A Study to Evaluate the Safety, Reactogenicity and Immunogenicity of GSK Biologicals' Investigational Unadjuvanted RSV Maternal Vaccine Compared to Placebo When Administered to Healthy Non-pregnant Women.
Phase: PHASE1
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’institut 89,
1330 Rixensart, Belgium
Primary Study 
vaccine(s)/product(s) and 
number(s)
GlaxoSmithKline (GSK) Biological investigational 
respiratory syncytial virus (RSV) maternal vaccine 
(GSK3888550A)
Other Study 
vaccine(s)/product(s)
Placebo
eTrack study number and 
Abbreviated Title
208068 (RSV MAT-001)
Investigational New Drug 
(IND) number
18434
EudraCT number
2018-001340-62
Date of protocol
Final Version 2: 13 August 2018
Title
A study to evaluate the safety, reactogenicity and 
immunogenicity of GSK Biologicals’ investigational 
unadjuvanted RSV maternal vaccine compared to 
placebo when administered to healthy non-pregnant 
women.
Detailed Title
A Phase 1/2 randomised observer-blind placebo 
controlled study to evaluate the safety, reactogenicity 
and immunogenicity of different dose levels of GSK 
Biologicals’ investigational unadjuvanted RSV 
maternal vaccine (GSK3888550A) compared to 
placebo when administered to healthy non-pregnant 
women aged 18-45 years.
Co-ordinating author(s)
!
, Science Writer
Contributing authors
!
, Study Delivery Lead
!
, Study Delivery Lead
!
, Clinical Research and 
Development Lead (CRDL)
!
, Lead Statistician
!
 Study Statistician
!
, Oversight Data Manager
!
, Clinical Readout Team Lead
!
, Clinical Readout Team Lead

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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eTrack study number and 
Abbreviated Title
208068 (RSV MAT-001)
Investigational New Drug 
(IND) number
18434
EudraCT number
2018-001340-62
Detailed Title
A Phase 1/2 randomised observer-blind placebo 
controlled study to evaluate the safety, reactogenicity 
and immunogenicity of different dose levels of GSK 
Biologicals’ investigational unadjuvanted RSV 
maternal vaccine (GSK3888550A) compared to 
placebo when administered to healthy non-pregnant 
women aged 18-45 years.
Contributing authors 
(Cont…)
!
, Clinical Trial Supply Manager 
!
, Senior Scientist, 
Immunology Platform
!
, Clinical Laboratory Sciences 
(CLS) Study Manager, Business & Decisions Life 
Sciences Contractor for GSK Biologicals
!
, Safety Physician
!
, Safety Scientist
!
, Safety Scientist
!
, Regulatory Affairs 
!
, Clinical & Epidemiology Project 
Lead (CEPL)
GSK Biologicals’ Protocol DS v 15.0
2018 GlaxoSmithKline group of companies or its licensor.

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PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Protocol Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
208068 (RSV MAT-001)
IND number
18434
EudraCT number
2018-001340-62
Date of protocol
Final Version 2: 13 August 2018
Detailed Title 
A Phase 1/2 randomised observer-blind placebo 
controlled study to evaluate the safety, reactogenicity
and immunogenicity of different dose levels of GSK 
Biologicals’ investigational unadjuvanted RSV 
maternal vaccine (GSK3888550A) compared to 
placebo when administered to healthy non-pregnant 
women aged 18-45 years.
Sponsor signatory
Ouzama Henry, Clinical and Epidemiological Project 
Lead (CEPL), US RDC
Signature
Date
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Protocol Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ study vaccine(s)/product(s) 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(s)/product(s), 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
208068 RSV MAT-001)
IND number
18434
EudraCT number
2018-001340-62
Date of protocol
Final Version 2: 13 August 2018
Detailed Title
A Phase 1/2 randomised observer-blind placebo 
controlled study to evaluate the safety, reactogenicity 
and immunogenicity of different dose levels of GSK 
Biologicals’ investigational unadjuvanted RSV 
maternal vaccine (GSK3888550A) compared to 
placebo when administered to healthy non-pregnant 
women aged 18-45 years.
Investigator name
Signature
Date
Leiter der klinischen 
Prüfung name, function and 
title
Signature
Date
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals,
Rue de l’institut 89, 1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event: 
Refer to the local study contact information document.
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 1/2 randomised observer-blind placebo controlled 
study to evaluate the safety, reactogenicity and 
immunogenicity of different dose levels of GSK Biologicals’ 
investigational unadjuvanted RSV maternal vaccine 
(GSK3888550A) compared to placebo when administered to 
healthy non-pregnant women aged 18-45 years.
Indication
Active immunization of pregnant women during the third 
trimester of pregnancy to prevent respiratory syncytial virus 
(RSV) associated lower respiratory tract infection (LRTI) in 
infants by transfer of maternal antibodies.
Rationale for the 
study and study 
design

Rationale for the study:
The purpose of this study is to evaluate the safety, 
reactogenicity and immunogenicity of three dose levels 
(30 µg, 60 µg and 120 µg) of the investigational RSV 
maternal vaccine antigen compared to placebo administered as 
a single intramuscular injection.

Rationale for the study design:
To assess the impact of the investigational RSV maternal 
vaccine in terms of safety, reactogenicity and immune 
response, four treatment groups will be evaluated.
Healthy, non-pregnant women aged 18 - 45 years will be 
enrolled, a population of the same gender and age of the 
vaccine’s target population

Rationale for the use of placebo:
The placebo group is included as a control for both the 
safety/reactogenicity and the immunogenicity assessments.
Objective(s)
Primary

To evaluate the safety and reactogenicity of three dose 
levels (30, 60, 120 µg) of the RSV maternal 
investigational vaccine administered as a single 
intramuscular injection, as compared to placebo up to 1 
month post vaccination (Day 31).
Secondary

To evaluate the safety of three dose levels (30, 60, 120
µg) of the RSV maternal investigational vaccine 
compared to placebo up to 6 months post vaccination 
(Day 181).
 
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
To evaluate the humoral immune response to three dose 
levels (30, 60, 120 µg) of the RSV maternal 
investigational vaccine compared to placebo up to 3 
months post vaccination (Day 91).
Tertiary

To further evaluate the humoral immune response to the 
RSV maternal vaccine.
Study design

Experimental design: Phase I/II, observer-blind, 
randomised, controlled, multi-centre, multi-country with 
four parallel groups.

Duration of the study:

Epoch 001: Screening Visit (Day -7 to Day 1)

Epoch 002: Active Vaccination phase starting at 
Visit 1 (Day 1) and concluding at, and including,
Visit 3 (Day 31)

Epoch 003: Long-term follow-up starting after Visit 
3 (Day 31) and concluding at Contact 1 (Day 181)

Primary completion Date (PCD): Visit 3 (Day 31) or last 
visit of Epoch 002

End of Study (EoS): Last testing results released of 
human biological samples collected at Visit 5 (Day 91) or 
Last Subject Last Visit (LSLV, i.e. last Contact 1), 
whichever comes last

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
Epoch 003
RSV MAT 30
~125
18 - 45 years
x
x
x
RSV MAT 60
~125
18 - 45 years
x
x
x
RSV MAT 120
~125
18 - 45 years
x
x
x
Placebo
~125
18 - 45 years
x
x
x
 
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Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/Product 
name
Study Groups
RSV MAT 30
RSV MAT 60
RSV MAT 120
Placebo
RSVPreF3 30
RSVPreF3 low dose
●
RSVPreF3 60
RSVPreF3 mid 
dose
●
RSVPreF3 120
RSVPreF3 high 
dose
●
Control
NaCl
●

Control: placebo control

Vaccination schedule: Single intramuscular injection at 
Visit 1 (Day 1)

Treatment allocation: Subjects will be randomised using a 
centralized randomisation system on internet (SBIR) at 
Visit 1 (Day 1). The randomisation algorithm will use a 
minimization procedure accounting for age (18 - 32 years 
or 33 - 45 years) and centre

Blinding:
Synopsis Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
N/A
Epoch 002
observer-blind
Epoch 003
single-blind *
* The study will be conducted in an observer-blind fashion 
through Day 91. After this day, the study will continue in a 
single-blind fashion. For more details about blinding see 
Section[s] 1.5.6, 5.3, 10.11.1. 

Sampling schedule: 

Blood samples for haematology/biochemistry: will 
be collected (~5.5 mL) from all subjects at Screening, 
Visit 2 (Day 8), Visit 3 (Day 31) and any Unscheduled 
Visit(s).

Blood samples for humoral immunogenicity: will be 
collected (~30 mL) from all subjects at Screening, 
Visit 2 (Day 8), Visit 3 (Day 31), Visit 4 (Day 61) and 
Visit 5 (Day 91).

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF)

Safety monitoring: 
 
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As this will be the first time that the RSV maternal vaccine will 
be administered in humans, the study will enrol subjects in two 
steps (Step 1 will enroll 60 subjects in the United States [US] 
only and Step 2 will enroll 440 subjects across multiple 
countries). Subjects will be randomised to all dose levels from 
the start. Both blinded and unblinded safety monitoring will be 
performed, as described below.
The Safety Review Team (SRT) will review blinded data on a 
regular basis throughout the study, and an internal Safety 
Review Committee (iSRC) will review unblinded data at 
specific study timepoints. (Refer to section[s] 8.10.1 and 8.10.2 
for more details on the safety monitoring for this study). 
During Step 1, until the first 30 subjects have been vaccinated, 
vaccination will be limited to 10 subjects/ per day across all 
sites. These subjects will be vaccinated sequentially and at least 
60 minutes apart. 
Subsequent vaccinations will continue without limitation to the 
number of subjects vaccinated per day or time lag between 
vaccination of consecutive subjects. 
Screening and enrolment of Step 2 subjects will only be 
initiated if the iSRC review of Day 31 data results in a 
recommendation to proceed with Step 2.
Number of subjects
Approximately 500 healthy women will be enrolled 
(~125/group).
Endpoint(s)
Primary

Occurrence of any adverse events (AEs) from vaccination 
during a 30-day follow-up period, for all subjects in all 
groups:

Occurrence of each solicited local and general 
symptom during a 7-day follow-up period.

Occurrence of any unsolicited AE during a 30-day 
follow-up period.

Occurrence of Serious AEs during a 30-day follow-up 
period.

Occurrence of any haematological (Leukocytes, 
Neutrophils, Lymphocytes, Eosinophils, Haemoglobin, 
Platelets) and biochemical (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], creatinine, 
blood urea nitrogen [BUN]) laboratory abnormalities 
at Day 8 and Day 31.
 
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Secondary

Occurrence of SAEs from vaccination up to Day 91 and up 
to Day 181 for all subjects, in all groups.

Humoral immune response to the investigational vaccine at 
Day 8, Day 31, Day 61 and Day 91 for all subjects in each 
investigational RSV vaccine group

RSV-A neutralising antibody (Nab) titres;

RSVPreF3 immunoglobulin G (IgG) antibody 
concentrations
Tertiary

Additional humoral response which may include but not 
limited to, RSVPreF3 specific IgG1 subclass antibody 
concentrations, RSV-B neutralising antibody titres, 
antibody competing for binding to specific epitopes on 
RSVPreF3 and antibody concentrations to residual host cell 
proteins in the RSVPreF3 vaccines.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................6
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS...........................................................................................19
GLOSSARY OF TERMS ...............................................................................................23
TRADEMARKS .............................................................................................................28
1.
INTRODUCTION....................................................................................................29
1.1.
Background ................................................................................................29
1.2.
Current Management of RSV Disease in Infants.........................................29
1.3.
Maternal Immunization................................................................................30
1.4.
GlaxoSmithKline (GSK) Biologicals’ Investigational RSV maternal 
vaccine .......................................................................................................31
1.5.
Rationale for the study and study design ....................................................31
1.5.1.
Rationale for the study.................................................................31
1.5.2.
Rationale for the study design......................................................31
1.5.3.
Rationale for dose selection.........................................................32
1.5.4.
Rationale for the use of placebo ..................................................32
1.5.5.
Safety considerations...................................................................32
1.5.6.
Study blinding ..............................................................................33
1.6.
Benefit: Risk Assessment ...........................................................................33
1.6.1.
Risk Assessment .........................................................................34
1.6.2.
Benefit Assessment.....................................................................35
1.6.3.
Overall Benefit: Risk Conclusion..................................................35
2.
OBJECTIVE(S) ......................................................................................................36
2.1.
Primary objective ........................................................................................36
2.2.
Secondary objectives..................................................................................36
2.3.
Tertiary objective ........................................................................................36
3.
STUDY DESIGN OVERVIEW ................................................................................36
4.
STUDY COHORT...................................................................................................39
4.1.
Number of subjects/centres ........................................................................39
4.2.
Inclusion criteria for enrolment....................................................................39
4.3.
Exclusion criteria for enrolment...................................................................40
5.
CONDUCT OF THE STUDY ..................................................................................43
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................43
5.2.
Subject identification and randomisation.....................................................44
5.2.1.
Subject identification....................................................................44
5.2.2.
Randomisation of treatment.........................................................44
5.2.2.1.
Randomisation of supplies..........................................44
5.2.2.2.
Treatment allocation to the subject.............................44
 
