A Phase II, Randomised, Observer-blind, Placebo Controlled Multi-country Study to Assess the Safety, Reactogenicity and Immunogenicity of a Single Intramuscular Dose of GSK Biologicals' Investigational RSV Maternal Unadjuvanted Vaccine (GSK3888550A), in Healthy Pregnant Women Aged 18 to 40 Years and Infants Born to Vaccinated Mothers
Phase: PHASE2
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline

 
 
 
 
 
 
Protocol Amendment 3 
 
A Phase II, randomised, observer-blind, placebo 
controlled multi-country study to assess the safety, 
reactogenicity and immunogenicity of a single 
intramuscular dose of GSK Biologicals’ 
investigational RSV Maternal unadjuvanted vaccine 
(GSK3888550A), in healthy pregnant women aged 
18 to 40 years and infants born to vaccinated 
Mothers 
 
NCT ID: NCT04126213 
EudraCT number: 2019-001991-12 
 
Amendment 3 Final: 30 September 2020 
 

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CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
3 
Protocol Amendment 3 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
209544 (RSV MAT-004) 
EudraCT number 
2019-001991-12 
Date of protocol 
Final Version 1: 09 July 2019 
Date of protocol amendment 
Amendment 3 Final: 30 September 2020 
Title 
A Phase II, randomised, observer-blind, placebo 
controlled multi-country study to assess the safety, 
reactogenicity and immunogenicity of a single 
intramuscular dose of GSK Biologicals’ 
investigational RSV Maternal unadjuvanted vaccine 
(GSK3888550A), in healthy pregnant women aged 
18 to 40 years and infants born to vaccinated mothers 
Sponsor signatory 
Ouzama Henry, MD MSc 
Clinical and Epidemiology Project Lead, RSV 
Maternal 
 
 
Signature 
 
 
 
Date 
 
 
 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
4 
Protocol Amendment 3 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 SA. 
• 
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 study vaccine/product and other study-related duties and functions as 
described in the protocol. 
• 
To supervise any individual or party to whom I have delegated trial-related duties 
and functions conducted at the trial site. 
• 
To ensure that any individual or party to whom I have delegated trial-related duties 
and functions conducted at the trial site are qualified to perform those trial-related 
duties and functions. 
• 
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 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. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the trial. 
• 
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/product, 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. 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
5 
Hence, I: 
• 
Agree to supply GSK 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 1 year following completion of the study. 
• 
Agree that GSK may disclose any information about such ownership interests and 
financial ties to regulatory authorities. 
• 
Agree to provide GSK with an updated Curriculum Vitae and other documents 
required by regulatory agencies for this study. 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
6 
eTrack study number and 
Abbreviated Title 
209544 (RSV MAT-004) 
EudraCT number 
2019-001991-12 
Date of protocol 
Final Version 1: 09 July 2019 
Date of protocol amendment 
Amendment 3 Final 30 September 2020 
Title 
A Phase II, randomised, observer-blind, placebo 
controlled multi-country study to assess the safety, 
reactogenicity and immunogenicity of a single 
intramuscular dose of GSK Biologicals’ 
investigational RSV Maternal unadjuvanted vaccine 
(GSK3888550A), in healthy pregnant women aged 
18 to 40 years and infants born to vaccinated 
mothers 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
7 
SPONSOR INFORMATION 
1. Sponsor 
GlaxoSmithKline Biologicals SA 
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 a Serious Adverse Event (SAE) 
GSK Central Back-up Study Contact for Reporting SAEs: refer to protocol Section 
8.3.3.1 
Study Contact for Reporting SAEs: refer to the local study contact information 
document. 
5. GSK Biologicals’ Helpdesk for Emergency Unblinding 
Refer to protocol section 6.3.4.1 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
8 
PROTOCOL AMENDMENT 3 SUMMARY OF CHANGES TABLE 
Document history 
Document 
Date 
Amendment 3 
30-SEP-2020 
Amendment 2 
19-MAY-2020 
Amendment 1 
27-JAN-2020 
Administrative Change 1 
08-OCT-2019 
Original Protocol 
09-JUL-2019 
Amendment 3: 30-SEP-2020 
Overall rationale for the current Amendment: 
This protocol amendment has been amended to take into account that as of analysis 2, the 
study is no longer considered observer blind; This amendment was developed because, 
following analysis 2 the possibility of inadvertent unblinding with the IB update my 
occur. 
In addition, this amendment outlines measures to implement a plan for additional 
contacts for safety monitoring in the event of problems with ERT. 
Changes pertaining to these changes in the amendment are listed below 
List of main changes in the protocol and their rationale 
Section # and Name 
Description of Change 
Brief Rationale 
Table 6 
4.2.5 Study blinding 
6.3.4 Blinding and 
unblinding 
9.5.1.1 First analysis 
9.5.1.12 Second 
analysis 
9.5.1.3 Third analysis 
10.3.8 Recording and 
follow-up of AEs, 
SAEs, AESIs and 
subsequent 
pregnancies  
Observer blind removed following 2nd 
analysis 
After the second analysis, the study will not 
be considered observer blind as the 
investigator brochure will be updated to 
include safety information presented by 
treatment group. This could lead to 
inadvertent unblinding of investigators and 
site staff to some subjects’ treatment 
assignments.  The subjects themselves will 
remain blinded throughout their 
participation in the study. 
Section 8, Study 
Procedures during 
special circumstances 
8.4.2. Surveillance 
New language pertaining to special 
circumstances has been added. 
Outlines measures that may be taken in 
case ERT portal/ alerts are not functioning, 
contacts will be conducted at least weekly 
until NB4/V8. Contact may be via 
telephone, SMS, email or other means 
(including videotelephony or telemedicine), 
depending on local laws and best practice. 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
9 
TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 7 
PROTOCOL AMENDMENT 3 SUMMARY OF CHANGES TABLE .................................. 8 
1. 
PROTOCOL SUMMARY ........................................................................................ 19 
1.1. 
Synopsis ..................................................................................................... 19 
1.2. 
Schema ...................................................................................................... 19 
1.3. 
Schedules of Activities (SoA) ...................................................................... 20 
2. 
INTRODUCTION .................................................................................................... 31 
2.1. 
Study Rationale .......................................................................................... 31 
2.2. 
Background ................................................................................................ 31 
2.3. 
Benefit/Risk assessment ............................................................................. 31 
3. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 32 
4. 
STUDY DESIGN .................................................................................................... 34 
4.1. 
Overall design ............................................................................................. 34 
4.2. 
Scientific rationale for study design ............................................................. 38 
4.2.1. 
Study population .......................................................................... 38 
4.2.2. 
Rationale for the use of placebo .................................................. 38 
4.2.3. 
Safety considerations................................................................... 38 
4.2.4. 
Sub-cohorts for blood sampling in infants .................................... 38 
4.2.5. 
Study blinding (Amended 30-SEP-2020)...................................... 38 
4.2.6. 
Case Definitions........................................................................... 39 
4.2.6.1. 
Maternal, medically attended respiratory tract 
illness (MA-RTI) .......................................................... 39 
4.2.6.2. 
Respiratory tract illness (RTI) / Lower 
respiratory tract illness (LRTI) in infants ...................... 39 
4.2.6.3. 
RSV infection .............................................................. 40 
4.3. 
Justification for dose ................................................................................... 40 
4.4. 
End of study definition................................................................................. 41 
5. 
STUDY POPULATION ........................................................................................... 41 
5.1. 
Inclusion criteria for enrolment .................................................................... 41 
5.1.1. 
Maternal subjects ......................................................................... 41 
5.1.2. 
Infant subjects ............................................................................. 42 
5.2. 
Exclusion criteria for enrolment ................................................................... 42 
5.2.1. 
Maternal subjects ......................................................................... 43 
5.2.1.1. 
Medical conditions ...................................................... 43 
5.2.1.2. 
Prior/Concomitant therapy .......................................... 45 
5.2.1.3. 
Prior/Concurrent clinical study experience .................. 45 
5.2.1.4. 
Other exclusions ......................................................... 45 
5.2.2. 
Infant subjects ............................................................................. 46 
5.3. 
Lifestyle considerations ............................................................................... 46 
5.4. 
Screen failures ............................................................................................ 46 
6. 
STUDY INTERVENTION ........................................................................................ 46 
6.1. 
Study Intervention(s) administered.............................................................. 46 
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CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
10 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 48 
6.3. 
Measures to minimize bias: randomization and blinding ............................. 48 
6.3.1. 
Subject identification .................................................................... 48 
6.3.2. 
Randomisation to study intervention ............................................ 48 
6.3.3. 
Intervention allocation to the subjects .......................................... 50 
6.3.4. 
Blinding and unblinding (Amended 30-SEP-2020) ....................... 50 
6.3.4.1. 
Emergency unblinding ................................................ 50 
6.3.4.2. 
Emergency unblinding before regulatory 
reporting of SAEs ....................................................... 51 
6.4. 
Study intervention compliance .................................................................... 51 
6.5. 
Concomitant therapy ................................................................................... 51 
6.5.1. 
Maternal subjects ......................................................................... 52 
6.5.2. 
Infant subjects ............................................................................. 52 
6.5.3. 
Maternal and Infant subjects ........................................................ 52 
6.6. 
Dose modification ....................................................................................... 53 
6.7. 
Intervention after the end of the study ......................................................... 53 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 53 
7.1. 
Discontinuation of study intervention ........................................................... 53 
7.1.1. 
Criteria for temporary delay of study vaccination .......................... 53 
7.1.2. 
Contraindications to subsequent vaccine administration .............. 54 
7.2. 
Subject discontinuation/withdrawal from the study ...................................... 54 
7.3. 
Lost to follow-up.......................................................................................... 55 
8. 
STUDY ASSESSMENTS AND PROCEDURES  (AMENDED 30-SEP-2020) ......... 55 
8.1. 
Efficacy and/or immunogenicity assessments ............................................. 57 
8.1.1. 
Biological samples ....................................................................... 57 
8.1.2. 
Laboratory assays ....................................................................... 60 
8.1.3. 
Immunological read-outs .............................................................. 61 
8.1.4. 
Clinical safety laboratory assessments ........................................ 62 
8.1.5. 
Immunological correlates of protection ......................................... 62 
8.2. 
Safety Assessments ................................................................................... 62 
8.2.1. 
Procedures for maternal subjects ................................................ 62 
8.2.1.1. 
Pre-vaccination procedures ........................................ 62 
8.2.1.1.1. 
Demographic data and lifestyle 
characteristics......................................... 62 
8.2.1.1.2. 
Medical/vaccination history ..................... 63 
8.2.1.2. 
Procedures carried out pre- and post-
vaccination ................................................................. 64 
8.2.1.2.1. 
Physical examination (General 
and obstetric examination) ...................... 64 
8.2.1.2.2. 
Pulse oximetry ........................................ 64 
8.2.2. 
Procedures for infant subjects ...................................................... 64 
8.2.2.1. 
Demographic data and lifestyle characteristics ........... 64 
8.2.2.2. 
Physical examination at Visits 1-NB through 5-
NB .............................................................................. 65 
8.2.3. 
Study holding rules and safety monitoring.................................... 65 
8.2.3.1. 
Limitation on number of doses administered 
per day (first 30 maternal subjects) ............................. 65 
8.2.3.2. 
Outcomes of safety evaluations .................................. 65 
8.2.3.3. 
Study holding rules ..................................................... 66 
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209544 (RSV MAT-004) 
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11 
8.2.3.3.1. 
Holding rules assessed by the 
investigator ............................................. 66 
8.2.3.3.2. 
Holding rules assessed during 
IDMC evaluations ................................... 67 
8.2.3.3.3. 
Overview of IDMC reviews...................... 68 
8.2.3.4. 
Risk assessment ........................................................ 69 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and other 
events of interest ........................................................................................ 71 
8.3.1. 
Time period and frequency for collecting AE, SAE and 
other safety information ............................................................... 71 
8.3.2. 
Method of detecting AEs, SAEs, other events of interest, 
and subsequent pregnancies ....................................................... 73 
8.3.2.1. 
COVID-19 Infection .................................................... 73 
8.3.2.2. 
Clinically significant abnormal laboratory 
findings ....................................................................... 73 
8.3.3. 
Regulatory reporting requirements for SAEs, subsequent 
pregnancies, and other events ..................................................... 74 
8.3.3.1. 
Contact information for reporting of serious 
adverse events (SAEs), AESIs, subsequent 
pregnancies and study holding rules .......................... 75 
8.3.3.2. 
Additional Reporting Guidance for the Study 
Pregnancy .................................................................. 75 
8.3.4. 
Subject card ................................................................................. 75 
8.4. 
Respiratory tract illnesses (RTIs) ................................................................ 76 
8.4.1. 
Definitions .................................................................................... 76 
8.4.1.1. 
Medically attended respiratory tract illnesses 
(MA-RTIs) in maternal subjects .................................. 76 
8.4.1.2. 
Respiratory tract illnesses (RTIs) in infant 
subjects ...................................................................... 76 
8.4.2. 
Surveillance (Amended 30-SEP-2020) ........................................ 76 
8.4.3. 
Treatment of adverse events ....................................................... 78 
8.4.4. 
When to conduct an assessment visit .......................................... 78 
8.4.4.1. 
For a maternal MA-RTI ............................................... 78 
8.4.4.2. 
For an infant RTI ........................................................ 79 
8.4.5. 
Assessment visit procedures ....................................................... 82 
8.4.5.1. 
Clinical evaluation ...................................................... 82 
8.4.5.2. 
Nasal swab collection ................................................. 83 
8.4.5.3. 
Missed assessment visit ............................................. 83 
8.4.6. 
RTI hospitalization during the surveillance interval ....................... 83 
8.4.7. 
Follow-up of infant respiratory tract illnesses ............................... 83 
8.5. 
Treatment of overdose ................................................................................ 83 
8.6. 
Pharmacokinetics ....................................................................................... 83 
8.7. 
Pharmacodynamics .................................................................................... 83 
8.8. 
Genetics ..................................................................................................... 83 
8.9. 
Biomarkers ................................................................................................. 83 
8.10. 
Health outcomes ......................................................................................... 84 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 84 
9.1. 
Statistical hypotheses ................................................................................. 84 
9.2. 
Sample size determination .......................................................................... 84 
9.2.1. 
Safety .......................................................................................... 84 
9.2.2. 
Immune response ........................................................................ 85 
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12 
9.3. 
Populations for analyses ............................................................................. 87 
9.3.1. 
Maternal Subjects ........................................................................ 87 
9.3.2. 
Infant subjects ............................................................................. 87 
9.3.3. 
Criteria for elimination from analysis ............................................ 87 
9.3.3.1. 
Intercurrent medical conditions and 
concomitant medications/products/vaccines 
that may lead to elimination of a subject from 
per-protocol analyses ................................................. 87 
9.3.3.1.1. 
Maternal subjects ................................... 87 
9.3.3.1.2. 
Infant subjects ........................................ 88 
9.3.3.1.3. 
Maternal and Infant subjects ................... 88 
9.3.3.2. 
Other situations that may lead to elimination of 
a subject from per-protocol analyses .......................... 88 
9.4. 
Statistical analyses ..................................................................................... 88 
9.4.1. 
General considerations ................................................................ 88 
9.4.1.1. 
Safety ......................................................................... 89 
9.4.1.2. 
Immunogenicity .......................................................... 89 
9.4.2. 
Subject disposition ....................................................................... 89 
9.4.3. 
Primary endpoints ........................................................................ 90 
9.4.3.1. 
Safety ......................................................................... 90 
9.4.3.2. 
Immunogenicity .......................................................... 92 
9.4.4. 
Secondary endpoints ................................................................... 93 
9.4.4.1. 
Safety ......................................................................... 93 
9.4.4.2. 
Immunogenicity .......................................................... 94 
9.4.5. 
Tertiary / exploratory endpoints .................................................... 95 
9.4.5.1. 
Immunogenicity .......................................................... 95 
9.4.5.2. 
Exploratory endpoints ................................................. 95 
9.4.6. 
Other analyses ............................................................................ 96 
9.4.6.1. 
Demography and baseline characteristics .................. 96 
9.4.6.2. 
Dose Characterization ................................................ 96 
9.4.6.3. 
Case accruals ............................................................. 96 
9.5. 
Interim analyses .......................................................................................... 96 
9.5.1. 
Sequence of analyses.................................................................. 97 
9.5.1.1. 
First analysis .............................................................. 97 
9.5.1.2. 
Second analysis (Amended 30-SEP-2020) ................. 97 
9.5.1.3. 
Third analysis (Amended 30-SEP-2020) ..................... 98 
9.5.1.4. 
Final analysis .............................................................. 99 
9.5.2. 
Statistical considerations for interim analysis ............................... 99 
9.6. 
Data Monitoring Committee (DMC) ............................................................. 99 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 100 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .......................................................................................... 100 
10.1.1. 
Regulatory and ethical considerations ....................................... 100 
10.1.2. 
Financial disclosure ................................................................... 100 
10.1.3. 
Informed consent process .......................................................... 101 
10.1.4. 
Data protection .......................................................................... 101 
10.1.5. 
Committees structure ................................................................. 102 
10.1.6. 
Dissemination of clinical study data ........................................... 102 
10.1.7. 
Data quality assurance .............................................................. 102 
10.1.8. 
Source documents ..................................................................... 103 
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10.1.9. 
Study and site start and closure ................................................. 104 
10.1.10. Publication policy ....................................................................... 104 
10.2. 
Appendix 2: Clinical laboratory tests ......................................................... 104 
10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting .......................................... 105 
10.3.1. 
Definition of an Adverse Event (AE) ........................................... 105 
10.3.2. 
Definition of a Serious Adverse Event (SAE) ............................. 107 
10.3.3. 
Solicited events.......................................................................... 108 
10.3.4. 
Unsolicited adverse events ........................................................ 108 
10.3.5. 
Adverse events of special interest (AESIs) ................................ 109 
10.3.6. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as AEs or SAEs .................................... 109 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs ................... 109 
10.3.7.1. Subsequent Pregnancy ............................................ 109 
10.3.8. 
Recording and follow-up of AEs, SAEs, AESIs and 
subsequent pregnancies (Amended 30-SEP-2020) ................... 109 
10.3.8.1. Time period for collecting and recording AEs, 
SAEs, AESIs, and subsequent pregnancies 
and other events of interest ...................................... 110 
10.3.8.2. Where to record AEs, SAEs, AESIs, 
subsequent pregnancies and other events of 
interest ..................................................................... 110 
10.3.8.3. Follow-up of AEs, SAEs, AESIs, subsequent 
pregnancies and other events of interest .................. 111 
10.3.8.3.1. Follow-up during the study .................... 111 
10.3.8.3.2. Follow-up after the subject is 
discharged from the study .................... 111 
10.3.8.3.3. Follow-up of subsequent 
pregnancies .......................................... 111 
10.3.8.4. Updating of SAE, AESI and subsequent 
pregnancy information after removal of write 
access to the subject’s eCRF ................................... 112 
10.3.9. 
Assessment of intensity and toxicity ........................................... 112 
10.3.9.1. Assessment of intensity ............................................ 112 
10.3.9.2. Assessment of causality ........................................... 113 
10.3.9.3. Medically attended visits ........................................... 114 
10.3.9.4. Assessment of outcomes.......................................... 114 
10.3.10. Reporting of SAEs, AESIs, subsequent pregnancies, and 
other events ............................................................................... 115 
10.3.10.1. Events requiring expedited reporting to GSK ............ 115 
10.3.10.2. Back-up system in case the electronic 
reporting system does not work ................................ 115 
10.4. 
Appendix 4: Contraceptive guidance and collection of subsequent 
pregnancy information .............................................................................. 115 
10.5. 
Appendix 5: Country-specific requirements ............................................... 116 
10.5.1. 
France ....................................................................................... 116 
10.5.1.1. Concerning the “SELECTION OF STUDY 
POPULATION AND WITHDRAWAL 
CRITERIA” ............................................................... 116 
10.5.1.2. Concerning the “STATISTICAL 
CONSIDERATIONS AND DATA ANALYSES” 
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and specially in the “SAMPLE SIZE 
ASSUMPTIONS” ...................................................... 117 
10.5.1.3. Concerning the “REGULATORY, ETHICAL, 
AND STUDY OVERSIGHT 
CONSIDERATIONS” ................................................ 117 
10.5.1.4. NOTIFICATION TO THE HOSPITAL 
DIRECTOR .............................................................. 118 
10.5.1.5. INFORMATION TO THE HOSPITAL 
PHARMACIST .......................................................... 118 
10.5.1.6. Concerning the “DATA MANAGEMENT” the 
following text is added: ............................................. 118 
10.5.1.7. SAE .......................................................................... 119 
10.5.1.8. Monitoring visits ........................................................ 119 
10.5.1.9. Data entry into the eCRF .......................................... 120 
10.5.1.10. CTR publication ........................................................ 120 
10.5.1.11. Data Protection French Law of 6th January 
1978 (CNIL) .............................................................. 121 
10.6. 
Appendix 6: Abbreviations and Glossary of terms ..................................... 121 
10.6.1. 
List of abbreviations ................................................................... 121 
10.6.2. 
Glossary of terms ....................................................................... 122 
10.7. 
Appendix 7: Gestational Age Assessment ................................................ 127 
10.7.1. 
GAIA Gestational Age Assessment Form .................................. 127 
10.7.2. 
Methods Of Gestational Age Assessment .................................. 128 
10.8. 
Appendix 8: Definitions of maternal, fetal and neonatal adverse 
events of special interest as per GAIA ...................................................... 129 
10.9 
Appendix 9: Protocol Amendment/Administrative change history .............. 162 
11. REFERENCES ..................................................................................................... 183 
 
