................................................... 62 
Table 13 
Study vaccines ....................................................................................... 63 
Table 14 
Dosage and administration ..................................................................... 64 
Table 15 
Solicited local adverse events ................................................................ 69 
Table 16 
Solicited general adverse events ............................................................ 69 
Table 17 
Reporting periods for collecting safety information ................................. 72 
Table 18 
Intensity scales for solicited adverse events ........................................... 74 
Table 19 
Timeframes for submitting serious adverse event and pregnancy 
to GSK Biologicals ................................................................................. 77 
Table 20 
Probability to observe at least one subject with an event of a 
given true incidence when looking after 25 enrolled 
subjects/group ........................................................................................ 82 
Table 21 
GSK Biologicals’ laboratories ............................................................... 111 
Table 22 
Outsourced laboratories ....................................................................... 111 

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Table 23 
FDA   toxicity   grading   scales   for   hematology/biochemistry 
parameters ........................................................................................... 114 
Table 24 
Immunogenicity  scenarios  used   for   the   desirability   index 
simulations ........................................................................................... 121 
Table 25 
Reactogenicity   scenarios   used   for   the   desirability   index 
simulations ........................................................................................... 121 
Table 26 
Result of the ranking of the formulations following simulations of 
the different scenarios with a sample size of 95 subjects per 
group .................................................................................................... 121 

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LIST OF FIGURES 
 
PAGE 
 
Figure 1 
Overview   of   staggered   enrolment/vaccination   and    safety 
evaluation ............................................................................................... 36 
Figure 2 
Study design overview ........................................................................... 41 
Figure 3 
Desirability function for the incidence rate of Grade 2/3 general 
AEs and related SAEs - for each investigational RSV vaccine 
formulation ........................................................................................... 117 
Figure 4 
Desirability function for the incidence rate of Grade 2/3 fever - for 
each investigational RSV vaccine formulation ...................................... 118 
Figure 5 
Desirability function for neutralising anti-RSV-A GMTs - for each 
investigational RSV vaccine formulation ............................................... 119 
Figure 6 
Desirability function for PCA concentrations - for each 
investigational RSV vaccine formulation ............................................... 120 

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LIST OF APPENDICES 
 
PAGE 
 
APPENDIX A  LIST OF POTENTIAL IMMUNE-MEDIATED DISEASES ...................... 106 
APPENDIX B DETAILED DESCRIPTION OF THE ASSAYS PERFORMED IN 
THE STUDY ......................................................................................... 108 
APPENDIX C CLINICAL LABORATORIES ................................................................ 111 
APPENDIX D FDA GUIDANCE FOR INDUSTRY: TOXICITY GRADING 
SCALE FOR HEALTHY ADULT AND ADOLESCENT 
VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE 
CLINICAL TRIALS (SEPTEMBER 2007) .............................................. 112 
APPENDIX E DESIRABILITY APPROACH ................................................................ 116 
APPENDIX F  AMENDMENTS TO THE PROTOCOL ................................................. 122 

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LIST OF ABBREVIATIONS 
 
AE: 
Adverse Event 
AIDS: 
Acquired Immunodeficiency Syndrome 
ANCOVA: 
Analysis of Covariance 
ALT: 
Alanine Aminotransferase 
AST: 
Aspartate Aminotransferase 
ATP: 
According-to-Protocol 
BLA: 
Biologicals License Application 
BMI: 
Body Mass Index 
CEPL: 
Clinical and Epidemiology Project Lead 
CHO: 
Chinese Hamster Ovary 
CI: 
Confidence Interval 
CFR: 
Code of Federal Regulations 
CLS: 
Clinical Laboratory Sciences 
CRA: 
Clinical Research Associate 
CRDL: 
Clinical Research and Development Lead 
CTR: 
Clinical Trail Register 
eCRF: 
electronic Case Report Form 
EGA: 
Estimated Gestational Age 
EMA: 
European Medicines Agency 
EoS: 
End of Study 
ERD: 
Enhanced RSV Disease 
eTDF: 
Electronic Temperature excursion Decision Form 
FDA: 
Food and Drug Administration, United States of America 
FI-RSV: 
Formalin-inactivated whole virus RSV vaccine 

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GCP: 
Good Clinical Practice 
GMC: 
Geometric Mean Concentration 
GMT: 
Geometric Mean Titre 
GP: 
General Practitioner 
GSK: 
GlaxoSmithKline 
HIV: 
Human Immunodeficiency Virus 
HRP: 
Horse Radish Peroxidase 
IB: 
Investigator Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Conference on Harmonisation 
IEC: 
Independent Ethics Committee 
IgG: 
Immunoglobulin G 
IMP: 
Investigational Medicinal Product 
IDMC: 
Independent Data Monitoring Committee 
IND: 
Investigational New Drug 
IRB: 
Institutional Review Board 
iSRC: 
Internal Safety Review Committee 
LLOQ: 
Lower Limit of Quantification 
LMP: 
Last Menstrual Period 
LRTI: 
Lower Respiratory Tract Infection 
LSLV: 
Last Subject Last Visit 
MACDP: 
Metropolitan Atlanta Congenital Defects Program 
MA-RTI: 
Medically Attended Respiratory Tract Infection 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NEO: 
Neogenin 

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NIH: 
National Institute of Health 
 
pIMD: 
Potential Immune-Mediated Disease 
 
PCA: 
Palivizumab Competing Antibodies 
 
PCR: 
Polymerase Chain Reaction 
 
PreF: 
Purified recombinant RSV F protein, engineered to preferentially 
maintain the pre-fusion conformation 
 
PCD: 
Primary Completion Date 
 
RNA: 
Ribonucleic Acid 
 
RSV: 
Respiratory syncytial virus 
 
SAE: 
Serious Adverse Event 
 
SAP: 
Statistical Analysis Plan 
 
SAS: 
Statistical Analysis System 
 
SBIR: 
Randomisation System on Internet 
 
SDV: 
Source Document Verification 
 
SPM: 
Study Procedures Manual 
 
SRT: 
TMB: 
Safety Review Team 
Tetramethylbenzidine 
TVC: 
Total Vaccinated Cohort 
 
VSMB: 
Vaccine Safety Monitoring Board 
 
WBC: 
White Blood Cells 

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Active Phase (of a 
clinical trial): 
GLOSSARY OF TERMS 
Active phase is defined as the time period in a clinical 
trial during which all study visits involving the main 
study activities (e.g. vaccination or study medication/ 
product administration; main blood collection) take place; 
this excludes follow-up periods aimed at monitoring the 
safety of a subject over a long period of time or checking 
long-term immunity persistence. 
 
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, 
• 
bilateral current tubal ligation, 
• 
male partner sterilisation (i.e. vasectomy) 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 and progesterone alone oral 
contraceptive. 
• 
male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), and 
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. 

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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 unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse. 
 
Blinding: 
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. 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). In a single-blind 
study, the investigator and/or his staff are aware of the 
treatment assignment but the subject is not. 
 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
 
End of Study: 
 
(Synonym of End of 
Trial) 
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV). For studies with collection of Human 
Biologicals Samples or imaging data, EoS is defined as 
the date of the last testing/reading released of the Human 
Biological Samples or imaging data, related to primary 
and secondary endpoints. EoS must be achieved no later 
than 8 months after LSLV. 
 
Epoch: 
An epoch is a self-contained set of consecutive timepoints 
or a single timepoint from a single protocol. Self- 
contained means that data collected for all subjects at all 
timepoints within that epoch allows to draw a complete 
conclusion to define or precise the targeted label of the 
product. Typical examples of epochs are primary 
vaccinations, boosters, yearly immunogenicity follow- 
ups, and surveillance periods for efficacy or safety. 

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eTrack: 
GSK’s tracking tool for clinical trials. 
 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the According-to-Protocol (ATP) analysis 
(see Sections 6.6.2 and 10.5 for details on criteria for 
evaluability). 
 
Immunological correlate 
of protection: 
 
Investigational vaccine: 
 
(Synonym of 
Investigational Medicinal 
Product) 
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. 
 
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
 
iSRC: 
The internal Safety Review Committee is a group of 
experts (a GSK Biologicals’ Safety Physician, a CRDL 
and a Biostatistician), external to the ongoing 
study/project and with lack of conflicts of interest in the 
outcome of the study, who assess the progress of the 
study and the safety and efficacy data in an unblinded (on 
a subject level or treatment group level) fashion. Based 
on its review, the iSRC gives recommendations to the 
Clinical Project Team regarding study modification, 
continuation or termination. 
 
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, the larche. However, a 
young female can become pregnant before her first 
menses. Thus, a conservative definition of non- 
childbearing potential in a pre-menarcheal female is a 
young female who has not yet entered puberty as 
evidenced by lack of breast development (palpable 
glandular breast tissue). 
 
Menopause: 
Menopause is the age associated with complete cessation 
of menstrual cycles, menses, and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses 
with an appropriate clinical profile at the appropriate age 
e.g. > 45 years. 

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Potential Immune- 
Mediated Disease: 
 
 
Primary completion 
date: 
Potential immune-mediated diseases (pIMDs) are a subset 
of AEs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. 
 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated. 
 
Randomisation: 
Process of random attribution of treatment to subjects in 
order to reduce bias of selection. 
 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
 
Site Monitor: 
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites. 
 
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. 
 
Sub-cohort: 
A group of subjects for whom specific study procedures 
are planned as compared to other subjects. 
 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine or as a control. 
 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation. 
 
Treatment number: 
A number identifying a treatment to a subject, according 
to the study randomisation or treatment allocation. 

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Unsolicited adverse 
event: 
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event. 
 
VSMB: 
Vaccine Safety Monitoring Board: an internal GSK 
governance with the mandate for oversight of safety 
information for GSK vaccines. 

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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 
and/or medications will be written without the superscript symbol ™ or ® and in italics. 
 
Trademarks not owned by the GSK 
group of companies 
Synagis (MedImmune LLC.) 
Allplex (Seegene) 
Generic description 
Recombinant humanized monoclonal anti- 
RSV antibody 
Respiratory panel assay 

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1. 
INTRODUCTION 
 
1.1. 
Background 
 
1.1.1. 
Disease burden 
 
RSV is a ribonucleic acid (RNA) virus of which two antigenically distinct subgroups 
exist, referred to as RSV-A and RSV-B. RSV is a highly contagious human pathogen that 
causes respiratory tract infections in people of all ages. In temperate climates throughout 
the world, RSV predictably causes fall-winter epidemics whereas viral activity is more 
endemic in tropical regions and outbreaks are less temporally focused. 
 
During the first year of life, 50-70% of infants are infected with RSV and essentially all 
children have had an RSV infection by their third birthday [Hall, 2004]. The risk for 
severe RSV-induced LRTIs is highest in infants below 6 months of age and it is the most 
common cause of hospitalisation in this age group. Approximately 2% of children < 1 
year of age are hospitalized for RSV-associated LRTIs each year in industrialized 
countries [Boyce, 2000; Deshpande, 2003; Hall, 2009; Holman, 2004; Iwane, 2004; 
Madhi, 2006; Nair, 2010; Paramore, 2004; Vicente, 2003]. 
 
In the early months of life, infants may have protection against RSV through the maternal 
antibodies transferred to them during pregnancy. High titres of maternally derived RSV- 
neutralising antibodies [Roca, 2002] have been shown to be inversely associated with the 
incidence of RSV associated-acute LRTI during the first 6 months of life, whereas 
incomplete transfer of maternally derived RSV-neutralising antibodies has been 
implicated in the increased risk of severe RSV infection in preterm infants [de Sierra, 
1993]. 
 
Previous infection with RSV does not prevent subsequent infections. Re-infection with 
RSV occurs throughout an individual’s lifetime and is common in all age groups 
[Simoes, 1999; Krilov, 2011]. These re-infections generally go undiagnosed because they 
usually present as common acute upper respiratory tract infections. In more vulnerable 
populations (e.g. immunocompromised individuals or elderly), re-infections can however 
also lead to severe disease and result in excess mortality [Graham, 2011]. 
 
Please refer to the current Investigator Brochure (IB) for information regarding the pre- 
clinical and clinical studies with the investigational RSV vaccine. 
 
1.1.2. 
Current management of RSV disease in infants 
 
To date, no vaccine is available for RSV and treatment for RSV disease is administered 
largely to alleviate symptoms. 
 
The antiviral drug ribavirin is currently the only approved therapy for treatment of RSV 
disease, but its use is restricted to severe hospitalized cases. Moreover, the efficacy of 
ribavirin against RSV disease in infants and young children is not well supported by 
strong evidence, [American Academy of Paediatrics Subcommittee on Diagnosis and 
Management of Bronchiolitis, 2006; Ventre, 2007]. 

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There is currently no preventive measure available for children who do not present major 
risk factors for severe RSV disease. Palivizumab (Synagis, Medimmune) an RSV-specific 
recombinant, humanised monoclonal antibody is indicated for the prevention of severe 
LRTI requiring hospitalisation caused by RSV in children at high risk for RSV disease. 
Synagis is only effective as prophylaxis and is not indicated or recommended in the 
general, healthy infant population, due to high cost and the need for monthly 
administration throughout the RSV season [Buck, 2004; Committee on Infectious 
Diseases and Committee on Fetus and Newborn, 2003]. 
 
1.1.3. 
RSV vaccination strategies 
 
In the late sixties, a formalin-inactivated whole virus RSV (FI-RSV) vaccine tested in 
clinical trials led to more severe clinical symptoms upon subsequent natural infection 
with RSV in children under the age of 2 years [Chin, 1969; Fulginiti, 1969; Kapikian, 
1969; Kim,1969]. This so-called ‘vaccine-induced enhanced RSV disease (ERD)’ is 
believed to have been due to the formalin inactivation step during vaccine production, 
leading to the induction of low-quality, non-neutralising antibodies in RSV naïve infants 
Delgado, 2004. These antibodies did not neutralise RSV infectivity and contributed to 
the formation of immune complexes that may have contributed to the severe clinical 
symptoms and potentially immunopathology of FI-RSV ERD [Polack, 2002]. In addition, 
it is hypothesized that enhanced RSV disease may have been linked to the induction of a 
Th2-skewed CD4-T cell immune response [Castilow, 2008]. This experience has led to 
increased safety monitoring of clinical trials with RSV vaccines. 
 
Another approach to protect young infants against severe RSV disease is by immunising 
pregnant women to increase the amount of protective RSV-neutralising antibodies 
transferred to the foetus to offer passive protection of the offspring. Administration of an 
RSV vaccine to adults (pregnant women in this case), all of whom will have been 
naturally infected with RSV before, is expected to boost the immunological memory 
induced by previous natural infections. The risk of vaccine-induced RSV disease is 
therefore considered negligible. Enhanced respiratory disease has not been observed with 
the use of Synagis. 
 
1.1.3.1. 
GSK Biologicals’ investigational RSV vaccine 
 
GlaxoSmithKline (GSK) Biologicals is currently developing a new RSV investigational 
vaccine to protect infants against RSV-associated severe LRTI through maternal 
immunization during the third trimester of pregnancy. GSK Biologicals’ RSV vaccine 
candidate is based on a recombinant RSV F protein, engineered to preferentially maintain 
the pre-fusion conformation (PreF). Different formulations of this candidate vaccine, 
non-adjuvanted or adjuvanted with aluminium, have been evaluated in a Phase I study in 
healthy men aged 18-44 years (study RSV F-001; NCT01905215) and are currently being 
evaluated in a Phase II study in healthy non-pregnant women aged 18-45 years (study 
RSV F-020; NCT02360475). Based on safety and immunogenicity data from study RSV 
F-001 and up to 90 days post-vaccination from study RSV F-020, aluminium-adjuvanted 
formulations will not be evaluated further. 

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1.1.3.2. 
Other RSV investigational vaccines 
 
Other investigational vaccines based on the RSV F protein have been and are currently 
tested in clinical trials. In 2014, Novavax, Inc. completed a dose-confirmatory Phase II 
trial (NCT01960686) in women of childbearing potential age receiving one dose of 
recombinant F protein micelles combined with aluminium. The candidate vaccine of 
Novavax, Inc. has been observed to be immunogenic with no safety signals reported. 
Further, Novavax Inc., has recently announced preliminary results of a Phase II clinical 
trial (NCT02247726) in healthy third-trimester pregnant women assessing safety and 
immunogenicity of the same candidate vaccine, as well as the impact of maternal 
immunization on infant safety through one year of life. The candidate RSV F vaccine was 
shown to be safe and well-tolerated by the vaccinated subjects. The study demonstrated 
robust anti-F, Palivizumab competing (PCA) and microneutralising antibody responses in 
mothers and efficient antibody transfer from mothers to infants. Based on these 
preliminary results, Novavax, Inc has initiated a Phase III trial (NCT02624947) for 
further evaluation of this vaccine in pregnant women [Novavax, press release, 2015]. 
 
In 2014, Novartis Vaccines & Diagnostics (now GSK Biologicals) started a Phase I 
clinical trial (NCT02298179) in 288 subjects to assess safety and immunogenicity of 
RSV F post-fusion protein subunit adjuvanted with aluminium or MF59. Results are 
expected by end 2017. 
 
Other RSV F protein vaccines are currently in preclinical phase (Crucell, National 
Institutes of Health [NIH]). 
 
Several other RSV vaccine candidates using different technologies (attenuated virus 
vaccines from NIH or Medimmune; adenovector-based vaccines from GSK or Crucell) 
are currently being evaluated in clinical trials. However, those technologies are not 
compatible with the maternal immunization approach and are tested in the context of 
paediatric or elderly vaccination. 
 
Besides vaccines, new generation MedImmune monoclonal antibodies with increased 
potency and extended half-life are currently being evaluated and the most advanced 
candidate is currently in Phase II. 
 
No RSV vaccine is licensed to date. 
 
1.1.4. 
GSK Biologicals’ investigational RSV vaccine composition 
 
The antigen used in the investigational RSV vaccine is a purified recombinant RSV F 
protein, engineered to preferentially maintain the pre-fusion conformation (PreF). The  
F protein has been selected because it is a major surface antigen of the RSV virus that is 
well conserved among RSV-A and RSV-B subtypes. The RSV F protein pre-fusion 
conformation is the target of most RSV-neutralising activity in human sera [Corti, 2013]. 
Moreover, these pre-fusion-specific antibodies targeting antigen binding site , are 
substantially more potent compared to the prophylactic monoclonal antibody 
Palivizumab. Palivizumab targets antigenic site II which is present in both pre- and post- 
fusion conformations [Ngwuta, 2015]. 