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5.2.2.2.1.
Study group and treatment 
number allocation ...................................44
5.3.
Method of blinding ......................................................................................45
5.4.
General study aspects ................................................................................45
5.5.
Outline of study procedures ........................................................................46
5.6.
Detailed description of study procedures ....................................................48
5.6.1.
Study procedure timings ..............................................................48
5.6.2.
Informed consent.........................................................................48
5.6.3.
Subject number allocation and Registration in SBIR-
“subject planning” module............................................................48
5.6.4.
Check inclusion and exclusion criteria .........................................48
5.6.5.
Collect demographic data ............................................................49
5.6.6.
Medical history.............................................................................49
5.6.7.
Physical examination ...................................................................49
5.6.8.
Pregnancy test.............................................................................49
5.6.9.
Check contraindications, warnings and precautions to 
vaccination...................................................................................49
5.6.10.
Assess pre-vaccination body temperature ...................................50
5.6.11.
Study group and treatment number allocation..............................50
5.6.12.
Blood sampling for safety or immune response 
assessments................................................................................50
5.6.13.
Study Vaccine administration.......................................................50
5.6.14.
60 minutes post-vaccination observation .....................................51
5.6.15.
Distribution of Subject Card .........................................................51
5.6.16.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................51
5.6.17.
Recording of AEs, SAEs and pregnancies...................................51
5.6.18.
Extension/Booster study ..............................................................52
5.6.19.
Day 181 Contact..........................................................................52
5.6.20.
Study conclusion..........................................................................52
5.7.
Biological sample handling and analysis.....................................................53
5.7.1.
Use of specified study materials ..................................................53
5.7.2.
Biological samples.......................................................................54
5.7.3.
Laboratory assays .......................................................................54
5.7.4.
Biological samples evaluation......................................................56
5.7.4.1.
Haematology/Blood Chemistry ...................................56
5.7.4.2.
Immunological read-outs ............................................56
5.7.5.
Immunological correlates of protection.........................................56
6.
STUDY VACCINES ADMINISTRATION.................................................................57
6.1.
Description of study vaccine .......................................................................57
6.2.
Storage and handling of study vaccine .......................................................57
6.3.
Dosage and administration of study vaccine...............................................58
6.4.
Replacement of unusable vaccine ..............................................................58
6.5.
Contraindications to vaccination .................................................................59
6.6.
Concomitant medications/products and concomitant vaccinations..............59
6.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................59
6.6.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from Per Protocol analyses ...........60
6.7.
Intercurrent medical conditions that may lead to elimination of a 
subject from Per Protocol analyses.............................................................60
 
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7.
HEALTH ECONOMICS ..........................................................................................60
8.
SAFETY.................................................................................................................61
8.1.
Safety definitions ........................................................................................61
8.1.1.
Definition of an adverse event......................................................61
8.1.2.
Definition of a serious adverse event ...........................................62
8.1.3.
Solicited adverse events..............................................................63
8.1.3.1.
Solicited local (injection-site) adverse events..............63
8.1.3.2.
Solicited general adverse events................................63
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................63
8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events (pregnancy)........................................................................64
8.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................65
8.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................65
8.3.2.
Post-Study adverse events and serious adverse events..............66
8.3.3.
Evaluation of adverse events and serious adverse events...........67
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................67
8.3.3.2.
Assessment of adverse events...................................67
8.3.3.2.1.
Assessment of intensity..........................67
8.3.3.2.2.
Assessment of causality .........................69
8.3.3.3.
Assessment of outcomes............................................70
8.3.3.4.
Medically attended visits.............................................70
8.4.
Reporting of serious adverse events, pregnancies and other events ..........70
8.4.1.
Prompt reporting of serious adverse events, pregnancies 
and other events to GSK..............................................................70
8.4.2.
Contact information for reporting serious adverse events 
and pregnancies ..........................................................................71
8.4.3.
Completion and transmission of SAE reports to GSK...................71
8.4.3.1.
Back-up system in case the electronic 
reporting system does not work..................................72
8.4.4.
Completion and transmission of pregnancy reports to GSK.........72
8.4.5.
Updating of SAE and pregnancy information after removal 
of write access to the subject’s eCRF ..........................................72
8.4.6.
Regulatory reporting requirements for serious adverse 
events..........................................................................................72
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies................................................................................................73
8.5.1.
Follow-up during the study...........................................................73
8.5.2.
Follow-up after the subject is discharged from the study..............73
8.5.3.
Follow-up of pregnancies.............................................................73
8.6.
Treatment of adverse events ......................................................................73
8.7.
Unblinding...................................................................................................74
8.8.
Emergency unblinding ................................................................................74
8.9.
Subject card................................................................................................75
8.10.
Holding rules and safety monitoring............................................................75
8.10.1.
Safety review team (SRT)............................................................75
8.10.2.
Internal Safety Review Committee (iSRC) Evaluation..................75
 
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8.10.3.
Holding rules................................................................................76
8.10.4.
Risk assessment..........................................................................77
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................78
9.1.
Subject completion .....................................................................................78
9.2.
Subject withdrawal......................................................................................78
9.2.1.
Subject withdrawal from the study ...............................................78
9.3.
Screening Failures......................................................................................79
9.4.
Extension study ..........................................................................................79
10. STATISTICAL METHODS......................................................................................80
10.1.
Primary endpoints.......................................................................................80
10.2.
Secondary endpoints ..................................................................................80
10.3.
Tertiary endpoints.......................................................................................80
10.4.
Determination of sample size......................................................................80
10.5.
Cohorts for Analyses ..................................................................................82
10.5.1.
Exposed Set (ES) ........................................................................82
10.5.2.
Per-protocol set (PPS) for analysis of immunogenicity.................82
10.6.
Derived and transformed data.....................................................................83
10.7.
Analysis of demographics...........................................................................84
10.8.
Analysis of safety........................................................................................84
10.8.1.
Within groups assessment...........................................................84
10.9.
Analysis of immunogenicity.........................................................................85
10.9.1.
Within groups assessment...........................................................86
10.9.2.
Between groups assessment.......................................................87
10.10. Interpretation of analyses............................................................................87
10.11. Conduct of analyses ...................................................................................87
10.11.1. Sequence of analyses..................................................................87
10.11.2. Statistical considerations for interim analyses..............................88
11. ADMINISTRATIVE MATTERS ...............................................................................88
11.1.
Case Report Form/electronic Case Report Form instructions .....................88
11.2.
Study Monitoring by GSK Biologicals..........................................................89
11.3.
Record retention .........................................................................................90
11.4.
Quality assurance.......................................................................................90
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................90
11.6.
Provision of study results to investigators ...................................................91
11.7.
Data Sharing...............................................................................................91
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................91
12.1.
Requirements for Germany.........................................................................91
13. REFERENCES.......................................................................................................92
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................38
Table 2
Study groups and treatment foreseen in the study .................................38
Table 3
Blinding of study epochs ........................................................................39
Table 4
List of study procedures .........................................................................46
Table 5
Intervals between study visits.................................................................48
Table 6
Biological samples .................................................................................54
Table 7
Humoral Immunity (Antibody determination)...........................................55
Table 8
Haematology, Serum Chemistry, Urine tests..........................................55
Table 9
Haematology/Blood Chemistry...............................................................56
Table 10
Immunological read-outs........................................................................56
Table 11
Study vaccine.........................................................................................57
Table 12
Dosage and administration.....................................................................58
Table 13
Solicited local adverse events ................................................................63
Table 14
Solicited general adverse events............................................................63
Table 15
Reporting periods for collecting safety information .................................66
Table 16
Intensity scales for solicited adverse events...........................................68
Table 17
Timeframes for submitting serious adverse event and pregnancy 
to GSK ...................................................................................................71
Table 18
Study holding rules.................................................................................77
Table 19
Exact 95% confidence interval on the percentage of subjects with 
adverse events following vaccination for 125 subjects per group ...........81
Table 20
Precision Estimation...............................................................................82
Table 21
GSK Biologicals’ laboratories .................................................................98
Table 22
Outsourced laboratories.........................................................................98
Table 23
FDA toxicity grading scales for hematology/biochemistry 
parameters...........................................................................................101
 
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LIST OF FIGURES
PAGE
Figure 1
Overview of staggered enrolment/vaccination and safety 
evaluation...............................................................................................33
Figure 2
Study Design Overview..........................................................................37
Figure 3
Risk assessment curve for one formulation based on the
proposed safety holding rules after 15 subjects/group at step 1 .............77
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .......................................................................96
APPENDIX B CLINICAL LABORATORIES ..................................................................98
APPENDIX C FDA GUIDANCE FOR INDUSTRY: TOXICITY GRADING 
SCALE FOR HEALTHY ADULT AND ADOLESCENT 
VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE 
CLINICAL TRIALS (SEPTEMBER 2007) ...............................................99
 
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LIST OF ABBREVIATIONS
AE
Adverse Event
AIDS
Acquired Immunodeficiency Syndrome
ANCOVA
Analysis of Covariance
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BLA
Biologicals License Application
BMI
Body Mass Index
BSH
Blood Sample for Humoral immunogenicity
BSS
Blood Sample for Safety
BUN
Blood urea nitrogen
CDC
Centers for Disease Control and Prevention
CEPL
Clinical & Epidemiology Project Lead 
CFR
Code of Federal Regulations
CI
Confidence Interval
CLS
Clinical Laboratory Sciences
CMO
Chief Medical Officer
CRDL
Clinical Research and Development Lead
DSM-5
Diagnostic and Statistical Manual of Mental Disorders
eCRF
electronic Case Report Form
EGA
Estimated Gestational Age
EMA
European Medicines Agency
EoS
End of Study 
ERD
Enhanced RSV Disease
ES
Exposed Set
 
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eTDF
Electronic Temperature excursion Decision Form 
FDA
Food and Drug Administration, United States of America
FI-RSV
Formalin-inactivated whole virus RSV vaccine
FTiH
First Time in Human
FU
Follow-up
GCP
Good Clinical Practice
GMC
Geometric Mean Concentration
GMT
Geometric Mean Titre
GSK
GlaxoSmithKline
HIV
Human Immunodeficiency Virus
IB
Investigator Brochure
ICD-10
International Classification of Diseases 10th Revision
ICF
Informed Consent Form
ICH
International Council for 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
LL
Lower limit
LMP
Last Menstrual Period
LRTI
Lower Respiratory Tract Infection
LSLV
Last subject last visit
 
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MACDP
Metropolitan Atlanta Congenital Defects Program
MATEX
MATerial EXcellence
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not applicable
Nab
Neutralising antibodies
NIH
National Institute of Health
PCA
Palivizumab Competing Antibodies
PCD
Primary Completion Date
PP
Per Protocol
PPS
Per Protocol Set 
RNA
Ribonucleic Acid
RSV
Respiratory syncytial virus 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SBIR
Source Database for Internet Randomisation 
SDV
Source Document Verification
SD
Standard Deviation
SE 
Safety event
SPM
Study Procedures Manual
SRT
Safety Review Team
TBD
To be determined
UL
Upper Limit
UP
Urine Pregnancy test
VSMB
Vaccines Safety Monitoring Board
 
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WBC
White Blood Cells
WHO
World Health Organization
 
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GLOSSARY OF TERMS
Active Phase (of a clinical 
trial):
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 oestrogen and progesterone oral 
contraceptives,

injectable progestogen,

implants of etonogestrel or levonorgestrel,

contraceptive vaginal ring,

percutaneous contraceptive patches,

intrauterine device or intrauterine system,

current bilateral 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 and 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 only.
 
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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). The method of 
blinding in this study is further defined in Section 1.5.6.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Enrolment:
Enrolment is defined as the point that a subject is 
determined as eligible to participate in the study and has 
been randomized to a treatment group.
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 or LSLV, whichever comes 
later. EoS must be achieved no later than 8 months after 
LSLV.
 
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Epoch:
An epoch is a self-contained set of consecutive time 
points or a single time point from a single protocol. Self-
contained means that data collected for all subjects at all 
time points within that epoch allows to draw a complete 
conclusion to define or precise the targeted label of the 
product. Typical examples of epochs are screening visits,
primary vaccinations, boosters, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the Per Protocol (PP) analysis (see Sections 
6.6.2, 6.7and 10.5 for details on criteria for evaluability).
Investigational vaccine:
(Synonym of 
Investigational Medicinal 
Product):
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing 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. 
Internal Safety Review 
Committee (iSRC):
The iSRC is a group of experts (a GSK Biologicals’ 
Safety Physician, a CRDL/CEPL and a Biostatistician), 
external to the on-going study/project and with lack of 
conflicts of interest in the outcome of the study, who 
assess the safety data in an unblinded (on a subject level 
or treatment group level) fashion. They may also assess 
other parameters (e.g. immunogenicity), if requested. 
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, thelarche. However, a 
young female can become pregnant before her first 
menses. Thus, a conservative definition of non-
childbearing potential in a pre-menarcheal female is a 
young female who has not yet entered puberty as 
evidenced by lack of breast development (palpable 
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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.
Primary completion date:
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated.
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.
Safety Review Team
(SRT):
Includes as core members, the GSK Biologicals’ Central 
Safety Physician, Central Safety Scientist, the Clinical 
and Epidemiology Project Lead (CEPL), Epidemiologist, 
Clinical Regulatory Affairs representative and the 
Biostatistician of the project.
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.
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.
 