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LIST OF TABLES 
PAGE 
Table 1 
Schedule of activities for maternal subjects ............................................ 21 
Table 2 
Intervals between study visits – maternal subjects ................................. 27 
Table 3 
Schedule of activities for infants ............................................................. 28 
Table 4 
Intervals between study visits – infant subjects ...................................... 30 
Table 5 
Study objectives and endpoints .............................................................. 32 
Table 6 
Study groups, subcohorts, interventions, epochs and blinding 
foreseen in the study (Amended 30 SEP 2020) ...................................... 37 
Table 7 
MA-RTI case definitions for data analysis in maternal subjects .............. 39 
Table 8 
RTI/LRTI case definitions for data analysis in infants ............................. 39 
Table 9 
Study interventions administered ........................................................... 47 
Table 10 
Contact information for emergency unblinding ....................................... 51 
Table 11 
Biological samples – maternal subjects .................................................. 58 
Table 12 
Biological samples – infant subjects ....................................................... 59 
Table 13 
Antibody determination........................................................................... 60 
Table 14 
Molecular Biology ................................................................................... 60 
Table 15 
Immunological read-outs ........................................................................ 61 
Table 16 
Molecular biology tests ........................................................................... 62 
Table 17 
Holding rules assessed by the investigator ............................................. 66 
Table 18 
Holding rules assessed during IDMC evaluations ................................... 67 
Table 19 
Examples of rates for AESIs................................................................... 69 
Table 20 
Rates of progression to more severe RSV disease or RSV 
associated hospitalization ...................................................................... 71 
Table 21 
Timeframes for collecting and reporting safety (and RTI) 
information ............................................................................................. 72 
Table 22 
Timeframes for submitting serious adverse event, subsequent 
pregnancy and other event reports to GSK ............................................ 74 
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Table 23 
Contact information for reporting of serious adverse events 
(SAEs), AESIs, subsequent pregnancies and study holding rules .......... 75 
Table 24 
Exact 95% confidence interval on the percentage of subjects with 
adverse events following vaccination per group ..................................... 85 
Table 25 
Effect of dose: Power and fold increase in terms of RSV-A 
neutralizing antibody titers with sample sizes of 45 and 90 
subjects per group at significance level of one- sided 5% ....................... 86 
Table 26 
Protocol-Required Safety Laboratory Assessments ............................. 105 
Table 27 
Solicited administration site events....................................................... 108 
Table 28 
Solicited systemic events ..................................................................... 108 
Table 29 
Intensity scales for solicited symptoms in adults................................... 112 
Table 30 
Fetal death / Stillbirth ........................................................................... 130 
Table 31 
Maternal Death .................................................................................... 132 
Table 32 
Hypertensive disorders of pregnancy (Gestational hypertension, 
Pre-eclampsia, Pre-eclampsia with severe features including 
eclampsia) ............................................................................................ 134 
Table 33 
Antenatal Bleeding ............................................................................... 136 
Table 34 
Postpartum hemorrhage ....................................................................... 138 
Table 35 
Fetal growth restriction ......................................................................... 138 
Table 36 
Gestational diabetes mellitus (pregnancy induced 
hyperglycemia) ..................................................................................... 139 
Table 37 
Non-reassuring fetal status .................................................................. 141 
Table 38 
Pathways to preterm birth .................................................................... 141 
Table 39 
Standard Definitions for Maternal Adverse Events of Special 
Interest not defined as events in GAIA ................................................. 143 
Table 40 
Small for Gestational Age ..................................................................... 145 
Table 41 
Low Birth Weight (LBW) ....................................................................... 146 
Table 42 
Neonatal encephalopathy ..................................................................... 147 
Table 43 
Congenital Microcephaly ...................................................................... 148 
Table 44 
Major Congenital anomalies ................................................................. 151 
Table 45 
Neonatal Death .................................................................................... 154 
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Table 46 
Neonatal Infections .............................................................................. 156 
Table 47 
Respiratory Distress in the Neonate ..................................................... 158 
Table 48 
Preterm Birth ........................................................................................ 159 
Table 49 
Failure to Thrive ................................................................................... 159 
Table 50 
Standard Definitions for Neonatal Adverse Events of Special 
Interest not defined as events in GAIA ................................................. 161 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Overall design – maternal subjects......................................................... 35 
Figure 2 
Overall design– infant subjects ............................................................... 35 
Figure 3 
Allocation of maternal subjects to study (intervention) groups ................ 49 
Figure 4 
Allocation of infant subjects to blood sampling subcohorts ..................... 49 
Figure 5 
Evaluations based on 16 active recipients - Risk assessment 
curve for one formulation based on the proposed safety holding 
rules across active groups ...................................................................... 70 
Figure 6 
Decision Tree for site personnel – maternal surveillance and 
assessment ............................................................................................ 79 
Figure 7 
Decision Tree for site personnel - infant surveillance and 
assessment ............................................................................................ 81 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Rationale:  
RSV MAT-004 will evaluate, for the first time: 
• 
The safety, reactogenicity, and immunogenicity of the investigational RSV maternal 
vaccine when administered to healthy women in the third trimester of pregnancy, and 
• 
The effects of maternal immunization on the infants born to these vaccinated women. 
A Phase I/II study of this vaccine is underway in healthy non-pregnant women (study 
RSV MAT-001; NCT02753413). The 2 dose levels considered to have the highest 
immunogenicity associated with an acceptable safety profile in RSV MAT-001 (60 and 
120 µg) will be further investigated in the current study (RSV MAT-004).  
RSV MAT-004 will only be initiated after a favorable evaluation of all available safety 
data from completed/ongoing non-clinical studies and from the ongoing RSV MAT-001 
study.  
Objectives and Endpoints are presented in Table 5. 
1.2. 
Schema  
This is a multi-center, randomized, observer-blinded, placebo-controlled study. Up to 300 
healthy maternal subjects 18 to 40 years of age (inclusive, at the time of informed 
consent) will be assigned to one of 3 study groups, and will receive a single intramuscular 
injection between 28 0/7 to 33 6/7 weeks of gestation (inclusive) as follows: 
• 
RSVPreF3, 60 µg (N up to ~ 100),  
• 
RSVPreF3, 120 µg (N up to ~ 100), or  
• 
Saline placebo (N up to ~ 100). 
Maternal subjects will participate for approximately 9 months (from informed consent 
until 6 months after delivery), and will be evaluated for reactogenicity, safety, and 
humoral immune response (including maternal – infant RSV-specific antibody transfer). 
Infant subjects will be followed for 12 months after birth and will be evaluated for safety 
and RSV-specific antibody levels. All safety data will be reviewed by a blinded Safety 
Review Team (SRT) and an unblinded Independent Data Monitoring Committee (IDMC) 
on an on-going basis.  
Section 4.1 provides an overview of the study design; Section 8.2.3 presents additional 
information about study holding rules and safety monitoring. 
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1.3. 
Schedules of Activities (SoA)  
For maternal subjects, Table 1 presents the Schedule of Activities (SoA) and Table 2 
describes the allowed study visit intervals. For infant subjects, Table 3 presents the SoA 
and Table 4 describes the allowed study visit intervals.  
Whenever possible, the investigator should arrange study visits within the allowed study 
visit intervals. Immunogenicity data from blood samples collected outside an allowed 
interval may not be considered in the associated per protocol set (PPS) for analysis. 
Please note: 
• 
Study visits, assessments and procedures do not replace local standards of care. If 
local standard of care recommends additional visits/medical evaluations (for 
maternal subjects or their infants), subjects should comply with these local 
recommendations.  
• 
Any adverse event / potential adverse event identified during a study visit or 
procedure should be treated according to local standards of care or by referral to an 
appropriate health care provider 
• 
When a maternal subject completes Visit 1 (enrolment), and again at Visit 5 
(delivery), site staff should ensure all site study obstetrician(s) and pediatrician(s) are 
informed. This will help to ensure that study pediatrician(s) and/or staff are aware of 
the maternal subject’s approximate date of delivery and potential enrolment of the 
neonate. 
• 
Maternal subject Visits 2 (day 8), 3 (day 31), 4 (Day 61), 7 (Day 121 post delivery) 
and 8 (Day 181 post delivery) and infant subject Visits 1-NB through 5-NB (birth to 
12 months after birth) may be conducted through a home visit by qualified site staff 
(or a designated third party), as appropriate per the judgment of the investigator (and 
as allowed by local law).  
• 
Respiratory tract illness (RTI) assessment visits and event-driven safety visits may 
take place at the investigator’s clinical facility or another medical facility, or via a 
home visit by qualified site staff (or a designated third party), as appropriate per the 
judgment of the investigator (and as allowed by local law). 
• 
The visit location must have appropriate infrastructure and logistics to support 
completion of all study procedures.  Blood samples must be centrifuged within 1 
hour after collection if used to assess biochemistry, or within 2 hours of collection if 
used to assess hematology or immune response.   
• 
Contact may be via telephone, SMS, email or other means (including videotelephony 
or telemedicine), depending on local best practice. If the study site is the subject’s 
primary healthcare facility, contact with study personnel may also be made in the 
context of a visit for routine or event-driven care.   
• 
Refer to Section 8 for information about special circumstances (e.g., the COVID 19 
pandemic) and their impact on study activities. 
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Table 1 
Schedule of activities for maternal subjects  
Epochs 
Epoch 001 
Epoch 002 
Additional 
Information 
 
 
 
May be replaced by V5, 
depending on delivery 
date 
 
To coincide with infant 
visits  
2-NB, 3-NB, 4-NB 
 
Event Driven 
 
Visit / Contact 
Screening 
V1 
V2  
V3  
V4 
V5 
V6 
V7 
V8 
Monthly 
contacts  
Safety 
Visit  
MA-RTI 
Visit  
For monthly contacts: 
Table 2 & Section 
8.4.2. After delivery, 
maternal & infant 
monthly contacts 
coincide. 
 