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Based on preclinical experiments and Phase I dose escalation study data (RSV F-001 
study; NCT01905215), the PreF antigen has shown to boost neutralising antibodies, 
which are considered essential for protection against RSV-associated severe disease 
[Magro, 2012]. No safety signals which would preclude further development were 
identified in any of the vaccine formulations containing different dosages of the PreF 
antigen evaluated in the Phase I study. Based on this Phase I data, vaccine formulations 
containing 10 µg of the PreF antigen were excluded from further development as they 
were less immunogenic. Boosting of pre-existing RSV-specific neutralising antibodies in 
adults was further confirmed by the Day 30 post-vaccination data of a Phase II study that 
evaluated the safety and immunogenicity of 30 µg of non-adjuvanted PreF and 60 µg of 
non-adjuvanted and aluminium-adjuvanted PreF formulations in non-pregnant women 
aged 18-45 years (study RSV F-020; NCT02360475). In addition, Day 90 post- 
vaccination immunogenicity data has recently become available indicating that, although 
there is a decline in the boosted RSV-specific neutralising antibodies as compared to 
D30, titres remain well above the baseline. No safety concerns which would preclude 
further development were identified in this Phase II study up to Day 90 post-vaccination. 
One SAE of diffuse panbronchiolitis, considered to be related to study vaccine as per 
investigator’s opinion, has been reported. Please refer to the current IB for further details. 
 
Since all adults have been naturally infected with RSV before, it was expected that a 
strong adjuvant was not needed in these primed individuals and that a non-adjuvanted or 
an aluminium-adjuvanted PreF antigen would sufficiently boost the pre-existing immune 
response. Data obtained from the Phase I study (study RSV F-001; NCT01905215) 
seemed to confirm this assumption because the study results did not show any difference 
between non-adjuvanted PreF formulations and aluminium-adjuvanted formulations with 
respect to immune response. In view of the limited number of subjects evaluated in RSV 
F-001 (~16/group), non-adjuvanted and aluminium-adjuvanted PreF formulations are 
being evaluated further in study RSV F-020 (NCT02360475) with ~125 subjects/group. 
The non-adjuvanted PreF antigen formulations have now been selected for further 
development because data from the RSV F-020 study up to 90 days post-vaccination 
showed a trend for higher reactogenicity in the aluminium-adjuvanted formulation group, 
while there was no significant difference in terms of immunogenicity between the 
different RSV PreF formulations evaluated. 
 
1.2. 
Rationale for the study and study design 
 
1.2.1. 
Rationale for the study 
 
The main goal of this study is the selection of the final RSV vaccine formulation for 
potential further evaluation in pregnant woman. 
 
The safety/reactogenicity and immunogenicity of 6 different formulations of the PreF- 
based investigational RSV vaccine (10, 30 and 60 µg of PreF antigen, non-adjuvanted or 
adjuvanted with aluminium [500 µg]) have been evaluated in a Phase I study in healthy 
men, aged 18-44 years (study RSV F-001; NCT01905215). No safety signal associated 
with the investigational RSV vaccines was identified which would preclude further 
clinical development. Based on data from that Phase I study, the safety/ reactogenicity 
and immunogenicity of 30 μg of non-adjuvanted PreF and 60 μg of non-adjuvanted and 

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aluminium-adjuvanted PreF formulations are currently being evaluated further in non- 
pregnant women aged 18-45 years (study RSV F-020; NCT02360475). 
 
The RSV F-020 study is still ongoing but safety/reactogenicity and immunogenicity data 
up to 90 days post-vaccination are already available for all subjects. Based on these 
results, the non-adjuvanted 30 µg and 60 µg PreF formulations were selected for further 
evaluation in the current RSV F-021 study. These two formulations are also foreseen to 
be evaluated in the first study in pregnant women (RSV F-004). In addition, the RSV F- 
021 study will also evaluate a formulation containing 120µg of PreF antigen. This will 
allow evaluation of a wider antigen dose range to determine if there is a dose response 
relationship in terms of antibody response at the higher dose range that was not present at 
the lower range. 
 
The purpose of this study is to rank the different vaccine formulations based on 
safety/reactogenicity and immunogenicity data. The formulations eliciting strong immune 
responses while maintaining an acceptable safety profile will be considered for further 
evaluation, including in studies vaccinating pregnant women. 
 
It is likely that the RSV vaccine may need to be administered during each pregnancy to 
further boost immunogenicity in the pregnant woman and achieve protective anti-RSV 
levels in the neonate. In order to assess whether a booster dose might induce a higher 
reactogenicity or immune-tolerance, subjects who participated in the study RSV F-021 
and who were part of the selected vaccine group or the control group may be invited to a 
booster study (study RSV F-021B). 
 
1.2.2. 
Rationale for the study design 
 
Healthy, non-pregnant women aged 18 - 45 years will be enrolled in this study: 
• 
Women aged 18 - 45 years are selected to match the vaccine’s target population, i.e. 
pregnant women, as closely as possible (gender, age). 
• 
Non-pregnant women are selected to avoid unnecessarily exposing a vulnerable 
population (pregnant women and the foetuses/children) to a higher dose of the 
vaccine that has not previously been studied in non-pregnant women. 
 
1.2.3. 
Rationale for the use of placebo 
 
The placebo group is included as a control for both the safety/reactogenicity and 
immunogenicity assessments. 
 
1.2.4. 
Safety considerations 
 
Safety data for the non-adjuvanted and aluminium (500 µg)-adjuvanted 30 and 60 µg 
PreF formulations up to one year post-vaccination from study RSV F-001 as well as 
safety/reactogenicity data for the non-adjuvanted 30 and 60 µg formulations and the 
aluminium (500 µg)-adjuvanted 60 µg formulation up to 90 days post-vaccination from 
study RSV F-020 are currently available. No safety concern which would preclude 
further development has been identified for any of the RSV groups in either study. 

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Additional safety data for these vaccine formulations from study RSV F-020 or from 
other ongoing/planned studies might also be available, prior to the start of the current 
study (study RSV F-021). 
 
As indicated above, safety information on the lower doses of the investigational RSV 
vaccines is already available from the clinical studies performed so far. However, this 
will be the first time that the 120 g PreF antigen formulation will be administered in 
humans. Therefore, the RSV F-021 study will follow a 2-step staggered 
enrolment/vaccination with unblinded safety review in between (Figure 1): 
 
Figure 1 
Overview of staggered enrolment/vaccination and safety evaluation 
 
SE up to Day 7 visit = safety evaluation by iSRC based on all available safety data from 25% of the vaccinated 
subjects [100 subjects] up to at least 7 days post-vaccination (including Day 7 haematology/ biochemistry parameters). 
• 
Step 1 will include the first 25% of subjects (i.e. ~100 subjects; ~25 subjects per 
study group) vaccinated in the study. When this cut-off is reached, further enrolment 
will be paused until completion of an unblinded review by a GSK internal Safety 
Review Committee (iSRC) not involved in the conduct of the study/project. 
• 
Continuation of study enrolment of the remaining 75% of subjects (i.e. ~300 
subjects; ~75 subjects per study group) in Step 2 will be conditional to a favourable 
outcome of the iSRC evaluation of all available safety and reactogenicity data 
collected up to at least 7 days post vaccination (including Day 7 haematology and 
biochemistry parameters). 
In addition to the unblinded review by iSRC after vaccination of the first 25% of subjects, 
the GSK Biologicals’ Safety Review Team (SRT) will perform blinded safety reviews on 
a regular basis throughout the study 
 
Refer to Sections 8.10.1 and 8.10.2 for more information on the SRT and the iSRC 
evaluation, respectively. 
 
Furthermore, the iSRC outputs and review outcome will be provided to the Independent 
Data Monitoring Committee (IDMC) of the RSV F-004 study (first study in which the 
investigational RSV vaccine will be administered to pregnant women). 
 
In case of a medically attended respiratory tract infection (MA-RTI) (e.g. visit to the 
General Practitioner [GP] for respiratory symptoms including but not limited to cough, 
sputum production, difficulty breathing), the subject will be asked to contact the 

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Investigator to enable the collection of a nasal swab within 72h after the medical 
attendance. Following the visit, the MA-RTI section of the eCRF will be completed to 
document key aspects of the case including vital signs and evidence of increased work of 
breathing. 
 
Should the 120µg PreF formulation be selected for further evaluation, an additional Phase 
II study will be initiated to evaluate the safety of the 120µg formulation in pregnant 
women and their infants before proceeding to Phase III studies. 
 
1.2.5. 
Study blinding 
 
Given the different presentation of the placebo and the investigational RSV vaccines, a 
double blinded study design is not possible. This study will be conducted in an 
observer-blind manner up to Day 90 post-vaccination after which it will be conducted in 
a single-blind manner. 
 
Please refer to the glossary of terms for the definitions of observer-blind and single-blind 
study. 
 
1.3. 
Benefit : Risk Assessment 
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of the investigational RSV vaccine. 
 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
 
1.3.1. 
Risk Assessment 
 
As with all injectable vaccines, immediate systemic allergic reactions to vaccination can 
occur. These are however very rare and are estimated to occur once per 450 000 to once 
per 1 000 000 vaccinations for vaccines which do not contain allergens such as gelatine 
or egg protein Zent, 2002. In order to be able to treat subjects with an immediate 
systemic allergic reaction to vaccination, all subjects will need to remain under 
observation at the study site for at least 30 minutes after vaccination. All study sites will 
have resuscitation equipment available in case of a rare anaphylactic reaction. 
 
Syncope (fainting) can occur following or even before, any vaccination as a psychogenic 
response to the needle injection. Therefore, it is important that procedures are in place to 
avoid injury from fainting. 
 
Intramuscular vaccination commonly precipitates a transient and self-limiting local 
inflammatory reaction. This may typically include pain at injection site, redness, and 
swelling. 

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Risks linked to the investigational RSV vaccine 
 
Non-adjuvanted and aluminium-adjuvanted investigational RSV vaccine formulations 
containing 10 to 60 µg PreF have previously been administered to a limited number of 
healthy men aged 18-44 years (~16/group) in the Phase I study RSV F-001 (116969) 
without any safety signals. The most frequently reported solicited local AE was pain at 
the injection site (up to 81.3%) and the most frequently reported solicited general AEs 
were fatigue and headache (both up to 43.8%). The most frequently reported unsolicited 
AE was headache (18.8%) after the solicited 7-day follow-up period. Overall, 4.2% of the 
subjects in the RSV vaccine groups (4 out of 95) reported Grade 3 AEs (solicited or 
unsolicited) in the 30-day follow-up period after vaccination compared to 6.1% (2 out of 
33 subjects) in the placebo control group. For 3 subjects (2 in the RSV vaccine groups 
and one in the placebo control group), the reported Grade 3 AEs were considered to be 
related to vaccination by the investigator: Grade 3 fatigue was reported in the non- 
adjuvanted 10 μg PreF group, Grade 3 gastrointestinal symptoms in the control group and 
Grade 3 pain at injection site in the alum-adjuvanted 60 μg PreF group. Please refer to the 
current IB for more detailed information on the safety results from the study RSV F-001 
(116969). 
 
In the ongoing study RSV F-020 (NCT02360475), 30 µg of non-adjuvanted PreF and 60 
µg of non-adjuvanted or aluminium (500 µg) adjuvanted PreF formulations have been 
administered to approximately 375 healthy women aged 18-45 years (~125/group). Data 
up to 90 days post-vaccination have not identified any safety concern that would preclude 
further development. A SAE of diffuse panbronchiolitis, considered by the investigator as 
being potentially related to the study vaccine, has been recently reported and is currently 
under further investigation. Please refer to the IB for further details on the case. 
 
At the time of initiation of this study (RSV F-021), additional safety data from the 
ongoing RSV F-020 study or other ongoing/planned studies might also be available. 
 
There is a potential risk of generating an immune response to neogenin (NEO), a host cell 
protein remaining in the purified antigen bulk. Release testing of vaccine lots used in 
studies RSV F-001 and RSV F-020 has detected residual host cell protein in a very low 
amount (below 0.1% of the amount of the purified PreF antigen bulk). The presence of 
residual host cell protein in the purified antigen bulk is not entirely unexpected as the 
PreF antigen is produced in the Chinese hamster ovary (CHO) cell line and current 
bioprocess technology cannot produce absolutely host cell protein-free material from 
cells Wang, 2009. Additional characterisation tests identified NEO as the main host cell 
protein. NEO is a cell surface trans-membrane protein that is ubiquitously expressed in 
all tissues and that serves as a multifunctional receptor Meyerhardt, 1997. NEO has 
been suggested to play a role in the regulation of diverse developmental processes, 
including the development of the central nervous system De Vries, 2008; Hagihara, 
2011; Hong, 2012; Lee, 2010. 
Human and hamster NEO have 93% amino acid sequence homology. The amount of 
NEO per vaccine dose for the purified bulk lot used for the clinical trial material in 
studies RSV F-001 and RSV F-020 was initially estimated (by relative densitometry 
measurement of the SDS-PAGE gel) to be 0.48 µg per vaccine dose containing 

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60 µg PreF. Further exploration using mass spectrometry revealed a content of 0.26 µg of 
NEO per 60 µg vaccine dose. Although the risk of inducing anti-NEO antibodies that 
could cross-react with the endogenous antigen and affect its function was considered to 
be low, it could not be completely excluded that the hamster NEO present in the vaccine 
may induce an anti-NEO immune response in human. For this reason, anti-NEO antibody 
concentrations were assessed in the Phase I study RSV F-001 (116969) and have been 
assessed in RSV F-020. No evidence of a vaccine-induced anti-NEO response emerges 
from the available data up to Day 360 after vaccination from study RSV F-001 and up to 
Day 90 after vaccination from study RSV F-020. In parallel, every effort is being made to 
reduce the amount of NEO in the vaccine. 
 
For RSV F-021 study, NEO-reduced lots will be used. However since the 120µg dose 
will be administered for the first time in human in the RSV F-021 study, as part of the 
safety assessment, the anti-NEO immune response will be evaluated again in this study, 
in order to be able to rule out that an immune response against NEO is induced by the 
investigational RSV vaccines. 
 
1.3.2. 
Benefit Assessment 
 
Benefits linked to the investigational RSV vaccine 
The subjects receiving the investigational RSV vaccines may not directly benefit from 
this vaccination as RSV infections in healthy adults generally go undiagnosed because 
they usually present as common acute upper respiratory tract infections. Moreover, 
vaccine efficacy has not been assessed yet and it is hence not known whether the 
investigational RSV vaccines are effective in protecting against RSV infection. 
 
An indirect benefit is that the information obtained in this study will aid the development 
of a maternal RSV vaccine, which is intended to prevent severe RSV disease in infants 
born to women vaccinated during pregnancy. 
 
Other benefits 
Subjects who are eligible and participate in the study will receive medical follow-up until 
the end of their participation in the study. 
 
1.3.3. 
Overall Benefit:Risk Conclusion 
 
The investigational RSV vaccine is currently in an early stage of clinical development 
and no vaccine efficacy has been demonstrated. However, no safety concerns which 
would preclude further development were identified in the completed or ongoing Phase 
I/II studies. Furthermore, the vaccine has been demonstrated to induce an immune 
response capable of boosting neutralising antibodies to both RSV serotype A and RSV 
serotype B. Given the measures taken to minimise the risk to subjects participating in this 
study, the potential risks are justified by the potential benefits linked to the development 
of a maternal RSV vaccine. 

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2. 
OBJECTIVES 
 
2.1. 
Primary objective 
• 
To rank different formulations of the investigational RSV vaccine based on 
safety/reactogenicity and immunogenicity data up to 1 month post-vaccination (Day 
30). 
 
Refer to Section 10.1 for the definition of the primary endpoints. 
 
2.2. 
Secondary objectives 
• 
To evaluate the reactogenicity and safety of a single intramuscular dose of the RSV 
investigational vaccines up to study conclusion. 
• 
To evaluate the immunogenicity of a single intramuscular dose of the RSV 
investigational vaccines up to 90 days after vaccination (Day 90). 
• 
To further assess the safety of the investigational RSV vaccines by evaluating 
whether a single dose of the vaccines induces antibodies against the residual host cell 
protein neogenin (NEO) up to 1 month post-vaccination (Day 30). 
 
• 
To estimate the incidence of medically attended RSV-associated RTIs up to study 
conclusion. 
 
Refer to Section 10.2 for the definition of the secondary endpoints. 
 
2.3. 
Tertiary objective 
• 
If deemed necessary, to further characterise the immune response of a single 
intramuscular dose of the RSV investigational vaccines. 
 
Refer to 5.7.3 for additional testing proposed to further characterise the immune response 
to the investigational RSV vaccine. 

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3. 
STUDY DESIGN OVERVIEW 
Figure 2 
Study design overview 
 
 
 
V = Visit; D = Day; VACC = vaccination; BS = blood sample; h/b = blood sample for haematology/biochemistry; Imm = 
blood sample for immunogenicity; C = contact; RSV = Respiratory Syncytial Virus; PCR = Polymerase Chain Reaction. 
1 Safety data up to (minimum) 7 days post-vaccination (including Day 7 haematology and biochemistry parameters) of 
the first 25% of subjects vaccinated in the study will be reviewed by iSRC. 
2 In case of a MA-RTI (e.g. visit to the GP for respiratory symptoms including but not limited to cough, sputum 
production, difficulty breathing), the subject will be asked to contact the Investigator to enable completion of the MA- 
RTI section of the eCRF and the collection of a nasal swab within 72h after the medical attendance. 
Vertical lines stand for analysis on all subjects. 
 
 
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 II, observer-blind, randomised, controlled, multi- 
country, study with four parallel groups. 
• 
Duration of the study: the intended duration of the study will be approximately 1 
year from Visit 1 to study conclusion (Day 360). 
 
Epoch 001: Primary starting at Visit 1 (Day 0) and ending at Visit 5 (Day 90). 

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 
Epoch 002 : Follow-up phase starting one day after Day 90 and ending at Day 
360 contact. 
• 
Primary completion Date: Visit 3 (Day 30). 
Refer to glossary of terms for the definition of PCD. 
• 
End of Study (EoS): Last testing results released for samples collected at Visit 5 
(i.e. last testing results released for the assays related to the primary and secondary 
endpoints). 
Refer to glossary of terms for the definition of EoS. 
• 
Study groups: 
Table 1 
Study groups and epochs foreseen in the study 
 
Study groups 
Number of 
subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
Epoch 002 
30 PreF 
~100 
18 - 45 years 
x 
x 
60 PreF 
~100 
18 - 45 years 
x 
x 
120 PreF 
~100 
18 - 45 years 
x 
x 
Control 
~100 
18 - 45 years 
x 
x 
Table 2 
Study groups and treatment foreseen in the study 
 
Treatment name 
Vaccine/ Product 
name 
Study Groups 
30 PreF 
60 PreF 
120 PreF 
Control 
30 µg PreF 
PreF-30 
NaCl 
X 
60 µg PreF 
PreF-60 
NaCl 
X 
120 µg PreF 
PreF-120 
NaCl 
X 
Placebo 
Formulation buffer S9b 
X 
• 
Control: placebo control 
• 
Vaccination schedule: One intramuscular vaccination at Day 0. 
• 
Treatment allocation: Subjects will be randomised using a centralised 
randomisation system on internet (SBIR) at Day 0. The randomisation algorithm will 
use a minimisation procedure accounting for age (18 - 32 years or 33 - 45 years) and 
centre. 
• 
Blinding: Observer-blind in Epoch 001 and single-blind in Epoch 002. 
Table 3 
Blinding of study epochs 
 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
Epoch 002 
single-blind 
• 
Sampling schedule: 
 
Blood samples for haematology/biochemistry will be collected (10 mL) from 
all subjects at Visit 1 (Day 0), Visit 2 (Day 7), Visit 3 (Day 30), Visit 4 (Day 60) 
and Visit 5 (Day 90). 