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Treatment number:
A number identifying a treatment to a subject, according 
to the study randomisation or treatment allocation.
Unsolicited adverse 
event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
Vaccines Safety 
Monitoring Board 
(VSMB):
Internal GSK Biologicals 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/products and/or medications will be written without the superscript symbol 
™ or ® and in italics.
Trademarks not owned by the 
GlaxoSmithKline group of companies
Generic description
Synagis (MedImmune LLC.)
Recombinant humanized monoclonal anti-
RSV antibody
 
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1.
INTRODUCTION
1.1.
Background
RSV is a negative-strand, 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 seasonally
focused.
The virus causes respiratory tract infections at all ages, but young infants below 1 year of 
age have the highest incidence of severe disease (bronchiolitis, pneumonia), peaking at 1-
3 months of age [Hall, 2013] and with a continuing burden of disease through the second 
year of life [EMA/CHMP, 2017]. Severe disease often leads to hospitalisation and may
be life threatening. The majority of children become infected with RSV within 2 years of 
birth [Hall2001; Nyiro, 2017; Kutsaya, 2016]. The impact continues into later life, 
specifically, episodes of wheezing and asthma during the first decade of life are more 
common in children who were hospitalized for RSV bronchiolitis during infancy than 
those who were not hospitalized [Wu, 2011].
The risk for severe RSV-induced lower respiratory tract infection is highest in infants 
below 6 months of age and it is the most common cause of hospitalisation in this age 
group. About 45% of the estimated 3.2 million hospital admissions for RSV –associated 
acute lower respiratory tract infections that occurred globally in 2015, occurred in infants 
younger than 6 months of age. Additionally, it was estimated globally that hospital deaths 
due to RSV-associated lower respiratory infection were approximately 59,600 in children 
younger than 5 years and 27, 300 in children <6 months of age [Shi, 2017].
Approximately 2% of children < 1 year of age are hospitalized for RSV-associated lower 
respiratory tract infections each year in industrialized countries [Blais, 2017; Boyce, 
2000; Deshpande, 2003; Hall, 2009; Holman, 2004; Iwane, 2004; Madhi, 2006; Nair, 
2010; Paramore, 2004; Vicente, 2003; Shi, 2017; Stein, 2017].
Previous infection with RSV does not prevent subsequent infections. Re-infection with 
RSV occurs throughout an individual’s lifetime [Simoes, 1999; Kapikian, 1969; 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 older adults), re-infections can also lead to severe 
disease and result in  mortality [Graham, 2011].
1.2.
Current Management of RSV Disease in Infants
To date, no licensed vaccine is available for RSV and treatment for RSV disease is 
limited to supportive care. 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, such as infants who were born prematurely or with bronchopulmonary dysplasia, 
 
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as well as with hemodynamically significant congenital heart 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].
1.3.
Maternal Immunization
Maternal immunization, and the protective effect of maternally transferred antibodies was 
initially demonstrated with the small pox vaccination in 1879 [Rasmussen, 2014]. 
Effective immune responses to vaccines and transmission of specific antibodies to infants 
through the placenta are observed when pregnant women are vaccinated [Vojtek, 2018]. 
Currently, the Advisory Committee on Immunization Practices recommends the 
inactivated influenza and Tdap (tetanus toxoid, reduced diphtheria toxoid and acellular 
pertussis) vaccines for pregnant women [CDC, 2017]. 
In a study evaluating maternal vaccination with influenza, there was a 63% reduction in 
laboratory proven influenza illness in infants up to 6 months of age and 29% and 36% 
reductions in rates of respiratory illness with fever in infants and mothers, respectively 
[Zaman, 2008]. Additionally, in a retrospective cohort study, it was concluded that 
infants with pertussis whose mothers received Tdap during pregnancy had a significantly 
lower risk of hospitalization and intensive care unit admission and shorter hospital stays 
[Winter, 2017]. Following maternal tetanus toxoid vaccination, neonatal tetanus mortality 
has been reduced by 92% in combination with improved hygienic birthing practices 
[Healy, 2012]. 
Based on the results seen with previous maternal vaccines, vaccinating mothers with an 
RSV vaccine could reduce RSV-associated morbidity and mortality in infants less than 6 
months of age. 
It was shown that most of the RSV neutralizing activity present in serum from previously 
infected individuals is directed to the pre-fusion conformation of RSV F protein 
[Ngwuta, 2015]. In addition, antibodies specific for the RSV F pre-fusion conformation 
are typically more potent than those which are common to both the post- and pre-fusion 
forms [Kwakkenbos, 2010].
Administration of an RSV vaccine to adults (pregnant women in this case), all of whom 
can be assumed to have been naturally infected with RSV before, is expected to boost the 
immunological memory induced by previous natural infections [Anderson, 2013]. High 
titers of maternally derived RSV-neutralizing antibodies have been shown to be 
associated with subsequent serologic protection against RSV infection and lower 
incidence of RSV-associated acute lower respiratory tract infection during the first 6 
months of life [Roca, 2002; Stensballe, 2009; Chu, 2014].
Enhanced respiratory disease (ERD) was seen in clinical trials of a formalin-inactivated 
whole virus RSV vaccine (FI-RSV) in seronegative children. Among seronegative 
children in those trials, the FI-RSV vaccine did not protect against RSV disease and more 
importantly led to more severe clinical symptoms upon subsequent natural infection of 
RSV [Chin, 1969; Kapikian, 1969; Kim, 1969]. In contrast, clinical data demonstrate a 
 
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decrease in severity of RSV infection among the non-naïve population following repeat 
exposure and the lack of ERD in the seropositive children who participated in the FI-RSV 
studies [Roberts, 2016].  With the transfer of vaccine-induced neutralizing antibodies 
from the mother to the infant, the risk of ERD in the infants is considered negligible. In 
support of this hypothesis, ERD has not been observed with the use of Synagis, nor with 
the transfer of serum from FI-RSV vaccinated animals to recipient animals [Kwon,
2014].
1.4.
GlaxoSmithKline (GSK) Biologicals’ Investigational RSV 
maternal vaccine
The RSV maternal vaccine is composed of the lyophilized RSVPreF3 antigen (Refer to 
the Investigational Medicinal Product (IMP) Dossier and Section 3.2.S.1.2 of the 
Investigational New Drug (IND). The vaccine is being developed for prevention of RSV 
LRTI disease in infants by transfer of maternal antibodies. 
Refer to the Investigator Brochure (IB) for more information on the RSV maternal 
vaccine
1.5.
Rationale for the study and study design
1.5.1.
Rationale for the study
GSK is developing a new investigational RSV maternal vaccine against RSV disease in 
infants through a maternal immunization program.
The purpose of this study is to evaluate the safety, reactogenicity and immunogenicity of 
three dose levels (30 µg, 60 µg and 120 µg) of the investigational RSV maternal vaccine 
antigen compared to placebo administered as a single intramuscular injection.
1.5.2.
Rationale for the study design
To assess the impact of the investigational RSV maternal vaccine in terms of safety, 
reactogenicity and immune response, four treatment groups will be evaluated:
Group Name (Product):

RSV MAT 30 (RSVPreF3 30 µg)

RSV MAT 60 (RSVPreF3 60 µg)

RSV MAT 120 (RSVPreF3 120 µg)

Control (Saline Placebo)
Healthy, non-pregnant women aged 18 - 45 years will be enrolled in this study, a 
population of the same gender and age of the vaccine’s target population.
 
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1.5.3.
Rationale for dose selection
GSK previously evaluated a different candidate RSV maternal vaccine at dose levels of 
30, 60, and 120 µg in a similar population, non-pregnant women 18-45 years of age. 
Building on this experience, the RSV MAT-001 study will evaluate 3 dose levels (30, 60 
or 120 µg) of the new investigational unadjuvanted RSV maternal vaccine administered 
intramuscularly as a single dose. Clinical experience with the previously evaluated 
vaccine candidate indicated that unadjuvanted formulations induced Nab levels similar to 
those of alum-adjuvanted formulations in adults [Langley, 2017; Beran, 2018]. Therefore, 
only unadjuvanted formulations will be used in RSV MAT-001.
The highest proposed dose level (120 µg) for RSV MAT-001 was well tolerated when 
given alone, 3 times at 2-week intervals, in a GLP toxicology study. Additionally, 
previous pharmacology studies of the RSVPreF3 antigen conducted in a bovine model 
demonstrated that the molecule is able to boost Nab titres. Refer to the Investigator 
Brochure for a summary of the nonclinical studies. 
This is a single-dose study so the maximum dose to be administered will be the dose to 
which the subject is randomised. 
1.5.4.
Rationale for the use of placebo
The placebo group is included as a control for both the safety/reactogenicity and the 
immunogenicity assessments.
1.5.5.
Safety considerations
As this will be the first time that the GSK investigational RSV maternal vaccine will be
administered in humans, the study will enrol subjects in 2 steps with randomisation to all 
dose levels (30, 60 and 120 µg) from the start, (See Figure 1). Step 1 (~ 60 subjects) will 
be conducted at sites in the United States only and additional countries will be added in 
Step 2.
During Step 1, until the first 30 subjects have been vaccinated, vaccination will be limited 
to 10 subjects per day across sites. These subjects will be vaccinated sequentially and at 
least 60 minutes apart across all sites. During the remainder of Step 1 and in Step 2, 
vaccination will continue without limitations to the number of subjects vaccinated per 
day or time lag between vaccination of consecutive subjects.
Refer to Sections 5.6.13 and 5.6.14 for more information on vaccine administration and 
subject monitoring.
Refer to Section 8.10.1 and 8.10.2 for more information on the Safety Review Team 
(SRT) and the internal Safety Review Committee (iSRC) evaluations, respectively.
 
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Figure 1
Overview of staggered enrolment/vaccination and safety evaluation
Safety Events (SE) up to Day 8 visit = safety evaluation by iSRC based on all available safety data from subjects up 
to at least 7 days post-vaccination (including Day 8 haematology/ biochemistry parameters).
SE up to Day 31 visit = safety evaluation by iSRC based on all available safety data from subjects up to 30 days post-
vaccination (Including Day 31 haematology/biochemistry parameters).
1.5.6.
Study blinding
Given the different presentation of the placebo and the investigational RSV vaccine, a 
double-blinded study design is not possible. This study will be conducted in an observer-
blind manner up to Day 91, after which it will be conducted in a single-blind manner.
Observer-blind, means that during the course of the study, the vaccine recipient, those 
responsible for the evaluation of any study endpoint (e.g. safety and reactogenicity), and 
the sponsor 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.
Single-blind, means that GSK statistician and data management staff will be unblinded 
(i.e. will have access to the individual subject treatment assignments), but individual 
listings will not be provided until the study report at the completion of the study. In 
addition, site staff involved in the clinical evaluation of study participants will not be 
aware of individual treatment assignments until the study report.
Please refer to Section 5.3 for further details regarding the methods of blinding used in 
this study. 
1.6.
Benefit: Risk Assessment
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of the investigational RSV maternal vaccine.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
 
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1.6.1.
Risk Assessment
Risks, Contraindications and 
Warnings
Data/Rationale for Risk 
Mitigation Strategy
All Study Vaccines
Hypersensitivity including 
allergic reactions such as 
anaphylaxis
Acute allergic reactions, such as an 
anaphylactic event, may occur with 
any vaccine administration. These are 
serious, but rare occurrences,
estimated in the range of 1 to 10 
cases per million of vaccinations, 
depending on the vaccine studied 
[Rueggeberg, 2007].
The onset of vaccine-related 
allergic symptoms is typically 
quite prompt. In order to treat 
subjects with a serious allergic 
reaction to vaccination, all 
subjects will need to remain 
under observation (i.e. visibly 
followed; no specific 
procedure) at the vaccination 
centre for at least 60 minutes 
after vaccination with 
appropriate medical treatment 
readily available, in case 
needed.
Syncope
Syncope (fainting) can occur following 
or even before any vaccination as a 
psychogenic or vasovagal response to 
the needle injection. 
All subjects will remain under 
observation at the vaccination 
centre for at least 60 minutes 
after vaccination.
Intramuscular Injection site 
reaction
Intramuscular vaccination commonly 
precipitates a transient and self-
limiting local inflammatory reaction. 
This may typically include pain at 
injection site, redness, and swelling.
Solicited local AEs will be 
collected and reviewed up to 7 
days post-vaccination
RSV maternal vaccine
Due to the lack of experience in 
human subjects to date, there 
is currently not enough 
information available to identify 
the risks of adverse events 
(AE) related to administration 
of the RSV maternal vaccine
Any untoward symptoms 
experienced by the subject 
after receiving the vaccine 
should be reported to the 
investigator. Ongoing safety
monitoring will be performed in 
a blinded fashion by the Safety 
Review Team, and unblinded 
review will be performed by the 
internal Safety Review 
Committee (independent from 
the RSV program). Established 
holding rules will be applied.
In step 1, for the first 30 
subjects there will be a
minimum interval of 60 minutes
between vaccinations and 
vaccination will be limited to 10 
subjects per day across all 
sites.
In addition to the above, all 
subjects will remain under 
observation at the vaccination 
centre for at least 60 minutes 
 
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Risks, Contraindications and 
Warnings
Data/Rationale for Risk 
Mitigation Strategy
after vaccination.
Study Procedures – Venipuncture
Pain and bruising
Pain or bruising at the site where 
blood is drawn.
A topical analgesic may be 
applied to the site where blood 
will be taken.
Syncope
Syncope (fainting) can occur following 
or even before any blood draw as a 
psychogenic or vasovagal response to 
the needle injection.
All subjects will remain under 
observation, post 
venepuncture, through 
completion of the applicable 
study visit.
1.6.2.
Benefit Assessment
Benefits linked to the investigational RSV maternal vaccine
RSV infections in healthy adults generally go undiagnosed because they usually present 
as mild acute upper respiratory tract infections. Moreover, vaccine efficacy has not been 
assessed yet and it is not known whether the investigational RSV maternal vaccine is
effective in protecting against RSV infection in infants.
As the proposed indication of the vaccine is to prevent RSV-associated lower respiratory 
tract illness (LRTI) in infants by transfer of maternal antibodies, the subjects in RSV 
MAT-001 (healthy, non-pregnant women) receiving the investigational RSV maternal
vaccine are not expected to directly benefit from this vaccination.
1.6.3.
Overall Benefit: Risk Conclusion
This is a FTiH study evaluating an investigational RSV maternal vaccine. The 
investigational RSV maternal vaccine is currently in an early stage of clinical 
development and although no vaccine efficacy has been demonstrated, the vaccine has 
been shown to boost Nab to both RSV serotype A and RSV serotype B in animal models
(refer to the IB).
 