Gestational Age (GA) 
 
28 0/7 - 
33 6/7 
 
 
 
 
 
 
 
 
 
 
Visit Day 
D-28 – D-1 
D1 
D8 
D31 
D61 
Delivery 
D1PD 
D43 
PD 
D121 
PD 
D181 
PD 
 
 
 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
Section 10.1.3 
Check 
Inclusion/exclusion 
criteria  
● 
O 
 
 
 
 
 
 
 
 
 
 
Sections 5.1.1, 5.2.1 
Assign maternal subject 
study number  
● 
 
 
 
 
 
 
 
 
 
 
 
Section 6.3.1 
Assign infant subject 
study number  
 
O 
 
 
 
 
 
 
 
 
 
 
Record Demographic 
data and lifestyle 
characteristics  
● 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1.1.1 
Review & collect Medical 
and vaccination history 
● 
O 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1.1.2 
Record outcome of 
Level 2 ultrasound (also 
known as a fetal 
anomaly ultrasound 
scan or fetal morphology 
assessment) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Record obstetric history 
from past and current 
pregnancies 
● 
 
 
 
 
 
 
 
 
 
 
 
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Epochs 
Epoch 001 
Epoch 002 
Additional 
Information 
 
 
 
May be replaced by V5, 
depending on delivery 
date 
 
To coincide with infant 
visits  
2-NB, 3-NB, 4-NB 
 
Event Driven 
 
Visit / Contact 
Screening 
V1 
V2  
V3  
V4 
V5 
V6 
V7 
V8 
Monthly 
contacts  
Safety 
Visit  
MA-RTI 
Visit  
For monthly contacts: 
Table 2 & Section 
8.4.2. After delivery, 
maternal & infant 
monthly contacts 
coincide. 
 
Gestational Age (GA) 
 
28 0/7 - 
33 6/7 
 
 
 
 
 
 
 
 
 
 
Visit Day 
D-28 – D-1 
D1 
D8 
D31 
D61 
Delivery 
D1PD 
D43 
PD 
D121 
PD 
D181 
PD 
 
 
 
Record Travel history to 
or living in Zika virus 
endemic 
countries/regions  
● 
● 
● 
● 
● 
● 
 
 
 
 
 
 
During the current 
pregnancy only 
General and obstetrical 
examination  
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
O 
O 
General exam is 
symptom directed at 
V7, V8, & event-
driven visits. Vaginal 
exams are symptom 
directed. See Section 
8.2.1.2 
Pre-vaccination body 
temperature  
 
● 
 
 
 
 
 
 
 
 
 
 
Preferred location for 
measurement will be 
the oral cavity. 
“Fever” = temperature 
≥38.0°C/100.4°F 
regardless of the 
location of 
measurement. 
Urine sample  
● 
● 
● 
● 
● 
 
 
 
 
 
 
 
Table 11 
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Epochs 
Epoch 001 
Epoch 002 
Additional 
Information 
 
 
 
May be replaced by V5, 
depending on delivery 
date 
 
To coincide with infant 
visits  
2-NB, 3-NB, 4-NB 
 
Event Driven 
 
Visit / Contact 
Screening 
V1 
V2  
V3  
V4 
V5 
V6 
V7 
V8 
Monthly 
contacts  
Safety 
Visit  
MA-RTI 
Visit  
For monthly contacts: 
Table 2 & Section 
8.4.2. After delivery, 
maternal & infant 
monthly contacts 
coincide. 
 
Gestational Age (GA) 
 
28 0/7 - 
33 6/7 
 
 
 
 
 
 
 
 
 
 
Visit Day 
D-28 – D-1 
D1 
D8 
D31 
D61 
Delivery 
D1PD 
D43 
PD 
D121 
PD 
D181 
PD 
 
 
 
Blood sample 
(hematology / 
biochemistry, ~ 5.5 ml) 
● 
● 
● 
 
 
 
 
 
 
 
● 
 
Table 11 
If screening sample ≤ 
15 days before V1, 
then V1 sample not 
required. During an 
event-driven safety 
visit, additional 
samples are per 
investigator’s 
discretion and 
standard of care and 
to be tested locally. 
Blood sample 
(hematocrit: ~ 3.0 ml) 
 
 
 
● 
 
● 
● 
 
 
 
 
 
Table 11 
Blood sample  
(immunogenicity ~ 10 
ml) 
 
● 
 
● 
 
● 
● 
 
 
 
 
 
Cord blood (~ 5 to 10 ml) 
 
 
 
 
 
● 
 
 
 
 
 
 
Nasal swab  
 
 
 
 
 
 
 
 
 
 
 
● 
Check contraindications 
to and criteria for 
temporary delay for 
vaccination 
 
O 
 
 
 
 
 
 
 
 
 
 
Sections 5.2.1 and 
7.1.1 
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Epochs 
Epoch 001 
Epoch 002 
Additional 
Information 
 
 
 
May be replaced by V5, 
depending on delivery 
date 
 
To coincide with infant 
visits  
2-NB, 3-NB, 4-NB 
 
Event Driven 
 
Visit / Contact 
Screening 
V1 
V2  
V3  
V4 
V5 
V6 
V7 
V8 
Monthly 
contacts  
Safety 
Visit  
MA-RTI 
Visit  
For monthly contacts: 
Table 2 & Section 
8.4.2. After delivery, 
maternal & infant 
monthly contacts 
coincide. 
 
Gestational Age (GA) 
 
28 0/7 - 
33 6/7 
 
 
 
 
 
 
 
 
 
 
Visit Day 
D-28 – D-1 
D1 
D8 
D31 
D61 
Delivery 
D1PD 
D43 
PD 
D121 
PD 
D181 
PD 
 
 
 
Allocate maternal study 
group, intervention 
number 
 
O 
 
 
 
 
 
 
 
 
 
 
Sections 6.3.2 and 
6.3.3 
 
Assign cohort for blood 
sampling of infants  
 
O 
 
 
 
 
 
 
 
 
 
 
Administer Intervention 
(study vaccine/product) 
 
● 
 
 
 
 
 
 
 
 
 
 
Sections 6.1 and 6.2 
 
Record administered 
intervention number 
 
● 
 
 
 
 
 
 
 
 
 
 
Observe for 60 minutes 
post-dose 
 
O 
 
 
 
 
 
 
 
 
 
 
 
Distribute maternal 
subject card 
O 
O 
 
 
 
 
 
 
 
 
 
 
At screening or at 
Visit 1 as per local 
practice. Section 
8.3.4 
Record Labor / Delivery 
information  
 
 
 
 
 
● 
 
 
 
 
 
 
 
Record pregnancy / 
delivery outcomes  
 
 
 
 
 
● 
 
 
 
 
 
 
Submit Expedited AE 
report for an adverse 
pregnancy outcome 
(Section 8.3.3) 
Train maternal subject 
/LAR on use of e-diary 
device 
 
O 
O 
 
 
 
 
 
 
 
 
 
Sections 8.4.2 and 
10.3.8  
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Epochs 
Epoch 001 
Epoch 002 
Additional 
Information 
 
 
 
May be replaced by V5, 
depending on delivery 
date 
 
To coincide with infant 
visits  
2-NB, 3-NB, 4-NB 
 
Event Driven 
 
Visit / Contact 
Screening 
V1 
V2  
V3  
V4 
V5 
V6 
V7 
V8 
Monthly 
contacts  
Safety 
Visit  
MA-RTI 
Visit  
For monthly contacts: 
Table 2 & Section 
8.4.2. After delivery, 
maternal & infant 
monthly contacts 
coincide. 
 
Gestational Age (GA) 
 
28 0/7 - 
33 6/7 
 
 
 
 
 
 
 
 
 
 
Visit Day 
D-28 – D-1 
D1 
D8 
D31 
D61 
Delivery 
D1PD 
D43 
PD 
D121 
PD 
D181 
PD 
 
 
 
Distribute e-diary device 
to maternal subject / 
LAR.  
 
O 
 
 
 
 
 
 
 
 
 
 
 
Review e-diary results 
 
O 
O 
O 
O 
O 
O 
O 
O 
 
 
 
 
Return e-diary device 
 
 
 
 
 
 
 
 
O 
 
 
 
At V8 or infant Visit 4-
NB, whichever is last. 
Concomitant 
medications / 
vaccinations. 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 6.5.1, 6.5.3 
Solicited administration 
site & systemic events 
(Days 1 to 7) 
 
● 
● 
 
 
 
 
 
 
 
 
 
Sections 10.3.3, 
10.3.8 
All unsolicited AEs 
(Days 1 to 30)  
 
● 
● 
● 
 
 
 
 
 
● 
● 
 
Sections 10.3.4, 
10.3.8  
Pregnancy-related 
AESIs  
 
● 
● 
● 
● 
● 
● 
 
 
● 
● 
● 
Sections 8.3.3.2,  
10.3.8 
Suspected, probable 
and confirmed cases of 
COVID-19 infection 
 
●  
●   
●   
●  
●  
●  
●  
●   
●   
●  
●  
Section 8.3.2.1 
MAEs 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Sections 8 and 
10.3.9.3 
MA-RTI signs, 
symptoms and 
corresponding (S)AEs  
 
 
 
 
 
 
 
 
 
● 
 
● 
Sections 8.3.3, 8.4 
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Epochs 
Epoch 001 
Epoch 002 
Additional 
Information 
 
 
 
May be replaced by V5, 
depending on delivery 
date 
 
To coincide with infant 
visits  
2-NB, 3-NB, 4-NB 
 
Event Driven 
 
Visit / Contact 
Screening 
V1 
V2  
V3  
V4 
V5 
V6 
V7 
V8 
Monthly 
contacts  
Safety 
Visit  
MA-RTI 
Visit  
For monthly contacts: 
Table 2 & Section 
8.4.2. After delivery, 
maternal & infant 
monthly contacts 
coincide. 
 
Gestational Age (GA) 
 
28 0/7 - 
33 6/7 
 
 
 
 
 
 
 
 
 
 
Visit Day 
D-28 – D-1 
D1 
D8 
D31 
D61 
Delivery 
D1PD 
D43 
PD 
D121 
PD 
D181 
PD 
 
 
 
SAEs, and AEs leading 
to study withdrawal  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Sections 7.2, 10.3.8 
SAEs related to study 
participation or 
concurrent GSK 
medication/vaccine 
● 
● 
 
 
 
 
 
 
 
 
 
 
Sections 8.3.3, 10.3.8 
Subsequent pregnancies 
 
 
 
 
 
 
● 
● 
● 
● 
● 
 
Section 10.3.8 
Record interest in joining 
future extension study 
 
 
 
 
 
 
 
O 
● 
 
 
 
Request at Visit 7, 
confirm at Visit 8; 
Section 6.7 
Screening conclusion  
● 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator sign-off on 
eCRF before analysis  
● 
 
 
● 
 
 
● 
 
● 
 
 
 
 
Study conclusion  
 
 
 
 
 
 
 
 
● 
 
 
 
Section 4.4 
The timing of an event-driven site visit (e.g., to further evaluate a potential AE or MA-RTIs) cannot be defined with precision in the protocol. Event-driven visits may occur throughout 
the study. Note:. ● 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. V = visit; D = day; GA = gestational age; MA-RTI = medically attended respiratory tract illness; PD = post delivery; Hct = hematocrit. 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
27 
Table 2 
Intervals between study visits – maternal subjects  
Interval 
Optimal 
interval 
Allowed interval 
Additional Information 
Screening → V1  
4 days  
1– 28 days  
The screening interval extends from Day -28 to Day -1 (the day before dosing). If a subject is screened but not 
vaccinated within the allowed interval, a re-screening can be done to establish the subject’s eligibility. Please make 
sure the subject’s gestational age is still within the allowed range, refer to Section 10.7 for guidance on gestational 
age assessment. 
V1 → V2  
7 days  
7 – 14 days  
 
V1 → V3  
30 days  
20 - 45 days  
 
V1 → V4 
60 days  
50–75 days  
 
V5 (delivery)  
0 days  
1 day before to 3 
days post delivery 
Collect maternal blood sample at any point from the day before up to delivery. If blood is not collected during 
delivery, collect maternal blood sample no later than 3 days after delivery.  
A cord blood sample should be collected at the time of each delivery. If cord blood cannot be collected at delivery, 
a blood sample should be collected from the infant subject as soon as possible and no later than 3 days after birth. 
V5 → V6 
42 days  
40 – 60 days  
 
V5 → V7  
120 days  
110 -140 days  
Visit may coincide with infant subject’s routine vaccination visit if consistent with the participating country’s routine 
infant vaccination schedule) 
V5 → V8 
180 days  
165 – 200 days  
 
Monthly contacts 
Approximately every 25 – 35 days  
Monthly until Visit 8. May occur more often between Visit 5 and Visit 6 at the discretion of study personnel. 
Contacts are additional to and do not replace protocol specified Visits. 
V=Visit 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
28 
Table 3 
Schedule of activities for infants  
Epochs 
Epoch 002 
Epoch 003 
Additional Information 
Visit / Contact 
 
To coincide with maternal 
visits 6, 7, 8  
 
Event-
Driven 
 
 
 
V1-NB 
V2-NB 
V3-NB  
V4-NB  
Monthly 
contacts  
RTI 
Visit  
 C1-NB 
V5-NB  
NB=Newborn 
Monthly Contacts coincide with maternal monthly 
contacts.  
RTI Visit: Sections 8.4.3 and 8.4.5. 
Age of infant 
 
6 
weeks 
4 
months 
6 
months 
 
 
9  
months 
12 
months 
 
Visit Day 
Birth 
D43 
D121 
D181 
 
 
D271 
D365 
Table 4 
Check Inclusion / exclusion criteria  
● 
 
 
 
 
 
 
 
Sections 5.1.2, 5.2.2 
Re-consent if required by local 
regulations  
● 
 
 
 
 
 
 
 
 
Record infant subject study number  
● 
 
 
 
 
 
 
 
 
Record subcohort for 
immunogenicity blood sampling 
● 
 
 
 
 
 
 
 
Section 6.3.3 
Distribute infant’s subject card  
O 
 
 
 
 
 
 
 
Section 8.3.4 
Demographic data and lifestyle 
characteristics 
● 
● 
● 
● 
 
 
● 
● 
Section 8.2.2.1, Record at Visit 1-NB and if 
changes in lifestyle characteristics thereafter 
Apgar score  
● 
 
 
 
 
 
 
 
At 1, 5 and 10 minutes, if available 
Weight, length, head circumference, 
physical examination  
● 
● 
● 
● 
 
 
 
● 
Section 8.2.2.2 
Blood sample if no cord blood  
~2.5 ml 
● 
 
 
 
 
 
 
 
Adjust volume if weight ≤ 2.5 Kg. Refer to Table 
12. 
Blood sample (immunology, infants) 
~2.5 ml 
 
● 
● 
●  
 
 
 
 
1 sample at one of these visits, as per infant’s 
assigned subcohort. Adjust volume if weight ≤ 
2.5 Kg. Refer to Table 12 
Concomitant medications / 
vaccinations  
● 
● 
● 
● 
● 
● 
● 
● 
Sections 6.5.2, 6.5.3 
Neonatal AESIs  
● 
● 
 
 
 
 
 
 
Sections 8.3.3, 10.3.8. Must submit an 
Expedited AE Report 
Suspected, probable and confirmed 
cases of COVID-19 infection 
● 
● 
● 
● 
● 
● 
● 
● 
 
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CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
29 
Epochs 
Epoch 002 
Epoch 003 
Additional Information 
Visit / Contact 
 
To coincide with maternal 
visits 6, 7, 8  
 
Event-
Driven 
 
 
 
V1-NB 
V2-NB 
V3-NB  
V4-NB  
Monthly 
contacts  
RTI 
Visit  
 C1-NB 
V5-NB  
NB=Newborn 
Monthly Contacts coincide with maternal monthly 
contacts.  
RTI Visit: Sections 8.4.3 and 8.4.5. 
Age of infant 
 
6 
weeks 
4 
months 
6 
months 
 
 
9  
months 
12 
months 
 
Visit Day 
Birth 
D43 
D121 
D181 
 
 
D271 
D365 
Table 4 
MAEs  
● 
● 
● 
● 
● 
 
● 
● 
Sections 8 and 10.3.9.3 
SAEs and AEs leading to study 
withdrawal  
● 
● 
● 
● 
● 
● 
● 
● 
Sections 7.2, 10.3.8 
Train maternal subject/LAR on use 
of electronic diary device 
O 
 