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 
Blood samples for humoral immune response evaluation will be collected 
(17 mL) from all subjects at Visit 1 (Day 0), Visit 3 (Day 30), Visit 4 (Day 60) 
and Visit 5 (Day 90). 
 
Nasal swabs will be collected from subjects in case of a MA-RTI from 
enrolment (Visit 1) until Contact 3. 
• 
Type of study: self-contained 
• 
Data collection: Electronic Case Report Form (eCRF). 
• 
Safety monitoring: When the first 25% of subjects are vaccinated in the study, 
enrolment will be paused until completion of an unblinded review by a GSK iSRC. 
Continuation of study enrolment will be conditional to a favourable outcome of the 
iSRC evaluation of all available safety and reactogenicity data collected up to at least 
7 days post-vaccination (including Day 7 haematology and biochemistry 
parameters). In addition, the blinded safety data will be reviewed by GSK 
Biologicals’ SRT on a regular basis throughout the study. 
Refer to Section 8.10 for description of safety monitoring. 
• 
In case of a MA-RTI (e.g. visit to the GP for respiratory symptoms including but not 
limited to cough, sputum production, difficulty breathing), the subject will be asked 
to contact the investigator to enable the collection of a nasal swab within 72 hours 
after the medical attendance. 
Refer to Section 5.6.11 for more information on the procedure of nasal swabbing. 
 
4. 
STUDY COHORT 
 
4.1. 
Number of subjects/centres 
This will be a multi-centre, multi-country study. 
 
The target is to enrol approximately 400 eligible women (~100 per group). Refer to 
Section 10.4 for a detailed description of the criteria used in the estimation of the sample 
size. 
 
4.2. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of Diary Cards, return for follow-up 
visits). 
• 
Written informed consent obtained from the subject prior to performance of any 
study specific procedure. 

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• 
Non-pregnant female between, and including, 18 and 45 years of age at the time of 
study vaccination. 
• 
Healthy subjects as established by medical history and clinical examination before 
entering into the study. 
• 
Female subjects of non-childbearing potential may be enrolled in the study 
 Non-childbearing potential is defined as pre-menarche, hysterectomy, 
ovariectomy or post-menopause. 
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 study vaccination, and 
 
Has a negative pregnancy test on the day of study vaccination, and 
 
Has agreed to continue adequate contraception up to 90 days after vaccination 
Refer to the glossary of terms for the definition of adequate contraception. 
 
4.3. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
 
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study: 
• 
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccines within 30 days prior to study vaccination (Day -29 to Day 0), or 
planned use during the study period. 
• 
Concurrently participating in the active phase of 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). 
Refer to glossary of terms for the definition of active phase. 
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs, as well as administration of 
long-acting immune-modifying drugs [e.g. infliximab]), within 6 months prior to 
study vaccination, or planned administration until 90 days post-vaccination. For 
corticosteroids, this will mean prednisone  10 mg/day, or equivalent. Inhaled and 
topical steroids are allowed. 
• 
Administration of immunoglobulins and/or any blood products during the period 
starting 3 months before the study vaccination, or planned administration until 90 
days post-vaccination. 

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• 
Planned administration/administration of a vaccine not foreseen by the study 
protocol within the period starting 30 days before and ending 30 days after study 
vaccination, with the exception of any licensed influenza vaccine which may be 
administered ≥ 15 days before or after study vaccination. 
• 
Previous experimental vaccination against RSV. 
• 
History of any neurological disorders or seizures (subjects with a history of febrile 
convulsion may be enrolled). 
• 
Family history of congenital or hereditary immunodeficiency. 
• 
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(for a list of potential immune mediated 
diseases, please refer to APPENDIX A. Note that this list should be used as a 
guidance to identify diseases that could be autoimmune in nature. However, not all 
reported diseases in the appendix will be autoimmune in nature and therefore 
represent an exclusion criterion. This will be based on the opinion of the investigator 
and/or specific available diagnostic data). 
• 
Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality as determined by physical examination and/or Medical 
History (including any previously performed laboratory tests). 
• 
Lymphoproliferative disorder or malignancy within previous 5 years (excluding 
effectively treated non-melanotic skin cancer). 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the study vaccine. 
• 
Hypersensitivity to latex. 
• 
Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe. 
• 
Current alcohol and/or drug abuse. 
• 
Acute disease and/or fever at the time of enrolment. 
 
Fever is defined as temperature ≥37.5°C for oral, axillary or tympanic route, or 
 38.0°C for rectal route. 
 
Subjects with a minor illness (such as mild diarrhoea, 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 will 
be rescheduled within the allowed recruitment period. 
• 
Body mass index (BMI) > 40 kg/m². 
• 
Pregnant or lactating female. 
• 
Planned move to a location that will prohibit participating in the trial until study 
conclusion. 

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• 
Any other condition that the investigator judges may interfere with study procedures 
(e.g. drawing blood) or findings (e.g. immune response). 
 
5. 
CONDUCT OF THE STUDY 
 
5.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with all applicable regulatory requirements. 
 
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki. 
 
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. 
 
Conduct of the study includes, but is not limited to, the following: 
• 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
• 
Subject informed consent. 
• 
Investigator reporting requirements as stated in the protocol. 
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both. 
 
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject 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. 
 
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. 

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5.2. 
Subject identification and randomisation of treatment 
 
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 centre. 
 
5.2.2. 
Randomisation of treatment 
 
5.2.2.1. 
Randomisation of supplies 
 
The randomisation 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 centres/ warehouse(s). 
 
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centres in this multi-centre study and to thus reduce the overall 
study recruitment period, an over-randomisation 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 enrol approximately 400 eligible subjects who will be randomly 
assigned to four study groups in a (1: 1: 1: 1) ratio (approximately 100 subjects in each 
group). 
 
Allocation of the subject to a study group at the investigator site will be performed using 
SBIR. The randomisation algorithm will use a minimisation procedure accounting for age 
(18 - 32 years or 33 - 45 years) and centre. Minimisation factors will have equal weight in 
the minimisation 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 administration will access 
SBIR. Upon providing the subject identification number, the randomisation system will 
determine the study group and will provide the treatment number to be used for the first 
dose. 
 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
 
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions. 

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5.3. 
Method of blinding 
Given the different presentation of the placebo and the investigational RSV vaccines, a 
double blinded study design is not possible. This study will be conducted in an observer 
blind manner up to Day 90 post-vaccination after which it will be conducted in a single- 
blind manner. By observer-blind, it is meant that during the course of the study, the 
vaccine recipient and those responsible for the evaluation of any study endpoint (e.g. 
safety and reactogenicity) will all be unaware of which vaccine was administered. To do 
so, vaccine preparation and administration will be done by authorised medical personnel 
who will not participate in any of the study clinical evaluation assays. 
 
Please refer to the glossary of terms for the definition single-blind study. 
 
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. 

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5.5. 
Outline of study procedures 
Table 4 
List of study procedures 
 
Epoch 
Epoch 001 
Epoch 002 
Epoch 001/002 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 Visit 5 Contact 
18 
Contact 
28 
Contact 
38 
Unscheduled 
visit 
Timepoint(s) 
Day 0 
Day 7 
Day 30 
Day 60 Day 90 Day 180 Day 270 Day 360 
- 
Sampling timepoints 
Pre-vacc Post-Vacc Post-Vacc Post- 
Vacc 
Post- 
Vacc 
Unscheduled 
nasal swab 
Informed consent 
● 
Check inclusion/exclusion criteria 
● 
Record demographic data 
●1 
Medical history including review of respiratory symptoms* 
● 
Physical examination 2 
● 
● 
O 
O 
O 
● 
Pregnancy test 3 
● 
Pre-vaccination body temperature 
● 
Distribution of subject card 
O 
Laboratory Assays 
Blood sampling for haematology/ biochemical analysis (~10 ml) 
●4 
● 
● 
● 
● 
Blood sampling for humoral immune responses including anti-neo antibody 
assay (~17 mL) 
●4 
● 
● 
● 
Nasal swab 
●9 
Vaccine 
Randomization and treatment number allocation 
O 
Vaccination 
● 
Recording of administered treatment number 
● 
30 minutes post-vaccination observation period 
O 
Distribution of diary cards and instruction on how to complete them 5 
O 
O 
Return of diary cards 
O 
O 
Diary card transcription by investigator 
● 
● 
Recording of solicited adverse events (Day 0-Day 6) 
● 
● 
Recording of unsolicited adverse events (Day 0-Day 29) 
● 
● 
● 
Recording of adverse events related to MA-RTIs 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of adverse events leading to withdrawal 
● 
● 
● 
● 
● 
● 
● 
● 

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Epoch 
Epoch 001 
Epoch 002 
Epoch 001/002 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 Visit 5 Contact 
18 
Contact 
28 
Contact 
38 
Unscheduled 
visit 
Timepoint(s) 
Day 0 
Day 7 
Day 30 
Day 60 Day 90 Day 180 Day 270 Day 360 
- 
Sampling timepoints 
Pre-vacc Post-Vacc Post-Vacc Post- 
Vacc 
Post- 
Vacc 
Unscheduled 
nasal swab 
Recording of serious adverse events 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of pregnancies 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of concomitant medications/products/vaccinations 6 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of intercurrent medical conditions 
● 
● 
● 
● 
Completion of MA-RTI case details 
● 
Check for interest in participating in future booster study 7 
O 
● 
Investigator sign-off on eCRF before analysis 
● 
● 
● 
Study Conclusion 
● 
Vacc = vaccination; MA-RTIs = Medically Attended Respiratory Tract Infections; eCRF = electronic Case Report Form. 
● 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 
* In addition to the medical history, a full respiratory review of symptoms (including shortness of breath, chest pain, symptoms of upper respiratory tract infection,including cough, 
sputum production, sore throat, nasal congestion, personal and family history of pulmonary illnesses including asthma, chronic obstructive pulmonary disease, cystic fibrosis, 
autoimmune diseases affecting the lungs and smoking, personal history of recurrent infections, pneumonia, sleep apnea and occupational exposure) should be completed and 
recorded in the eCRF. 
1 Date of birth (year only), geographic ancestry, ethnicity and childbearing potential (if subject not of childbearing, the specific reason should be documented in the CRF: hysterectomy, 
ovariectomy, post-menopause, pre-menarche or other) 
2 Complete physical examination including resting vital signs (blood pressure, heart rate and respiratory rate) after at least 10 minutes of rest. In addition, a pulmonary examination, 
including measurement of blood oxygen saturation and chest auscultation should be performed at Visit 1 and Unscheduled visit. Weight, height and BMI will also only be collected at 
Visit 1. Physical examination at Visit 3, 4 and 5 will be performed only if deemed necessary by the investigator. 
3 Only for women of childbearing potential. Urine pregnancy test is sufficient to determine the eligibility to enter the study. Serum pregnancy test (instead of urine test) may be 
performed if required by country, local or ethics committee regulations. 
4 Blood sampling for haematology/biochemical analysis and for immunogenicity assays must be done before vaccination at Visit 1. Refer to Table 7 and Table 8 for the list of 
parameters to be tested. 
5 Two diary cards will be distributed. The first one will be distributed at the day of vaccination and will be used for recording solicited and unsolicited AEs and concomitant 
medications/products and vaccinations on the day of vaccination and for 6 subsequent days. The second one will be distributed at Visit 2 (Day 7) and will be used for recording 
unsolicited AEs and concomitant medications/products and vaccinations from 7 to 29 days after vaccination. 
6 Concomitant medications/products/vaccinations as described in Section 6.6 need to be recorded in the eCRF. 
7 It is likely that the RSV vaccine may need to be administered during each pregnancy to further boost immunogenicity in the pregnant woman and achieve protective anti-RSV levels in 
the neonate. In order to assess whether a booster dose might induce a higher reactogenicity or immune-tolerance, subjects who participated in the study RSV F-021 and who were part 
of the selected vaccine group or the control group may be invited to a booster study (study RSV F-021B). 

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8 Contact should be preferably performed via telephone, or alternatively, if phone contact is not possible, through email/other means where the information can be fully collected. 
9 In case of a MA-RTI (e.g. visit to the GP for respiratory symptoms including but not limited to cough, sputum production, difficulty breathing), the subject will be asked to contact the 
Investigator to enable the collection of a nasal swab within 72h after the medical attendance. Refer to Table 9 for sequence and method of testing for respiratory viruses of collected 
samples. 
Note: The double-line border following Day 30 and Day 90 indicates the analyses which will be performed on all data (i.e. data that are as clean as possible) obtained up to Day 30 and 
Day 90 respectively. 

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Table 5 
Intervals between study visits 
 
Interval 
Optimal length of interval1 
Allowed interval 
Visit 1 (Day 0)  Visit 2 (Day 7) 
7 days 
7 - 9 days 
Visit 1 (Day 0)  Visit 3 (Day 30) 
30 days 
30 - 44 days2 
Visit 1 (Day 0)  Visit 4 (Day 60) 
60 days 
56 - 70 days2 
Visit 1 (Day 0)  Visit 5 (Day 90) 
90 days 
86 - 100 days2 
Visit 1 (Day 0)  Contact 1 (Day 180) 
180 days 
150 -210 days 
Visit 1 (Day 0)  Contact 2 (Day 270) 
270 days 
240 - 300 days 
Visit 1 (Day 0)  Contact 3 (Day 360) 
360 days 
330 - 390 days 
1Whenever possible the investigator should arrange study visits within this interval. 
2Subjects will not be eligible for inclusion in the ATP cohort for analysis of immunogenicity if they make the study visit 
outside this interval. 
 
5.6. 
Detailed description of study procedures 
 
5.6.1. 
Informed consent 
 
The signed/witnessed/ thumb printed 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, as 
appropriate 
 
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 (year only), geographic ancestry* and 
ethnicity* as well as information on subject’s childbearing potential (if subject is not of 
childbearing potential, the specific reason be documented: pre-menarche, hysterectomy, 
ovariectomy, post-menopause or other) in the subject’s eCRF. 
 
* Differences in the safety and efficacy of certain medical products, including vaccines 
[Haralambieva, 2013;Pérez-Losada, 2009; Kollmann, 2013], have been observed in 
racially and ethnically distinct subgroups. These differences may be attributable to 
intrinsic factors (e.g. genetics, metabolism, elimination), extrinsic factors (e.g. diet, 
environmental exposure, sociocultural issues), or interactions between these factors. 
Therefore, both geographic ancestry and ethnicity will be collected for all subjects 
participating in the RSV F-021 study. 
 
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 

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subject prior to the study vaccination in the eCRF. In addition to the medical history, a 
full respiratory review of symptoms (including shortness of breath, chest pain, symptoms 
of upper respiratory tract infection, including cough, sputum production, sore throat, 
nasal congestion, personal and family history of pulmonary illnesses including asthma, 
chronic obstructive pulmonary disease, cystic fibrosis, autoimmune diseases affecting the 
lungs, and smoking, personal history of recurrent infections, pneumonia, sleep apnea and 
occupational exposure) should be completed and recorded in the eCRF. 
 
5.6.5. 
Physical examination 
 
At Visit 1, Visit 2 and unscheduled visits, perform a physical examination of the subject, 
including assessment of resting vital signs: systolic and diastolic blood pressure, heart 
rate, respiratory rate after at least 10 minutes of rest. In addition, a pulmonary 
examination, including measurement of blood oxygen saturation and chest auscultation 
should be performed at Visit 1 and unscheduled visits. Also at Visit 1 only, collect height, 
weight and BMI. Collected information needs to be recorded in the eCRF. 
 
At subsequent study visits, perform a physical examination only if the subject indicates 
during questioning that there might be some underlying pathology(ies) or if deemed 
necessary. 
 
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. 
 
5.6.6. 
Pregnancy test 
 
Female subjects of childbearing potential are to have a pregnancy test prior to any study 
vaccine administration. The study vaccines may only be administered if the pregnancy 
test is negative. Urine pregnancy test is sufficient to determine the eligibility to enter the 
study. 
 
Serum pregnancy test (instead of urine test) may be performed if required by country, 
local or ethics committee regulations. 
 
Note: The pregnancy test must be performed even if the subject is menstruating at the 
time of the study visit. 
 
5.6.7. 
Check contraindications, warnings and precautions to 
vaccination 
 
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of the vaccination visit. Refer to Section 6.5 for more details. 
 
5.6.8. 
Assess pre-vaccination body temperature 
 
Record the axillary, oral or tympanic body temperature of the subject prior to study 
vaccination. The preferred route for recording temperature in this study will be oral. 

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If the subject has fever (fever is defined as temperature  37.5°C for oral, axillary or 
tympanic route, or  38.0°C for rectal route) on the day of vaccination, Visit 1 can be 
rescheduled within the allowed recruitment period. 
 
5.6.9. 
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. 
 
5.6.10. 
Blood sampling 
 
A volume of ~10 mL of whole blood should be drawn from all subjects for analysis of 
the haematology/biochemistry parameters at each study visit. Haematology and 
biochemistry assessments will be performed in a central laboratory (Q2 solutions). 
A volume of ~17 mL of whole blood (to provide ~6 mL of serum) should be drawn from 
all subjects at study visits 1, 3, 4 and 5, for analysis of humoral immune responses, 
including anti-NEO antibody assay which is only performed at Visits 1 and 3. Refer to 
Table 6 and Table 11. 
 
Refer to the SPM for details on blood sample handling. 
 
5.6.11. 
Collection of nasal swab samples 
 
In case of a MA-RTI (e.g. visit to the GP for respiratory symptoms including but not 
limited to cough, sputum production, difficulty breathing), the subject will be asked to 
contact the Investigator to enable the collection of a nasal swab within 72h after the 
medical attendance. 
 
Investigator will decide if nasal swab is collected through subject visiting the site or 
through home visit by qualified site staff (or delegated to a third party). 
 
The nasal swab will be used to assess a potential intercurrent infection with RSV and 
other respiratory viruses. 
 
Cells and secretions from the nose will be collected using sterile swabs. Refer to the SPM 
for more details about nasal swabbing. 
Note: For cases that are hospitalised and treated for an LRTI, it is recommended to take 
an additional specimen for testing at the local laboratory in order to establish a fast and 
accurate diagnosis for the SAE. 
 
5.6.12. 
Study Vaccine administration 
 
After completing all prerequisite procedures prior to vaccination, administer one dose of 
study vaccine intramuscularly in the deltoid of the non-dominant arm. In case of 
anatomical features, medical indication or skin colouration (e.g. tattoos) preventing 

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vaccination in the non-dominant arm, the vaccine may be administered in the dominant 
arm. Refer to Section 6.3 for detailed description of the vaccine administration procedure. 
 
If the subject’s health on the day of vaccination temporarily precludes vaccine 
administration, Visit 1 can be rescheduled within the allowed recruitment period. 
 