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2.
OBJECTIVE(S)
2.1.
Primary objective

To evaluate the safety and reactogenicity of three dose levels (30, 60, 120 µg) of the 
RSV maternal investigational vaccine administered as a single intramuscular 
injection, as compared to placebo up to 1 month post vaccination (Day 31).
Refer to Section 10.1 for the definition of the primary endpoint(s).
2.2.
Secondary objectives

To evaluate the safety of three dose levels (30, 60, 120 µg) of the RSV maternal 
investigational vaccine compared to placebo up to 6 months post vaccination (Day 
181).

To evaluate the humoral immune response to three dose levels (30, 60, 120 µg) of 
the RSV maternal investigational vaccine compared to placebo up to 3 months post 
vaccination (Day 91).
Refer to Section 10.2 for the definition of the secondary endpoint(s).
2.3.
Tertiary objective

To further evaluate the humoral immune response to the RSV maternal vaccine.
Refer to Section 10.3 for the definition of the tertiary endpoint(s).
3.
STUDY DESIGN OVERVIEW
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), is essential and 
required for study conduct.
 
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Figure 2
Study Design Overview
AE – Adverse Events: solicited (Day 1 to Day 7); unsolicited (Day 1 to Day 30) and serious (Enrolment to Study 
conclusion)
BSS – Blood samples for haematology/biochemistry will be collected (5.5 mL) from all subjects at Screening, Visit 2 
(Day 8), and Visit 3 (Day 31).
BSH – Blood samples for humoral immunogenicity will be collected (30 mL) from all subjects at Screening, Visit 2 
(Day 8) Visit 3 (Day 31), Visit 4 (Day 61), and Visit 5 (Day 91).
iSRC – Internal Safety Review Committee (See Section 8.10.2).
Contact 1- will be completed for all subjects at Day 181 (preferred contact is Phone Call).
RSV MAT 30/60/120 – RSV maternal 30/60/120µg, respectively, of the RSV maternal vaccine.
Screening can occur ≤ 7 days prior to Visit 1 or on the same day, when possible.
UP – Urine Pregnancy test (or serum pregnancy test if country/local specific regulation) from all subjects (if Screening 
and Visit 1 are on the same day UP will not be repeated).

Experimental design: Phase I/II, randomised, observer-blind, placebo control, 
multicentre study with four parallel groups.

Duration of the study for each subject enrolled will be approximately 6 months 
from Visit 1:

Epoch 001: Screening Visit (Day -7 to Day 1)

Epoch 002: Active Vaccination phase starting at (Day 1) and concluding at, and 
including, Visit 3 (Day 31).
 
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
Epoch 003: Long Term Follow-up starting after Visit 3 (Day 31) and concluding 
at Contact 1 (Day 181).
Any safety data collected beyond Day 31 will be collected in Epoch 003.

Primary Completion Date: Visit 3 (Day 31) or last visit of Epoch 002.
Refer to GLOSSARY OF TERMS for the definition of PCD

End of Study: Last testing results released for samples collected at Visit 5 (Day 91)
or LSLV (i.e. last Contact 1), whichever comes last.
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
Epoch 003
RSV MAT 30
~125
18 - 45 years
x
x
x
RSV MAT 60
~125
18 - 45 years
x
x
x
RSV MAT 120
~125
18 - 45 years
x
x
x
Placebo
~125
18 - 45 years
x
x
x
Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/Product 
name
Study Groups
RSV MAT 30
RSV MAT 60
RSV MAT 120
Placebo
RSVPreF3 30
RSVPreF3 low dose
●
RSVPreF3 60
RSVPreF3 mid dose
●
RSVPreF3 120
RSVPreF3 high dose
●
Control
NaCl
●

Control: placebo control

Vaccination schedule: Single intramuscular injection at Visit 1 (Day 1)

Treatment allocation: Subjects will be randomised using a centralized randomisation
system on internet (SBIR) at Visit 1 (Day 1). The randomisation algorithm will use a 
minimization procedure accounting for age (18 - 32 years or 33 - 45 years) and 
centre.

Blinding:
 
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Table 3
Blinding of study epochs
Study Epochs
Blinding
001
N/A
002
observer-blind
003
single-blind *
* The study will be conducted in an observer-blind fashion through Day 91. After this 
day, the study will continue in a single-blind fashion. For more details about blinding see 
Section(s) 1.5.6, 5.3, 10.11.1.

Sampling schedule:

Blood samples for haematology/biochemistry: will be collected (~5.5 mL) 
from all subjects at Screening, Visit 2 (Day 8), Visit 3 (Day 31) and any 
Unscheduled Visit(s).

Blood samples for humoral immunogenicity: will be collected (~30 mL) from 
all subjects at Screening, Visit 2 (Day 8),Visit 3 (Day 31), Visit 4 (Day 61) and 
Visit 5 (Day 91).

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF)

Safety monitoring: This study will be monitored by a blinded SRT and by an 
unblinded iSRC. 
Refer to Section(s) 1.5.5 and 8.10 for detailed description of holding rules and safety 
monitoring.
4.
STUDY COHORT
4.1.
Number of subjects/centres
This will be a multi-centre, multi-country study. It is planned that enrolment will be 
equally distributed to the participating countries. 
The target is to enrol approximately 500 eligible women (~125 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, regulatory acceptability of the study or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential.
 
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All subjects must satisfy ALL the following criteria at study entry:

Subjects who the investigator believes will comply with the requirements of the 
protocol (e.g. completion of the diary cards/questionnaires, return for follow-up 
visits, have regular contact to allow evaluation during the study);

Written informed consent obtained from the subject;

Healthy female subjects; as established by medical history and clinical examination, 
aged 18 to 45 years at the time of the vaccination;

Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced adequate contraception for 30 days prior to vaccination, and

has a negative pregnancy test on the day of vaccination, and

has agreed to continue adequate contraception until 90 days after vaccination
Please 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, regulatory acceptability of the study or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY 
exclusion criterion applies, the subject must not be included in the study:

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine within 30 days preceding vaccination or any 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);

Chronic administration (defined as more than 14 days in total) of 
immunosuppressant or other immune-modifying drugs, as well as administration of 
long acting immune modifying drugs (e.g. infliximab), within 6 months prior to the
vaccine dose (for corticosteroids, this will mean prednisone ≥ 5 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;

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;
 
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
Previous experimental vaccination against RSV;

Presence of neurological or psychiatric diagnoses which, although stable, are deemed 
by the investigator to render the potential subject unable/unlikely to provide accurate 
safety reports;

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 allergic disease or reactions likely to be exacerbated by any component of 
the vaccine;

Any acute or chronic, clinically significant disease, as determined by physical 
examination, laboratory screening tests, subject personal report and/or health care 
provider information. The following conditions will be exclusionary:

Diabetes mellitus,

Respiratory diseases, such as: 
o
Chronic Pulmonary diseases, including COPD,
o
Bronchopulmonary dysplasia (note: history of past bronchopulmonary 
dysplasia as a neonate/infant will not be exclusionary),
o
Uncontrolled asthma or asthma necessitating treatment with chronic 
systemic glucocorticoids (please refer to the exclusion criterion on use of 
immunosuppressants or other immune-modifying drugs for the definition of 
chronic corticoids use)

Significant and/or uncontrolled psychiatric illness: 
o
hospitalization for psychiatric illness, history of suicide attempt(s) or 
confinement for danger to self or others within 10 years 
o
clinically significant depression (as deemed by the investigator)

Major neurological disease including:
o
seizure or adulthood epilepsy (note: history of febrile convulsion in 
childhood is not exclusionary) 
o
myasthenia gravis
o
history of repetitive migraine mal/status migrainosus (i.e. severe or 
debilitating migraine attack that lasts for more than 72 hours)

Significant cardiovascular disease, including:
o
Uncontrolled arterial hypertension,
o
Congenital heart disease (with the exception of corrected atrial or ventricular 
septal defects), 
o
Previous myocardial infarction, 
o
Valvular heart disease or history of rheumatic fever, 
 
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o
Previous bacterial endocarditis, 
o
History of cardiac surgery (with the exception of corrected atrial or 
ventricular septal defects), 
o
Personal or family history of cardiomyopathy or sudden adult death.

Known or suspected Hepatitis B or Hepatitis C infection,

Any other significant uncontrolled medical illness (acute or chronic), defined as 
any illness requiring new medical and/or surgical treatment or significant 
modification of treatment dose due to uncontrolled symptoms or drug toxicity, 
within 3 months prior to study vaccination. 

History of or current autoimmune disease;

Body mass index (BMI) > 40 kg/m2;

Pregnant or lactating female;

Female planning to become pregnant or planning to discontinue contraceptive 
precautions (if of childbearing potential);

Hypersensitivity to latex;

Lymphoproliferative disorder or malignancy within previous 5 years (excluding 
effectively treated non-melanotic skin cancer);

Acute disease and/or fever at the time of enrolment;

Fever is defined as temperature ≥ 38○C/100.4○F

For subjects with acute disease and/or fever at the time of enrolment, Visit 1 will 
be rescheduled within the allowed window for the visit (see Table 5).

Subjects with fever at screening may be re-screened 1 time at a later date.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.

Any clinically significant or any ≥ Grade 2* haematological (haemoglobin level, 
white blood cell, lymphocyte, neutrophil, eosinophil, and platelets) and biochemical 
(alanine aminotransferase [ALT] aspartate aminotransferase [AST], creatinine, blood 
urea nitrogen [BUN]) laboratory abnormality detected at the last screening blood 
sampling;
*Grading of laboratory parameters will be based on the FDA Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials” [APPENDIX C].
For Grade 1 laboratory abnormalities, the investigator should use clinical judgement 
to decide which ones are clinically relevant. 
Subjects with haematological/biochemical values out of normal range at screening
which are expected to be temporary, may be re-screened 1 time at a later date.

Any other condition that the investigator judges may interfere with study procedures 
(e.g. drawing blood) or findings (e.g. immune response);
 
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
Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe;

Alcoholism, drug abuse and/or use disorder within the past two years (as defined in 
DSM-5 Diagnostic Criteria) [Hasin, 2013];

Planned move to a location that will prohibit participating in the trial until study end.
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 will prepare a model Informed Consent Form (ICF) which will embody the ICH 
GCP and GSK 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 
 
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GSK and be approved (along with the protocol, and any other necessary documentation) 
by the IRB/IEC.
5.2.
Subject identification and randomisation
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.
In order to allow for proper control of recruitment as per the Step 1 and Step 2 
recruitment targets, consented subjects will be registered in the SBIR application. 
5.2.2.
Randomisation of treatment
5.2.2.1.
Randomisation of supplies
The randomisation of supplies within blocks will be performed at GSK, using MATerial 
EXcellence (MATEX), a program developed for use in Statistical Analysis System 
(SAS®) (Cary, NC, USA) by GSK. Entire blocks will be shipped to the study centres/ 
warehouse(s).
To allow GSK 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 500 eligible subjects who will be randomly 
assigned to four study groups in a (1: 1: 1: 1) ratio (~125 subjects in each group).
Allocation of each 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.
At Visit 1, after having fully checked the eligibility of the subject, the site staff in charge 
of the vaccine administration will access SBIR. Upon selecting the subject identification 
number previously entered in the application, the randomisation system will determine 
the study group and will provide the treatment number to be used for vaccination.
 