 
 
 
 
 
 
Sections 8.4.2 and 10.3.8 
Distribute electronic diary device to 
maternal subject/LAR  
O 
 
 
 
 
 
 
 
 
Review electronic diary results 
 
O 
O 
O 
 
O 
 
 
 
Return eDiary device 
 
 
 
O 
 
 
 
 
At maternal Visit 8 or infant Visit 4-NB, 
whichever is last 
Symptom-directed physical 
examination (includes RTI signs, 
symptoms) 
 
 
 
 
 
● 
 
 
Section 8.4.5 
Nasal swab 
 
 
 
 
 
● 
 
 
Sections 8.1.1, 8.4.5.2, Table 12 
Study conclusion  
 
 
 
 
 
 
 
● 
Section 4.4 
Investigator sign-off on eCRF before 
analysis  
 
● 
 
● 
 
 
 
● 
 
The timing of an event-driven visit cannot be defined with precision in the protocol. Note: ● indicates a study procedure that requires documentation in the individual eCRF. ○ indicates 
a study procedure that does not require documentation in the individual eCRF. LAR = legally acceptable representative; V=visit; D=day; NB = newborn. 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
30 
Table 4 
Intervals between study visits – infant subjects 
Interval 
Optimal 
interval 
Allowed interval 
Additional Information 
Birth → V1-NB 
0 days  
0 - 3 days (for 
blood sample 
collection) 
If no cord blood was obtained, a blood sample should be collected at this visit.  
If consent is not obtained within the allowed interval, but the parent(s) /LAR(s) still wish the infant to 
participate, consent may be obtained at any time until the Day 43 visit.  Refer to the SPM for additional details. 
Birth → V2-NB 
42 days  
28 – 60 days  
 
Birth → V3-NB 
120 days  
110 -140 days  
Visit may coincide with infant subject’s routine vaccination visit if consistent with the participating country’s 
routine infant vaccination schedule 
Birth → V4-NB 
180 days  
165 – 200 days  
 
Monthly Contacts 
Approximately every 25 – 35 days 
from birth through Visit 4-NB.  
May occur more often between Birth and Visit 2-NB at the discretion of study personnel. Should coincide with 
Monthly post-delivery contacts described in Table 1 and Table 2. Contacts are additional to and do not replace 
protocol specified Visits. 
Birth → C1-NB 
270 days  
256 – 286 days  
 
Birth → V5-NB  
365 days  
330 - 400 days  
 
V= Visit;NB=Newborn 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

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CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
32 
The balance of anticipated benefits and apparent risks associated with the RSV maternal 
(RSVPreF3) vaccine continues to be acceptable following ongoing systematic review of 
the safety data. 
3. 
OBJECTIVE(S) AND ENDPOINT(S) 
Table 5 
Study objectives and endpoints 
Primary Safety objectives 
Primary Safety endpoint(s) 
To evaluate the safety and 
reactogenicity of a single IM dose of 
study vaccine administered to 
maternal subjects, from Visit 1 up to 6 
weeks after delivery  
Occurrence of solicited administration site and systemic events) during a 7-
day follow-up period after vaccination (i.e. the day of vaccination and 6 
subsequent days).  
Occurrence of any hematological (complete blood count with differential and 
platelet count) or biochemical (alanine amino-transferase, aspartate amino-
transferase, creatinine, blood urea nitrogen) laboratory abnormality at baseline 
(up to 15 days before vaccination) and Day 8 (Visit 2)  
Occurrence of unsolicited AEs that occur during a 30-day follow-up period 
after vaccination (i.e. the day of vaccination and 29 subsequent days).  
Occurrence of serious adverse events (SAEs), AEs leading to study 
withdrawal, and medically attended AEs (MAEs) from Visit 1 (Day 1) up to 6 
weeks after delivery (Day 43 post-delivery, Visit 6).  
To evaluate pregnancy outcomes and 
pregnancy-related AESIs after a single 
IM dose of study vaccine administered 
to maternal subjects, from Visit 1 up to 
6 weeks after delivery (Visit 6). 
Pregnancy outcomes from Day 1 (Visit 1) up to 6 weeks after delivery (Day 43 
post-delivery, Visit 6). These include live birth with no congenital anomalies, 
live birth with congenital anomalies, fetal death/still birth (antepartum or 
intrapartum) with no congenital anomalies, fetal death/still birth (antepartum or 
intrapartum) with congenital anomalies, elective/therapeutic termination with 
no congenital anomalies and elective/therapeutic termination with congenital 
anomalies. 
Pregnancy-related AESIs from Day 1 (Visit 1) up to 6 weeks after delivery 
(Day 43 post-delivery, Visit 6). These include but are not limited to maternal 
death, hypertensive disorders of pregnancy (gestational hypertension, pre-
eclampsia, pre-eclampsia with severe features including eclampsia), antenatal 
bleeding (morbidly adherent placenta, placental abruption, cesarean scar 
pregnancy, uterine rupture), postpartum hemorrhage, fetal growth restriction, 
gestational diabetes mellitus, non-reassuring fetal status, pathways to preterm 
birth (premature preterm rupture of membranes, preterm labor, provider-
initiated preterm birth), chorioamnionitis, oligohydramnios, polyhydramnios, 
gestational liver disease (intrahepatic cholestasis of pregnancy, acute fatty 
liver of pregnancy), maternal sepsis.* 
To evaluate the safety of the study 
vaccine, including neonatal AEs of 
special interest, in infants born to 
maternal subjects who were 
vaccinated with a single IM dose of 
study vaccine, up to 6 weeks after 
birth. 
The occurrence of neonatal AEs of special interest (reported up to 6 weeks 
after birth). These include but are not limited to small for gestational age, low 
birth weight including very low birth weight, neonatal encephalopathy, 
congenital microcephaly (postnatally or prenatally diagnosed), congenital 
anomalies (major external structural defects, internal structural defects, 
functional defects), neonatal death (in a preterm live birth or in a term live 
birth), neonatal infections (blood stream infections, meningitis, respiratory 
infection), respiratory distress in the neonate, preterm birth, failure to thrive, 
large for gestational age, macrosomia.* 
Occurrence of SAEs, AEs leading to study withdrawal and MAEs from birth up 
to 6 weeks after birth. 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
33 
Primary Immunogenicity objectives Primary Immunogenicity endpoints 
To evaluate the immunogenicity of a 
single IM dose of study vaccine in 
maternal subjects at Day 31 and at 
Delivery.  
RSVPreF3 IgG-specific antibody concentration, and  
Neutralizing antibody titers against RSV-A 
Measured on blood samples collected from vaccinated maternal subjects at 
Day 1 before vaccination (Visit 1), Day 31 (Visit 3), and at Delivery (Visit 5). 
To evaluate RSV-specific antibody 
levels in infants born to maternal 
subjects who were vaccinated with a 
single IM dose of study vaccine at 
birth  
RSVPreF3 IgG-specific antibody concentration, and  
Neutralizing antibody titers against RSV-A. 
Measured on the cord blood sample collected at delivery, or on a blood 
sample collected from the infant within 3 days after birth (if no cord blood 
sample can be obtained). 
To evaluate the transfer of RSV-
specific antibodies from maternal 
subjects vaccinated with a single IM 
dose of study vaccine to their infants 
at the time of delivery. 
The ratio between cord blood* and maternal RSVPreF3 IgG-specific antibody 
concentrations  
*or an infant blood sample collected within 3 days after birth (if no cord blood 
sample can be obtained).  
Secondary Safety objectives 
Secondary Safety endpoints 
To evaluate the safety of a single IM 
dose of study vaccine in maternal 
subjects, up to 6 months after delivery  
From Day 1 (Visit 1) through 6 months after delivery (Visit 8), occurrences of 
SAEs, MAEs, and AEs leading to study withdrawal. 
To evaluate the safety of the vaccine 
in infants born to maternal subjects 
who were vaccinated with a single IM 
dose of study vaccine, up to 1 year of 
age  
From birth through 6 months (Visit 4-NB) after birth, occurrences of SAEs, 
AEs leading to study withdrawal, and MAEs  
From birth through 1 year (Visit 5-NB) after birth, occurrences of SAEs, AEs 
leading to study withdrawal, and MAEs.  
To estimate the incidence of RSV-
associated, medically attended RTIs 
(MA-RTIs) in maternal subjects 
vaccinated with a single IM dose of 
study vaccine, from vaccination up to 
6 months post-delivery (Visit 8).  
Occurrence of RSV-associated MA-RTIs (RSV-MA-RTIs) up to 6 months post-
delivery (Visit 8)  
To estimate the incidence of RSV-
associated lower respiratory tract 
illness (LRTI), severe LRTI and very 
severe LRTI and RSV-associated 
hospitalization in infants born to 
maternal subjects who were 
vaccinated with a single IM dose of 
study vaccine, from birth up to 6 
months of age.  
From birth to 6 months (Visit 4-NB), occurrences of RSV-associated LRTI(s), 
Severe LRTI(s), very severe LRTIs and RSV-associated hospitalizations 
(according to the case definitions).  
Secondary immunogenicity 
objectives 
Secondary Immunogenicity endpoints 
To evaluate the immunogenicity of a 
single IM dose of study vaccine in 
maternal subjects in terms of 
RSVPreF3 IgG-specific antibody 
concentrations and neutralizing 
antibodies against RSV-A at Day 43 
after Delivery (Visit 6).  
RSVPreF3 IgG-specific antibody concentration  
Neutralizing antibody titers against RSV-A  
Measured on the blood sample collected at Day 43 post- delivery (Visit 6). 
To evaluate the immunogenicity of a 
single IM dose of study vaccine in 
maternal subjects in terms of RSV-B 
neutralizing antibodies at Day 1 before 
vaccination (Visit 1), Day 31 (Visit 3), 
at Delivery (Visit 5) and at Day 43 
post-delivery (Visit 6).  
Neutralizing antibody titers against RSV-B  
Measured on blood samples collected from vaccinated maternal subjects at 
Day 1 before vaccination (Visit 1), Day 31 (Visit 3), at Delivery (Visit 5) and at 
Day 43 post-delivery (Visit 6). 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

CONFIDENTIAL 
209544 (RSV MAT-004) 
Protocol Amendment 3 Final 
30-SEP-2020 
34 
Secondary immunogenicity 
objectives 
Secondary Immunogenicity endpoints 
To evaluate RSV-specific antibodies in 
infants born to maternal subjects who 
were vaccinated with a single IM dose 
of study vaccine, up to 6 months after 
birth.  
RSVPreF3 IgG-specific antibody concentration  
Neutralising antibody titres against RSV-A  
Neutralising antibody titres against RSV-B 
For neutralizing antibody titers against RSV-B only: measured on the cord 
blood sample collected at delivery, or on a blood sample collected from the 
infant within 3 days after birth (if no cord blood sample can be obtained). 
(Note: RSV-A neutralizing antibody at birth is a primary immunogenicity 
objective). 
For all 3 RSV-specific antibody assessments: measured in a subcohort of 
infants at Day 43 after birth (sub-cohort V2-NB), in a subcohort of infants at 
Day 121 (sub-cohort V3-NB) after birth and in a subcohort of infants at D181 
after birth (sub-cohort V4-NB). Each infant will be randomly assigned to 1 of 
these 3 cohorts at the time of maternal randomization to treatment study 
intervention. 
Tertiary objectives:  
To further evaluate the humoral response to the RSV maternal vaccine, which may include RSVpreF3 specific IgG 
subclasses, antibodies competing for binding to specific RSVpreF3 epitopes, and other exploratory endpoints. 
To evaluate the presence of other respiratory viruses in nasal swabs collected from maternal subjects and their infants 
(via an Allplex Respiratory Viruses Panel or alternative, performed for RSV A/B-positive samples and if deemed 
necessary for RSV A/B-negative samples.) 
*Maternal and neonatal AESI and pregnancy outcomes should be recorded in the eCRF along with GAIA assessment 
and level of diagnostic certainty when applicable. Of note, some adverse events of special interest fall under a single 
category but have multiple subcategories. For example, hypertensive disorders of pregnancy is an event with three 
subcategories that include: 1) gestational hypertension; 2) pre-eclampsia; and 3) pre-eclampsia with severe features 
(including eclampsia). For each event, the investigator should identify the event and select the applicable sub-
category.” 
4. 
STUDY DESIGN 
4.1. 
Overall design 
Figure 1 and Figure 2 provide overviews of the study design for maternal and infant 
subjects, respectively. Section 1.3 provides Schedules of Activities (SoAs) for maternal 
and infant subjects. Section 9.5.1 describes the sequence of analyses for maternal and 
infant subject data. 
209544 | Protocol Amendment 3 01 Oct 2020 | TMF-2127399 | 1.0

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H/B= hematology/biochemistry, Hct- hematocrit; I= humoral immune response 
If Screening blood sample collected ≤ 15 days before Visit 1, hematology/biochemistry not required at Visit 1 
Subjects will be vaccinated year-round and will not be limited to seasonal enrolment 
*Pregnancy-related AESIs identified after Day 43 will continue to be reported as such. 
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NB = Newborn; I=humoral immune response: infants will be randomized 1:1:1 to one of the 3 subcohorts shown. 
*Blood sample to be collected within 3 days after birth ONLY if a cord blood sample is not collected 
**Neonatal AESIs identified after Day 43 (e.g., congenital anomalies) will continue to be reported as such. 
***Infant subjects’ parent(s)/LAR(s) will be contacted at least monthly to ensure RTI eDiary compliance. 
Safety and disease surveillance data collected after Visit 4-NB will be reported in the database in Epoch 003.  
Screening
Day - 28 to 
Day -1
VISIT 2
Day 8
VISIT 3
Day 31
VISIT 4
Day 61
VISIT 5
Delivery
VISIT 7
Day 121
Post-
Delivery 
Visit 8
Day 181 
Post-
Delivery 
VISIT 6
Day 43 
Post-
Delivery
SAEs related to study participation; SAEs; AEs leading to study discontinuation
Solicited administration site and 
systemic events
All Unsolicited AEs
MAEs
VISIT 1
GA: 280/7-336/7
Day 1
Study 
vaccination
Blood Sample: 
H/B, I
Urine Sample
Blood Sample: 
H/B
Urine Sample
Blood 
Sample:Hct, I
Urine Sample
Blood Sample: 
Hct, I
Cord Blood: I
Blood 
Sample: Hct, I
Blood Sample:
H/B
Urine Sample
Pregnancy Outcomes
Pregnancy related AESIs
Epoch 001
Epoch 002
Urine Sample
MA-RTI surveillance
Visit 1-NB
Birth*
VISIT 3-NB
Day 121 post-
birth 
VISIT 4-NB
Day 181 
post-birth 
Contact 1-NB
Day 271
post-birth
VISIT 5-NB
12 months of age
VISIT 2-NB
Day 43 post-
birth
Blood Sample: I
Day 43 
subcohort
Blood Sample: I
Day 121 
subcohort
Blood Sample:  I
Day 181 
subcohort
SAEs; MAEs, AEs leading to study discontinuation
Neonatal/Infant AESIs**
RTI surveillance***
Epoch 002
Epoch 003
_3URWRFRO$PHQGPHQW2FW_70)_

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• 
Study Type: self-contained. 
• 
Experimental design: Phase II, observer-blind, randomised, placebo controlled, 
multi-centric, multi-country study with 3 parallel groups. 
• 
Study Duration: Approximately 9 months (including the screening visit) for 
participating pregnant women; approximately 1 year after birth for participating 
infants.  
• 
Control: Placebo. 
• 
Epochs 001, 002 and 003 begin and end as described in Table 6.  
• 
Blinding is as described in Table 6. 
• 
Randomized intervention allocation is described in Section 6.2. 
• 
Study (intervention) groups are described in Table 6. 
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Table 6 
Study groups, subcohorts, interventions, epochs and blinding foreseen in the study (Amended 30-SEP-2020) 
 