5.6.13. 
30 minutes post-vaccination observation 
 
Closely observe the subject for at least 30 minutes following study vaccination, with 
appropriate medical treatment readily available in case of anaphylaxis. 
 
5.6.14. 
Distribution of Subject Card 
 
For information regarding the Subject Card, please refer to Section 8.9. 
 
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 6.6. 
 
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.7. 
 
5.6.16. 
Recording of AEs, SAEs and pregnancies 
 
• 
Refer to Section 8.3 for procedures for the investigator to record AEs, SAEs and 
pregnancies, as well as the time period for detecting and recording of the different 
events. Refer to Section 8.4 for guidelines and how to report SAE and pregnancy 
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 or if they have visited a 
health care professional for a respiratory tract infection. 
 
• 
At the vaccination visit (Visit 1), a first diary card will be provided to the subject. 
The subject will record body (oral preferred) temperature, any solicited local/general 
AEs, any unsolicited AEs and concomitant medications/products/vaccination as from 
the day of vaccination and during the next 6 days. The subject will be instructed to 
return the completed diary card to the investigator at the next study visit (Visit 2). 
• 
A second diary card will be provided to the subject at Day 7 (Visit 2) to record any 
unsolicited AEs and concomitant medications/products/vaccination from Day 7 until 
Day 29. The subject will be instructed to return the completed diary card to the 
investigator at the next study visit (Visit 3). 
• 
Collect and verify completed diary cards during discussion with the subject on Visit 
2 and 3. 

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• 
Any unreturned diary cards will be sought from the subject through telephone call(s) 
or any other convenient procedure. The investigator will transcribe the collected 
information into the eCRF in English. 
 
• 
From Visit 1 until Contact 3, all medically attended visits for a respiratory tract 
infection will need to be recorded in the subject’s eCRF to document key aspects of 
the case including vital signs and evidence of increased work of breathing. 
 
5.6.17. 
Extension/Booster study 
 
It is likely that the RSV vaccine may need to be administered during each pregnancy to 
further boost immunogenicity in the pregnant woman and achieve protective anti-RSV 
levels in the neonate. In order to assess whether a booster dose might induce a higher 
reactogenicity or immune-tolerance, subjects who participated in the study RSV F-021 
and who were part of the selected vaccine group or the control group may be invited to a 
booster study (study RSV F-021B). 
 
For this purpose, at Visit 5, the investigator will ask each subject if she is interested in 
participating in a booster study and will document this in the source documents only. 
Then, at study conclusion for each subject (D360 contact), the investigator will check 
again to confirm subject’s interest and report it in the eCRF. 
 
If a subject is not interested in participating in the booster study, the reason for refusal 
will also be documented in the subject’s eCRF. 
 
5.6.18. 
D180, D270 and D360 Contacts 
 
Contact should be preferably performed via telephone, or alternatively, if phone contact 
is not possible, through email/other means where the information can be fully collected. 
When the contact was not done by telephone, if questions remain, the study site may 
follow up with the subject via telephone. During these contacts, the investigator (or 
delegate) will ask the subject if she has experienced any serious adverse events and/or 
any AEs leading to study withdrawal since visit 5/last contact (as applicable), as well as if 
she has become pregnant during the post-vaccination period. The investigator (or 
delegate) will also ask the subject for concomitant vaccinations/products/medications that 
she has received since Visit 5/ last contact (as applicable). 
 
Subject’s interest in participating in a booster study will also be re-confirmed at D360 
contact, and the corresponding information will be reported in the eCRF (refer to section 
5.6.17) 
 
Please refer to the SPM for further guidance. 
 
5.6.19. 
Study conclusion 
 
The investigator will: 
• 
review data collected to ensure accuracy and completeness. 

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• 
complete the Study Conclusion screen in the eCRF. 
 
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 5.7.4.2 
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. 
 
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 According-to-Protocol (ATP) analysis (See Section 10.5 

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for the definition of cohorts to be analysed). 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 6 
Biological samples 
 
Sample type 
Timepoint 
Cohort 
N° of 
subjects 
Quantity 
Unit 
Blood sample 
Visit 1 (Day 0) 
All enrolled subjects 
~400 
~10 
ml 
Blood for 
haematology/biochemical 
Visit 2 (Day 7) 
Visit 3 (Day 30) 
All enrolled subjects 
All enrolled subjects 
~400 
~400 
~10 
~10 
ml 
ml 
analysis 
Visit 4 (Day 60) 
All enrolled subjects 
~400 
~10 
ml 
Visit 5 (Day 90) 
All enrolled subjects 
~400 
~10 
ml 
Blood for Humoral immune 
responses including anti-NEO 
antibody assay* 
Visit 1 (Day 0) 
Visit 3 (Day 30) 
Visit 4 (Day 60) 
Visit 5 (Day 90) 
All enrolled subjects 
All enrolled subjects 
All enrolled subjects 
All enrolled subjects 
~400 
~400 
~400 
~400 
~17 
~17 
~17 
~17 
ml 
ml 
ml 
ml 
Total quantity of blood for each subject 
~118 
ml 
Nasal swab 
Nasal swab 
From Visit 1 until 
Contact 3 
All subjects with a MA- 
RTI 
Event- 
driven# 
- 
- 
*Anti-NEO antibody assay will only be performed at visit 1 and visit 3. 
#For each MA-RTI, a nasal swab will be collected within 72 hours at the investigator site or at the subject’s home by 
qualified site staff (or delegated to a third party). 
5.7.3. 
Laboratory assays 
 
Please refer to APPENDIX B for a detailed description of the assays performed in the 
study. Please refer to APPENDIX C for the address of the clinical laboratories used for 
sample analysis. 
 
Laboratory assays as described in Table 7, Table 8 and Table 9 will be performed at a 
GSK Biologicals’ laboratory or in a laboratory designated by GSK Biologicals. 
 
Table 7 
Haematology/Serum Chemistry 
 
System 
Discipline 
Component 
Method 
Scale 
Laboratory 
Whole 
blood 
Haematology 
Leukocytes (White Blood Cells) 
As per local practice Quantitative Central 
laboratory (Q2 
Solutions)* 
Lymphocytes 
Eosinophils 
Haemoglobin 
Platelets 
Neutrophils 
Serum 
Biochemistry 
Alanine Aminotransferase (ALT) 
As per local practice Quantitative 
Aspartate Aminotransferase (AST) 
Creatinine 
* See APPENDIX Cfor address of the clinical laboratory used for sample analysis. 

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Table 8 
Humoral Immunity (Antibody determination) 
 
System 
Component 
Method 
Kit/ 
Manufact 
urer 
Unit 
Cut-off 
Laboratory*** 
Serum 
RSV-A neutralising 
Antibody 
NEUTRALISATION 
In house 
ED60 
TBD** 
GSK Biologicals* or 
NÉOMED-LABS 
Serum 
PCA 
ELISA 
NA 
µg/mL 
TBD** 
GSK Biologicals* or 
NÉOMED-LABS 
Serum 
RSV-B neutralising 
Antibody 
NEUTRALISATION 
In house 
ED60 
TBD** 
GSK Biologicals* or 
NÉOMED-LABS 
Serum 
Anti-NEO antibody 
for safety 
assessment 
ELISA 
NA 
ng/mL 
55 
GSK Biologicals* or 
NÉOMED-LABS 
ELISA = Enzyme-linked immunosorbent assay; ED60 = serum dilution inducing 60% inhibition in plaque forming units; 
TBD = to be determined; PCA = Palivizumab Competing Antibodies; anti-NEO = anti-neogenin; NA = not applicable 
* GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. 
** Assay cut-offs could be subject to change and will be described in the statistical analysis plan (SAP). 
*** See APPENDIX Cfor address of the clinical laboratories used for sample analysis. 
 
Table 9 
Molecular biology (PCR tests) (Amended 8 August 2018) 
 
System 
Component 
Method 
Unit 
Laboratory 
Nasal swab* 
Influenza A virus (Flu A) 
Influenza B virus (Flu B) 
Human respiratory syncytial virus A 
(RSV A) 
Human respiratory syncytial virus B 
(RSV B) 
Human influenza A virus subtype H1 
(Flu A- H1) 
Human influenza A virus subtype H3 
(Flu A-H3) 
Human influenza A virus subtype 
H1pdm09 (Flu A-H1pdm09) 
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 1/2/3/4 (HBoV) 
Human rhinovirus A/B/C (HRV) 
Human coronavirus 229E (229E) 
Human coronavirus NL63 (NL63) 
Human coronavirus OC43 (OC43) 
Multiplex PCR 
(PCRMTX) 
(Allplex 
Respiratory 
Panel or 
equivalent)** 
Qualitative assay 
(positive/negative) 
GSK 
Biologicals*** 
or designated 
laboratory 
Nasal swab* 
RSV-A/B RNA 
Quantitative 
Reverse 
Transcription 
PCR 
(QRTPCR) 
**** 
Copies/ml 
GSK 
Biologicals*** 

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* In case of MA-RTI (e.g. visit to the General Practitioner [GP] for respiratory symptoms including but not limited to 
cough, sputum production, difficulty breathing), the subject will be asked to contact the Investigator to enable the 
collection of a nasal swab within 72h after the medical attendance. 
** Respiratory Viruses Panel (Multiplex PCR) will be performed on all specimens. Refer to APPENDIX B for the 
laboratory addresses. 
*** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. 
****Additional testing with RSV-A/B RNA quantitative reverse transcription PCR may be performed. 
(Amended 08-August-2017) 
 
For subjects having a MA-RTI in the period from Visit 1 until Contact 3, a nasal swab 
will be collected. 
 
For subjects admitted to hospital and treated for an LRTI, it is recommended to take an 
additional specimen for testing at the local laboratory in order to establish a fast and 
accurate diagnosis of the SAE. 
 
Additional Testing 
 
Additional testing on serum samples to characterise the immune response to RSV/ to the 
investigational RSV vaccines, such as, but not limited to, immunoglobulin G (IgG) 
antibody concentrations against the RSV F protein by subclass or further characterisation 
of the immune response against different protein F epitopes may be performed if deemed 
necessary for accurate interpretation of the data and/or should such test(s) become 
available in the GSK Biologicals laboratory or a laboratory designated by GSK 
Biologicals. 
 
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 
IRB/IEC has approved this research. 
 
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. 
Haematology/Blood Chemistry 
Table 10 
 
Haematology/Blood Chemistry 
Blood sampling timepoint 
Sub-cohort 
Name 
No. subjects 
Component 
Type of contact 
(timepoint) 
Sampling 
timepoint 
Visit 1 (Day 0) 
Pre-vaccination 
All subjects 
~400 
Haematology (Leukocytes, 
Neutrophils, Lymphocytes, 
Eosinophils, Haemoglobin, 
Platelets) 
Biochemistry (ALT, AST, 
Creatinine) 
Visit 2 (Day 7) 
Post-vaccination 
All subjects 
~400 
Visit 3 (Day 30) 
Post-vaccination 
All subjects 
~400 
Visit 4 (Day 60) 
Post-vaccination 
All subjects 
~400 
Visit 5 (Day 90) 
Post-vaccination 
All subjects 
~400 
ALT = Alanine Amino-transferase; AST = Aspartate Amino-transferase 

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5.7.4.2. 
Immunological read-out 
Table 11 
 
Immunological read outs 
Blood sampling timepoint 
Sub-cohort 
Name 
No. 
subjects 
Component 
Components 
priority rank 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 1 (Day 0) 
Visit 3 (Day 30) 
Pre-Vaccination 
Post-vaccination 
All subjects 
~400 
RSV-A neutralising antibody 
PCA 
RSV-B neutralising antibody 
Anti-NEO 
1 
2 
3 
4 
Visit 4 (Day 60) 
Visit 5 (Day 90) 
Post-vaccination 
All subjects 
~400 
RSV-A neutralising antibody 
PCA 
RSV-B neutralising antibody 
1 
2 
3 
RSV = Respiratory Syncytial Virus; NEO = Neogenin; PCA = Palivizumab Competing Antibodies 
 
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 11 
 
5.7.4.3. 
Molecular biology 
 
Table 12 
Molecular biology tests (Amended 8 August 2017) 
 
Nasal swab sampling timepoint 
Group 
No. Subjects 
Component 
Type of contact 
(timepoint) 
Sampling 
timepoint 
Unscheduled visit 
for MA-RTI* 
Unscheduled 
All subjects 
All subjects with a 
nasal swab sample* 
Influenza A virus (Flu A) 
Influenza B virus (Flu B) 
Human respiratory syncytial virus A 
(RSV A) 
Human respiratory syncytial virus B 
(RSV B) 
Human influenza A virus subtype H1 
(Flu A- H1) 
Human influenza A virus subtype H3 
(Flu A-H3) 
Human influenza A virus subtype 
H1pdm09 (Flu A-H1pdm09) 
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 1/2/3/4 (HBoV) 
Human rhinovirus A/B/C (HRV) 
Human coronavirus 229E (229E) 
Human coronavirus NL63 (NL63) 
Human coronavirus OC43 (OC43) 
RSV-A/B RNA** 
* For each MA-RTI, a nasal swab will be collected within 72 hours of the medical attendance either at the investigator 
site or at the subject’s home by qualified site staff (or delegated to a third party). 
**Additional testing with RSV-A/B RNA quantitative reverse transcription may be performed. 

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5.7.5. 
Immunological correlates of protection 
(Amended 08-August-2017 
 
No generally accepted immunological correlate of protection has been established so far 
for the antigen used in the investigational RSV vaccine. 
 
6. 
STUDY VACCINES ADMINISTRATION 
 
6.1. 
Description of study vaccines 
All candidate vaccines to be used have been developed and manufactured by GSK 
Biologicals. 
 
The Quality Control Standards and Requirements for the candidate vaccines are 
described in separate Quality Assurance documents (e.g. release protocols, certificate of 
analysis) and the required approvals have been obtained. 
 
The vaccines are labelled and packed according to applicable regulatory requirements. 
 
Table 13 
Study vaccines 
 
Treatment 
name 
Vaccine/product 
name 
Formulation 
Presentation 
Volume to be 
administered 
Number 
of 
doses 
30 µg PreF 
PreF-30 
PreF=30µg 
NaCl=150mM 
Freeze-dried antigen in 
monodose vial 
Liquid in monodose, 
prefilled syringe 
0.5 ml 
1 
60 µg PreF 
PreF-60 
PreF=60µg 
NaCl=150mM 
Freeze-dried antigen in 
monodose vial 
Liquid in monodose, 
prefilled syringe 
0.5 ml 
1 
120 µg PreF 
PreF-120 
PreF=120µg 
NaCl=150mM 
Freeze-dried antigen in 
monodose vial 
Liquid in monodose, 
prefilled syringe 
0.5 ml 
1 
Placebo 
Formulation 
buffer S9b 
Na₂HPO₄=1.3mg; 
KH₂PO₄=186µg; NaCl=3.85mg; 
KCl=100µg; MgCl₂=50µg 
Clear liquid in monodose 
vial 
0.5 ml 
1 
6.2. 
Storage and handling of study vaccines 
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. For the observer-blind part of this study (up to Visit 5), access to the 
storage space by study personnel is further detailed in the guidance on observer-blind 
studies in the SPM. The storage conditions will be assessed during pre-study activities 
under the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines. 

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Temperature excursions must be reported in degree Celsius. 
 
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C label 
storage condition) impacting investigational medicinal products (IMPs) must be reported 
in the appropriate (electronic) temperature excursion decision form ([e]TDF). The 
impacted IMPs must not be used and must be stored in quarantine at label temperature 
conditions until usage approval has been obtained from the sponsor. 
 
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to +8°C 
label storage temperature conditions. The impacted IMP(s) may still be administered, but 
the site should avoid re-occurrence of such temperature excursion. Refer to the Module 
on Clinical Trial Supplies in the SPM for more details on actions to take. 
 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines. 
 
6.3. 
Dosage and administration of study vaccines 
Table 14 
Dosage and administration 
 
Type of contact 
and timepoint 
Study group 
Treatment name 
Volume to be 
administered 
Route 
Site 
Side 
Visit 1 (Day 0) 
30 PreF 
30 µg PreF 
0.5 ml 
IM 
Deltoid 
Non- 
dominant* 
60 PreF 
60 µg PreF 
0.5 ml 
IM 
Deltoid 
Non- 
dominant* 
120 PreF 
120 µg PreF 
0.5 ml 
IM 
Deltoid 
Non- 
dominant* 
Control 
Placebo 
0.5 ml 
IM 
Deltoid 
Non- 
dominant* 
IM = intramuscular; 
*In case of anatomical features, medical indication or skin colouration (e.g. tattoos) that prevent vaccination in the non- 
dominant arm, the vaccine may be administered in the dominant arm. 
 
6.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 10% additional vaccine doses will be 
supplied to replace those that are unusable. 
 
The investigator will use SBIR to obtain the replacement number. The replacement 
numbers will be allocated by dose. The system will ensure, in a blinded manner, that the 
replacement vial matches the formulation the subject was assigned to by randomisation. 

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6.5. 
Contraindications to vaccination 
The following events constitute contraindications to administration of the study vaccine 
at that point in time; if any of these events occur at the time scheduled for vaccination 
(Visit 1), Visit 1 will be rescheduled at a later date, within the allowed recruitment 
period, and the subject may be vaccinated at that time: 
• 
Acute disease and/or fever at the time of vaccination. 
 
Fever is defined as temperature  37.5°C for oral, axillary or tympanic route, or 
≥38.0°C for rectal route. The preferred route for recording temperature in this 
study will be oral. 
 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines. 
 
6.6. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit, the investigator should question the subject about any 
medications/products taken and vaccinations received by the subject. 
 
6.6.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF. 
• 
All concomitant medications/products, except vitamins and dietary supplements, 
administered as of study vaccination and up to 29 days after vaccination (Day 0 to 
Day 29). 
• 
Any concomitant vaccination, administered during the study period. 
• 
Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination). 
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature  37.5°C for oral, axillary or tympanic route, or  38.0°C for rectal 
route]. 
• 
Any concomitant medications/products/vaccines listed in Section 6.6.2 during the 
period specified in that section. 
• 
Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered during the study period for the treatment of a SAE. In 
addition, concomitant medications relevant to SAEs need to be recorded on the 
expedited Adverse Event report. 
• 
Any prescribed treatment for the MA-RTIs as of study vaccination till end of study. 

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6.6.2. 
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses 
 
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analysis. See Section 10.5 for cohorts to be analysed. 
• 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used during the study period. 
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days in total) or any long-acting immune-modifying drugs (e.g. 
infliximab) administered any time up to 90 days post-vaccination. For 
corticosteroids, this will mean ≥10mg/day, or equivalent. Inhaled and topical steroids 
are allowed. 
• 
A vaccine not foreseen by the study protocol administered during 30 days following 
vaccination*, with the exception of seasonal influenza vaccine which may be 
administered  15 days after the dose of study vaccine. 
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation 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 
Products Characteristics (SmPC)/Prescribing Information and according to the local 
governmental recommendations and provided a written approval of the Sponsor is 
obtained. 
• 
Immunoglobulins and/or any blood products administered up to 90 days post- 
vaccination. 
 