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The number of the 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.
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. Refer to Section 1.5.6 for more information 
on study blinding.
Data will be collected in an observer–blinded manner up to Day 91 (Visit 5). During this 
time, vaccine recipients and those responsible for the evaluation of any study endpoints 
will be unaware of which vaccine was administered. To achieve this, vaccine preparation 
and administration will be done by authorised medical personnel who will not participate 
in any of the study clinical evaluations. Additionally, vaccine recipients will receive the 
same volume (0.5 mL) of the study product on Day 1. 
Analyses for the iSRC review will be performed by an independent statistician to ensure 
that the study team remains blinded to individual subject listings. Refer to Section 10.11
for more information on analyses. 
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
001
002
003
Type of contact
Screening Visit 
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Contact 1
Unsch 
Visit
Time point (s)
Day -7 to Day 1
Day 1
Day 8
Day 31
Day 61
Day 91
Day 181
Sampling time point(s)
Pre-Vacc
Vacc
Post-
Vacc
Post-Vacc
Post-
Vacc
Post-
Vacc
Post-Vacc
Informed consent
●
Assign subject number
●
Register subject in SBIR
O
Check inclusion/exclusion criteria
●
O 1
Collect demographic data
●2
Medical history
O
●
Physical examination 3
●
●1
●
O *
O *
O *
O *
Urine pregnancy test 4
●
●1
Pre-vaccination body temperature
●
Distribution of subject card
O
Blood sampling for humoral immune response (~30 mL) 5
●
●
●
●
●
Blood sampling for haematology/ biochemical analysis (~5.5 ml) 5
●
●
●
●
Study group and treatment number allocation (SBIR)
O
Vaccine administration
●
Recording of administered treatment number
●
60 minutes post vaccination observation period
O
Training on use of diary cards
O
O
Distribution of diary cards6
O
O
Collection of diary cards
O
O
Diary card transcription by investigator
●
●
Recording of solicited adverse events
●
●
Recording of unsolicited adverse events
●
●
●
●
Recording of AE leading to withdrawal
●
●
●
●
●
●
●
Recording of serious AE 7
●
●
●
●
●
●
●
●
Recording of pregnancies
●
●
●
●
●
●
●
Recording of concomitant medications/vaccinations
●
●
●
●8
●8
●8
●8
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Epoch
001
002
003
Type of contact
Screening Visit 
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Contact 1
Unsch 
Visit
Time point (s)
Day -7 to Day 1
Day 1
Day 8
Day 31
Day 61
Day 91
Day 181
Sampling time point(s)
Pre-Vacc
Vacc
Post-
Vacc
Post-Vacc
Post-
Vacc
Post-
Vacc
Post-Vacc
Record any intercurrent medical conditions
●
●
●
●
●
●
Check for interest in participating in future booster study
O
●
Screening conclusion
●
Investigator sign-off on eCRF before analysis
●
●
Study Conclusion
●
Vacc: vaccination. 
● 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 
1When Screening Visit and Visit 1 are performed on the same day, Inclusion and Exclusion Criteria check, Physical examination and Urine pregnancy test will not be repeated.
2Date of birth (month and year or year only, as per local regulations), race, ethnicity and childbearing potential (if subject not of childbearing, the specific reason should be documented 
in the eCRF: hysterectomy, ovariectomy, post-menopause, pre-menarche or other)
3 Physical examination including resting vital signs (blood pressure, heart rate and respiratory rate, temperature) after at least 10 minutes of rest. Weight, height and BMI will only be 
collected at Screening.* Physical examination at Visits 3, 4 and 5, as well as any unscheduled visit, will be performed only if deemed necessary by the investigator
4 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.
5 Method, cut-off, and laboratory locations are defined in Section 5.7.
6 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 on the day of vaccination and for 6 subsequent days. The second one will be distributed at Visit 2 (Day 8) and will be used for recording unsolicited AEs and 
concomitant medications/products and vaccinations from Day 8 to Day 30.
7. For Screening and Visit 1 (prior to study vaccine administration), only those SAEs that are considered related to study participation need to be recorded. 
8Recording of Concomitant medications/vaccinations/products as described in Section 6.6.
Note: 
The dashed line border between Screening and Visit 1 indicates the ability for investigator/subject to be screened and vaccinated on the same day, when possible. Prior to vaccination 
all study procedures in the screening visit must be recorded in eCRF and signed by investigator.
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Table 5
Intervals between study visits
Interval
Optimal length of interval1
Allowed interval2
Screening Visit Visit 1 (Day 1)
≤7 days
0 – 7 days
Visit 1 (Day 1) Visit 2 (Day 8)
7 days
7 - 10 days
Visit 1 (Day 1) Visit 3 (Day 31)
30 days
30 - 45 days
Visit 1 (Day 1) Visit 4 (Day 61)
60 days
56 – 70 days
Visit 1 (Day 1) Visit 5 (Day 91)
90 days
86 - 100 days
Visit 1 (Day 1) Contact 1 (Day 181)
180 days
165 - 195 days
1Whenever possible the investigator should arrange study visits within this interval.
2For a study visit where a sample is collected, subjects will not be eligible for inclusion in the Per Protocol (PP) cohort 
for analysis of immunogenicity if the visit takes place outside this interval.
5.6.
Detailed description of study procedures
5.6.1.
Study procedure timings
When the Screening Visit and Visit 1 are performed on the same day, the following study 
procedures will not be repeated:

Physical Examination (note: temperature [including pre-vaccination temperature] 
will only be measured once but recorded twice).

Urine (or serum, if required) Pregnancy test.
5.6.2.
Informed consent
During the Screening Visit the signed/witnessed/ thumb printed informed consent of the 
subject must be obtained before study participation.
Refer to Section 5.1 for the requirements for informed consent, as appropriate.
5.6.3.
Subject number allocation and Registration in SBIR- “subject 
planning” module
Upon signature of the ICF and a first check on eligibility, the subject will be assigned a 
subject number (refer to section 5.2.1).
The assigned subject number must be recorded in the eCRF.
In addition, the site staff will register the subject into the SBIR application. This will 
allow to properly control recruitment per the established Step 1 and Step 2 recruitment 
targets. 
5.6.4.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 during the 
Screening Visit and verify prior to randomisation.
 
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5.6.5.
Collect demographic data
During the Screening Visit, record demographic data such as date of birth (month and 
year or year only, as per local regulations), race and ethnicity as well as information on 
subject’s childbearing potential (if subject is not of childbearing potential, the specific 
reason should be documented: hysterectomy, ovariectomy, post-menopause, pre-
menarche or other) in the subject’s eCRF.
5.6.6.
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 the 
subject prior to the study vaccination (Visit 1) in the eCRF.
5.6.7.
Physical examination
During the Screening Visit, Visit 1 and Visit 2, perform a physical examination of the 
subject, including assessment of resting vital signs: systolic and diastolic blood pressure, 
heart rate, respiratory rate and temperature, after at least 10 minutes of rest. In addition, at 
Screening 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.
5.6.8.
Pregnancy test
Female subjects of childbearing potential are to have a pregnancy test during the
Screening Visit and Visit 1 (prior to 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, however,
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.
5.6.9.
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 Sections 6.5 and 6.6 for more details.
 
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5.6.10.
Assess pre-vaccination body temperature
Record the body temperature of the subject prior to study vaccination. The preferred 
route for recording temperature in this study will be oral using the provided GSK
thermometers.
If the subject has fever (defined as temperature ≥38.0°C/100.4°F regardless of the 
location of measurement) on the day of vaccination, Visit 1 can be rescheduled within the 
allowed interval for this visit (see Table 5).
If meeting the allowed interval between Screening and Visit 1 in such cases is not 
possible, subject may be re-screened at a later date (per investigator’s discretion).
5.6.11.
Study group and treatment number allocation
Study group and treatment number allocation will be performed as described in Section
5.2.2. The number of the administered treatment must be recorded in the eCRF.
5.6.12.
Blood sampling for safety or immune response assessments
A volume of ~5.5 mL of whole blood should be drawn from all subjects for analysis of 
the haematology/biochemistry parameters at Screening, Visit 2, Visit 3 and Unscheduled 
Visits (if any). In the event any re-test is needed; as per investigator discretion, (e.g. 
laboratory abnormalities) the volume required will also be ~5.5mL. Haematology and 
biochemistry assessments will be performed in the investigator’s laboratory as per local 
practice (see Table 8 and Table 9).
A volume of ~30 mL of whole blood should be drawn from all subjects at Screening, 
Visit 2, Visit 3, Visit 4 and Visit 5 for analysis of humoral immune responses (see Table 
7 and Table 10).
Refer to the SPM for details on blood sample handling.
5.6.13.
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 
vaccination in the non-dominant arm, the vaccine may be administered in the dominant 
arm. Refer to Section 6.3 for information on the dosage and administration of the 
vaccine. 
If the investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccines administration, the vaccination visit will 
be rescheduled within the allowed interval (refer to Table 5).
Vaccination in Step 1 will be limited to 10 subjects a day for the first 30 subjects. These 
subjects should be vaccinated sequentially and at least 60 minutes apart.
 
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5.6.14.
60 minutes post-vaccination observation
All subjects across all steps will be observed closely at least 60 minutes following study 
vaccination, with appropriate medical treatment readily available in case of anaphylaxis
and syncope related issues/injuries.
5.6.15.
Distribution of Subject Card
For information regarding the Subject Card, please refer to Section 8.9.
5.6.16.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.6.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.7.
5.6.17.
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.

The subjects will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.

At the vaccination visit (Visit 1), the first diary card will be provided to the subjects.
The subject will be instructed to measure and record body temperature at home 
(using GSK supplied thermometers) and any solicited local/general AEs, as well as
unsolicited AEs and concomitant medications/products/vaccinations as from the time 
of vaccination up to Day 7. The subject will be instructed to return the diary card to 
the investigator at the next study visit (Visit 2).

A second diary card will be provided to the subject at Day 8 (Visit 2) to record any 
unsolicited AEs and concomitant medications/products/vaccinations from Day 8 
until Day 30. The subject will be instructed to return the completed diary card to the 
investigators at the next study visit (Visit 3).

The investigator will collect and verify completed diary cards during discussion with 
the subject and transcribe the information into the eCRF (in English) at Visit 2 and 
Visit 3. 

Any unreturned diary cards will be sought from the subject through telephone call(s) 
or any other convenient procedure. 
 
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5.6.18.
Extension/Booster study
It is likely that the RSV antibodies elicited by the vaccine may wane during the period 
between pregnancies, therefore there may be a need to administer the vaccine during each 
pregnancy to achieve optimal anti-RSV antibody 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 MAT-001 study may be invited to participate 
in a booster study.
The investigator will ask each subject, at the time of informed consent, if she is interested 
in participating in a booster study and will document this in the source documents only. 
At study conclusion (Day 181 contact), the investigator will 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. Refusal to participate in the extension 
study will not prevent subjects from enrolling in the RSV MAT-001 study. 
5.6.19.
Day 181 Contact
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 is not done by telephone, if questions remain, the study site may 
follow-up with the subject via telephone.
During this contact, 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 and/ or whether she has become pregnant. The investigator (or delegate) will also 
ask the subject for concomitant vaccinations/products/medications that she has received 
since Visit 5. 
Subject’s interest in participating in a booster study will also be re-confirmed at Day 181
contact, and the corresponding information will be reported in the eCRF (refer to Section 
5.6.18).
Please refer to the SPM for further guidance.
5.6.20.
Study conclusion
The investigator will:

Review all data collected from all source documents (e.g. ICF, Diary Cards, etc.) to 
ensure accuracy and completeness.

Complete the Study Conclusion screen in the eCRF.
 
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5.7.
Biological sample handling and analysis
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be asked to give a specific consent 
to allow GSK or a contracted partner to use the samples for future research. Future 
research will be subject to the laws and regulations in the respective countries and 
will only be performed once an independent Ethics Committee or Review Board has 
approved this research.
Information on further investigations and their rationale can be obtained from GSK.
Any sample testing will be done in line with the consent of the individual subject.
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed.
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study contact), 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.
5.7.1.
Use of specified study materials
When materials are provided by GSK, it is MANDATORY that all clinical samples 
(including serum samples) be collected and stored exclusively using those materials in 
the appropriate manner. The use of other materials could result in the exclusion of the 
subject from the Per Protocol (PP) analysis (See Section 10.5 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 does not provide material for collecting and storing clinical samples, appropriate 
 
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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
Time point
Cohort
N° of 
subjects
Quantity
Unit
Blood for 
haematology/biochemical 
analysis
Screening Visit
All screened subjects
≥500
~5.5
ml
Visit 2 (Day 8)
All enrolled subjects
~500
~5.5
ml
Visit 3 (Day 31)
All enrolled subjects
~500
~5.5
ml
Unsch Visit
All enrolled subjects 
Event 
driven
~ 5.5
ml
Blood sampling for humoral 
immune response
Screening Visit*
All screened subjects
≥500
~30
ml
Visit 2 (Day 8)
All enrolled subjects
~500
~30
ml
Visit 3 (Day 31)
All enrolled subjects
~500
~30
ml
Visit 4 (Day 61)
All enrolled subjects
~500
~30
ml
Visit 5 (Day 91)
All enrolled subjects
~500
~30
ml
Urine1
Screening Visit
All screened subjects
≥500
Visit 1 (Day 1)
All enrolled subjects
~500
Total quantity of blood for each subject
~167¥
ml
*Humoral blood sample will not be tested and will be discarded if subject fails screening
¥Volume of blood sample collected at the unscheduled visits is not taken into account
1 Serum pregnancy test (instead of urine test) may be performed if required by country, local or ethics committee 
regulations.
5.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the serological assays 
performed in the study. 
Serological assays described in Table 7 will be performed at a GSK laboratory or in a 
laboratory designated by GSK and those in Table 8 will be performed at the 
investigator’s laboratory.
Please refer to APPENDIX B for the address(es) of the laboratories used for assessment 
of humoral immunity analysis.
 