Epochs (Blinding) 
Study 
groups 
(Maternal 
subjects, 
allocated 
1:1:1) 
Approximate 
Number of 
maternal 
subjects 
Age of 
maternal 
subject at 
enrolment 
(Min/Max) 
Interven- 
tion name 
Blood sample 
subcohorts (infant 
subjects, allocated 
1:1:1 within each 
maternal study group) 
Approximate 
Number of 
infant subjects 
Study groups for 
randomization 
(Allocation 
1:1:1:1:1:1:1:1:1) 
Epoch 001 
Maternal 
subjects 
Only 
(Screening) 
Epoch 002 
Maternal subjects 
V1-V8 
Infant subjects 
V1-NB – V4NB 
(observer-blind)* 
Epoch 003 
Infant subjects 
only 
Contact 1-NB – V5-
NB  
(single-blind) 
RSV MAT 
60 
Up to 100 
18 – 40 years RSVPreF3_60  
BS1_60 
Up to 33 
RSVMAT60_BS1  
● 
●  
● 
BS2_60 
Up to 33 
RSVMAT60_BS2 
● 
BS3_60 
Up to 33 
RSVMAT60_BS3  
●  
RSV MAT 
120 
Up to 100 
18 – 40 years RSVPreF3_120 
BS1_120 
Up to 33 
RSVMAT120_BS1 
● 
●  
● 
BS2_120 
Up to 33 
RSVMAT120_BS2 
●  
BS3_120 
Up to 33 
RSVMAT120_BS3 
●  
Control 
Up to 100 
18 – 40 years 
Control 
BS1_C 
Up to 33 
Control_BS1 
● 
●  
● 
BS2_C 
Up to 33 
Control_BS2 
●  
BS3_C 
Up to 33 
Control_BS3 
●  
M=maternal subject; I=infant; Control = Placebo; Blood sampling subcohorts are abbreviated “BS1;” “BS2;” BS3” and correspond to visits 2-NB (Day 43), 3-NB (Day 121) and 4-NB 
(Day 181), respectively. 
* After the second analysis, the study will not be considered observer blind as the investigator brochure will be updated to include safety information presented by treatment group. This 
could lead to inadvertent unblinding of investigators and site staff to some subjects’ treatment assignments. The subjects themselves will remain blinded throughout their participation 
in the study. 
• 
Data collection: standardized Electronic Case Report Form (eCRF). Electronic diaries (e-diaries) for solicited event data, and 
notifications regarding occurrence of unsolicited events (including medically attended events and SAEs), and symptoms of 
respiratory tract illnesses in infant subjects.  
• 
Safety monitoring: Refer to section 8.2.3 for detailed description of holding rules and safety monitoring. 
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4.2. 
Scientific rationale for study design 
4.2.1. 
Study population  
The study population mirrors that of the intended indication: healthy women in the third 
trimester of pregnancy. 
4.2.2. 
Rationale for the use of placebo 
The placebo group serves as a control for safety, reactogenicity, and immunogenicity 
assessments.  
4.2.3. 
Safety considerations 
As this is the first time the RSV maternal (RSVPreF3) vaccine will be administered to 
pregnant women, enrolment will be limited to 10 subjects per day across all sites until the 
first 30 subjects have been dosed. Within any given study site, these subjects will be 
vaccinated sequentially and at least 60 minutes apart.  
In addition, throughout the study: 
• 
All subjects will be required to remain at the site for 60 minutes following 
vaccination, and  
• 
The data will be reviewed by a safety review team (SRT) and by an independent data 
monitoring committee (IDMC), and  
• 
Holding rules will be applied. 
The risk of Enhanced Respiratory Disease related to boosting pre-existing maternal 
antibody and transfer of vaccine-induced neutralizing antibodies from mother to infant is 
considered negligible. However, as data evaluating this risk are expected before 
vaccinating larger numbers of pregnant women, surveillance and evaluation (Section 8.4) 
of all RTIs in infants and medically attended-RTIs in mothers through 6 months post-
delivery has been implemented. 
4.2.4. 
Sub-cohorts for blood sampling in infants 
Sub-cohorts for blood sampling have been defined to limit discomfort and risk to infants 
while ensuring enough observations to support robust evaluation of immune response 
(see Figure 4 and Table 6).  
4.2.5. 
Study blinding (Amended 30-SEP-2020) 
The RSV maternal vaccine and the placebo differ in appearance. In addition, the RSV 
maternal vaccine formulations must be reconstituted before administration, whereas the 
placebo does not. Therefore, double blinding is not feasible and the study will be 
conducted in an observer-blinded manner until the second analysis is conducted, as 
described in Section 6.3.4. After the second analysis, the study will not be considered 
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observer-blind as the investigator brochure will be updated to include safety information 
presented by treatment group. This could lead to inadvertent unblinding of investigators 
and site staff to some subjects’ treatment assignments. The subjects themselves will 
remain blinded throughout their participation in the study. 
Please refer to the Glossary of terms for the definition of “observer-blind.”  
4.2.6. 
Case Definitions  
Cases will be classified (during data analyses) according to the definitions that follow. 
Case definitions should not be confused with the definitions study personnel use during 
RTI surveillance (Section 8.4). 
4.2.6.1. 
Maternal, medically attended respiratory tract illness (MA-RTI) 
Table 7 
MA-RTI case definitions for data analysis in maternal subjects 
RSV-MA-RTI 
Medically attended visit for RTI symptoms  
AND 
Confirmed RSV infection 1, 2 
RSV hospitalization 
Confirmed RSV infection AND 
Hospitalized for acute medical condition 3 
All-cause MA- RTI 
Medically attended visit for RTI symptoms 
1 Confirmed RSV infection defined in Section 4.2.6.3 
2 RSV (nasal swab) sampling and testing as specified in Table 11. 
3 Hospitalization is defined as admission for observation or treatment based on the judgement of a health care 
provider. 
4.2.6.2. 
Respiratory tract illness (RTI) / Lower respiratory tract illness (LRTI) in 
infants 
Table 8 
RTI/LRTI case definitions for data analysis in infants 
RSV-RTI 
Runny nose, OR Blocked nose, OR Cough 
AND 
Confirmed RSV infection 4 
RSV-LRTI 
History of cough OR difficulty in breathing 1 
AND  
SpO2 < 95%2, OR RR increase 3 
AND  
Confirmed RSV infection 4 
RSV-severe 
LRTI 
Meeting the case definition of RSV-LRTI 
AND 
SpO2 < 93%2, OR lower chest wall in-drawing 
RSV-very severe 
LRTI 
Meeting the case definition of RSV-LRTI  
AND  
SpO2 < 90%2, OR inability to feed OR failure to respond / unconscious 
RSV 
hospitalization 
Confirmed RSV infection 5 
AND 
Hospitalized for acute medical condition 6 
All-cause RTI 
Runny nose, OR Blocked nose, OR Cough 
All-cause LRTI 
History of cough OR difficulty in breathing 1  
AND  
SpO2 < 95% 2, OR RR increase 3 
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Definitions based on [Modjarrad, 2016] 
RTI = respiratory tract illness; LRTI = lower respiratory tract illness; RR = respiratory rate; SpO2 = blood oxygen 
saturation by pulse oximetry. 
1 Based on history reported by parents/LARs and includes difficulty in breathing (e.g. showing signs of wheezing or 
stridor, tachypnoea, flaring [of nostrils], chest in-drawing, apnea). 
2 For blood oxygen saturation (SpO2), the lowest value monitored will be used. In high altitudes (>2500m), SpO2 <92% 
for LRTI, <90% for severe LRTI, <87% for very severe LRTI.  
3 RR increase defined as: 
> 60/minute (< 2 months of age) 
> 50/minute (2 to < 12 months of age) 
> 40/minute (12 to 24 months of age) 
4 Confirmed RSV infection defined in Section 4.2.6.3 
5 RSV (nasal swab) sampling and testing as specified in Table 12. 
6 Hospitalization is defined as admission for observation or treatment based on the judgement of a health care 
provider. 
4.2.6.3. 
RSV infection 
The sponsor will analyze nasal swabs by quantitative reverse transcription polymerase 
chain reaction (qRT-PCR) for the presence of RSV A/B. A positive (RSV A or B) test 
result constitutes a case of RSV infection. Refer to Table 11, Table 12 and Section 8.1. 
4.3. 
Justification for dose  
Two formulations (containing 60 and 120 µg of the RSVPreF3 antigen, respectively) 
have been selected from RSV MAT-001 for evaluation in the current study, RSV MAT-
004, as they elicited a more robust immune response than the 30µg dose. Selection of the 
doses for RSV MAT-004 was based on the review of safety data through 90 days and 
immunogenicity data through 30 days post-vaccination for all 500 subjects enrolled and 
dosed, and safety data through 180 days and immunogenicity data through 90 days for 
the first 60 subjects enrolled and dosed. This data will be included in the Investigator 
Brochure to support RSV MAT-004. Evaluating 2 dose levels supports efforts to 
determine if there is a dose response relationship in the maternal antibody response to the 
vaccine and placental transfer of antibodies to the fetus.  
Because re-infection with RSV occurs throughout an individual’s lifetime, it is extremely 
unlikely that an adult (in this case, a maternal subject) would not have been naturally 
infected with RSV before. Therefore, a single dose of the study vaccine should be 
sufficient to boost the neutralizing antibodies induced by previous natural infections. 
The study vaccine will be administered at 280/7 - 336/7 weeks of gestation. This gestational 
age range is considered optimal for both immunogenicity and safety. It allows enough 
time to (a) induce high neutralizing antibody levels in maternal subjects before delivery 
and (b) ensure these antibody levels are elevated during the period of greatest placental 
antibody transfer to the fetus. Moreover, it is after the critical period for organogenesis 
(i.e. after the period when most congenital abnormalities develop). 
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4.4. 
End of study definition  
A subject is considered to have completed the study if he/she returns for the last visit 
(Visit 8 for maternal subjects / Visit 5-NB for infant subjects) as described in the 
protocol. 
The Primary Completion Date (PCD) occurs on completion of the Day 43 post-delivery 
visit in Epoch 002 (Visit 6 for the maternal subjects and Visit 2-NB for the infant 
subjects). 
End of study (EoS) occurs with the last (infant) subject last visit (LSLV; Visit 5-NB). 
Refer to the Glossary of terms for the definitions of PCD and EoS. 
5. 
STUDY POPULATION 
5.1. 
Inclusion criteria for enrolment 
Adherence to these criteria as specified in the protocol is essential. Inclusion criteria 
deviations are not allowed because they can jeopardise the scientific integrity or 
regulatory acceptability of the study or subject safety.  
5.1.1. 
Maternal subjects 
Maternal subjects must satisfy all the following criteria at study entry: 
• 
Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the electronic diaries, return for 
follow-up visits). 
• 
Subjects who give written or witnessed/thumb printed informed consent after the 
study has been explained according to local regulatory requirements, and before any 
study specific procedure are performed. The informed consent given at screening 
should (consistent with local regulations / guidelines) either: 
− 
include consent for both the maternal subject’s participation and participation of 
the infant after the infant’s birth, or  
− 
include consent for the maternal subject’s participation and expressed 
willingness to consider permitting the infant to take part after the infant’s birth 
(if local regulations/guidelines require parent(s) to provide an additional 
informed consent after the infant’s birth).  
− 
Both mother and father should consent if local regulations/guidelines require it. 
• 
Age 18 to 40 years, inclusive, when informed consent is given (i.e., at enrolment).  
• 
Pre-pregnancy BMI (based on subject’s report) 18.5 to 34.9, inclusive 
• 
Healthy as established by medical history and clinical examination before entering 
into the study. 
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• 
At 28 0/7 to 33 6/7 weeks of gestation at the time of study vaccination (Visit 1), as 
established by last menstrual period (LMP) date corroborated by first or second 
trimester ultrasound examination (U/S). 
* If LMP and U/S do not correlate, default to U/S gestational age assessment. The 
level of diagnostic certainty of the gestational age should be established by using the 
Global Alignment of Immunisation safety Assessment in pregnancy (GAIA) 
gestation age assessment tool (Section 10.7) 
• 
Subject satisfying screening requirements 
• 
Singleton pregnancy 
• 
HIV negative, as assessed by local standard of care serologic tests conducted during 
the current pregnancy and before enrolment (Visit 1). 
• 
No fetal genetic abnormalities (based on genetic testing, if performed). 
• 
No significant congenital malformations (such as abnormal fetal morphology, 
abnormal amniotic fluid levels, significant abnormalities in placenta or umbilical 
cord), as assessed by level 2 ultrasound (also known as a fetal anomaly ultrasound 
scan or fetal morphology assessment) conducted after 18 weeks of gestation  
• 
Willing to provide cord blood 
• 
Willing to have the infant followed-up after delivery for a period of 12 months  
• 
Does not plan after delivery to give the infant for adoption or place the infant in care 
Note that women whose pregnancies resulted from Assisted Reproductive Technologies 
may be enrolled if they meet all inclusion criteria and none of the exclusion criteria.  
5.1.2. 
Infant subjects 
Infant subjects must satisfy all the following criteria at study entry: 
• 
Live-born from the study pregnancy.  
• 
Re-signed (confirmed) written or witnessed/thumb printed informed consent for 