6.7. 
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses 
At each study visit subsequent to Visit 1 and up to Visit 5, it must be verified if the 
subject has experienced or is experiencing any intercurrent medical condition. If it is the 
case, the condition(s) must be recorded in the eCRF. 
 
Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study 
period up to Day 90 (Visit 5), they incur a condition that has the capability of altering 
their immune response or if they are diagnosed with an immunological disorder. 
 
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 adverse event (AE) or serious 
adverse event (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 unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
 
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 investigational vaccine administration 
even though they may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational vaccine or a concurrent medication (overdose per se should not be 
reported as an AE/SAE). 
• 
Signs, symptoms temporally associated with vaccine(s) 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 
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 hospitalisation or prolongation of existing hospitalisation, 
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition (known 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, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study subject. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation. 

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8.1.3. 
Solicited adverse events 
 
8.1.3.1. Solicited local (injection-site) adverse events 
The following local (injection-site) AEs will be solicited: 
Table 15 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 local (injection-site) AEs will be solicited: 
 
Table 16 
Solicited general adverse events 
 
Fatigue 
Fever* 
Gastrointestinal symptoms† 
Headache 
* Fever is defined as temperature  37.5°C for oral, axillary or tympanic route, or  38.0°C for rectal route. The 
preferred route for recording temperature in this study will be oral. 
† Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain. 
 
Note: Temperature will be recorded in the evening. Should additional temperature 
measurements be performed at other times of day, the highest temperature will be 
recorded in the eCRF. 
 
8.1.4. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments that are judged by the 
investigator to be clinically significant will be recorded as AE or SAE if they meet the 
definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). All Grade  3* abnormal 
laboratory findings should be reported as AE/SAE. 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. If a diagnosis is associated with the abnormal findings, the diagnosis should be 
reported as AE/SAE. 
 
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
 
*Grading will be based on the Food & Drug Administration (FDA) Guidance for 
Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials” [APPENDIX D] 

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8.1.5. 
Medically Attended Respiratory Tract Infections 
 
A MA-RTI is defined as a subject’s visit to a health care professional (e.g. GP) for any 
respiratory symptom, including (but not limited to) cough, sputum production and 
difficulty breathing. 
 
All AEs related to MA-RTIs occurring during the period starting with the administration 
of study vaccine up to Contact 3 must be recorded in a specific eCRF form for MA-RTI, 
irrespective of intensity or whether or not they are considered administration-related. 
 
8.2. 
Events or outcomes not qualifying as adverse events or 
serious adverse events (pregnancy) 
Female subjects who become pregnant after the vaccination may continue the study at the 
discretion of the investigator. 
 
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE. 
 
Note: The pregnancy itself should always be recorded on an electronic pregnancy report. 
 
The following should always be considered as SAE and will be reported as described in 
Sections 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 foetus after 22 weeks of gestation). 
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different. 
• 
Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life). 
• 
Any congenital anomaly or birth defect (as per [CDC MACDP, 1996] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus 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 investigational vaccines 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. 

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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 30 days following administration of the dose of study vaccines (Day 0 to 
Day 29) must be recorded into the appropriate section of the eCRF, irrespective of 
intensity or whether or not they are considered vaccination-related. 
 
The time period for collecting and recording SAEs will begin at the receipt of study 
vaccines and will end at the contact at Day 360 following administration of the dose of 
study vaccines for each subject. 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 receipt of study vaccines. 
 
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she is discharged from the study. 
 
The time period for collecting and recording pregnancies will begin at the receipt of study 
vaccines and will end at the contact at Day 360 following administration of the dose of 
study vaccines. See section 8.4 for instructions on reporting of pregnancies. 
 
An overview of the protocol-required reporting periods for AEs, SAEs, pregnancies is 
given in Table 17. 

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Table 17 
Reporting periods for collecting safety information 
 
Event 
Visit 1 Day 6 Visit 2 Day 29 Visit 3 Visit 4 Visit 5 
Contact 1 Contact 2 Contact 3 
end of 
end of 
Day 0 7-day Day 7  30-day  Day 30  Day 60  Day 90 
FU 
FU 
Day 360 
Day 180 
Day 270 
Study 
conclusion 
Solicited local and 
general AEs 
Unsolicited AEs 
AEs/SAEs leading 
to withdrawal from 
the study 
SAEs 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine* 
Pregnancies 
AEs related to MA- 
RTIs 
The double-bordered line indicates timing of vaccination.*i.e. SAEs related to study participation will be collected as 
from informed consent signing. AE = Adverse event; FU = Follow-up; SAE = Serious adverse event; MA-RTI = 
Medically Attended Respiratory Tract Infection. 
 
Type 
Solicited adverse events /Unsolicited adverse 
events/ Serious adverse events/ Adverse events 
related to MA-RTIs 
 
Method of ‘solicited’ follow-up 
Diary cards 
 
Method of ‘unsolicited’ follow-up 
Diary cards/ Questioning at study visits/ contacts 
up to D360 
 
Method for reporting SAEs 
Electronic Expedited Adverse Events Report 
 
Method for reporting AEs related to 
MA-RTIs 
Subject contacting Investigator 
 
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 17. 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 

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event reasonably related to the investigational vaccines, 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 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. 

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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: 
 
Table 18 
Intensity scales for solicited adverse events 
 
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 
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, diarrhoea 
and/or abdominal pain) 
0 
Normal 
1 
Mild: Gastrointestinal symptoms that are easily tolerated 
2 
Moderate: Gastrointestinal symptoms that interfere with normal activity 
3 
Severe: Gastrointestinal symptoms that prevent normal activity 
*Fever is defined as temperature  37.5°C for oral, axillary or tympanic route, or  38.0°C for rectal route. The 
preferred route for recording temperature in this study will be oral. 
 
The maximum intensity of local injection site redness/swelling will be scored at GSK 
Biologicals according to the standard GSK Biologicals’ scoring system for adults: 
0: 
 20 mm 
1: 
> 20 mm to  50 mm 
2: 
> 50 mm to  100 mm 
3: 
> 100 mm 
 
The maximum intensity of fever will be scored at GSK Biologicals according to the 
standard GSK Biologicals’ scoring system for adults (via the preferred route for 
recording temperature in this study which is oral): 
0: 
< 37.5 °C 
1: 
 37.5 °C to  38.5 °C 
2: 
> 38.5 °C to  39.5°C 
3: 
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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. 
 
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. 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. 
 
8.3.3.2.2.       Assessment of causality 
 
The investigator is obligated to assess the relationship between investigational vaccines 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational vaccines will be considered and 
investigated. The investigator will also consult the RSV maternal IB to determine his/her 
assessment. 
 
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
 
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of general AEs to the individual vaccine administered. 
The investigator should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccines. 

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All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question: Is there a reasonable possibility that the AE may have been caused 
by the investigational vaccine? 
 
YES: 
There is a reasonable possibility that the study vaccination contributed to the 
AE. 
NO: 
There is no reasonable possibility that the AE is causally related to study 
vaccination. There are other, more likely causes and study vaccination 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, 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 visits 
 
For each solicited and unsolicited symptom the subject experiences, the subject will be 
asked if she received medical attention defined as hospitalisation, 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 19, 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 19, once the investigator becomes 
aware of the pregnancy. 
 
Table 19 
Timeframes for submitting serious adverse event and pregnancy to 
GSK Biologicals 
 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours*‡ 
Expedited Adverse Events 
Report 
24 hours* 
Expedited Adverse Events Report 
Pregnancies 
2 weeks* 
Electronic pregnancy report 
2 weeks* 
Electronic pregnancy report 
*Timeframe allowed after receipt or awareness of the information. 
‡The investigator will be required to confirm 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. 
 
8.4.2. 
Contact information for reporting serious adverse events and 
pregnancies 
 
Study Contact for Reporting SAEs and pregnancies 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs and pregnancies 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Fax: +PPD 
or +PPD 
Email address: PPD 
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. 

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The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE. 
 
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. 
 
8.4.5. 
Updating of SAE and pregnancy information after removal of 
write access to the subject’s eCRF 
 
When additional SAE, pregnancy 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 19. 
 
8.4.6. 
Regulatory reporting requirements for serious adverse events 
 
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 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 

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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/are both attributable to the investigational vaccines and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation. 
 
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 19). 
 
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study. 
 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination. 
 
8.5.1.2. 
Follow-up after the subject is discharged from the study 
 
The investigator will follow subjects with SAEs or subjects withdrawn from the study as 
a result of an AE, until the event has resolved, subsided, stabilised, disappeared, or until 
the event is otherwise explained, or the subject is lost to follow-up. 
 
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 recognised 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 an AE should 
be recorded in the subject’s eCRF (refer to Section 6.6). 
 
8.7. 
Unblinding 
GSK Biologicals’ policy (which incorporates ICH E2A guidance, EU Clinical Trial 
Directive and US Federal Regulations) is to unblind the report of any SAE which is 
unexpected and attributable/suspected to be attributable to the investigational vaccines, 
prior to regulatory reporting. The GSK Biologicals’ Central Safety Physician is 
responsible for unblinding the treatment assignment in accordance with the specified 
timeframes for expedited reporting of SAEs (refer to Section 8.4.1). 
 
8.8. 
Emergency unblinding 
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of 
the treatment is essential for the clinical management or welfare of the subject, as judged 
by the investigator. 
 
The emergency unblinding process consists of the automated system SBIR that allows the 
investigator to have unrestricted, immediate and direct access to the subject’s individual 
study treatment. 
 
The investigator has the option of contacting a GSK Biologicals’ On-call Central Safety 
Physician (or Backup) if he/she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e. he/she cannot access SBIR). 
 
Any emergency unblinding must be fully documented by using the Emergency 
Unblinding Documentation Form, which must be appropriately completed by the 
investigator and sent within 24 hours to GSK Biologicals. 

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GSK Biologicals’ Central Safety Physician: 
+PPD 
(GSK Biologicals Central Safety Physician on-call) 
GSK Biologicals’ Central Safety Physician Back-up: 
+PPD 
Emergency Unblinding Documentation Form transmission: 
GSK Biologicals’ Contact information for Emergency Unblinding 
24/24 hour and 7/7 day availability 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.9. 
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. 
 
8.10. 
Safety monitoring 
 
8.10.1. 
Safety review team 
 
The SRT includes as core members the GSK Biologicals’ Central Safety Physician, the 
Clinical & Epidemiology Project Lead (CEPL), Epidemiologist, Clinical Regulatory 
Affairs representative and the Biostatistician of the project. The SRT is responsible for 
on-going safety monitoring of the entire project and will meet on a regular basis. In order 
to keep all people involved in the conduct, cleaning and final analysis of the study 
blinded, the SRT will monitor safety in a blinded manner. 
 
In addition to the existing SRT, an unblinded safety evaluation will be performed by an 
iSRC. The SRT will inform the iSRC about any potential safety concern relevant to the 
study and vice versa. 
 
8.10.2. 
Internal safety review committee 
 
Since this will be the first time that the investigational RSV vaccine formulation 
containing 120 g of the PreF antigen will be administered in humans, a staggered 
vaccination and monitoring by an iSRC, authorised by the GSK Biologicals’ Vaccine 
Safety Monitoring Board (VSMB), have been established to ensure maximum safety of 
the subjects in the study. 
 
The iSRC will include the following GSK personnel: a Safety Physician (Vaccines 
Clinical Safety & Pharmacovigilance representative [VCSP]), a Clinical Research and 

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Development Leader (CRDL), and a Biostatistician, external to the study/project and 
with no conflicts of interest in the outcome of the study. The GSK Safety Physician will 
act as the Chair of the iSRC. Additionally, the iSRC will have one ad hoc, non-voting 
member: an independent statistician in charge of providing unblinded data to the iSRC. 
 
When the first 25% of the subjects are vaccinated in the study (Step 1), enrolment will be 
paused until completion of an unblinded iSRC review of all safety data collected up to 
(minimum) 7 days post-vaccination (including Day 7 haematology and biochemistry 
parameters). 
 
It was deemed appropriate to place the sample size “cut-off” at the first 25% of subjects 
vaccinated based on the rate of Grade 3 AEs (solicited and unsolicited) during the 7-day 
post vaccination period observed in the RSV F-020 study with the non-adjuvanted 60µg 
PreF formulation, which was approximately 5%. 
 
The table below shows that with 25% of subjects vaccinated (25 subjects per group) we 
have ~90% chance to observe a given Grade 3 event if the true incidence is 10% (i.e. 
~2fold of what we would expect , based on RSV F-020 study data). 
 
Table 20 
Probability to observe at least one subject with an event of a given 
true incidence when looking after 25 enrolled subjects/group 
 
True incidence 
N = 25 
1% 
0.222 
2% 
0.397 
5% 
0.723 
10% 
0.928 
15% 
0.983 
20% 
0.996 
30% 
1 
N = subjects per group 
 
During the planned (and any ad-hoc iSRC safety evaluations, if applicable), the iSRC 
will review all available safety data in an unblinded manner, while taking into account 
any other findings that could have an impact on the safety of the subjects, and will 
determine whether there is a safety signal or not. 
 
If no safety signal is observed during the planned safety evaluation after the first 25% of 
subjects have been vaccinated (Step 1), the favourable outcome of the safety review will 
be documented and provided in writing to the RSV study team and investigator(s) and 
enrolment/vaccination of the remaining subjects (Step 2) can start. 
 
If a safety signal is observed during the planned safety evaluation, the iSRC leader is 
responsible for urgent communication and escalation of the concern to the GSK 
Biologicals’ VSMB and communication to the study team. The VSMB will then decide 
during an ad hoc meeting whether to suspend, modify or continue the conduct of the 
study. Already vaccinated subjects will continue all planned visits, including the capture 
of all safety data. However, further enrolment/vaccination cannot proceed until VSMB 
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The decision of the GSK Biologicals’ VSMB will be documented and provided in writing 
to the investigator(s). Ethics Committees and Competent Authorities will also be notified, 
as applicable. 
 
In addition to the planned iSRC evaluation, ad hoc iSRC reviews can be organized, if 
deemed necessary, at any time during the study. 
 
Details about the working of the iSRC will be documented in an iSRC Charter. 
 
In addition to the above, the RSV F-021 iSRC outputs and review outcome will be 
provided to the Independent Data Monitoring Committee (IDMC) of the RSV F-004 
study (first study in which the investigational RSV vaccine will be administered to 
pregnant women). 
 
9. 
SUBJECT COMPLETION AND WITHDRAWAL 
 
9.1. 
Subject completion 
A subject who is available for the contact at Day 360 foreseen in the protocol 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 is 
not available for the contact at Day 360 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 at least 3 documented attempts (e.g. 2 phone calls and a letter 
sent by certified mail to the last known address) to contact those subjects who do not 
return for scheduled visits and/or are not available for the contact at Day 360. 
 
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 herself, or by the investigator, as well as which of the following possible 
reasons was responsible for withdrawal: 
• 
Serious adverse event. 
• 
Non-serious adverse event. 

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• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an adverse event*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because 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). 
 
10. 
STATISTICAL METHODS 
 
10.1. 
Primary endpoints 
• 
Occurrence of AEs from vaccination up to Day 7, for all subjects in each 
investigational RSV vaccine group: 
 
Occurrence of any Grade 2 and Grade 3 general AE (solicited and unsolicited); 
 
Occurrence of Grade 2 and Grade 3 fever; 
 
Occurrence of any vaccine-related SAE. 
• 
Functional antibody titres against RSV at Day 0 and Day 30, for all subjects in each 
investigational RSV vaccine group. 
 
Neutralising antibody titres against RSV-A . 
• 
PCA concentrations at Day 0 and Day 30 for all subjects in each investigational RSV 
vaccine group. 
 
10.2. 
Secondary endpoints 
• 
Occurrence of AEs from vaccination up to study conclusion: 
 
Occurrence of each solicited local and general AE, during a 7-day follow-up 
period after vaccination (i.e. the day of vaccination and 6 subsequent days), for 
all subjects in all groups; 
 
Occurrence of any unsolicited AE, during a 30-day follow-up period after 
vaccination (i.e. the day of vaccination and 29 subsequent days), for all subjects 
in all groups; 
 
Occurrence of any haematological (haemoglobin level, White Blood Cells 
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(alanine amino-transferase [ALT], aspartate amino-transferase [AST] and 
creatinine) laboratory abnormality at Day 0, Day 7, Day 30, Day 60 and Day 90 
for all subjects in all groups; 
 
Occurrence of any SAE, for all subjects in all groups. 
• 
Functional antibody titres against RSV for all subjects in all groups: 
 
Neutralising antibody titres against RSV-A at Day 0, Day 30, Day 60 and Day 
90; 
 
Neutralising antibody titres against RSV-B at Day 0, Day 30, Day 60 and Day 
90. 
• 
PCA concentration at Day 0, Day 30, Day 60 and Day 90 for all subjects in all 
groups. 
• 
Humoral immune response to the residual host cell protein NEO in the 
investigational RSV vaccine at pre-vaccination (Day 0), and 1 month post- 
vaccination (Day 30) for all subjects in all groups. 
 
Neutralising antibody titres against NEO 
• 
Occurrence of medically attended RSV-associated RTIs up to study conclusion. 
10.3. 
Tertiary endpoints 
See section 5.7.3 for additional testing proposed to further characterise the immune 
response to the investigational RSV vaccine. 
 
10.4. 
Determination of sample size 
The main objective of the study is to rank different formulations of the investigational 
RSV vaccine based on immunogenicity and safety/reactogenicity data up to 1 month 
post-vaccination (Day 30). 
 
The sample size was determined to allow reliable ranking of the investigational RSV 
vaccine formulations based on a desirability index (see details in APPENDIX E) 
combining the following endpoints: 
• 
Incidence rate of any Grade 2 and any Grade 3 general AE (solicited and unsolicited) 
and any vaccine-related SAE during the 7-day follow-up period after vaccination for 
each investigational RSV vaccine formulation. 
• 
Incidence rate of Grade 2 and Grade 3 fever during the 7-day follow-up period after 
vaccination for each investigational RSV vaccine formulation. 
• 
Neutralising antibody titres against RSV-A at 1 month post-vaccination. 
• 
PCA concentrations at 1 month post-vaccination. 
Different plausible scenarios (2 for immunogenicity and 2 for reactogenicity) were 
simulated several times and the desirability analysis for formulation selection was applied 
on each simulated data package, as described below. 

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Immunogenicity 
1. The functional antibody response covers a range from 10 log2 (30 PreF) to 12 log2 
(120 PreF) for neutralising RSV-A titres, and from 100 to 200 for the PCA 
concentrations. 
2. The functional antibody response covers a range from 10 log2 (30 PreF) to 11 log2 
(120 PreF) for neutralising RSV-A titres, and from 100 to 150 for the PCA 
concentrations. 
 