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Table 7
Humoral Immunity (Antibody determination)
System
Component
Method
Kit / 
Manufacturer
Unit
Cut-off
Laboratory
Serum
Anti-RSV A 
Neutralizing 
Antibody
NEUTRALIZATION 
In house
ED60
TBD**
GSK Biologicals* 
Serum
RSVPreF3 IgG 
antibody 
concentrations
ELISA
In house at 
Neomed Labs
ELU/
mL
TBD**
Neomed Labs
ELISA = Enzyme-linked immunosorbent assay; ELU laboratory units; ED60 = serum dilution inducing 60% inhibition in 
plaque forming units; TBD = to be determined; IgG = immunoglobulin G
*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).
NA = not applicable
Table 8
Haematology, Serum Chemistry, Urine tests
System
Discipline
Component
Method
Scale
Laboratory
Whole 
blood
Haematology
Leukocytes (White Blood Cells)
As per local practice
Quantitative
At 
investigator’s 
laboratory
Lymphocytes
Eosinophils
Haemoglobin
Platelets
Neutrophils
Serum
Biochemistry
Alanine Aminotransferase (ALT)
As per local practice
Quantitative
Aspartate Aminotransferase (AST)
Creatinine
Blood Urea Nitrogen (BUN)/urea]*
Urine1
Pregnancy
As per local 
practice; dipstick 
provided by GSK 
Biologicals 
Ordinal
At 
investigator’s 
laboratory
* Sites not able to directly test for BUN, will test for urea and then convert urea values into BUN using the applicable 
established conversion factor(s). Only BUN values will be entered into the eCRF.
1 Serum pregnancy test (instead of urine test) may be performed if required by country, local or ethics committee 
regulations.
Additional Testing
Additional exploratory testing on serum samples to characterise the immune response to 
the RSV infection or the investigational RSV maternal vaccine, such as but not limited to,
RSVPreF3 IgG1 subclass antibody concentrations, RSV-B neutralising antibody titres, 
antibodies competing for binding to specific epitopes on RSVPreF3, and antibody 
concentrations to residual host cell proteins in the RSVPreF3 vaccines may be performed 
if deemed necessary for accurate interpretation of the data or should such test(s) become 
available in the GSK laboratory or a laboratory designated by GSK.
The GSK's clinical laboratories have established a Quality System supported by 
procedures. The activities of GSK's 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 9
Haematology/Blood Chemistry
Blood sampling time point
Sub-cohort 
Name 
No. subjects
Component
Type of contact 
(time point)
Sampling time 
point
Screening
Pre-vaccination
All Subjects
~500
Haematology (Leukocytes, 
Neutrophils, Lymphocytes, 
Eosinophils, Haemoglobin, 
Platelets)
Biochemistry (ALT, AST, 
Creatinine, and BUN/Urea*)
Visit 2 (Day 8)
Post-vaccination
All subjects
~500
Visit 3 (Day 31)
Post- vaccination
All subjects
~500
Unscheduled Visit
Post-vaccination
All subjects
event driven
ALT = Alanine Amino-transferase; AST = Aspartate Amino-transferase; BUN = Blood Urea Nitrogen 
* Sites not able to directly test for BUN, will test for urea and then convert urea values into BUN using the applicable 
established conversion factor(s). Only BUN values will be entered into the eCRF.
5.7.4.2.
Immunological read-outs
Table 10
Immunological read-outs
Blood sampling time point
Sub-cohort 
Name 
No. 
subjects
Component
Components 
priority rank 
Type of contact 
and time point
Sampling 
time point
Screening Visit
Pre-Vacc
All subjects
~500
RSV-A neutralising antibody
RSVPreF3 IgG antibody concentrations
1
2
Visit 2 (Day 8)
Visit 3 (Day 31)
Visit 4 (Day 61)
Visit 5 (Day 91)
Post-
vaccination
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 10.
5.7.5.
Immunological correlates of protection
No generally accepted immunological correlate of protection has been established so far 
for the antigen used in the investigational RSV vaccine.
 
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6.
STUDY VACCINES ADMINISTRATION
6.1.
Description of study vaccine
All candidate vaccines to be used have been developed and manufactured by GSK.
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 11
Study vaccine
Treatment name
Vaccine/product 
name
Formulation
Presentation
Volume to be 
administered
Number 
of 
doses
RSVPreF3 30
RSVPreF3 low 
dose
RSVPreF3=30µg
Freeze-dried Antigen 
(174µg/vial)
0.5 ml
1
NaCl
NaCl=150mM
Clear liquid in 
monodose ampule or 
vial
RSVPreF3 60
RSVPreF3 mid 
dose
RSVPreF3=60µg
Freeze-dried Antigen 
(174µg/vial)
0.5 ml
1
NaCl
NaCl=150mM
Clear liquid in 
monodose ampule or 
vial
RSVPreF3 120
RSVPreF3 high 
dose
RSVPreF3=120µg
Freeze-dried Antigen 
(174µg/vial)
0.5 ml
1
NaCl
NaCl=150mM
Clear liquid in 
monodose ampule or 
vial
Control
NaCl
NaCl=150mM
Clear liquid in 
monodose ampule or 
vial
0.5 ml
1
6.2.
Storage and handling of study vaccine
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 Day 91), 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.
Temperature excursions must be reported in degree Celsius.
 
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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 details and instructions on
the storage, the temperature excursion reporting and usage decision process, packaging 
and accountability of the study vaccines.
6.3.
Dosage and administration of study vaccine
Table 12
Dosage and administration
Type of 
contact and 
time point
Study group
Treatment name
Volume to be 
administered
Route
Site
Location
Laterality
Visit 1 (Day 1)
RSV MAT 30
RSV MAT 60
RSV MAT 120
Placebo
RSVPreF3 30
RSVPreF3 60
RSVPreF3 120
Control
0.5 ml
IM
Deltoid
Non-
dominant*
IM = intramuscular
*In case of anatomical features, medical indication or skin colouration (e.g. tattoos) that prevents vaccination in the 
non-dominant arm, the vaccine may be administered in the dominant arm.
6.4.
Replacement of unusable vaccine
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. 
The subject may be vaccinated at a later date, within the time window specified in the 
protocol (See Table 5) or the subject may be re-screened or withdrawn at the discretion of 
the investigator:

Acute disease and/or fever at the time of vaccination.

Fever is defined as temperature 38.0°C / 100.4°F by any 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 the study vaccine.
6.6.
Concomitant medications/products and concomitant 
vaccinations
At each study visit/contact, the investigator should question the subject about any 
medications/products taken and vaccinations received.
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/vaccinations/products, except vitamins and dietary 
supplements, administered as of study vaccination and up to 29 days after 
vaccination (Day 1 to Day 30).

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring (Fever is defined as 
temperature 38.0°C/100.4°F regardless the location of measurement).

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 requirements 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.
 
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6.6.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from Per Protocol analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
PP analysis. See Section 10.5 for cohorts to be analysed.

The use of any investigational or non-registered product (drug or vaccine) other than 
the study vaccine up to study completion (Contact 1 [Day 181]).

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 ≥5mg/day prednisone 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/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 Per Protocol analyses
At each study visit subsequent to vaccination and up to study end it must be verified if 
the subject has experienced or is experiencing any intercurrent medical condition. If it is 
the case, the condition(s) must be recorded in the eCRF.
Subjects may be eliminated from the Per Protocol Set (PPS) for immunogenicity if, 
during the study period up to Day 91 (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/the 
subject 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.
 
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Examples of an AE DO NOT include:

Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
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 
 
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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.
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 13
Solicited local adverse events
Pain at injection site
Redness at injection site
Swelling at injection site
8.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 14
Solicited general adverse events
Fatigue
Fever *
Gastrointestinal symptoms †
Headache
* Fever is defined as temperature 38.0°C/100.4°F regardless the location of measurement (oral is preferred)
†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 diary card and 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) or other abnormal assessments that are judged by the investigator to be 
clinically significant will be recorded as an 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. 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.
 
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*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 C].
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, but will be followed to determine the outcome of the 
pregnancy. 
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, 2017]. It is recognized that national 
regulations might be different.

Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life). 

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the 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 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 within 30 days following administration of the study vaccine (Day 1 to 
Day 30) 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 the study 
vaccine and will end at the contact at Day 181. 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 the study vaccine.
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 the 
study vaccine and will end at the contact at Day 181. See section 8.4 for instructions on 
reporting of pregnancies.
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in Table 15.
 
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Table 15
Reporting periods for collecting safety information
Event
Screening Visit 1
Day 7
Visit 2
Day 30
Visit 3
Visit 4
Visit 5
Contact 
Day 1
end of 7-
day FU
Day 8
end of 
30-day 
FU
Day 31
Day 61
Day 91
Day 181
Study 
conclusion
Solicited local 
and general 
AEs
Unsolicited 
AEs
AEs/SAEs 
leading to 
withdrawal 
from the study
Serious 
adverse 
events
SAEs related to 
study 
participation* 
or concurrent 
GSK 
medication/vacci
ne 
Pregnancies 
*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
Type
Solicited adverse events /Unsolicited adverse 
events/ Serious adverse events
Method of ‘solicited’ follow-up
Diary cards
Method of ‘unsolicited’ follow-up
Diary cards/Questioning at study visits
Method for reporting SAEs
Electronic Expedited Adverse Events Report
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 15. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccines, the investigator will promptly 
notify the Study Contact for Reporting SAEs.
 
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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 vaccine(s) 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) related 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 instead of appropriately completing the eCRF. However, there may be 
instances when copies of medical records for certain cases are requested by GSK. In this 
instance, all subject identifiers will be blinded on the copies of the medical records prior 
to submission to GSK.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms.
8.3.3.2.
Assessment of adverse events
8.3.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
 
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Table 16
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(defined as temperature ≥38°C /100.4°F)*
Record temperature in °C/°F
Temperature will be analysed in 0.5°C increments from ≥
38.0°C /100.4°F)
Grade 3 fever is defined as > 39.0°C /102.2°F
Headache
0
Normal
1
Mild: Headache that is easily tolerated
2
Moderate: Headache that interferes with normal activity
3
Severe: Headache that prevents normal activity
Fatigue
0
Normal
1
Mild: Fatigue that is easily tolerated
2
Moderate: Fatigue that interferes with normal activity
3
Severe: Fatigue that prevents normal activity
Gastrointestinal symptoms
0
Normal
(nausea, vomiting, diarrhoea and/or 
abdominal pain)
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 38.0°C/100.4°F [Marcy, 2004] regardless of the location of measurement (oral is 
preferred)
The maximum intensity of local injection site (redness and swelling) will be scored at 
GSK Biologicals as follows:
0
:
≤ 20 mm
1
:
> 20 mm to ≤50 mm
2
:
> 50 mm to ≤100 mm
3
:
>100 mm
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
 
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The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities. 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 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. 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. 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.
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.
 
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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 vaccine(s), 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.
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
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to
GSK within the timeframes described in Table 17, once the investigator determines that 
the event meets the protocol definition of a SAE.
 
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Pregnancies that occur in the time period defined in Section 8.3 will be reported promptly 
to GSK within the timeframes described in Table 17, once the investigator becomes 
aware of the pregnancy.
Table 17
Timeframes for submitting serious adverse event and pregnancy to 
GSK 
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours*‡
Electronic SAE report
24 hours*
Electronic SAE 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 hour and 7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US sites:
Fax: 
or 
Email address:
US sites only:
Fax: 
8.4.3.
Completion and transmission of SAE reports to GSK
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
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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 Event Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 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 
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
should be estimated by ultrasound examination and recorded in the pregnancy report.
8.4.5.
Updating of SAE and pregnancy information after removal of 
write access to the subject’s eCRF
When additional SAE or 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 Clinical Safety and Pharmacovigilance department 
within the designated reporting time frames specified in Table 17.
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 has a legal responsibility to promptly notify, as 
appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for (a)
SAE(s) that is/are both attributable to the study vaccine and unexpected. The purpose of 
the report is to fulfil specific regulatory and GCP requirements, regarding the product 
under investigation.
 
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8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies
8.5.1.
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 
(within 24 hours for SAEs; refer to Table 17).
All AEs/SAEs documented at a previous visit and designated as either on-going, not 
recovered/not resolved or recovering/resolving will be reviewed at subsequent visits until 
the end of the study.
8.5.2.
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 using a paper/ electronic Expedited Adverse 
Events Report and/or pregnancy report as applicable.
GSK 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 will be 
provided with any available post-mortem findings, including histopathology.
8.5.3.
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 using the electronic pregnancy report and the 
Expedited Adverse Events Report if applicable. Generally, the follow-up period does not
need to be longer than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as a 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)
 
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8.7.
Unblinding
GSK’s 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’s 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 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.
GSK Biologicals’ Contact information for Emergency Unblinding
24/24 hour and 7/7 day availability
GSK Biologicals’ Central Safety Physician:
Outside US:
(GSK Biologicals Central Safety Physician on-call)
For US Only:
(GSK Biologicals Central Safety Physician on-call)
GSK Biologicals’ Central Safety Physician Back-up:
Outside US:
For US Only:
Emergency Unblinding Documentation Form transmission:
Outside US
Fax: 
or 
For US Only:
Fax: 
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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 during 
the study duration.
8.10.
Holding rules and safety monitoring
8.10.1.
Safety review team (SRT)
The SRT includes as core members the GSK’s Central Safety Physician, Central Safety 
Scientist, the Clinical and 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, unblinded safety evaluations will be performed by an 
iSRC at regular intervals and ad hoc as needed. 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 (iSRC) Evaluation
As this will be the first time that the RSV maternal vaccine will be administered in 
humans, the study will enrol subjects in two steps with randomisation to all dose levels
from the start (see also Figure 1). Safety monitoring will be performed by an iSRC, 
authorised by the GSK’s Vaccines Safety Monitoring Board (VSMB), and holding rules 
have been established to ensure the safety of the subjects in the study.
The iSRC will include the following GSK personnel: a Safety Physician (Vaccines 
Clinical Safety and Pharmacovigilance representative), a Clinician (CEPL or CRDL), and 
a Statistician, all 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 (a) ad hoc, non-voting member(s): (an) independent 
statistician(s) in charge of providing unblinded data to the iSRC.
This study has 3 planned iSRC reviews.
Only if no safety signal is observed during each of the 2 (Day 8 and Day 31) planned 
safety evaluations after the first 12% of subjects have been enrolled (Step 1) [See Figure 
1 and Figure 2], the screening and enrolment/vaccination of the remaining subjects (Step 
2) can start. 
 
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Another iSRC review is planned to review the safety data up to at least Day 91 and 
immunogenicity data up to at least Day 31 for all subjects (Step 1 and Step 2) enrolled in 
the study.
In addition to the above planned iSRC evaluations, ad hoc iSRC reviews can be 
organized, as deemed necessary at any time during the study.
During the planned (and any ad-hoc, if applicable) iSRC safety evaluations, 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.
Favourable outcome of the safety reviews will be documented and provided in writing to 
the RSV study team and investigator(s). 
If a safety signal is observed during the planned safety evaluations or during ad hoc
reviews, the iSRC Chair is responsible for urgent communication and escalation of the 
concern to the GSK’s Chief Medical Officer (CMO), who may choose to involve the 
VSMB or VSMB sub-team, and will communicate the outcome to the study team. The 
CMO will then decide during an ad hoc meeting whether to suspend, modify or continue 
the conduct of the study. 
Already vaccinated subjects will continue with all planned visits, including the capture of 
all safety data. However, further enrolment/vaccination cannot proceed until CMO (with 
or without the involvement of VSMB) review and corresponding outcome is available.
The decision of the GSK’s iSRC will be documented and provided in writing to the 
Primary Contact for the study (study CRDL) who will ensure further communication of 
the outcome to investigator(s). Ethics Committees and Competent Authorities will also be 
notified, as applicable.
Details about the working procedures of the iSRC will be documented in an iSRC 
Charter.
8.10.3.
Holding rules
The safety holding rules 1a through 1d, as defined in Table 18, will be applied throughout 
the enrollment period of the study. In addition, the safety holding rules 2a through 2c will 
be applied for the iSRC reviews.
 