study participation of the infant obtained from the infant’s mother and/or father 
and/or LAR, as applicable by local law, before performing any study specific 
procedure. 
5.2. 
Exclusion criteria for enrolment 
Adherence to criteria specified in the protocol is essential. Exclusion criteria deviations 
are not allowed because they can potentially jeopardise the scientific integrity or 
regulatory acceptability of the study or safety of the subject. 
The following criteria should be checked at the time of study entry. The potential subject 
MUST NOT be included in the study if ANY exclusion criterion applies: 
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5.2.1. 
Maternal subjects 
5.2.1.1. 
Medical conditions  
• 
History of allergic disease or reactions likely to be exacerbated by any component of 
the RSV vaccine 
• 
Hypersensitivity to latex  
• 
Significant (as per Investigator’s judgement) complications in the current pregnancy 
such as: 
− 
Gestational hypertension (defined as systolic blood pressure ≥140 mmHg and/or 
diastolic blood pressure ≥90 mmHg) at ≥20 weeks of gestation in the absence of 
proteinuria in a woman with a previously normal blood pressure [ACOG, 2019a] 
− 
Gestational diabetes which is not controlled by diet and exercise (Gestational 
diabetes is defined as absence of pre-gestational diabetes and hyperglycemia 
during pregnancy, which is not due to other known causes, confirmed based on 
positive oral glucose tolerance test or based on fasting plasma glucose levels in 
venous or capillary blood samples [Kachikis, 2017].) 
− 
Pre-eclampsia (defined as Systolic blood pressure of 140 mm Hg or more or 
diastolic blood pressure of 90 mm Hg or more on two occasions at least 4 hours 
apart after 20 weeks of gestation in a woman with a previously normal blood 
pressure and proteinuria or, in the absence of proteinuria, the new onset of 
thrombocytopenia, renal insufficiency, impaired liver function, pulmonary 
edema or headache unresponsive to medication [ACOG, 2019a] 
− 
Eclampsia (defined as occurrence of new-onset seizures, in the absence of other 
causative conditions, in a woman with a hypertensive disorder of pregnancy) 
[ACOG, 2019a] during current pregnancy 
− 
Intrauterine growth restriction (defined as sonographically estimated fetal 
weight that is less than the 10th percentile for gestational age) [ACOG, 2019b] 
− 
Placenta previa (unless there is documented sonographic evidence that the 
placenta has moved up before enrolment),  
− 
Placental abruption, placenta accreta/percreta/increta, chorioamnionitis or any 
abnormalities that in the opinion of Investigator can impair the maternal-fetal 
circulation 
− 
Polyhydramnios (defined as either a deepest vertical pocket of >8 cm or an 
amniotic fluid index of >24 cm on ultrasound examination) [Dashe, 2018]  
− 
Oligohydramnios (defined as a maximum vertical pocket shorter than 2 cm or 
amniotic fluid index < 5 cm on the ultrasound examination) [Reddy, 2014] 
− 
Cervical suture in place 
− 
Preterm labour or history of preterm labour in the current pregnancy 
− 
Ongoing medical intervention to prevent preterm delivery or medical treatment 
for suspected preterm delivery 
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− 
Cholestasis (defined as unexplained pruritus and/or abnormal liver function tests 
and/or raised bile acids, based on investigator’s clinical judgement) [RCOG, 
2011] 
− 
Other pregnancy-related complications that in the Investigator’s judgement 
would preclude participation of the subjects in an investigational vaccine trial or 
might pose risk to the subject due to participation in the study 
• 
Significant (as per Investigator’s judgement) structural abnormalities of the uterus or 
cervix. 
• 
History of prior stillbirth or neonatal death 
• 
History of preterm birth (< 37 weeks gestation) 
• 
History of ≥2 spontaneous abortions.  
• 
Known or suspected HBV or HCV infection, based on medical history and clinical 
presentation (no laboratory testing is required) 
• 
Known or suspected infection during the current pregnancy with Toxoplasma, 
Parvovirus B19, Syphilis, Zika, Rubella, Varicella, CMV or primary genital Herpes 
Simplex, based on medical history and clinical presentation (no laboratory testing is 
required). 
• 
Active infection with tuberculosis, based on medical history and clinical presentation 
(no lab testing is required). 
• 
Known or suspected impairment of the immune system or autoimmune disorder 
(based on medical history and physical examination; no laboratory testing required). 
• 
Lymphoproliferative disorder or malignancy within 5 years before vaccination 
(excluding effectively treated non-melanoma skin cancer).  
• 
Any clinically significant grade 1 haematological and/or biochemical laboratory 
abnormalities identified at screening. The investigator should use clinical judgement 
to decide which abnormalities are clinically significant based on reference ranges for 
pregnant women in the second and third trimester, as provided in [Sheffield, 2013] 
and the SPM for this study. 
• 
Grade ≥ 2 haematological and/or biochemical laboratory abnormalities identified at 
screening based on reference ranges for pregnant women in the second and third 
trimester, as provided in [Sheffield, 2013] and the SPM for this study. 
• 
Acute or chronic clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality or poorly controlled pre-existent co-morbidities or any other 
clinical conditions, as determined by physical examination or laboratory screening 
tests, that, in the opinion of the investigator, might pose additional risk to the subject 
due to participation in the study 
• 
Any conditions that, in the investigator’s judgement, may interfere with subject’s 
ability to comply with study procedures or receipt of prenatal care, such as 
behavioral or cognitive impairment or neuropsychiatric illness.  
• 
Any condition which, in the investigator’s opinion, would increase the risks of study 
participation to the unborn infant. 
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5.2.1.2. 
Prior/Concomitant therapy  
• 
Prior receipt of a COVID-19 vaccine. 
• 
Prior receipt of an RSV vaccine. 
• 
Use of any investigational or non-registered product (drug, vaccine or medical 
device) other than the study vaccine(s)/product(s) during the period beginning 29 
days before the dose of study vaccine/product (Day -28 to Day 1), or planned use 
during the study period. 
• 
Planned administration/administration of any vaccine within 29 days before study 
vaccine administration (Day -28 to Day 1) and through delivery (Visit 5), except 
seasonal influenza vaccines and dTpa/Tdap or tetanus, which may be administered 
according to standard of care ≥ 15 days before or after study vaccination  
Note that if public health authorities organize an emergency mass vaccination for an 
unforeseen public health threat (e.g.: a pandemic) outside the routine immunisation 
program, then the intervals described above can be reduced if necessary for that 
mass vaccination vaccine, provided the vaccine is licensed and used according to its 
Product Information.  
• 
Administration of immunoglobulins, blood products (except anti-Rh0D IG) or 
plasma derivatives within 3 months before study vaccination or planned 
administration through Visit 5 (the delivery visit).  
• 
Administration of immune-modifying therapy within 6 months before the study 
vaccine/product dose, or planned administration through delivery. This includes but 
is not limited to:  
− 
Azathioprine, mycophenolate mofetil, 6-mercaptopurine, cyclosporine, 
tacrolimus, monoclonal or polyclonal antibodies; 
− 
Prednisone ≥ 5 mg/day or equivalent for ≥ 14 days. Topical steroids are allowed. 
Inhaled steroids are allowed if ≤ 500µg/day of beclomethasone or fluticasone, or 
≤ 800µg/day of budesonide.  
5.2.1.3. 
Prior/Concurrent clinical study experience  
• 
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (drug or medical device). 
5.2.1.4. 
Other exclusions  
• 
Alcoholism or substance use disorder within the past 24 months based on the 
presence of two or more of the following abuse criteria: hazardous use, 
social/interpersonal problems related to use, neglected major roles to use, withdrawal 
tolerance, use of larger amounts or longer, repeated attempts to quit or control use, 
much time spent using, physical or psychological problems related to use, activities 
given up to use, craving (based on the DSM-5 criteria, [Hasin, 2013]) 
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• 
A local condition that in the opinion of the Investigator precludes injection of the 
study drug or precludes assessment of local (administration site) reactogenicity. 
• 
Consanguinity of maternal subject and her partner (second degree cousins or closer) 
• 
Any study personnel or their immediate dependants, family, or household members 
5.2.2. 
Infant subjects 
• 
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (drug or medical device). 
• 
Child in care (Please refer to the Glossary of terms for the definition of child in care) 
5.3. 
Lifestyle considerations 
For lifestyle considerations pertaining to inclusion /exclusion criteria, refer to Sections 
5.1 and 5.2. For data collection pertaining to lifestyle characteristics, refer to Section 
8.2.1.1.1. 
5.4. 
Screen failures 
Screen failures are subjects who consent to participate in this study but are not 
subsequently randomly assigned to a study intervention. 
Limited data for screening failures (including reason for screening failure and any SAEs 
that occurred at the visit) will be collected and reported in the eCRF. 
6. 
STUDY INTERVENTION  
A ‘study intervention’ is defined as a set of investigational or marketed product(s) or 
placebo intended to be administered to a subject during the study.  
Refer to the Study Procedures Manual (SPM) for additional details. 
6.1. 
Study Intervention(s) administered  
After completing all prerequisite pre-dosing procedures and confirming the maternal 
subject’s eligibility, 1 dose of study vaccine/product will be prepared and administered as 
shown in Table 9.  
Note that the active vaccines (RSVPreF3_60 and RSVPreF3_120) must be reconstituted 
before administration. 
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Table 9 
Study interventions administered  
Study intervention name: 
RSVPreF3_60 
RSVPreF3_120 
Placebo 
Study intervention formulation: 
RSVPreF3  
(60 µg) 
Sodium chloride (NaCl) 
(0.9%); Water for injections 
q.s, 0.5 mL 
RSVPreF3  
(120 µg) 
Sodium chloride (NaCl) 
(0.9%); Water for injections 
q.s, 0.5 mL 
Sodium chloride (NaCl) 
(0.9%); Water for injections 
q.s, 0.5 mL 
Presentation: 
Powder for 
suspension for 
injection, vial 
Solution for injection; vial 
Powder for 
suspension for 
injection, vial 
Solution for injection; vial 
Solution for injection; vial 
Route of administration: 
Intramuscular use 
Intramuscular use 
Intramuscular use 
Administration site: 
• 
Location 
Deltoid 
Deltoid 
Deltoid 
• 
Laterality * 
Non-Dominant 
Non-Dominant 
Non-Dominant 
Number of doses to be 
administered: 
1 
1 
1 
Volume to be administered: 
0.5 ml 
0.5 ml 
0.5 ml 
Packaging, labelling and TM: 
Refer to the SPM 
Refer to the SPM 
Refer to the SPM 
Manufacturer: 
GSK Biologicals 
GSK Biologicals 
GSK Biologicals 
*The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the non-dominant arm, an injection in the dominant arm may be 
performed. 
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Maternal subjects must be observed closely for at least 60 minutes after administration of 
the study vaccine/product. Appropriate medical treatment must be readily available in 
case of anaphylaxis and syncope. 
Refer to the Study Procedures Manual (SPM) for additional details. 
6.2. 
Preparation/Handling/Storage/Accountability  
The study vaccine(s)/product(s) must be stored in a safe, locked place at the temperature 
specified on the vaccine/product label. The storage temperature should be continuously 
monitored with calibrated (if not validated) temperature monitoring device(s) and 
recorded. Only authorised study personnel should be allowed access to the study 
vaccine/product. Storage conditions will be assessed by a sponsor study contact during 
pre-study activities. Refer to the section on Study Supplies in the SPM for more details 
on storage and handling of the study vaccine(s)/product(s).  
6.3. 
Measures to minimize bias: randomization and blinding 
6.3.1. 
Subject identification 
Maternal identification numbers will be assigned sequentially to pregnant women who 
have consented to participate in the study, according to the range of subject identification 
numbers allocated to each study center. 
When a maternal subject is randomized at Visit 1, an identification number will be 
assigned to her (as yet unborn) infant. Maternal and infant identification numbers will be 
linked. 
6.3.2. 
Randomisation to study intervention  
Up to 300 eligible pregnant women will be randomly assigned to 3 study (intervention) 
groups in a 1:1:1 ratio and at the same time, their (as yet unborn) infants will be randomly 
assigned to 3 blood sampling subcohorts (also in a 1:1:1 ratio). This yields up to 100 
pregnant women per group and up to 33 infants per blood sampling subcohort within 
each group, for an overall allocation of 1:1:1:1:1:1:1:1:1. Refer to Table 6, Figure 3 and 
Figure 4. 
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Figure 3 
Allocation of maternal subjects to study (intervention) groups  
 