Reactogenicity 
1. The incidence rate varies between 25% (30 PreF) and 30% (120 PreF) for the Grade 
2/3 general AEs, and between 2% and 4% for Grade 2/3 fever. 
2. The incidence rate varies between 25% (30 PreF) and 50% (120 PreF) for the Grade 
2/3 general AEs, and between 4% and 10% for Grade 2/3 fever. 
These four combinations of scenarios were simulated 10000 times in SAS, with a sample 
size of 95 evaluable subjects per group (see details in APPENDIX E). The percentages 
for ranking each formulation at the first place and for selecting the best formulation were 
computed. 
 
Simulations in SAS shows that a sample size of 100 subjects enrolled per group (N=95 
evaluable subjects) allows to reach a percentage >80% for selecting one of the best 
formulations, i.e. with a high immune response and acceptable reactogenicity. Moreover, 
this sample size will allow to have a small percentage (<5%) for selecting formulations 
with an unacceptable reactogenicity. 
 
10.5. 
Cohorts for Analyses 
Two cohorts will be defined for the purpose of the analysis: the Total Vaccinated Cohort 
(TVC) and the ATP cohort for analysis of immunogenicity. All analyses will be 
performed per treatment actually administered. 
 
10.5.1. 
Total vaccinated cohort 
 
The TVC will include all subjects with study vaccine administration documented: 
• 
A safety analysis based on the TVC will include all vaccinated subjects 
• 
An immunogenicity analysis based on the TVC will include all vaccinated subjects 
for whom immunogenicity data are available. 
 
10.5.2. 
According-to-protocol cohort for analysis of immunogenicity 
 
The ATP cohort for immunogenicity will be defined by time point and will include all 
vaccinated subjects: 
• 
Meeting all eligibility criteria (i.e. no protocol violation linked to the inclusion/ 
exclusion criteria, including age). 

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• 
Who received the study vaccine according to protocol procedures. 
• 
Who did not receive a concomitant vaccination/medication/product leading to 
exclusion from an ATP analysis up to the corresponding timepoint as described in 
Section 6.6.2. 
• 
Who did not present with an intercurrent medical condition leading to exclusion 
from an ATP analysis up to the corresponding timepoint, as described in Section 6.7. 
• 
Who complied with the post-vaccination blood sampling schedule at the 
corresponding timepoint, as specified in Table 5. 
• 
For whom post-vaccination immunogenicity results are available for at least 1 assay 
at the corresponding timepoint. 
 
When presenting different timepoints, the ATP cohort for immunogenicity will be 
adapted for each timepoint (up to D30 and up to D90). 
 
10.6. 
Derived and transformed data 
The study groups will be defined by treatment actually administered. 
 
Demography 
• 
For a given subject and a given demographic variable, missing measurements will 
not be replaced. 
 
Safety 
• 
For a given subject and the analysis of solicited symptoms during the 7-day 
follow-up period after vaccination, missing or non-evaluable measurements will not 
be replaced. Therefore the analysis of the solicited symptoms based on the TVC will 
include only vaccinated subjects with documented safety data (i.e., symptom screen 
completed). 
• 
For analysis of unsolicited AEs, SAEs and for the analysis of concomitant 
medications, all vaccinated subjects will be considered. Subjects who did not report 
an event or concomitant medication will be considered as subjects without the event 
or the concomitant medication respectively. 
 
Immunogenicity 
• 
Any missing or non-evaluable immunogenicity measurement will not be replaced: 
 
For the within-group assessment, the descriptive analysis performed for each 
assay at each timepoint will exclude subjects with a missing or non-evaluable 
measurement. 
 
For the between group assessments, the Analysis of covariance (ANCOVA) 
model will be fitted at each timepoint based on the subjects having a result at 
both the baseline and the considered timepoint. 

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• 
A seronegative subject will be defined as a subject whose antibody 
titre/concentration is below the cut-off value of the assay. A seropositive subject is a 
subject whose antibody titre/concentration is greater than or equal to the cut-off 
value of the assay. 
• 
The geometric mean titres (GMTs)/geometric mean concentrations (GMCs) will be 
computed by taking the anti-logarithm of the arithmetic mean of the log10 
transformed titres/concentrations. 
• 
Vaccine response in terms of RSV neutralising antibodies will be defined as: 
 
At least a 4-fold increase from pre-vaccination if pre-vaccination neutralising 
antibody titre <7 log2 (<128). 
 
At least a 3-fold increase from pre-vaccination if pre-vaccination neutralising 
antibody titre in [7-8 log2 ([128-256). 
 
At least a 2.5-fold increase from pre-vaccination if pre-vaccination neutralising 
antibody titre in >8-10 log2 (>256-1024). 
 
At least 1-fold from pre-vaccination if pre-vaccination neutralising antibody titre 
>10 log2 (>1024). 
• 
The handling of data below the assay LLOQs for GMT/GMC calculations and 
evaluation of vaccine response will be described in the SAP. 
 
10.7. 
Analysis of demographics 
The analysis of demography will be performed on the TVC and on the ATP cohort for 
immunogenicity. 
 
Demographic characteristics (age at vaccination in years, race, ethnicity, vital signs and 
BMI) and cohort description will be summarised by group using descriptive statistics: 
• 
Frequency tables will be generated for categorical variable such as race. 
• 
Mean, median, standard error and range will be provided for continuous data such as 
age. 
 
The distribution of subjects will be tabulated as a whole and per group and for each age 
category (18 - 32 years and 33 - 45 years). 
 
Withdrawal status will be summarised by group using descriptive statistics: 
• 
The number of subjects enrolled into the study as well as the number of subjects 
excluded from ATP analyses will be tabulated. 
• 
The number of withdrawn subjects will be tabulated according to the reason for 
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10.8. 
Analysis for ranking RSV formulations 
A desirability approach will be used to rank the formulations and guide the formulation 
selection, based on safety/reactogenicity and immunogenicity data up to 1 month post- 
vaccination. 
 
This method is a multi-criteria decision making approach based on desirability functions. 
The main idea is to identify for each endpoint a desirability function that associates any 
value to another one between 0 and 1 depending on its desirability (‘0’ being considered 
as not desirable at all and ‘1’ as the most desirable). An index with values between 0 and 
1 will be created for each endpoint. An overall desirability index can be calculated by 
computing a weighted geometric mean of the endpoint indexes. By definition, this overall 
index also takes values between 0 and 1 and characterises the level of desirability of any 
candidate formulation by a single value Dewé, 2015. 
The desirability index calculations will include reactogenicity and safety data up to Day 7 
post vaccination (on the TVC) and immunogenicity data at 30 days post-vaccination (on 
the ATP cohort for immunogenicity up to Day 30). The formulations will be ranked 
based on the values obtained with this overall desirability index. Refer to APPENDIX E 
for more details on the desirability analysis. 
 
10.9. 
Analysis of safety 
The analysis of safety will be performed on the TVC. 
 
Within group evaluation 
 
The percentage of subjects with at least one local AE (solicited and unsolicited), with at 
least one general AE (solicited and unsolicited) and with any AE during the 7-day or 
30-day follow-up period after vaccination will be tabulated with exact 95% CI. The same 
computations will be done for  Grade 2 and Grade 3 AEs, for any AEs considered 
related to vaccination, for any Grade 3 AEs considered related to vaccination and for AEs 
resulting in medically attended visit. 
 
The percentage of subjects reporting each individual solicited local AE (any grade, 
 Grade 2, Grade 3, resulting in medically attended visit) during the 7-day follow-up 
period after vaccination will be tabulated for each study vaccine for each group. The 
percentage of subjects reporting each individual solicited general AE (any grade, 
 Grade 2, Grade 3, any related,  Grade 2 related, Grade 3 related, resulting in medically 
attended visit) during the 7-day follow-up period after vaccination will be tabulated for 
each group. 
 
For fever during the 7-day follow-up period after vaccination, the number and percentage 
of subjects reporting fever will be reported by half degree (°C) cumulative increments. 
Similar tabulations will be performed for causally related fever, Grade 3 (> 39.5°C) 
causally related fever and fever resulting in a medically attended visit. In addition, the 
prevalence of any and Grade 3 fever will be presented graphically over time after 
vaccination. 

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The percentage of subjects with any unsolicited symptoms within 30 days after 
vaccination with its exact 95% CI will be tabulated by group and by Medical Dictionary 
for Regulatory Activities (MedDRA) preferred term. Similar tabulation will be done for 
Grade 3 unsolicited symptoms, for any causally related unsolicited symptoms, for Grade 
3 causally related unsolicited symptoms and for unsolicited symptoms resulting in a 
medically attended visit (The verbatim reports of unsolicited symptoms will be reviewed 
by a physician and the signs and symptoms will be coded according to the MedDRA 
Dictionary for Adverse Reaction Terminology. Every verbatim term will be matched with 
the appropriate Preferred Term). 
 
SAEs reported throughout the study will be described in detail. 
 
Pregnancy exposures throughout the study and pregnancy outcomes will be described in 
detail (if applicable). 
 
The percentage of subjects using concomitant medication (any medication, any 
antipyretic and any antipyretic taken prophylactically) during the 7-day (Day 0 to Day 6) 
or 30-day (Day 0 to Day 29) follow-up period after vaccination will be summarised by 
group. 
 
For all subjects in each group and each haematology and biochemistry parameter: 
• 
The percentage of subjects having haematology and biochemistry results below or 
above the local laboratory normal ranges will be tabulated for each timepoint. 
• 
The maximum grading post-vaccination (from Day 7 to Day 90) versus baseline 
(Day 0) and the percentage of subjects with laboratory parameters above or equal to 
Grade 1, Grade 2, Grade 3 and Grade 4 will be tabulated (Grades will be based on 
the FDA Guidance for Industry “Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”, see 
APPENDIX D. Those laboratory parameters not included on FDA Toxicity Grading 
Scale will not be graded). 
 
Assessment of anti-NEO immune response at Day 30 post-vaccination for each group: 
• 
GMCs pre-and post-vaccination will be tabulated with 95% CI and represented 
graphically. 
• 
Individual post-vaccination versus pre-vaccination results will be plotted using 
scatter plots. Results of the control group will be used as a reference. 
• 
Geometric mean of ratios of antibody concentrations at Day 30 over pre-vaccination 
will be tabulated with 95% CI. 
• 
Distribution of the antibody concentrations pre-and post-vaccination and of fold 
increase after vaccination will be tabulated. 
 
Between group evaluation 
 
Exploratory comparisons between each investigational RSV vaccine group and (minus) 
the control group (placebo), and between the RSV vaccine groups (PreF-120 minus PreF 
30, PreF-120 minus PreF-60, PreF-60 minus PreF 30) will be done in terms of the 

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percentage of subjects reporting any  Grade 2, Grade 3 AE (solicited and unsolicited), 
and/or any fever > 38.5°C, and/or any vaccine-related SAE during the 7-day follow-up 
period after vaccination. 
 
The standardised asymptotic 95% CI for the difference between the investigational RSV 
vaccine groups as well as between the investigational RSV groups and (minus) the 
control group will be computed. 
 
10.10. 
Analysis of immunogenicity 
The analysis will be performed on the applicable ATP cohort for immunogenicity and, if 
in any group the percentage of vaccinated subjects with serological results excluded from 
the ATP cohort for analysis of immunogenicity is  5%, a second analysis will be 
performed on the TVC. 
 
Within group evaluation 
 
Humoral Immune response to RSV vaccine 
 
For each group, at each timepoint that blood samples are collected and for each assay 
(unless specified otherwise): 
• 
GMTs/GMCs will be tabulated with 95% CI and represented graphically. 
• 
Percentage of subjects above the seropositivity threshold will be tabulated with exact 
95% CI. 
• 
Pre- and post-vaccination antibody titres/concentrations will be displayed using 
reverse cumulative curves. 
• 
The distributions of neutralising antibody titres will be tabulated. 
• 
Percentage of responders in terms of neutralising antibody titres will be tabulated 
with exact 95% CI. 
• 
Individual post-vaccination versus pre-vaccination results will be plotted using 
scatter plots. Results of the control group will be used as a reference. 
• 
Geometric mean of ratios of antibody titres/concentrations at each post-vaccination 
timepoint over pre-vaccination will be tabulated with 95% CI. 
• 
Distribution of the fold increase of neutralising antibody titres will be tabulated: by 
pre-vaccination titre category: < 7, 7-8, > 8-9, > 9-10, > 10-11, > 11-12, > 12 log2, 
and by cumulative categories: < 7,  7,  8,  9,  10,  11,  12 log2. 
• 
The kinetics of individual antibody titres/concentrations will be plotted as a function 
of time for subjects with results available at all timepoints. 
• 
An analysis of variance model for repeated measures will be fitted to assess the mean 
profile in each group. 
 
If deemed necessary, the same analyses may be done by age category (18 - 32 years and 
33 - 45 years). 

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Between group evaluation 
 
Exploratory comparisons will be performed for RSV neutralising antibody titres and 
PCA concentrations post-vaccination (Day 30, Day 60 and Day 90) between the different 
RSV vaccine groups: 
• 
Estimation of GMT/GMC ratios between groups with corresponding 95% CI using 
an ANCOVA model on the logarithm10 transformation of the titres/concentrations. 
The ANCOVA model will include the vaccine group as fixed effect and the pre- 
vaccination titre/concentration as regressor. If a statistically significant difference is 
found (p <0.05), pairwise comparisons will be made using Tukey’s multiple 
comparison adjustment. 
 
10.11. 
Analysis of medically attended RTIs 
The analysis will be performed on the TVC by study group. 
 
The proportion of subjects with at least one medically attended RSV-associated RTI 
(with 95 % CI) will be calculated. 
 
Descriptive analyses (mean, median, min, max) of viral load assessed by the quantitative 
PCR (RSV-A/B) of RSV-RTI cases will be tabulated for any cases where this assay is 
performed. 
 
Medically attended RSV-associated RTI co-infected or colonised with another viral 
etiology identified by multiplex PCR will be described. 
 
Medically attended RTI with any viral etiology identified by multiplex PCR will be 
described. 
 
The proportion of subjects (with 95% CI) with at least one medically attended RTI (all 
causes) will be calculated by group. 
 
10.12. 
Interpretation of analyses 
All comparative analyses will be descriptive with the aim to characterise the difference in 
reactogenicity/immunogenicity between groups. These descriptive analyses should be 
interpreted with caution considering that there is no adjustment for multiplicity for these 
comparisons. 
 
10.13. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 

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10.13.1. 
Sequence of analyses 
 
The statistical analyses will be performed in several steps: 
• 
In preparation of the planned iSRC evaluation, analysis of safety and reactogenicity 
data up to at least 7 days post-vaccination of the first 25% of all subjects will be 
performed (see Section 8.10.2 for more information). 
• 
The first main analysis on all subjects will be performed when all data up to 30 days 
post-vaccination are available (primary endpoints). In order to maintain the blind, 
this analysis by group will be performed by an independent statistician and the 
results which would lead to the unblinding of some subjects (e.g. a specific AE 
reported by one subject only) will be blinded (i.e. the group in which this event 
occurred will not be identified). No individual data listings will be provided. 
• 
A second analysis will be performed when all data up to 90 days post-vaccination are 
available (secondary endpoints). At this point, the GSK statistician will be unblinded 
(i.e. will have access to the individual subject treatment assignments), but no 
individual listings will be provided. Given that summary results may unblind some 
specific subjects, the study will be conducted in a single-blind manner from this 
point onwards, with subjects remaining blinded up to study conclusion and the 
investigators will not have access to the treatment allocation up to study conclusion. 
• 
The final analysis will be performed when all data up to study conclusion are 
available. All available tertiary endpoints will also be analysed in this step. 
Individual listings will only be provided at this stage. 
• 
An integrated study report presenting all analyses will be written and made available 
to the investigators at that time. 
• 
If 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. 
 
10.13.2. 
Statistical considerations for interim analyses 
 
No interim analysis will be performed. 
 
11. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality 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 

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or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 
 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties. 
 
11.2. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst others, the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
 
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form. 
 
For eCRF, the monitor freezes completed and approved screens at each visit. 
 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures. 

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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. 
 
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 primary completion date (PCD) and to 

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have secondary endpoint disclosed at latest 12 months after the Last Subject Last Visit 
(LSLV) as described in the protocol. 
 
As per EU regulation, summaries of the results of GSK interventional studies (phase I- 
IV) in adult population conducted in at least one EU member state will be posted on 
publicly available EMA registers within 12 months of EoS (as defined in the protocol) in 
the concerned EU member state. However, where, for scientific reasons detailed in the 
protocol, it is not possible to submit a summary of the results within one year in the 
concerned EU member state, the summary of results shall be submitted as soon as it is 
available. 
 
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. 

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12. 
COUNTRY SPECIFIC REQUIREMENTS 
 
12.1. 
Requirements for Germany 
Explanatory statement concerning Gender Distribution (Article 7, paragraph 2 (12) 
of the German GCP ORDER) 
 
GSK Biologicals’ investigational RSV vaccine (GSK3003891A) is being developed for 
prevention of severe RSV disease in infants by transfer of maternal antibodies following 
active single dose immunisation of pregnant women between 28 and 34 weeks of 
gestation. Therefore, only women will be recruited in the study RSV F-021. 
 
12.2. 
Requirements for France 
This section includes all the requirements of the French law (n 2004-806 of 9th August 
2004), and identifies, item per item, the mandatory modifications or additional 
information to the study protocol and includes specifics GSK requirements. 
 
1. Concerning the «STUDY POPULATION» 
• 
In line with the local regulatory requirements, the following text about «PAYMENT 
TO SUBJECTS» is added: 
Subjects will be paid for the inconvenience of participating in the study. The amount 
of payment is stated in the informed consent form. Subjects not completing the study 
for whatever reason could be paid at the discretion of the Investigator, generally on a 
pro rata basis. 
• 
In line with the local regulatory requirements, the following text about «NATIONAL 
FILE» is added: 
All subjects who will be paid, will be recorded into the “National File” by the 
investigator. They could be identified and monitored under the «Fichier national». 
The following details will be described: 
 
Reference of the study 
 
Surname and first name 
 
Date and place of birth 
 
Sex 
 
Dates of beginning and termination of the study 
 
Exclusion period 
 
The total amount of allowance. 

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• 
In line with the local regulatory requirements, the following text in section «OTHER 
STUDY ELIGIBILITY CRITERIA CONSIDERATIONS» is added: 
A subject will be eligible for inclusion in this study if he/she is either affiliated to or 
beneficiary of a social security category. 
It is the investigator’s responsibility to ensure and to document (in source document - 
patient notes) that the patient is either affiliated to or beneficiary of a social security 
category. 
 
2. Concerning the “DATA ANALYSIS AND STATISTICAL 
CONSIDERATIONS” and specially in the “SAMPLE SIZE ASSUMPTION” 
The expected number of patients to be recruited in France is declared to the French 
regulatory authority. 
 
3. Concerning the “STUDY CONDUCT CONSIDERATIONS” 
• 
In section “REGULATORY AND ETHICAL CONSIDERATIONS, INCLUDING 
THE INFORMED CONSENT PROCESS” 
 
Concerning the process for informing the patient or his/her legally authorized 
representative, the following text is added: 
French Patient Informed Consent form is a document which summarizes the 
main features of the study and allows collection of the patient's written consent 
in triplicate. It also contains a reference to the authorisation of ANSM and the 
approval from the French Ethic committee and the maintenance of 
confidentiality of the returned consent form by GSK France. 
 