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Table 18
Study holding rules
1 Grading of laboratory parameters will be based on the FDA Guidance for Industry [APPENDIX C]“Toxicity Grading 
Scale for Healthy Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”. Those laboratory 
parameters not included in the FDA Toxicity Grading Scale will not be graded.
8.10.4.
Risk assessment
Figure 3
Risk assessment curve for one formulation based on the proposed 
safety holding rules after 15 subjects/group at step 1
Holding 
Rule
Event
Number of 
Subjects per 
group/ % of 
subjects per 
group
1a
Death or any life-threatening SAE
≥ 1
1b
Any non-life threatening SAE that cannot reasonably be attributed to a cause 
other than vaccination
≥ 1
1c
Any withdrawal from the study (by investigator or subject request) following a 
Grade 3 AE that cannot reasonably be attributed to a cause other than 
vaccination
≥ 1
1d
Any local or general solicited AE leading to hospitalization, or fever > 40°C
(104°F) that cannot reasonably be attributed to a cause other than vaccination, 
or necrosis at the injection site, within the 7-day (day 1-7) post-vaccination 
period 
≥ 1
2a
Any Grade 3 solicited local AE lasting 48h or more in an investigational group, 
within the 7-day (day 1-7) post-vaccination period 
≥3 AND ≥20%
2b
Any Grade 3 solicited general AE lasting 48h or more in an investigational 
group, that cannot reasonably be attributed to a cause other than vaccination, 
within the 7-day (day 1-7) post-vaccination period
≥3 AND ≥20%
2c
Any Grade 3 unsolicited AE in an investigational group, that cannot reasonably 
be attributed to a cause other than vaccination, within the 7-day (day 1-7) post-
vaccination period
OR
Any Grade 3 abnormality in pre-specified hematological or biochemical 
laboratory parameters in an investigational group, that cannot reasonably be 
attributed to a cause other than vaccination, at day 8 post-vaccination 1
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Figure 3 above illustrates that, with 15 subjects per group:

Each holding rule 1 (a-d) has more than 40% chance of not being met for a vaccine 
with a true incidence rate below 5% and has more than 90% chance of being met for 
a vaccine with a true incidence rate above 20%.

Each holding rule 2 (a-c) has more than 80% chance of not being met for a vaccine 
with a true incidence rate below 10% and more than 80% chance of being met for a 
vaccine with a true incidence rate above 30%.
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who is available for Contact 1 at Day 181 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 Contact 1 at Day 181 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 Contact 1 at Day 181.
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, or by the investigator, as well as which of the following possible reasons was 
responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.
 
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
Lost to follow-up.

Sponsor study termination.

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 a result of a SAE/AE until 
resolution of the event (see Section 8.5.2).
9.3.
Screening Failures
Screening failures are defined as subjects who are withdrawn from the study after giving 
informed consent, but who do not meet the inclusion and exclusion criteria. 
The following information will be collected for screening failures:

Informed consent.

Inclusion/Exclusion Criteria.

Demographic Data.

Physical Examination.

Blood Sample for haematology/biochemistry.

Pregnancy test results.

SAEs related to study participation or any fatal SAE.

Screening conclusion.
In order to allow a proper control of recruitment and not jeopardize the enrolment of 
eligible subjects into the study, as soon a subject is identified as being a screening failure, 
the site staff will access SBIR and withdraw that subject from the application.
9.4.
Extension study
During the study conclusion contact (Contact 1 / Day 181) the investigator will re-
confirm a subject’s interest to participate in a booster /re-vaccination study and the 
corresponding information will be reported in the eCRF.
If a subject is not interested in participating in the booster study the reason for refusal will 
be documented in the subject’s eCRF (refer to Section(s) 5.6.18 and 5.6.19).
 
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10.
STATISTICAL METHODS
10.1.
Primary endpoints

Occurrence of any adverse events (AEs) from vaccination during a 30-day follow-up 
period, for all subjects in all groups:

Occurrence of each solicited local and general symptom during a 7-day 
follow-up period.

Occurrence of any unsolicited AE during a 30-day follow-up period.

Occurrence of Serious AEs during a 30-day follow-up period.

Occurrence of any haematological (Leukocytes, Neutrophils, Lymphocytes, 
Eosinophils, Haemoglobin, Platelets) and biochemical (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], creatinine, blood urea nitrogen 
[BUN]) laboratory abnormalities at Day 8 and Day 31.
10.2.
Secondary endpoints

Occurrence of SAEs from vaccination up to Day 91 and up to Day 181 for all 
subjects, in all groups.

Humoral immune response to the investigational vaccine at Day 8, Day 31, Day 61 
and Day 91 for all subjects in each investigational RSV vaccine group

RSV-A neutralising antibody (Nab) titres

RSVPreF3 IgG antibody concentrations
10.3.
Tertiary endpoints
Additional humoral response which may include but not limited to, RSVPreF3 specific 
IgG1 subclass antibody concentrations, RSV-B neutralising antibody titres, antibody 
competing for binding to specific epitopes on RSVPreF3 and antibody concentrations to 
residual host cell proteins in the RSVPreF3 vaccines
10.4.
Determination of sample size
This section provides justification of sample size in terms of safety and immunogenicity. 
Table 19 illustrates the precision with exact 95% confidence interval on the percentage of 
subjects with AEs following vaccination with 125 subjects per group. If an AE is not 
observed in a given treatment group, we are 95% confident that the true incidence rate of 
an AE is less than or equal to 2.9%, in the treatment group. Furthermore, a sample size of 
125 subjects per group provides a probability of 80% or 90% to observe at least one AE 
if the true incidence rate is 1.3% or 1.8% respectively. 
 
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Table 19
Exact 95% confidence interval on the percentage of subjects with 
adverse events following vaccination for 125 subjects per group
Number (%) of 
subjects with an AE
Exact 95% Confidence Interval
Lower Limit (%)
Upper Limit (%)
0 (0%)
0.00
2.9
13 (10%)
5.4
16.6
25 (20%)
13.4
28.1
38 (30%)
22.1
38.8
50 (40%)
31.3
49.1
63 (50%)
40.9
59.1
75 (60%)
50.9
68.7
88 (70%)
61.2
77.9
100 (80%)
71.9
86.6
113 (90%)
83.4
94.6
125 (100%)
97.1
100
CI = confidence interval; LL/UL = lower/upper limit 
Exact 95% CI computed based on Clopper/Pearson formula
Based on the results of Day 30 analysis from previous RSV vaccine studies, the standard 
deviation (SD) of RSV-A Nab titre is approximately 0.4 on its log10 transformation. 
Table 20 (below) presents the precision estimation on fold increases in RSV-A Nab titres 
between two investigational RSV vaccine dose groups, when the sample size is 125
subjects/group, with a range of SD 0.3-0.5 and 95% confidence interval for assumed fold 
increases of 1.3-2.
Assuming a 2-fold increase of RSV-A Nab between the high and low dose groups, with 
125 subjects per group, the 95% confidence interval on the fold increase will be (1.5, 
2.67) if a standard deviation of log10 transformed RSV-A Nab of 0.5 is assumed. There 
is a very small (0.3%) chance that the SD will be larger than 0.5 assuming a chi-square 
distribution with degree of freedom 124 and mean 0.4.
The power to detect 1.5 fold increase between two groups using one-sided Z test with 
2.5% significant level will be at least 90%  with SD 0.4 and 80% with SD 0.5 assumed.
The power to detect 1.3 fold increase between two groups using one-sided Z test with 
2.5% significant level will be 85%  with SD 0.3 and 62% with SD 0.4 assumed.
 
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Table 20
Precision Estimation 
Fold 
increase 
btw 2 
groups 
No. of 
Subjects per 
group
SD**
Precision*
95% CI
LL
95% CI
UL
1.3
125:125
0.3
0.075
1.09
1.55
1.3
125:125
0.4
0.1
1.03
1.64
1.3
125:125
0.5
0.125
0.97
1.73
1.5
125:125
0.3
0.075
1.26
1.78
1.5
125:125
0.4
0.11
1.19
1.89
1.5
125:125
0.5
0.125
1.12
2
2
125:125
0.3
0.075
1.68
2.38
2
125:125
0.4
0.1
1.59
2.52
2
125:125
0.5
0.125
1.5
2.67
*Precision estimation using PASS 12.0.2 (Confidence Interval for two means), LL: Lower Limit, UL: Upper Limit
**Standard deviation of log10 of RSV-A Nab titre. The highest standard deviation observed 30 days after vaccination in 
a previous GSK RSV study was 0.4.
10.5.
Cohorts for Analyses
In order to align to ICH and CDISC terminology, the Total Vaccinated Cohort and the 
According To Protocol cohort have been renamed Exposed Set (ES) and Per Protocol Set
(PPS) respectively. Two cohorts will be defined for the purpose of the analysis: the ES 
and the PPS for analysis of immunogenicity. All analyses will be performed per treatment 
actually administered.
10.5.1.
Exposed Set (ES)
The ES will include all subjects with study vaccine administration documented: 

A safety analysis based on the ES will include all vaccinated subjects.

An immunogenicity analysis based on the ES will include all vaccinated subjects for 
whom immunogenicity data are available. 
10.5.2.
Per-protocol set (PPS) for analysis of immunogenicity
The PPS 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).

Who received the study vaccine according to protocol procedures.

Who did not receive a concomitant vaccination/medication/product leading to 
elimination from the PPS analysis up to the corresponding time-point as described in 
Section 6.6 of the Protocol.
 
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
Who did not present with an intercurrent medical condition leading to elimination
from the PPS analysis up to the corresponding time-point, as described in Section 6.7
of the Protocol. 

Who complied with the post-vaccination immunogenicity blood sampling schedule 
at the corresponding time-point, as specified in Table 6 of the Protocol. 

For whom post-vaccination immunogenicity results are available for at least 1 assay 
at the corresponding time-point, as specified in Table 10 of the Protocol.
When presenting different time-points, the PPS for immunogenicity will be adapted for 
each time-point (Day 8, Day 31, Day 61 and Day 91).
10.6.
Derived and transformed data
The study groups will be defined by treatment actually administered.
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 within 7 days post-
vaccination, missing or non-evaluable measurements will not be replaced. Therefore 
the analysis of the solicited symptoms based on the ES will include only vaccinated 
subjects for doses with documented safety data (i.e., symptom screen completed).

For analysis of unsolicited adverse events (including SAEs) categorized by primary 
Medical Dictionary for Regulatory Activities (MedDRA) term, all vaccinated subjects 
will be considered. Subjects who did not report the event will be considered as 
subjects without the event.

For the analysis of concomitant medications, all vaccinated subjects will be 
considered and analysis will be performed on the ES. Subjects who did not report the 
concomitant medication will be considered as subjects without concomitant 
medication.
Immunogenicity

For a given subject and given immunogenicity measurements, missing or non-
evaluable measurements will not be replaced. Therefore, an analysis will exclude 
subjects with missing or non-evaluable measurements.

A seronegative subject is 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/Concentrations(GMT/GMCs) calculations are 
performed by taking the anti-log of the mean of the log titre transformations. 
Antibody titres below the cut-off of the assay will be given an arbitrary value of half 
the cut-off of the assay for the purpose of GMT/GMC calculation. The cut off values 
are defined by the laboratory before the analysis and will be described in the 
Statistical Analysis Plan (SAP).
 
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
In order to compute fold increase of antibody titres/concentrations (ratio) between 
post-vaccination and pre-vaccination titres/concentrations, antibody 
titres/concentrations below the assay cut-off will be given an arbitrary value of half 
the cut-off.

The handling of data below the assay cut offs for GMT/GMC calculations will be 
described in the SAP.
10.7.
Analysis of demographics
The analysis of demographics will be performed on the ES and on the PPS for 
immunogenicity.
Demographic characteristics such as age at vaccination in years, race, ethnicity, vital 
signs 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 PPS analyses will be tabulated. 

The number of withdrawn subjects will be tabulated according to the reason for 
withdrawal. 
10.8.
Analysis of safety
10.8.1.
Within groups assessment
The primary analysis of safety will be performed on the ES. 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 any Grade 2 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, each grade, 
resulting in medically attended visit) during the 7-day follow-up period after vaccination 
will be tabulated based on maximum intensity per subject for each study vaccine group. 
The percentage of subjects reporting each individual solicited general AE (any, each 
grade, any related, any Grade 2 related, any Grade 3 related, resulting in medically 
attended visit) during the 7-day follow-up period after vaccination will be based on 
maximum intensity per subject for each study vaccine group.
 
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For fever during the 7-day follow-up period after vaccination, the number and percentage 
of subjects reporting any fever (i.e., temperature ≥38 °C) and fever by half degree (°C ) 
cumulative increments will be reported. Similar tabulations will be performed for 
causally related fever, Grade 3 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.
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 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, respectively ) during the 7-day 
follow-up period (Day 1 - 7), 30 days follow-up (Day 1 – 30), between Day 1 – Day 91 
and between Day 1- Day 181 after vaccination will be summarized 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 time point. 