*Numbers are approximate and represent maximum subject enrolment. 
Figure 4 
Allocation of infant subjects to blood sampling subcohorts  
 
*Numbers are approximate and represent maximum subject enrolment. 
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 in this multi-centre study 
and to thus reduce the overall study recruitment period, an over-randomisation of 
supplies will be prepared.  
100
Pregnant 
Women
All Enrolled 
Subjects
Receiving RSVPreF3 120µg
Receiving RSVPreF3 60 µg
300 Pregnant 
Women
100
Pregnant 
Women
100
Pregnant 
Women
Receiving Placebo
Visit    
2-NB
100
Pregnant 
Women
300 Pregnant 
Women
100
Pregnant 
Women
100
Pregnant 
Women
~33
Infants
~ 33
Infants
~ 33
Infants
~ 33
Infants
~ 33
Infants
~ 33
Infants
~ 33
Infants
~ 33
Infants
~ 33
Infants
Visit    
2-NB
Visit    
3-NB
Visit    
4-NB
Visit    
3-NB
Visit    
4-NB
Visit    
2-NB
Visit    
3-NB
Visit    
4-NB
Infants of Pregnant Women 
Receiving RSVPreF3 120µg
Infants of Pregnant Women 
Receiving RSVPreF3 60µg
All Enrolled 
Subjects
Pregnant Women Receiving 
RSVPreF3 120µg
Pregnant Women Receiving 
RSVPreF3 60µg
Pregnant Women 
Receiving Placebo
Infants of Pregnant Women 
Receiving Placebo
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6.3.3. 
Intervention allocation to the subjects 
Upon providing the maternal subject identification number, an automated internet based 
system (SBIR) will allocate the maternal subject to an intervention number and her (as 
yet unborn) infant subject to a blood sampling subcohort. The system’s randomisation 
algorithm will use a minimisation procedure accounting for maternal age at the time of 
vaccination ( ≥18 and <35 years of age or ≥ 35 years of age), gestational age at the time 
of vaccination (280/7-310/7; 31 1/7-336/7) and center. Minimisation factors will have equal 
weight in the minimisation algorithm.  
When the automated Internet-based system (SBIR) is not available, please refer to the 
SBIR user guide or SPM for specific instructions. 
Refer to the SPM for additional information about intervention number allocation. 
6.3.4. 
Blinding and unblinding (Amended 30-SEP-2020) 
Data will be collected in an observer-blind manner. To do so, vaccine/product will be 
prepared and administered by qualified study personnel who will not participate in data 
collection, evaluation, review or entry of any study endpoint (i.e., reactogenicity, safety, 
efficacy). 
The laboratory in charge of the sample testing will be blinded to the intervention 
assignment. Codes will be used to link the subject and study (without any link to the 
intervention attributed to the subject) to each sample. 
Investigators will remain blinded to each subject’s assigned study intervention until the 
second analysis. After the second analysis, the investigator’s brochure will be updated to 
include safety information presented by treatment group. This could lead to inadvertent 
unblinding of investigators and site staff to some subjects’ treatment assignments.   
6.3.4.1. 
Emergency unblinding 
Unblinding a subject’s individual intervention number should occur ONLY in case of a 
medical emergency when knowledge of the intervention is essential for the clinical 
management or welfare of the subject. 
A subject may continue in the study if that subject’s intervention assignment is 
unblinded. 
The emergency unblinding process enables the investigator to have unrestricted, 
immediate and direct access to the subject’s individual study intervention via an 
automated Internet-based system (SBIR). 
As a back-up process, the investigator has the option of contacting a GSK Biologicals’ 
Helpdesk (refer to Table 10) if he/she needs support to perform the unblinding (i.e. he/she 
cannot access the automated Internet-based system). 
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The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF. 
The Local Medical Lead (LML) should be contacted if there are any questions about 
concomitant (or prior) therapy. 
6.5.1. 
Maternal subjects  
• 
All folate and iron supplements beginning the month before the estimated date of 
conception and continuing through delivery (i.e., through Visit 5). These 
supplements should be reported when taken independently and/or when included in a 
multivitamin mineral supplement. 
• 
All concomitant vaccines beginning the month before the estimated date of 
conception and throughout the study (i.e., through Visit 8). 
• 
Prophylactic medication related to the effects (actual or anticipated) of study 
vaccine/product administration (e.g., medication administered either in the absence 
of ANY symptom and in anticipation of a reaction to the dose, or to prevent re-
occurrence of one or more post-dose AEs such as headache).  
• 
Any concomitant medications/products associated with a solicited event or with an 
unsolicited adverse event, beginning at Visit 1 and ending at Visit 3 (Day 1 to Day 
31). 
• 
Any concomitant medications/products associated with a medically attended 
adverse event (MAE) (and/or an MA-RTI) beginning at Visit 1 and ending at Visit 8 
(Day 1 to Day 181 post delivery). 
6.5.2. 
Infant subjects 
• 
Vaccinations administered from Birth (Visit 1-NB) through the 12-month visit (Visit 
5-NB)  
• 
Medications/products administered in relation to RTIs/LRTIs from Birth 
(Visit 1-NB) through the six-month visit (Visit 4-NB). 
• 
Medications/products administered in relation to MAEs from Birth (Visit 1-NB) 
through the 12-month visit (Visit 5-NB). 
6.5.3. 
Maternal and Infant subjects 
• 
Any concomitant medications/products/vaccines leading to a subject’s non-eligibility 
(Sections 5.2.1 and 5.2.2) or potential non-evaluability (Section 9.3.3.1), or to a 
subject’s withdrawal from the study.  
• 
Any concomitant medications/products/vaccines relevant to an SAE/Adverse Event 
of Special interest (AESI) to be reported as per protocol or administered at any time 
during the study period for the treatment of an SAE/AESI. Concomitant medications 
relevant to SAEs / AESIs must be recorded on the Expedited Adverse Event report. 
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6.6. 
Dose modification 
Not applicable. 
6.7. 
Intervention after the end of the study 
At Visit 7 the investigator will ask each maternal subject if she is interested in 
participating in a study of a second (booster) dose of the RSV maternal vaccine, to be 
administered within 3 years after the study pregnancy. At the study conclusion visit (Visit 
8), the investigator will confirm whether the subject is interested and record the subject’s 
response in the eCRF. 
Among maternal subjects interested in joining such a study: 
• 
Those who become pregnant again within 3 years may be invited to receive a booster 
dose while pregnant. They will be followed (along with the infant, when delivered) 
in a manner similar to that described in this protocol.  
• 
Those who do not become pregnant again may be invited to receive a booster dose 
and be followed for safety and immune response. 
For maternal subjects who are not interested, the reason for refusal will be documented, 
when available, in the subject’s eCRF  
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
Criteria for discontinuation of study vaccines / products do not apply since this is a single 
dose study. However, administration of the study’s single dose may be delayed if the 
criteria presented in Section 7.1.1 are met. 
7.1.1. 
Criteria for temporary delay of study vaccination  
Vaccination may be postponed within the permitted time interval until transient 
circumstances cited below have been resolved: 
• 
Clinically significant Grade 1 hematological/biochemical values, if expected to be 
temporary. Subjects may be re-screened at a later date within the allowed time 
interval (Table 2). Reference ranges are as provided in [Sheffield, 2013] and in the 
SPM. 
• 
Acute disease and/or fever within 48 hours before study vaccination. Fever is defined 
as temperature ≥38ºC by any age appropriate route (oral route preferred). Subjects 
with a minor illness (such as mild diarrhoea, mild upper respiratory infection) 
without fever may be vaccinated at the discretion of the investigator 
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• 
Use of systemic antibiotic or antiviral treatment within 7 days before study 
vaccination.  
• 
Use of antipyretics and/or analgesics within 3 days before study vaccination. 
7.1.2. 
Contraindications to subsequent vaccine administration 
Not applicable. 
7.2. 
Subject discontinuation/withdrawal from the study  
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. 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not return for the concluding visit/was not available for the concluding contact foreseen 
in the protocol.  
Investigators will attempt to contact those subjects who do not return for scheduled visits 
or follow-up. 
All data and samples collected until the date of withdrawal of/last contact with the subject 
will be used for the analysis. 
The primary reason for study withdrawal will be documented in the eCRF based on 
the list below: 
• 
Adverse events requiring expedited reporting to GSK (Section 8.3.3) 
• 
Unsolicited non-serious adverse event 
• 
Solicited adverse event (maternal subjects) 
• 
Protocol deviation  
• 
Withdrawal by maternal subject / infant subject’s parent(s)/LAR(s), not due to an 
adverse event* 
• 
Migrated/Moved from the study area 
• 
Lost to follow-up 
• 
Sponsor study termination 
• 
Other (specify) 
*If a maternal or infant subject is withdrawn from the study because the maternal subject 
/ infant subject’s parent(s)/LAR(s) has withdrawn consent and provided the reason for its 
withdrawal, the investigator will document this reason 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 
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follow subjects who are withdrawn from the study as result of an SAE/AE until 
resolution of the event (see Section 10.3.8). 
7.3. 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she fails to return for scheduled 
visits and is unable to be contacted by the study site.  
Please refer to the SPM for a description of the actions to be taken before considering the 
subject as lost to follow-up.  
8. 
STUDY ASSESSMENTS AND PROCEDURES  
(AMENDED 30-SEP-2020) 
Study procedures and their timing are summarised in the SoAs (Section 1.3). Information 
not provided in the SoAs follows. 
Readers are reminded that study visits /contacts, assessments and procedures do not 
replace local standards of care, and that any adverse event / potential adverse event 
identified during a study visit/contact or procedure should be treated according to local 
medical practice or by referral to an appropriate health care provider. 
Adherence to the protocol is essential and required for study conduct. 
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. 
The investigator is not allowed to do testing on samples outside of what has been agreed 
upon by the IEC/IRB. 
Immediate safety concerns should be discussed with the sponsor as soon as they occur or 
when the study team is aware of them. 
All screening evaluations must be completed and the results reviewed before confirming 
that potential subjects meet all eligibility criteria. 
The investigator will maintain a screening log of all subjects screened. All relevant 
information, such as confirmation of eligibility and reasons for screening failure will be 
mentioned in this screening log.  
Procedures conducted as part of routine clinical management (e.g. hematologic profiles) 
and obtained before the subject signed the Informed Consent Form (ICF) may be used for 
screening and/or for establishing a clinical baseline, provided the procedure met protocol-
specified criteria and was performed within the time frame defined in the SoA (Section 
1.3). 
The SPM provides the investigator and site personnel with administrative and detailed 
technical information that does not impact subject safety. 
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Study Procedures During Special Circumstances: COVID-19 pandemic 
• 
During special circumstances (e.g., the COVID-19 pandemic), the specific 
guidance from local public health and other competent authorities regarding the 
protection of individuals’ welfare must be applied.  
For the duration of such special circumstances: 
• 
Enrolment of ADDITIONAL maternal subjects may be placed on hold.  Decisions 
on re-starting enrolment to achieve the planned sample size will be made in a 
manner consistent with guidance from public health and other competent 
authorities. 
• 
The following measures may be implemented for enrolled participants:  
− 
If it is not possible to conduct a protocol-specified, scheduled or event-driven 
visit as described in Section 1.3, the visit may be replaced with a contact 
conducted by telephone, videotelephony or telemedicine. SMS and email are 
not allowed.  
− 
Biological samples may be collected at a different location* other than the 
study site or the subject’s home. Biological samples should not be collected if 
they cannot be obtained within the visit interval (Table 2, Table 4), processed 
in a timely manner or appropriately stored until the intended use.  
o 
Nasal swabs and blood samples for assessment of immune response 
should only be collected using centrally provided supplies. 
o 
Hematocrit and dipstick urinalysis may be evaluated locally, using local 
supplies, if collection using centrally provided supplies is not feasible.  
− 
If hematocrit is evaluated locally, date, result and normal range should be 
recorded in the eCRF in the Comment section for the relevant visit. 
− 
If any other missing data were collected during a visit for standard care in the 
appropriate interval (Table 2 for maternal subjects; Table 4 for infant 
subjects), and if the medical records for this visit are accessible to site staff (as 
allowed by local law), then the data from the medical record may be recorded 
in the subject’s study source document and entered into the eCRF.  
• 
“Medically attended visits” will include actual visits to or from medical personnel 
and instances where, due to the special circumstances, the subject cannot seek 
medical advice for symptoms/an illness by visiting a medical facility or arranging 
for a home visit, and seeks this advice instead via telephone, SMS, email, 
videotelephony or telemedicine, or other means.  
• 
The eDiary device provided to the maternal subject may be returned to the site by 
conventional mail after Day 181 post-delivery/birth, if the Day 181 post- delivery / 
birth visits (Visit 8 / Visit 4-NB) cannot be performed. 
*It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH GCP requirements, such as 
adequate facilities to perform study procedures, appropriate training of the staff and 
documented delegation of responsibilities in this location. This alternate location 
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should be covered by proper insurance for the conduct of study on participants by 
investigator and staff at a site other than the designated study site. Refer to EMA 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
pandemic (version 2, 27 March 2020) for more details. 
The impact of measures taken during special circumstances on the per protocol set for 
immunogenicity will be determined on a case by case basis. 
 
8.1. 
Efficacy and/or immunogenicity assessments  
Collected biological 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. 
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 prior IEC/IRB 
approval if required per local legislation. 
Information on further investigations and their rationale can be obtained from GSK. 
Sample testing will be done in accordance with the recorded consent of the individual 
maternal subject/ infant subject’s parent(s)/LAR(s). 
If additional testing is performed, the marker priority ranking given in Section 8.1.3 may 
be changed. 
Collected samples will be stored for a maximum of 20 years. This storage period begins 
when the last subject performed the last study visit, unless local rules, regulations or 
guidelines require different timeframes or procedures, which would then be in line with 
subject consent. These extra requirements need to be communicated formally to, and 
discussed and agreed with GSK. 
8.1.1. 
Biological samples 
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). 
Study Procedures During Special Circumstance: E-diary failure 
• 
In case ERT portal/ alerts are not functioning, contacts will be conducted at least 
weekly until Visit 8 (maternal subjects) / 4-NB (infant subjects). Contact may be 
via telephone, SMS, email or other means (including videotelephony or 
telemedicine), depending on local laws and best practice. 
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Table 11 
Biological samples – maternal subjects  
Maternal 
Sample type 
Collected to 
Evaluate 
Minimum Quantity 
per subject 
Unit 
Time point 
Additional Information 
Whole Blood  
Hematology, 
Biochemistry 
~5.5 
ml 
Screening 
As needed to achieve up to 300 eligible subjects at Visit 1. 
Hematology, 
Biochemistry 
Immune response 
~15.5* 
ml 
Visit 1 
(Day 1) 
Hematology, chemistry: ~5.5 ml. This sample is NOT required if the screening sample 
was collected ≤15 days before Visit 1.  
Immune response: ~10 mL. Must be collected at Visit 1 before dosing.  
*Volume of sample collected to assess immune response may be reduced to ~5 ml at 
investigator’s discretion. Refer to the Laboratory Manual. 
Hematology, 
Biochemistry 
~5.5 
ml 
Visit 2(Day 8)  
 
Hematocrit 
Immune response 
~13* 
ml 
Visit 3 (Day 31)  
Hematocrit: ~3 mL 
Immune response: ~10 ml.  
*Volume of sample collected to assess immune response may be reduced to ~5 ml at 
investigator’s discretion. Refer to the Laboratory Manual. 
~13* 
ml 
Visit 5 (Delivery)  
~13* 
ml 
Visit 6 (Day 43 
post delivery)  
 
~65.5 
ml 
Minimum Total, not including repeat or unscheduled samples 
Cord blood 
Immune Response 
~5, up to ~10 
ml 
Visit 5 (Delivery) 
 
Urine  
Protein, Glucose 
Dipstick 
NA 
Screening 
As needed to achieve up to 300 eligible subjects at Visit 1. 
Visit 1 (Day 1) 
 
Visit 2 (Day 8) 
Visit 3 (Day 31) 
Visit 4 (Day 61) 
Nasal Swab  
Presence of:RSV 
A / B 
- 
- 
MA RTI 
Assessment Visit  
Collect a nasal swab from any maternal subject who reports a medically attended (MA) 
RTI 
 
 
- 
- 
RTI 
hospitalization 
Collect a nasal swab (if possible) from any subject hospitalized with a RTI (or soon after 
discharge, as long as symptoms are ongoing).  
NOTE: Collection of a nasal swab for sponsor testing is additional to and DOES NOT 
REPLACE any specimen collection (per local standard of care) for testing by the local 
laboratory to establish a fast and accurate diagnosis for the hospitalization. In the case 
of hospitalization, local testing for RSV infection should be performed if feasible.  
If other specimens are collected and tested locally as per local standard of care, results 
will be recorded in the eCRF. However, only the sponsor laboratory results will be used 
when applying the case definitions for data analysis in Section 4.2.6 Thus, where 
mandated by the protocol, every effort should be made to obtain samples that can be 
analyzed by the sponsor (or sponsor-designated) laboratory. 
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Table 12 
Biological samples – infant subjects  
Infant 
Sample 
type 
Collected to 
Evaluate 
Minimum 
Quantity per 
subject 
Unit 
Time point 
Additional Information 
Blood 
Immune 
response 
~2.5  
ml 
Visit 1-NB (Within 3 
days after birth 
ONLY if cord blood 
cannot be collected.  
Volume must be reduced if weight ≤ 2.5 kg. [Trial-related blood loss for 
infant subjects should be ≤ 1 % at each timepoint. Total blood volume 
is estimated at 80 to 90 ml/kg body weight, and venipuncture should 
not exceed ~ 1.6 ml for a 2kg baby or 2.0 ml for a 2.5 kg baby.] Refer 
to the Laboratory Manual for additional information. 
~2.5* 
ml 
Visit 2-NB (Day 43) 
 
~2.5* 
ml 
Visit 3-NB (Month 4) 
 
~2.5* 
ml 
Visit 4-NB (Month 6) 
 
~ 2.5 
 ~5.0 
ml 
Minimum TOTAL, assuming body weight > 2.5 kg and cord blood (Table 11) collected 
Minimum TOTAL, assuming body weight > 2.5 kg and cord blood NOT collected 
Nasal 
swab 
Presence of 
RSV A / B 
- 
- 
Assessment Visit 
(Infant RTI) 
Collect at least one nasal swab for each RTI reported 
A nasal swab should be collected at the first RTI assessment visit and at the first follow-up RTI 
assessment visit (if criteria for follow-up are met – see Sections 8.4.4.2 and 8.4.7 
If more than one follow-up assessment visit is conducted, additional nasal swabs may be collected 
at the Investigator’s discretion. 
 
 
- 
- 
RTI hospitalization 
Collect (if possible) from any subject hospitalized with a RTI (or soon after release, as long as 
symptoms are ongoing). 
Collection of a nasal swab for sponsor testing is additional to and DOES NOT REPLACE any 
specimen collection (per local standard of care) for testing by the local laboratory to establish a 
fast and accurate diagnosis for the hospitalisation. In the case of hospitalization, local testing for 
RSV infection should be performed if feasible. 
If other specimens are collected and tested locally as per local standard of care, results will be 
recorded in the eCRF. However, only the sponsor laboratory results will be used when applying the 
case definitions for data analysis in Section 8.4.7. Thus, where mandated by the protocol, every 
effort should be made to obtain samples that can be analyzed by the sponsor (or sponsor-
designated) laboratory. 
*Only from infant subjects in the sample collection subcohort for the visit. Each infant is assigned to a single subcohort.  
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8.1.2. 
Laboratory assays 
Assays performed to evaluate immune response / the presence of RSV infection are listed 
below.  
Table 13 
Antibody determination 
System 
Component 
Method 
Laboratory  
SERUM 
RSV-A NAb (RSV-A 
Neutralizing Antibody) 
NEUT 
GSK Biologicals** or 
GSK designated lab 
SERUM 
RSV-B NAb (RSV-B 
Neutralizing Antibody)  
NEUT 
GSK Biologicals** or 
GSK designated lab  
SERUM 
Respiratory Syncytial 
Virus PreF3 Ab.IgG 
(RSVPreF3 IgG 
antibody concentration) 
ELISA 
GSK Biologicals** or 
GSK designated lab 
ELISA = enzyme-linked immunosorbent assay; NEUT = Neutralization;** GSK Biologicals laboratory refers to the 
Clinical Laboratory Sciences (CLS) facilities in Rixensart, Belgium, Marburg, Germany and Wavre, Belgium. 
Table 14 
Molecular Biology 
System 
Component* 
Method 
Unit 
Laboratory 
NASMUC (Nasal 
swab) 
Respiratory Syncytial Virus A RNA  
QRTPCR  
Copies/mL  
GSK Biologicals or 
GSK designated lab** 
NASMUC (Nasal 
swab) 
Respiratory Syncytial Virus B RNA  
QRTPCR 
Copies/mL 
GSK Biologicals or 
GSK designated lab** 
* RSV-A/B quantitative reverse transcription PCR will be performed on all specimens collected to evaluate RTI as 
specified in Section 8.4.5. To evaluate tertiary objectives, an Allplex Respiratory Viruses Panel or alternative may be 
performed for RSV A/B-positive samples, and (if deemed necessary) for RSV A/B-negative samples 
** GSK Biologicals laboratory refers to Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium, 
Marburg, Germany. 
Additional testing on the vaccine and/or on the disease under study may be performed 
within the framework of the study if deemed necessary for accurate interpretation of the 
data or should such assay(s) become available at GSK. These additional tests may not be 
represented in the objectives/endpoints of the study protocol.  
Additional tests that may be performed on remaining blood samples to explore tertiary 
study objectives include, but are not limited to: evaluation (in blood samples) of 
RSVpreF3 specific IgG subclasses, antibodies competing for binding to specific 
RSVpreF3 epitopes, and other exploratory endpoints. Additional tests that may be 
performed on remaining nasal swab specimens to explore tertiary study objectives 
include, but are not limited to: evaluation for the presence of other respiratory viruses, via 
Allplex Respiratory Viruses Panel or alternative, in RSV A/B-positive samples, and if 
deemed necessary, in RSV A/B negative samples. 
The addresses of clinical laboratories used for sample analysis are provided in a separate 
document accompanying this study protocol.  
GSK clinical laboratories have established a Quality System supported by procedures. 
The activities of GSK clinical laboratories are audited regularly for quality assessment by 
an internal (sponsor-dependent) but laboratory-independent Quality Department. 
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8.1.3. 
Immunological read-outs 
Table 15 
Immunological read-outs  
Blood sampling timepoint 
No. subjects 
Component 
Components 
priority rank  
Type of contact and 
timepoint 
Sampling 
timepoint 
Maternal subjects 
V1 (Day 1) 
pre 
vaccination 
up to 300  
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V3 (Day 31) 
post 
vaccination 
up to 300 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V5 (Delivery) 
(venous blood and 
cord blood)* 
delivery  
up to 300 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V6 (Day 43 post-
Delivery 
post delivery  
up to 300 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
Infant subjects 
V1-NB (Birth)* 
birth (only if 
cord blood 
cannot be 
collected) 
Event-driven 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V2-NB (Day 43) 
post birth 1  
up to 100 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V3-NB (Day 121) 
post birth 2  
up to 100 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V4-NB (Day 181) 
post birth 3  
up to 100 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V = Visit; RSV-A/B: respiratory syncytial virus subtype A/B; NA: Not applicable; NB: Newborn. IgG: immunoglobulin G;  
* Refer to Table 11 and Table 12 
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Table 16 
Molecular biology tests 
Nasal swab sampling timepoint 
No. subjects 
Component*** 
Type of contact (timepoint) 
Sampling timepoint 
Maternal MA-RTI * 
Event driven 
Event-driven* 
Respiratory Syncytial Virus A RNA  
 