Concerning the management of the Patient Informed Consent forms, the 
following text is added: 
The first copy of the Patient Informed Consent form is kept by the investigator. 
The second copy is kept by the Medical Direction of GSK France and the last 
copy is given to the patient or his/her legally authorized representative. 
The second copy of all the consent forms will be collected by the investigator 
under the Clinical Research Assistant’s (CRAs) control, and placed in a sealed 
envelope bearing only: 
 
the study number, 
 
the identification of the Centre: name of the principal investigator and 
centre number, 
 
the number of informed consents, 
 
the date, 
 
and the principal investigator’s signature. 
Then, the CRA hands the sealed envelope over to the Medical Direction, for 
confidential recording, under the responsibility of the Medical Director. 

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• 
In section concerning the “NOTIFICATION TO THE HOSPITAL DIRECTOR” the 
following text is added: 
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 
Hospital Director is supplied with the protocol and any information needed for the 
financial disposition, the name of the investigator(s), the number of sites involved in 
his establishment and the estimated time schedule of the trial (R.1123-63). 
• 
In section concerning the “INFORMATION TO THE HOSPITAL PHARMACIST” 
the following text is added: 
In accordance with Article R.1123-64 of the Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning 
the product(s) of the trial (e.g. included in the CIB), the name of the investigator(s), 
the number of sites involved in his establishment and the estimated time schedule of 
the trial. 
• 
In section “DATA MANAGEMENT” the following text is added: 
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, involved in 
this clinical trial, and data regarding the patients recruited in this clinical trial (patient 
number, treatment number, patient status with respect to the clinical trial, dates of 
visit, medical data) will be collected and computerized in GSK data bases by GSK 
Laboratory or on its behalf, for reasons of follow up, clinical trial management and 
using the results of said clinical trial. According to the Act n° 78-17 of 6th January 
1978 further modified, each of these people aforesaid has a right of access, 
correction and opposition on their own data through GSK Laboratory (Clinical 
Operations Department). 
• 
In the section concerning “DEMOGRAPHIC DATA”, the following text is added: 
In accordance with the data processing and freedom French law dated on 6th of 
January 1978 modified on the 6th of August 2004 - article 8, the ethnic origin can 
only be collected if the collection of this data is justified within the framework of this 
study. 
• 
In the section concerning “TESTING OF BIOLOGICAL SAMPLES” the following 
text is added: 
In accordance with the Article L1211-2 of the French Public Health Code, a 
biological sample without identified purpose at the time of the sample and subject’s 
preliminary information is not authorized. 

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PD 
4. Concerning the «SAE» 
• 
In section “TRANSMISSION OF THE SAE REPORTS”: 
In case of paper CRF, the SAE Reports have to be transmitted to the GSK France 
Drug Safety Department, which name, address and phone number are: 
Département de Pharmacovigilance 
Laboratoire GlaxoSmithKline 
100 Route de Versailles 
78163 MARLY LE ROI 
Tel: P 
Fax: 
5. Monitoring visits 
The Health Institution and the Investigator agree to receive on a regular basis a 
Clinical Research Assistant (CRA) of GSK or of a service provider designated by 
GSK. The Health Institution and the Investigator agree to be available for any phone 
call and to systematically answer to all correspondence regarding the Study from 
GSK or from a service provider designated by GSK. In addition, the Health 
Institution and the Investigator agree that the CRA or the service provider designated 
by GSK have direct access to all the data concerning the Study (test results, medical 
record, etc. …). This consultation of the information by GSK is required to validate 
the data registered in the electronic Case Report Form (eCRF), in particular by 
comparing them directly to the source data. In accordance with the legal and 
regulatory requirements, the strictest confidentiality will be respected. 
6. Data entry into the eCRF 
The Health Institution and the Investigator agree to meet deadlines, terms and 
conditions of the Study’s eCRF use here below: 
The Health Institution and the Investigator undertake: 
i. 
That the Investigator and the staff of the investigator center make themselves 
available to attend the training concerning the computer system dedicated to the 
eCRF of the Study provided by GSK or by a company designated by GSK. 
ii. 
That the Investigator and the staff of the investigator center use the IT 
Equipment loaned and/or the access codes only for the purpose of which they 
are intended and for which they have been entrusted to them, namely for the 
Study achievement, to the exclusion of any other use. 
iii. That the Investigator and the staff of the investigator center use the IT 
Equipment loaned according to the specifications and manufacturer’s 
recommendations which will have been provided by GSK. 
iv. To keep the IT Equipment and/or access codes in a safe and secure place and to 
only authorize the use of this IT Equipment by investigator center staff 
designated by the principal investigator to enter the data of the Study. 
PPD 
PPD 

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v. 
That the Investigator and the staff of the investigator center enter the data of the 
eCRF related to a patient visit in the 3 days following the date of the patient visit 
or, for the patient test results, in the 3 days following the reception of the results 
of such tests. 
vi. That the Investigator resolves and returns to GSK the data queries issued by 
GSK or a service provider designated by GSK within 7 days after the reception 
of the request of clarification or in a period of one (1) day during the final stage 
of clarification of the data base or in such other period as provided by GSK 
and/or a company designated by GSK. 
vii. To be responsible for the installation and payment of the required Internet 
connections needed for the use of the IT Equipment, Computer systems and/or 
access codes. 
viii. To return at the end of the Study the IT Equipment and/or access codes to GSK 
or to any company designated by GSK and any training material and 
documentation. The IT Equipment cannot under any circumstances be kept by 
the Health Institution or the Investigator for any reason whatsoever. 
7. CTR publication 
It is expressly specified that GSK and/or the Sponsor can make available to the 
public the results of the Study by the posting of the said results on a website of the 
GSK GROUP named Clinical Trial Register (CTR) including the registration of all 
the clinical trials conduct by the GSK Group and this before or after the publication 
of such results by any other process. 
8. Data Protection French Law of 6 January 1978 (CNIL) 
In accordance with the Data Protection French Law of 6 January 1978 as modified, 
computer files used by GSK to monitor and follow the implementation and the 
progress of the Study are declared with the CNIL by GSK. The Investigator has 
regarding the processing data related to him a right of access, of rectification and of 
opposition with GSK in accordance with the legal provisions. This information can 
be transferred or be accessed to other entities of GSK Group in France, Britain or 
United States, what the Investigator agrees by the signature of the present Protocol. 

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13. 
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parainfluenza viruses among young children. Pediatrics. 2004; 113: 1758-64. 
 
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Kollmann TR. Variation between Populations in the Innate Immune Response to Vaccine 
Adjuvants. Front Immunol. 2013; 4: 81. 
 
Krilov LR. Respiratory syncytial virus disease: update on treatment and prevention. 
Expert Rev. Anti. Infect. Ther. 2011; 9(1), 27-32. 
 
Lee DH, Zhou LJ, Zhou Z et al. Neogenin inhibits HJV secretion and regulates BMP- 
induced hepcidin expression and iron homeostasis. Blood. 2010; 115: 3136-45. 
 
Madhi SA, Kuwanda L, Cutland C, et al. Five-year cohort study of hospitalization for 
respiratory syncytial virus associated lower respiratory tract infection in African children. 
J Clin Virol. 2006; 36: 215-21. 
 
Magro M, Mas V, Chappell K et al. Neutralizing antibodies against the preactive form of 
respiratory syncytial virus fusion protein offer unique possibilities for clinical 
intervention. Proc Natl Acad Sci U S A. 2012; 109: 3089-94. 
 
Meyerhardt JA, Look AT, Bigner SH et al. Identification and characterization of 
neogenin, a DCC-related gene. Oncogene. 1997; 14: 1129-36. 
 
Nair H, Nokes JD, Gessner BD, et al. Global burden of acute lower respiratory infections 
due to respiratory syncytial virus in young children: a systematic review and meta- 
analysis. Lancet. 2010; 375:1545-55. 
 
Ngwuta JO, Chen M, Modjarrad K et al. Prefusion F-specific antibodies determine the 
magnitude of RSV neutralizing activity in human sera. Sci Transl Med. 2015; 
7(309):309ra162. 
 
Novavax, press release http://ir.novavax.com/phoenix.zhtml?c=71178&p=irol- 
newsArticle&ID=2091286, 25 September 2015 accessed: 04 February 2016. 
 
Paramore LC, Ciuryla V, Ciesla G et al. Economic impact of respiratory syncytial virus- 
related illness in the US: an analysis of national databases. Pharmacoeconomics. 2004; 
22: 275-84. 
 
Pérez-Losada M, Posada D, Arenas M, et al. Ethnic differences in the adaptation rate of 
HIV gp120 from a vaccine trial. Retrovirology. 2009; 6: 67. 
 
Polack FP, Teng MN, Collins PL, et al. A role for immune complexes in enhanced 
respiratory syncytial virus disease. J Exp Med. 2002; 196: 859-865. 
 
Roca A., F. Abacassamo, M.P. Loscertales, et al. Prevalence of respiratory syncytial 
virus IgG antibodies in infants living in a rural area of Mozambique. J Med Virol. 2002; 
67, pp. 616-623. 
 
Simoes EAF. Respiratory syncytial virus infection. Lancet. 1999; 354: 847-52. 
 
Ventre K and Randolph A. Ribavirin for respiratory syncytial virus infection of the lower 
respiratory tract in infants and young children. Cochrane Database Syst Rev. 2007 Jan 
24; (1): CD000181. 

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Vicente D, Montes M, Cilla G et al. Hospitalization for respiratory syncytial virus in the 
paediatric population in Spain. Epidemiol. Infect. 2003; 131: 867-72. 
 
Wang X, Hunter AK and Mozier NM. Host cell proteins in biologics development: 
Identification, quantitation and risk assessment. Biotechnol Bioeng. 2009; 103: 446-58. 
 
Zent O, Arras-Reiter C, Broeker M et al. Immediate allergic reactions after vaccinations-- 
a post-marketing surveillance review. Eur J Pediatr. 2002; 161: 21-5. 

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APPENDIX A 
LIST OF POTENTIAL IMMUNE-MEDIATED 
DISEASES 
Please note that this list should be used as a guidance to identify diseases that could be 
autoimmune in nature. However, not all reported diseases in appendix will be 
autoimmune in nature and therefore represent an exclusion criterion. This will be based 
on the opinion of the investigator and/or specific available diagnostic data. 
 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, including 
paralyses/paresis (e.g. Bell’s palsy) 
• 
Optic neuritis 
• 
Multiple sclerosis 
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants 
• 
Acute disseminated 
encephalomyelitis, including site 
specific variants: e.g. non-infectious 
encephalitis, encephalomyelitis, 
myelitis, myeloradiculoneuritis 
• 
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome 
• 
Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with 
monoclonal gammopathy). 
• 
Narcolepsy 
• 
Systemic lupus erythematosus 
and associated conditions 
• 
Systemic scleroderma (Systemic 
sclerosis), including diffuse 
systemic form and CREST 
syndrome 
• 
Idiopathic inflammatory 
myopathies, including 
dermatomyositis 
• 
Polymyositis 
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis, and 
associated conditions including 
juvenile chronic arthritis and 
Still’s disease 
• 
Polymyalgia rheumatica 
• 
Spondyloarthritis, including 
ankylosing spondylitis, reactive 
arthritis (Reiter's Syndrome) and 
undifferentiated 
spondyloarthritis 
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Mixed connective tissue disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis) 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Localised Scleroderma 
(Morphoea) 

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Vasculitides 
Blood disorders 
Others 
• 
Large vessels vasculitis including: 
giant cell arteritis such as 
Takayasu's arteritis and temporal 
arteritis. 
• 
Medium sized and/or small vessels 
vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, 
microscopic polyangiitis, Wegener's 
granulomatosis, Churg–Strauss 
syndrome (allergic granulomatous 
angiitis), Buerger’s disease 
(thromboangiitis obliterans), 
necrotizing vasculitis and anti- 
neutrophil cytoplasmic antibody 
(ANCA) positive vasculitis (type 
unspecified), Henoch-Schonlein 
purpura, Behcet's syndrome, 
leukocytoclastic vasculitis. 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune thrombocytopenia 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune aplastic anaemia 
• 
Autoimmune neutropenia 
• 
Autoimmune pancytopenia 
• 
Autoimmune 
glomerulonephritis 
(including IgA 
nephropathy, 
glomerulonephritis 
rapidly progressive, 
membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis) 
• 
Ocular autoimmune 
diseases (including 
autoimmune uveitis and 
autoimmune 
retinopathy) 
• 
Autoimmune 
myocarditis/cardiomyop 
athySarcoidosis 
• 
Stevens-Johnson 
syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary 
fibrosis 
• 
Goodpasture syndrome 
• 
Raynaud’s phenomenon 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
• 
Autoimmune cholangitis 
• 
Inflammatory Bowel disease, 
including Crohn’s disease, 
ulcerative colitis, microscopic 
colitis, ulcerative proctitis 
• 
Celiac disease 
• 
Autoimmune pancreatitis 
• 
Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis) 
• 
Grave's or Basedow’s 
disease 
• 
Diabetes mellitus type I 
• 
Addison’s disease 
• 
Polyglandular 
autoimmune syndrome 
• 
Autoimmune 
hypophysitis 

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APPENDIX B 
DETAILED DESCRIPTION OF THE ASSAYS 
PERFORMED IN THE STUDY 
Neutralisation assay 
 
The serum neutralisation assay is a functional assay that measures the ability of serum 
antibodies to neutralise the cytopathic effects of RSV (for example, strains A and B) on 
the host cell line, hence RSV replication. 
 
First, virus neutralization is performed by incubating a fixed amount of RSV-A long 
strain (ATCC No. VR-26) with serial dilutions of the test serum. Then, the serum-virus 
mixture is transferred onto a monolayer of Vero cells (African Green Monkey, kidney, 
Cercopitheus aethiops, ATCC CCL-81) and incubated for three days to allow infection of 
Vero cells by non-neutralized viruses and the formation of plaques in the cell monolayer. 
Following the fixation period, RSV-infected cells are detected using a primary antibody 
directed against RSV (anti-RSV IgG) and a secondary antibody conjugated with 
fluorescein isothiocyanate (FITC), allowing the visualization of plaques by 
immunofluorescence. Viral plaques are counted using an automated microscope coupled 
to an image analyzer (Scanlab system with Axiovision software). For each serum 
dilution, a ratio, expressed as a percentage, is calculated between the number of plaques 
at that dilution and the number of plaques in the virus control wells (no serum added). 
The serum neutralizing antibody titer is expressed in ED60 (Estimated Dilution 60) and 
corresponds to the inverse of the interpolated serum dilution that yields a 60% reduction 
in the number of plaques compared to the virus control wells. 
 
Anti-NEO ELISA 
 
The anti-NEO ELISA assay is based on a direct ELISA format. This ELISA assay allows 
the quantification of NEO-specific IgG antibodies in human serum samples. 
 
In summary, full-length recombinant human NEO is adsorbed onto a 96-well polystyrene 
microplate. After washing and blocking steps and dilutions of serum samples, controls 
and standards are added to the coated microplate. The standard curve is prepared with 
known concentrations of affinity purified rabbit anti-NEO polyclonal antibodies. After 
incubation, the microplate is washed to remove unbound primary antibodies. Bound 
primary antibodies are detected by the addition of a purified monoclonal mouse 
anti-human IgG antibody, conjugated to horse-radish peroxidase (HRP). This conjugated 
antibody cross-reacts with rabbit IgG (e.g. anti-NEO antibodies from rabbit used as 
positive control and standards) and detects human and rabbit IgG with a comparable 
sensitivity. Unbound HRP is removed by washing. Bound antibodies are quantified by 
the addition of the HRP substrate, tetramethylbenzidine (TMB), whereby a coloured 
product develops proportionally to the amount of anti-NEO antibodies present in the 
serum sample. The optical density (OD) of each sample dilution is then interpolated on a 
standard curve established with a non-weighted, 4-parameter logistic regression fitting 
algorithm and the corresponding antibody concentration, corrected for the dilution factor, 
is expressed in ng/mL. 

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PCA 
 
The Palivizumab Competitive Assay is based on the competitive binding process between 
labelled antibody (Palivizumab-biotin) versus non-labelled antibody (Palivizumab-like 
antibodies in serum) targeting the same epitope on a coated antigen. 
 
First, F protein antigens purified from CHO expression system are coated onto 96-well 
microplates. Then, after a washing and a blocking step, serial two-fold dilutions of test 
sera, positive control serum, and Palivizumab antibody reference standard are added in 
sequence with competitor antibodies (HRP-conjugated Palivizumab) and incubated to 
allow specific binding of antibodies directed against the F protein antigens. If 
Palivizumab-like antibodies are present in serum samples, they will compete with the 
HRP-conjugated Palivizumab antibodies for binding to the F protein coated antigen. 
After a washing step, the HRP substrate solution (TMB/H2O2) is added and a coloured 
product develops in a manner that is inversely proportional to the amount of 
Palivizumab-like antibodies contained in the test serum. The colour is quantified by 
reading the optical densities at 450-620 nm using a spectrophotometer. Antibody 
concentrations of individual serum and control samples are determined after interpolation 
from the ELISA standard curve using a four-parameter equation and are expressed as 
Palivizumab-equivalent antibodies in microgram per millilitre (µg/mL). 
 
PCR (Amended 31 July 2017) 
 
Quantitative PCR able to discriminate RSV-A and RSV-B subtypes 
 
Briefly, RSV A and RSV B RNA extraction from the nasal/throat swabs are detected in 
a duplex PCR format using specific amplification primers and fluorescent probes 
designed in the RSV N gene, encoding the RSV nucleocapsid protein. The process 
involves nucleic acids extractions, conversion of RNA to complementary 
deoxyribonucleic acid by reverse transcription and detection by real-time PCR reaction 
using a calibration curve (absolute quantiation). The RSV viral load is reported as 
copies of RSV RNA per mL of sample. 
 
Qualitative multiplex PCR for detection of a panel of viruses: 
 
A qualitative PCR multiplex assay is used for the detection and identification of 
multiple respiratory virus nucleic acid in nasal/throat swab from subjects with an 
assessment visit for MA-RTI. The following virus types and subtypes can be indentified 
in the assay 
 
 
Influenza A virus (Flu A) 
 
Influenza B virus (Flu B) 
 
Human respiratory syncytial virus A (RSV A) 
 
Human respiratory syncytial virus B (RSV B) 
 
Human Influenza A virus subtype H1 (Flu-A-H1) 
 
Human Influenza A virus subtype H3 (Flu-A-H3) 

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 
Human Influenza A virus subtype H1pdm09 (Flu A-H1pdm09) 
 
Human adenovirus (AdV) 
 
Human metapneumovirus (MPV) 
 
Human entrovirus (HEV) 
 
Human parainfluenza virus 1 (PIV1) 
 
Human parainfluenza virus 2 (PIV2) 
 
Human parainfluenza virus 3 (PIV3) 
 
Human parainfluenza virus 4 (PIV4) 
 
Human bocavirus 1/2/3/4 (HBoV) 
 
Human rhinovirus A/B/C (HRV) 
 
Human coronavirus 229E (229E) 
 
Human coronavirus NL63 (NL63) 
 
Human coronavirus OC43 (OC43) 
Following total nucleic acids extraction, viruses are detected by multiplex real-time 
RT-PCR assays targeting the avove mentioned viruses. A comparative analysis of the 
fluorescence intensities of each target is preformed to detect the viruses present in the 
sample. 