The maximum grading post-vaccination (from Day 8 to Day 31) versus baseline 
(Screening) 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 C of the Protocol: FDA toxicity grading scale. Those laboratory 
parameters not included on FDA Toxicity Grading Scale will not be graded). 
10.9.
Analysis of immunogenicity
The analysis will be performed on the applicable PPS cohort for immunogenicity and, if 
in any group the percentage of vaccinated subjects with serological results excluded from 
the PPS for analysis of immunogenicity is ≥5%, a second analysis will be performed on 
the ES. 
 
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10.9.1.
Within groups assessment
Humoral Immune response to RSV vaccine 
For each group, at each time point that blood samples are collected and for each assay 
(Anti-RSV-A Nab and RSVPreF3 IgG ) (unless specified otherwise): 

GMTs/GMCs will be tabulated with 95% CI based on log-transformed values and 
represented graphically. 

Percentage of subjects above the seropositivity threshold will be tabulated with exact 
95% CI. 

Pre- and Post- Nab titres/concentrations will be displayed using reverse cumulative 
curves. 

The distributions of Nab titres (Percentage of subjects greater than or equal to 
specified thresholds) will be tabulated. 

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 post-vaccination over pre-
vaccination will be tabulated with 95% CI. 

Distribution of the fold increase of the antibody titres will be tabulated.

The kinetics of individual antibody titres/concentrations will be plotted as a function 
of time for subjects with results available at all time points. 

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 performed by age category (18 - 32 years 
and 33 - 45 years).
Fold increase of RSVPreF3 immunoglobulin G (IgG) antibody concentrations over fold 
increase of RSV-A Nab titres will be calculated. This analysis will include calculation on:

Geometric mean ratios with corresponding 95% CIs of RSVPreF3 immunoglobulin 
G (IgG) antibody concentration over anti-RSV-A plaque reduction Nab titres at pre-
vaccination for each group and 

Geometric mean ratios with corresponding 95% CIs of fold increase post/pre (Day 8, 
Day 31, Day 61 and Day 91/Day 1) between RSVPreF3 immunoglobulin G (IgG) 
antibody concentration and anti-RSV-A plaque reduction Nab titres for each group.
Details of statistical analysis on exploratory endpoints will be described in Statistical 
Analysis Plan (SAP).
 
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10.9.2.
Between groups assessment
Exploratory comparisons will be performed for RSV-A Nab titres and RSVPreF3 IgG 
antibody concentrations between the different RSV vaccine groups at Day 31. If deemed 
necessary this exploratory comparisons may also be done at other time-points.

The three RSV formulations will be first compared to the Placebo in order to identify 
groups whose means are significantly different from the mean of the Placebo group, 
(alpha=2.5%, Dunnett’s adjustment test for multiplicity). 

Estimation of GMT/GMC ratios between groups with corresponding 95% CI using 
an ANCOVA model on the logarithm10 transformation of the titres/concentrations. 
This model includes: 

The vaccine group as the fixed effect

The pre-vaccination titre/concentration as the covariate

Age groups (18 - 32 years and 33 - 45 years) and/or centre as the categorical 
covariate if deemed necessary

GMT/GMC ratios with corresponding 95% CI will be computed between the RSV 
vaccine groups

Linear and quadratic trend of dose response will be tested using appropriate 
contrasts.
10.10.
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.
10.11.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
10.11.1.
Sequence of analyses
In preparation of the three planned iSRC evaluations, analyses of all available safety data, 
and if applicable all available immunogenicity data will be performed (see Section 8.10.2
for more information). These analyses will be done by an unblinded statistician outside 
GSK to maintain the study blinding, and will be documented in the statistical analysis 
report. Only the outcome of the iSRC review will be communicated to the RSV study 
team (no safety signal or safety signal). No clinical study report will be written at this 
time. 
 
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In order to obtain early immunogenicity data of the different formulations of the 
investigational RSV Maternal vaccine, an interim analysis will be performed when 
immunogenicity data up to Day 31 for the Step 1 subjects becomes available. This 
analysis will be performed on data as available (i.e partially clean or non-clean data). 
To ensure the study team remains blinded, the analysis will be performed by an
unblinded statistician outside GSK and the iSRC will act as a firewall team, to review the 
aggregated summaries for risk of unblinding of individual subjects, before these are 
released to the team.
For this analysis only a statistical report will be prepared
The final statistical analyses will be performed in 2 steps:

A first analysis will be performed when all safety and immunogenicity data up to at 
least Day 91 is available in all subjects. At this point, the study statistician will be 
unblinded (i.e. will have access to the individual subject treatment assignments), but 
no individual listings will be provided to investigators until the study report.
However, summary results may lead to the unblinding of some specific subjects in 
case an event occurred only in one group; steps will be taken to minimize this risk. 

The final analysis covering all primary and secondary endpoints as well as any 
evaluated tertiary endpoint(s) will be performed when all data up to study conclusion 
are available. A clinical study report will only be written at this stage and individual 
listings will be provided as part of it.
If the data for tertiary endpoints becomes available at a later stage, (an) additional 
analysis/analyses will be performed. These data will be documented in annex(es) to the 
study report and will be made available to the investigators at that time. 
10.11.2.
Statistical considerations for interim analyses
All analyses are descriptive. Therefore, the conduct of interim analyses has no impact on 
interpretation of study results. 
11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled. 
11.1.
Case Report Form/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 by the investigator or appropriately qualified designee. In all 
cases, the investigator remains accountable for the study data. 
The investigator will be provided with the final version of the data generated at the 
investigational site once the database is archived and the study report is complete and 
approved by all parties.
11.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst other items, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform 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 investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form. 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
 
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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 30 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 and to have 
 
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secondary endpoint disclosed at latest 12 months after the last subject last visit 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. In this case, the protocol shall specify when the results are going to be 
submitted, together with a justification.
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors.
11.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures and relevant reports, and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
11.7.
Data Sharing
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non- GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions.
12.
COUNTRY SPECIFIC REQUIREMENTS
12.1.
Requirements for Germany
Explanatory statement concerning Gender Distribution (Article 7, paragraph 2 (12) 
of the German GCP ORDER)
GSK’s investigational RSV maternal vaccine (GSK3888550A) is 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 RSV MAT-001 study.
 
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13.
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formalin inactivated response syncytial virus confer protection without vaccine-enhanced 
disease. Antiviral Res. 2014;104:1-6.
Langley JM, Aggarwal N, Toma A, et al. A randomized, controlled, observer-blinded 
phase 1 study of the safety and immunogenicity of a respiratory syncytial virus vaccine 
with and without alum adjuvant. J Infect Dis.2017;215(1):24-33.
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.
Marcy SM, Kohl KS, Dagan R, et al. The Brighton Collaboration Fever Working Group -
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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-
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Ngwuta JO, Chen M, Modjarrad K, et al. Prefusion F-specific antibodies determine the 
magnitude of RSV-neutralising activity in human sera. Sci Transl Med. 2015; 
7(309):309ra162.
Nyiro JU, Kombe IK, Cande CJ, et al. Defining the vaccination window for respiratory 
syncytial virus (RSV) using age-seroprevalence data for children in Kilifi, Kenya. Plos 
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paediatric population in Spain. Epidemiol. Infect. 2003; 131: 867-72.
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APPENDIX A
LABORATORY ASSAYS
Descriptions of available assays are provided below. Assay descriptions could be subject
to change, due to assay re-development and/or qualification. Assay Standard Operating 
Procedures and characterization/qualification reports will be submitted to FDA upon 
availability.
RSV A/B neutralization assay
The serum neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralize RSV entry and replication in a host cell line.
First, virus neutralization is performed by incubating a fixed amount of RSV-A strain 
(Long) or RSV-B strain (B18537) 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 horse-radish peroxidase (HRP), allowing the visualization of plaques after 
coloration with TrueBlueTM peroxidase substrate. 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 Nab titres 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 as 
described by others [Barbas, 1992; Bates, 2014].
RSVPreF3 ELISA
The RSVPreF3 IgG and IgG1 ELISA’s are under development. The assays will be based 
on an indirect ELISA allowing the detection and the quantification of total IgG or IgG1 
antibodies directed against RSVPreF3 in human serum samples.
The principle of this assay will be as follows: RSVPreF3 antigen will be adsorbed onto a 
96-well polystyrene microplate. After a washing and a blocking step, dilutions of serum 
samples, controls and standards will be added to the coated microplate. A reference 
standard curve will be prepared using a pool of commercial human serum containing 
anti-RSV antibodies. After incubation, the microplate will be washed to remove unbound 
primary antibodies. Bound IgG or IgG1 will be detected by the addition of a secondary 
anti-human antibody conjugated to HRP. Bound antibodies are quantified by the addition 
of the HRP substrate, tetramethylbenzidine and hydrogen peroxide, whereby a colored 
product develops proportionally to the amount of anti-RSVPreF3 IgG or IgG1 antibodies 
present in the serum sample. The optical density of each sample dilution is then 
interpolated on the reference standard. The corresponding antibody concentration, 
corrected for the dilution factor, is expressed in arbitrary ELISA Laboratory Units per 
milliliter (ELU/mL).
 
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Epitope specific competition assay
Epitope specific competition assays are based on the competitive binding between a 
labelled epitope-specific monoclonal antibody and non-labelled antibodies present in 
serum samples and targeting the same epitope on a coated antigen. A competition assay 
specific for the site 0 epitope, using RSVPreF3 protein as coating antigen, is under 
development.
The principle of competition assays is as follows: The RSVPreF3 protein antigen will be 
coated onto an assay plate. After blocking, dilutions of control serum or sample, as well 
as labelled, epitope-specific, monoclonal antibody, are added to the coated plate. If 
epitope-specific antibodies are present in serum samples, they will compete with the 
monoclonal antibody for binding to the epitope on the antigen-coated plate. After 
washing, the bound, labelled antibody is then quantitated using a validated chromogenic 
detection system. The intensity of the detected signal is inversely proportional to the 
concentration of the epitope-specific antibodies present in the sample. 
The antibody concentrations are calculated for each control and sample by transforming 
the OD values corresponding to the dilutions into a % competition value, and from this, 
the epitope-specific antibody concentration of the samples and controls is calculated.
References:
Barbas, C. F., J. E. Crowe et al. “Human Monoclonal Fab Fragments Derived from a 
Combinatorial Library Bind to Respiratory Syncytial Virus F Glycoprotein and 
Neutralize Infectivity.” Proceedings of the National Academy of Sciences of the United 
States of America 89, no. 21 (November 1, 1992): 10164–68.
Bates, John T., Christopher J. Keefer et al. “Escape from Neutralization by the 
Respiratory Syncytial Virus-Specific Neutralising Monoclonal Antibody Palivizumab Is 
Driven by Changes in on-Rate of Binding to the Fusion Protein.” Virology 454–455 
(April 2014): 139–44. 
 
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APPENDIX B
CLINICAL LABORATORIES
The samples for Haematology and Biochemistry assessment as well as the pregnancy 
status of the subject will be tested locally at the investigators’ laboratory.
The samples for immunogenicity assessment will be tested at GSK Biologicals’ 
laboratories or at outsourced laboratories designated by GSK. 
Table 21
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biological’s Clinical 
Laboratory Sciences, Rixensart 
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart –
Belgium 
GSK Biological’s Clinical 
Laboratory Sciences, Wavre-
Nord Noir Epine
Avenue Fleming, 20 - B-1300 Wavre - Belgium
Table 22
Outsourced laboratories
Laboratory
Address
NÉOMED-LABS Inc.
525, Cartier Ouest Laval
Quebec Canada H7V 3S8
 
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APPENDIX C
FDA GUIDANCE FOR INDUSTRY: TOXICITY 
GRADING SCALE FOR HEALTHY ADULT AND 
ADOLESCENT VOLUNTEERS ENROLLED IN 
PREVENTIVE VACCINE CLINICAL TRIALS 
(SEPTEMBER 2007)
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking 
on this topic. It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public. You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes and regulations. If you want to 
discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify 
the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance.

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 categorise 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
Blood Urea Nitrogen BUN mg/dL
23 – 26
27 – 31
> 31
Requires 
dialysis
Liver Function Tests -ALT, AST
increase by factor
1.1 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10 x ULN
> 10 x ULN
ULN = upper limit of the normal range.
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium value that falls within a 
Grade 3 parameter (125-129 mE/L) should be recorded as a Grade 4 hyponatremia event if the subject had a new 
seizure associated with the low sodium value.
 
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Hematology*
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially 
Life 
Threatening 
(Grade 4)
Hemoglobin (Female) - gm/dL
11.0 – 12.0
9.5 – 10.9
8.0 – 9.4
< 8.0
Hemoglobin (Female)
change from baseline value -
gm/dL
Any decrease -
1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
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
Hypereosino
philic
Platelets Decreased - cell/mm3
125 000 –
140 000
100 000 –
124 000
25 000 – 99 000
< 25 000
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.

REFERENCES for the Appendix C
1.
National Cancer Institute Common Toxicity Criteria, April 30, 1999. 
(http://ctep.cancer.gov/reporting/CTC-3.html) 
2.
Division of AIDS Table for Grading Severity of Adult Adverse Experiences; August 
1992. (http://rcc.tech-res-intl.com/tox_tables.htm) 
3.
The Brighton Collaboration. Finalized Case Definitions and Guidelines. 
(http://brightoncollaboration.org/internet/en/index/definition___guidelines.html) 
4.
HIV Vaccine Trials Network Table for Grading Severity of Adverse Experiences; 
September 18, 2002. (http://rcc.tech-res-intl.com/tox_tables.htm) 
5.
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, December 2004. 
(http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/Safety/DAID
SAEGradingTable.pdf) 
6.
Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. 
New England Journal of Medicine. 2004;351:1548-1563.
 
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