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APPENDIX C 
CLINICAL LABORATORIES 
Table 21 
GSK Biologicals’ laboratories 
 
Laboratory 
Address 
GSK Biologicals Clinical Laboratory 
Sciences, Rixensart 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
GSK Biologicals Clinical Laboratory 
Sciences, Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
 
Table 22 
Outsourced laboratories 
 
Laboratory 
Address 
NÉOMED-LABS Inc. 
525, Cartier Ouest Laval, Québec 
Canada H7V 3S8 
Q2 Solutions Clinical Trials 
The Alba Campus (Rosebank) 
Livingston 
West Lothian, EH54 7EG 
Scotland, UK 

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APPENDIX D 
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. 
• 
INTRODUCTION 
Preventive vaccines are usually developed to prevent disease in a healthy population. The 
Office of Vaccines Research and Review, Center 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 enrollment 
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). 
 
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. 

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• 
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 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 adverse events 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. 
 
• 
TOXICITY GRADING SCALE TABLES 
Adverse events 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 adverse events 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. 
 
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 adverse events, or previous experience with a similar licensed 
product. 

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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. 
 
• 
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. 
 
• 
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 23 
FDA toxicity grading scales for hematology/biochemistry 
parameters 
 
Serum* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
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 
Hematology*** 
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 
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 
Hypereosinophilic 
Platelets Decreased - cell/mm3 
125 000 – 
140 000 
100 000 – 
124 000 
25 000 – 99 000 
< 25 000 
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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*** 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. 
 
• REFERENCES for the Appendix D 
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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⎧ 
- 
1
⎪
APPENDIX E 
DESIRABILITY APPROACH 
• 
DERIVED ENDPOINTS 
The following endpoints will be computed and taken into account in the desirability 
analysis: 
1. 
Incidence rate of any Grade 2 and any Grade 3 general AE (solicited and unsolicited) 
and any vaccine-related SAE during the 7-day follow-up period after vaccination for 
each investigational RSV vaccine formulation. 
2. 
Incidence rate of Grade 2 and Grade 3 fever during the 7-day follow-up period after 
vaccination for each investigational RSV vaccine formulation. 
3. 
Geometric mean of neutralising antibody titres against RSV-A at Day 30 adjusted for 
pre-vaccination titres. 
4. 
Geometric mean of PCA concentrations at Day 30 adjusted for pre-vaccination titres. 
 
• 
STATISTICAL COMPUTATION 
Reactogenicity 
A logistic regression model will be fitted on each reactogenicity endpoint (any Grade 2/3 
general AE and any related SAE, Grade 2/3 fever) reported during the 7-day follow-up 
period after vaccination, including all RSV formulations. 
For any Grade 2/3 general AEs and any related SAEs, the incidence rate estimate (I-R) 
will be transformed in a [0,1] desirability index using the following function: 
  
1 
 , 
if I-R ≤ 0.25 
⎪1 + exp (−50 ∗ (0.25 − IR)) 
DR1 = ⎨ 
- 
 
, 
ifIR ≥ 0.25 
⎩  1 + exp (−25 ∗ (0.25 − I-R)) 
 
where I-R is the incidence rate estimated by the model. This function will allocate a 
desirability value of 1, 0.5 and 0 to incidence rate equal to 0.1, 0.25 and 0.5 respectively 
(see Figure 3). 

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Figure 3 
Desirability function for the incidence rate of Grade 2/3 general AEs 
and related SAEs - for each investigational RSV vaccine formulation 
 
For Grade 2/3 fever, the incidence rate estimate (I-R) will be transformed in a [0,1] 
desirability index using the following function: 
DR2 = 
1 
1 + exp(−120 ∗ (0.05 − I-R)) 
where I-R is the incidence rate estimated by the model. As illustrated in Figure 4, the 
function will allocate desirability values of 1, 0.5 and 0 to incidence rate equal to 0, 0.05 
and 0.1 respectively. 

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Figure 4 
Desirability function for the incidence rate of Grade 2/3 fever - for 
each investigational RSV vaccine formulation 
 
 
Finally, the reactogenicity index will be computed by taking the geometric mean of the 2 
indexes: 
 
DR  = √DR1 ∗ DR2 
 
Immunogenicity 
 
A response-surface model will be fitted on the log-transformed titre for each immune 
response (neutralising anti-RSV-A and PCA), including all RSV formulations. 
 
As formulations inducing a high immune response will be considered suitable, the lower 
limit (LL) of the estimated GMT/C adjusted for pre-vaccination titres will be the 
statistical criterion considered for decision making. 
 
Neutralising anti-RSV-A titres 
 
The LL of the GMT estimate will be transformed into a [0,1] desirability index using the 
function: 
 
DI1 = 
1 
1 + exp(1.5 ∗ (9.5 − LL)) 
where LL is the lower limit of the 95% confidence interval of the GMT adjusted for pre- 
vaccination titres in log base 2. The function was chosen to have a desirability of 0 at LL 
value  6 log2 (=128), and a desirability of 1 at LL value  13 log2. This function is 
illustrated in Figure 5. 

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Figure 5 
Desirability function for neutralising anti-RSV-A GMTs - for each 
investigational RSV vaccine formulation 
 
PCA concentrations 
 
The LL of the GMC adjusted for pre-vaccination titres estimate will be transformed using 
the following function: 
 
 
 
DI2 = 
1 
 
 
1 + exp(0.05 ∗ (150 − LL)) 
1 
 
, 
if LL ≤ 150 
 
, 
if LL ≥ 150 
⎩ 1 + exp(0.025 ∗ (150 − LL)) 
 
As illustrated in Figure 6, a PCA response of 25, 150 and 400 µg/mL will have a 
desirability value of 0, 0.5 and 1 respectively. 

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Figure 6 
Desirability function for PCA concentrations - for each 
investigational RSV vaccine formulation 
 
Finally, the immunogenicity index will be computed by taking the geometric mean of the 
2 indexes: 
 
 
DI  = √DI1 ∗ DI2 
 
Overall desirability index 
 
The overall desirability index will be obtained by computing the following weighted 
geometric mean: D = DR0.4 * DI0.6 
Finally, to address the robustness of the ranking, an evaluation of the uncertainty will be 
performed using a bootstrap approach. 
 
• 
SAMPLE SIZE EVALUATION THROUGH SIMULATION 
Two scenarios were envisaged with regards to immune response induced by the three 
RSV formulations (Table 24). 

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Table 24 
Immunogenicity scenarios used for the desirability index 
simulations 
 
Endpoint included in 
the desirability index 
Formulation 
Scenario 1 
Scenario 2 
RSV-A 
30 PreF 
10 log2 
10 log2 
60 PreF 
11 log2 
10.5 log2 
120 PreF 
12 log2 
11 log2 
PCA 
30 PreF 
100 
100 
60 PreF 
150 
125 
120 PreF 
200 
150 
 
Scenario 1 is assuming a higher increase of the immune response with the increased dose 
compared to scenario 2. 
 
Two scenarios were also envisaged with regards to adverse event reactions induced by 
the three RSV formulations (Table 25). 
 
Table 25 
Reactogenicity scenarios used for the desirability index simulations 
 
Endpoint included in 
the desirability index 
Formulation 
Scenario 1 
Scenario 2 
Grade 2/3 
general AEs 
30 PreF 
25% 
25% 
60 PreF 
27.5% 
35% 
120 PreF 
30% 
50% 
Grade 2/3 
fever 
30 PreF 
2% 
4% 
60 PreF 
3% 
6% 
120 PreF 
4% 
10% 
 
Scenario 2 is assuming a higher increase of the incidence of AEs with the increased dose 
compared to scenario 1. 
 
These 4 combinations of scenarios were simulated 10000 times with a sample size of 95 
evaluable subjects per group. The percentages for ranking each formulation at first place 
and for selecting the best one were computed and are described in the table below. 
 
Table 26 
Result of the ranking of the formulations following simulations of 
the different scenarios with a sample size of 95 subjects per group 
 
Immuno 
scenario 
Ranking #1 for immuno 
Reacto 
scenario 
Ranking#1 for reacto 
Ranking #1 overall 
1 
120 PreF in 85.2% of 
simulations 
1 
30 PreF or 60 PreF in 
90.2% of simulations 
60 PreF or 120 PreF in 96.9% 
of simulations 
2 
30 PreF in 91.2% of 
simulations 
30 PreF or 60 PreF in 95.2% of 
simulations (4.8% for 120 PreF) 
2 
60 PreF or 120 PreF in 
94% of simulations 
1 
30 PreF or 60 PreF in 
90.2% of simulations 
60 PreF or 120 PreF in 82.4% 
of simulations 
2 
30 PreF in 91.6% of 
simulations 
30 PreF or 60 PreF in 98.7% of 
simulations (1.3% for 120 PreF) 

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PPD 
PPD 
PPD 
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PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
APPENDIX F 
AMENDMENTS TO THE PROTOCOL 
 
GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 1 
eTrack study number 
and Abbreviated Title 
204812 (RSV F-021) 
IND number 
15487 
EudraCT number 
2016-001135-12 
Amendment number: 
Amendment 1 
Amendment date: 
21 August 2017 
Co-ordinating author: 
PPD 
(XPE Pharma & Science for GSK 
Biologicals) 
PPD 
, Senior Science Writer 
Rationale/background for changes: 
The following minor changes have been made: 
• 
The kit used for multiplex respiratory viral panel testing has been changed. 
• 
Changes to the study personnel have been included on the protocol cover page. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
 
Throughout the document, the following changes have been made: 
On the protocol cover page, the following changes have been made: 
Co-ordinating author(s) 
(Amended 31 July 2017) 
• 
(XPE Pharma & Science for GSK 
Biologicals) 
• 
, Senior Science Writer 
Contributing authors 
• 
and PPD 
& Epidemiology Project Lead 
, Clinical 
(Amended 31 July 2017) 
• 
PPD 
, PPD 
, and PPD 
, Clinical Research & Development Leads 
• 
, Lead Statistician 
• 
, Project Statistician 
• 
, 
, and 
, Study Delivery 
Leads 
• 
(Aixial for GSK Biologicals) 

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PPD 
 
 
 
 
 
(CVO-Europe for GSK 
Biologicals), Vaccine Supply Coordinator 
• 
, Clinical Read-Out Team Leader 
Copyright© 2016-2017 the GlaxoSmithKline GSK group of companies or its licensor. All rights 
reserved. Unauthorized copying or use of this information is prohibited. 
 
 
In Section Trademarks, the following changes have been made: 
 
 
 
In Section 5.7.3 Laboratory assays, the following changes have been made. 
 
The following laboratory assay is planned: 
Table 9 
Molecular biology (PCR tests) 
 
System 
Component 
Method 
Unit 
Laboratory 
Nasal swab* 
RSV 
Influenza A, including subtypes H1 and H3 
Influenza A H1N1 2009 
Influenza                     B 
Parainfluenza virus type 1, 2, 3, and 4 
Human Metapneumovirus 
Enterovirus/Rhinovirus 
Adenovirus 
Bocavirus 
Coronavirus - 229E, OC43, NL63, HKU1 
Influenza A virus (Flu A) 
Influenza B virus (Flu B) 
Human respiratory syncytial virus A 
(RSV A) 
Human respiratory syncytial virus B 
(RSV B) 
Human influenza A virus subtype H1 
(Flu A- H1) 
Human influenza A virus subtype H3 
(Flu A-H3) 
Human influenza A virus subtype 
H1pdm09 (Flu A-H1pdm09) 
Human adenovirus (AdV) 
Human metapneumovirus (MPV) 
Human enterovirus (HEV) 
Human parainfluenza virus 1 (PIV1) 
Multiplex PCR 
(PCRMTX) 
(Luminex)** 
(Allplex 
Respiratory 
Panel or 
equivalent)** 
Qualitative assay 
(positive/negative) 
GSK 
Biologicals*** 
or designated 
laboratory 
Trademarks not owned by the 
GlaxoSmithKline GSK group of 
companies 
SynagisTM (MedImmune LLC.) 
Allplex (Seegene) 
Generic description 
Recombinant humanized monoclonal anti- 
RSV antibody 
Respiratory panel assay 

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Human parainfluenza virus 2 (PIV2) 
Human parainfluenza virus 3 (PIV3) 
Human parainfluenza virus 4 (PIV4) 
Human bocavirus 1/2/3/4 (HBoV) 
Human rhinovirus A/B/C (HRV) 
Human coronavirus 229E (229E) 
Human coronavirus NL63 (NL63) 
Human coronavirus OC43 (OC43) 
Nasal swab* 
RSV-A/B RNA 
Quantitative 
Reverse 
Copies/ml 
GSK 
Biologicals*** 
Transcription 
real-time PCR 
(QRTPCR) 
**** 
**Respiratory Viruses Panel (Multiplex PCR) will be performed on all specimens. Refer to APPENDIX B 
for the 
laboratory addresses. 
****Additional testing with RSV-A/B RNA quantitative real-time reverse transcription PCR may be performed. 
 
 
Table 12 
Molecular biology tests 
 
Nasal swab sampling timepoint 
Group 
No. Subjects 
Component 
Type of contact 
(timepoint) 
Sampling 
timepoint 
Unscheduled visit 
for MA-RTI* 
Unscheduled 
All subjects 
All subjects with a 
nasal swab sample* 
Influenza A virus (Flu A) 
Influenza B virus (Flu B) 
Human respiratory syncytial virus A 
(RSV A) 
Human respiratory syncytial virus B 
(RSV B) 
Human influenza A virus subtype H1 
(Flu A- H1) 
Human influenza A virus subtype H3 
(Flu A-H3) 
Human influenza A virus subtype 
H1pdm09 (Flu A-H1pdm09) 
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 1/2/3/4 (HBoV) 
Human rhinovirus A/B/C (HRV) 
Human coronavirus 229E (229E) 
Human coronavirus NL63 (NL63) 
Human coronavirus OC43 (OC43) 
RSV 
Influenza A, including subtypes H1 and 
H3 
Influenza A H1N1 2009 
Influenza B 
Parainfluenza virus type 1, 2, 3, and 4 
Human Metapneumovirus 

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Enterovirus/Rhinovirus 
Adenovirus 
Bocavirus 
Coronavirus - 229E, OC43, NL63, 
HKU1 
RSV-A/B RNA** 
**Additional testing with RSV-A/B RNA quantitative reverse transcription real-time PCR may be performed. 
 
In Appendix B Detailed Description of the Assays Performed in the Study, the 
following changes have been made: 
 
PCR 
 
Quantitative PCR able to discriminate RSV-A and RSV-B subtypes 
 
Briefly, RSV A and RSV B RNA extraction from the nasal/throat swabs are detected in 
a duplex PCR format using specific amplification primers and fluorescent probes 
designed in the RSV N gene, encoding the RSV nucleocapsid protein. The process 
involves nucleic acids extractions, conversion of RNA to complementary 
deoxyribonucleic acid by reverse transcription and detection by real-time PCR reaction 
using a calibration curve (absolute quantiation). The RSV viral load is reported as 
copies of RSV RNA per mL of sample. 
 
Qualitative multiplex PCR for detection of a panel of viruses: 
 
A qualitative PCR multiplex assay is used for the detection and identification of 
multiple respiratory virus nucleic acid in nasal/throat swab from subjects with an 
assessment visit for MA-RTI. The following virus types and subtypes can be indentified 
in the assay 
 
 
Influenza A virus (Flu A) 
 
Influenza B virus (Flu B) 
 
Human respiratory syncytial virus A (RSV A) 
 
Human respiratory syncytial virus B (RSV B) 
 
Human Influenza A virus subtype H1 (Flu-A-H1) 
 
Human Influenza A virus subtype H3 (Flu-A-H3) 
 
Human Influenza A virus subtype H1pdm09 (Flu A-H1pdm09) 
 
Human adenovirus (AdV) 
 
Human metapneumovirus (MPV) 
 
Human entrovirus (HEV) 
 
Human parainfluenza virus 1 (PIV1) 
 
Human parainfluenza virus 2 (PIV2) 

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 
Human parainfluenza virus 3 (PIV3) 
 
Human parainfluenza virus 4 (PIV4) 
 
Human bocavirus 1/2/3/4 (HBoV) 
 
Human rhinovirus A/B/C (HRV) 
 
Human coronavirus 229E (229E) 
 
Human coronavirus NL63 (NL63) 
 
Human coronavirus OC43 (OC43) 
Following total nucleic acids extraction, viruses are detected by multiplex real-time RT- 
PCR assays targeting the avove mentioned viruses. A comparative analysis of the 
fluorescence intensities of each target is preformed to detect the viruses present in the 
sample. 
 
RSV A/B Quantitative PCR 
 
Quantitative PCR able to discriminate RSV-A and RSV-B subtypes: RSV-A and RSV-B 
RNAs, extracted from the nasal swab are detected in a duplex format using specific 
amplification primers and fluorescent TaqMan™ probes. The process involves viral RNA 
extraction, conversion of RNA to complementary deoxyribonucleic acid by reverse 
transcription and detection by real- time PCR reaction using a calibration curve (absolute 
quantification). 
 
Multiplex Viral Qualitative PCR 
 
Qualitative multiplex PCR for detection of a panel of 17 viruses: xTAG™ RVP FAST 
assay: xTAG™ RVP FAST assay is a qualitative nucleic acid multiplex tests intended for 
the simultaneous detection and identification of multiple respiratory virus nucleic acids in 
nasal/nasopharyngeal swabs from individuals suspected of respiratory tract infections. 
After nucleic acid extraction, a multiplexed PCR reaction is performed to amplify the 
regions of interest in the targeted infectious agent genes. The PCR reaction product is 
then subjected to a hybridization/detection step and attached to an xTAG universal tag 
sequence. The 5’ universal tag sequence is hybridized to the complementary anti-tag 
sequence coupled to a particular bead set. The hybridized beads are detected and results 
are analyzed by the data analysis software. 

 
 
 
 
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Protocol Amendment 1 Sponsor Signatory Approval 
eTrack study number and 
204812 (RSV F-021) 
Abbreviated Title 
 
IND number 
15487 
EudraCT number 
2016-001135-12 
 
Date of protocol amendment 
Amendment 1 Final 21 August 2017 
 
Detailed Title 
A Phase II, randomised, observer-blind, controlled, 
multi-country study to rank different formulations of 
OSK Biologicals' investigational RSV vaccine 
(GSK3003891A), based on immunogenicity, 
reactogenicity and safety, when administered to 
healthy women, aged 18 - 45 years. 
 
Sponsor signatory 
Alexander Schmidt 
   Clinical & Epidemiology Project Lead 
 
 
Signature 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
 
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