 
 
Respiratory Syncytial Virus B RNA  
Infant RTI** 
Event driven 
Event-driven* 
Respiratory Syncytial Virus A RNA  
 
 
 
Respiratory Syncytial Virus B RNA  
*Includes maternal RTI hospitalizations 
**Includes infant RTI hospitalizations 
***Quantitative reverse transcription PCR will be performed on all specimens collected to evaluate RTI as specified in 
Section 8.4.5. To evaluate tertiary objectives, an Allplex Respiratory Viruses Panel or alternative may be performed for 
RSV A/B-positive samples, and (if deemed necessary) for RSV A/B-negative samples 
8.1.4. 
Clinical safety laboratory assessments 
Refer to Section 10.2 for the list of clinical laboratory tests for safety assessments 
required by the protocol. These tests must be conducted according to the clinical 
laboratory manual and the SoA (Section 1.3). 
8.1.5. 
Immunological correlates of protection 
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigen(s) used in the RSV maternal (RSVPreF3) vaccine. 
8.2. 
Safety Assessments 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE, SAE, or AESI. The investigator and 
any designees remain responsible for following up AEs that are serious, considered 
related to the study intervention or participation in the study, are AESIs, or that caused 
the subject to discontinue the study. 
Surveillance for / evaluation of respiratory tract illness is described in Section 8.4. 
Electronic diary use is also described in Section 8.4. 
8.2.1. 
Procedures for maternal subjects 
8.2.1.1. 
Pre-vaccination procedures  
8.2.1.1.1. Demographic data and lifestyle characteristics 
Demographic data may include (but are not limited to) geographic ancestry (race)*, 
ethnicity*, month of birth (if allowed per local regulation) and year of birth. 
Lifestyle characteristics may include (but are not limited to) highest level of education, 
smoking status/exposures, household environment, and other factors that could place 
them at risk of adverse study outcomes. 
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*Differences in the safety and efficacy of certain medical products, including vaccines 
[Haralambieva, 2013; Pérez-Losada, 2009; Kollmann, 2013] have been observed in 
racially and ethnically distinct subgroups. These differences may be attributable to 
intrinsic factors (e.g., genetics, metabolism, elimination), extrinsic factors (e.g., diet, 
environmental exposure, sociocultural issues), or interactions between these factors. 
Therefore, both geographic ancestry (race) and ethnicity will be collected for all subjects 
participating in this study.  
8.2.1.1.2. Medical/vaccination history 
Obtain the maternal subject’s medical/vaccination history by interviewing her and/or 
reviewing her medical records. Record any pre-existing maternal subject conditions, 
signs and/or symptoms present before the study vaccination in the eCRF. 
• 
Record outcome of Level 2 ultrasound (also known as a fetal anomaly ultrasound 
scan or fetal morphology assessment). Please see the Glossary of terms for a 
description. If results are not available at screening, then the ultrasound can be 
performed as a study procedure under certain conditions. Refer to the SPM for 
further details. If abnormal, subjects will be referred per local standard of care. 
• 
Information from additional antenatal / medical evaluations (external to study 
visits/procedures) may be collected before, during, or after a scheduled study visit 
but should only be recorded in the additional antenatal/medical evaluations eCRF. 
• 
Record number of past pregnancies, their outcome(s) and any pregnancy-related 
complications. 
• 
For the current pregnancy, record: 
− 
the subject’s pre-pregnancy weight (i.e., weight during the months before the 
subject became pregnant). This information can be obtained either via medical 
record review or subject interview. 
− 
gestational age, along with GAIA level of certainty as defined in Section 10.7 
− 
expected date of delivery (EDD) and method of estimation 
− 
number of prenatal visits attended up to the date of the study Screening visit, 
− 
approximate date of first prenatal visit, 
− 
results of any clinically significant, abnormal pregnancy screening laboratory 
tests, 
− 
any pregnancy-related complications 
− 
results of any procedures intended to screen for congenital anomalies. 
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8.2.1.2. 
Procedures carried out pre- and post-vaccination 
8.2.1.2.1. Physical examination (General and obstetric examination)  
Screening and Visits 1 through 6 
General examination should include: 
• 
Height (only at screening) 
• 
Weight, temperature, and systolic/diastolic blood pressure, heart rate and respiratory 
rate after at least 10 minutes of rest (at screening and at Visits 1 through 6). At Visit 
1, temperature need only be measured once, pre-vaccination. 
• 
Pulmonary examination including measurement of blood oxygen saturation (by pulse 
oximetry) and chest auscultation (at screening and at Visits 1 through 6). 
Obstetric examination should include: 
• 
Fetal heart tones, fetal movement and fundal height (at screening and visits 1-5) 
• 
Presence of edema (at screening and visits 1 – 5) 
• 
Symptom directed vaginal examinations (speculum and and/or manual). If 
performed, results (normal/abnormal: specify) will be recorded. 
Visits 7 and 8, and all unscheduled visits 
General and obstetric examination should be symptom-directed.  
Any unscheduled visit for a medically attended respiratory tract illness must include the 
maternal subject assessments listed in Section 8.4.5.  
8.2.1.2.2. Pulse oximetry 
Measurement of blood oxygen saturation by trained site personnel, using pulse oximeters 
provided by GSK, is strongly preferred. The SPM presents additional information about 
GSK-provided pulse oximeters and their use.  
8.2.2. 
Procedures for infant subjects 
8.2.2.1. 
Demographic data and lifestyle characteristics 
Demographic data may include (but are not limited to) geographic ancestry (race)*, 
ethnicity*, month of birth (if allowed per local regulation) and year of birth.  
Lifestyle characteristics may include but are not limited to living environment, household 
composition, breastfeeding (breastfeeding only / breastfeeding with supplementation / no 
breastfeeding), passive smoking, and extent of contact with children less than 6 years of 
age. 
*Refer to Section 8.2.1.1.1 for additional information about collection of geographic 
ancestry (race) and ethnicity. 
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8.2.2.2. 
Physical examination at Visits 1-NB through 5-NB  
A physical examination will be performed at each protocol-specified visit (Visits 1-NB 
through 5-NB).   
The examination will include (but need not be limited to) assessment of the following: 
• 
Weight, length, head circumference  
• 
Temperature, heart rate and respiratory rate.  
• 
Age-appropriate organ system examination including (but not limited to): eyes, ears, 
musculoskeletal, pulmonary (chest auscultation), cardiovascular, neurological and 
genitourinary. 
• 
Presence of congenital anomalies. 
8.2.3. 
Study holding rules and safety monitoring  
8.2.3.1. 
Limitation on number of doses administered per day (first 30 maternal 
subjects)  
Dosing will be limited to 10 maternal subjects per day across all sites until the first 30 
maternal subjects have been dosed. During this period, within any given study site, 
subjects will be dosed sequentially and at least 60 minutes apart.  
Additional enrolment and dosing may not proceed without written authorization. After 
this authorization has been provided, enrolment and dosing may continue without 
limitation on the number of subjects dosed per day or the time between consecutive 
subjects dosed at a given study site.  
As noted in Section 6.1, all (up to 300) maternal subjects must be closely observed at the 
study site for at least 60 minutes after dose administration. 
8.2.3.2. 
Outcomes of safety evaluations 
Safety evaluations will include those performed by investigators, by a blinded safety 
review team (SRT) composed of GSK RSV team members, and by an unblinded, 
independent data monitoring committee external to GSK (IDMC). Details regarding SRT 
and IDMC safety evaluations are provided in a separate IDMC charter. 
• 
If no safety signal is observed after the first 30 maternal subjects have been enrolled 
and dosed, this will be documented. GSK will provide investigators with written 
authorization to enroll and dose the remaining ~ 270 maternal subjects. 
• 
If the IDMC’s decision(s) after a safety evaluation require(s) them to take some 
action (e.g., to suspend, modify, or continue the conduct of the study for all groups 
or for selected groups), the IDMC Chair (or his/her representative) will notify the 
study CRDL. The study CRDL will be accountable for notifying investigators in 
writing of the IDMC’s decision(s). 
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8.2.3.3. 
Study holding rules 
8.2.3.3.1. Holding rules assessed by the investigator  
The investigator and /or designees will assess on an ongoing basis whether any of the 
holding rules in Table 17 have been met, irrespective of the number of subjects enrolled 
and/or timing of the event relative to dosing.  
Table 17 
Holding rules assessed by the investigator  
Holding 
Rule 
Event 
Number of 
mothers/infants 
1a 
Maternal death or any life-threatening SAE, or fetal death or unexplained 
neonatal/infant death up to 1 year of age 
≥ 1 
1b 
Any non-life-threatening SAE that cannot be reasonably attributed to a cause other 
than vaccination (applies to both maternal subjects and infants of vaccinated 
mothers). 
≥ 1  
1c 
Any withdrawal from the study (by the investigator or subject request) following a 
Grade 3 AE that cannot reasonably be attributed to a cause other than vaccination. 
≥ 1 
1d 
Any solicited administration site or systemic event leading to hospitalization, or 
fever > 40°C (104°F) (oral route) or necrosis at the injection site, within the 7-days 
(Day 1-7) post-vaccination period. 
≥ 1 
If the investigator becomes aware of a holding rule (e.g., 1a-1d in Table 17) being met, 
he/she will suspend enrolment and study vaccine/product administration and inform GSK 
as soon as possible (no later than within 24 hours). 
The investigator is not permitted to start the administration of the next dose or enrol 
additional subjects until provided with written documentation of the favourable outcome 
of the safety evaluation, and written authorization to proceed. 
Refer to Table 23 for contact information.  
The below flow of communication must be followed.  
• 
Investigator (or a designee) informs their local sponsor contact as soon as possible 
(no later than within 24 hours). (Table 23). 
• 
The local sponsor contact informs the central sponsor contact (e.g., the SDL; the 
CRDL) as soon as possible (no later than within 24 hours).  
• 
The central sponsor team ensures that SBIR is blocked, all sites administering study 
vaccine/product are informed, and all country or region- specific regulatory 
authorities are informed. 
• 
Study sites confirm that they have been notified and have taken appropriate action, 
providing appropriate documentation to their local sponsor contact. 
• 
The GSK Vaccine Safety Monitoring Board evaluates the case after receipt of the 
IDMC’s recommendations / and takes the decision to stop or to restart dose 
administration. 
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• 
Where required per local / regional regulation, the central sponsor team submits a 
substantial amendment to the local/regional authority requesting authorization to re-
start the study.  
• 
When all required authorizations to re-start the study in a country / region have been 
provided, the central sponsor team provides written notification to local sponsor 
contacts; local sponsor contacts then provide written notification to study sites. 
8.2.3.3.2. Holding rules assessed during IDMC evaluations  
The Holding rules in Table 18 will be assessed by the IDMC during safety evaluations of 
unblinded data. 
Note that these rules have been written under the assumption that the safety data from all 
expected subjects will be available. If the data from all subjects are not available (i.e. in 
case a subject is lost to follow-up), then the holding rules will be assessed on a pro-rata 
basis. 
Further note that the IDMC may recommend that the study be placed on hold for reasons 
not covered by the holding rules if deemed necessary. Any available safety data may be 
reviewed as requested by the IDMC to allow for an overall assessment of the benefit/risk 
ratio of vaccination. 
If the study is placed on hold, the investigator must suspend enrolment and study 
vaccine/product administration. As noted in Section 8.2.3.3.1, the investigator is not 
permitted to start the administration of the next dose or enrol additional subjects until 
provided with written documentation of the favourable outcome of the IDMC evaluation, 
and written authorization to proceed. 
Table 18 
Holding rules assessed during IDMC evaluations 
Holding 
Rule 
Event 
Number of mothers/infants1 
2a 
Any Grade 3 solicited administration site event lasting 48h or 
more in an investigational RSV group, within the 7-days (Day 1-7) 
post-vaccination period. 
≥ 4 subjects  
and ≥ 25% across active 
vaccine groups  
2b 
Any Grade 3 solicited systemic event lasting 48h or more in an 
investigational RSV group, within the 7-days (Day 1-7) post-
vaccination period. 
≥ 4 subjects and ≥ 25% 
across active vaccine groups  
2c 
Any Grade 3 unsolicited AE in an investigational RSV group that 
cannot be reasonably attributed to a cause other than vaccination, 
within the 7-days (Day 1-7) post-vaccination period. 
OR 
Any Grade 3 abnormality in pre-specified hematological or 
biochemical laboratory parameters in an investigational RSV group, 
at Day 8 post-vaccination2. 
≥ 4 subjects and ≥ 25% 
across active vaccine groups  
1 Across active vaccine groups, both conditions need to be achieved together: at least 4 subjects with the 
corresponding symptoms and at least 25% of subjects with the corresponding symptoms. 
2 Grading of laboratory parameters will be based on reference ranges as provided in [Sheffield, 2013] and in the SPM 
for this study.  
GSK will inform the investigator of any holding rules in Table 18 (2a-2c) that are met. 
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The below flow of communication must be followed. 
• 
IDMC Chair (or his/her representative) notifies the Clinical Research & 
Development Lead (CRDL).  
• 
CRDL informs local sponsor contacts / Local Medical Leads (LMLs) and ensures 
that SBIR is blocked. 
• 
The central sponsor team ensures that all country or region- specific regulatory 
authorities are informed. 
• 
LMLs inform study sites to place a hold on screening activities and dose 
administration. 
• 
Informed study sites confirm to their local sponsor contact(s) that action has been 
taken, providing appropriate documentation to their local GSK sponsor contact. 
• 
The GSK Vaccine Safety Monitoring Board evaluates the case after receipt of the 
IDMC’s recommendations and takes the decision to stop or to restart dose 
administration.   
• 
Where required per local / regional regulation, the central sponsor team submits a 
substantial amendment to the local/regional authority requesting authorization to re-
start the study and will not re-start the study until approval of the substantial 
amendment.   
• 
When all required authorizations to re-start the study have been provided, the CRDL 
/ central sponsor team provides written notification to local sponsor contacts; local 
sponsor contacts then provide written notification to study sites. 
8.2.3.3.3. Overview of IDMC reviews 
The IDMC will receive an unblinded report approximately monthly, once enrolment has 
started. For each report, the IDMC will be provided with available safety data, including 
but not limited to SAEs, pregnancy outcomes, pregnancy-related and neonatal adverse 
events of special interest, medically attended RTIs in maternal subjects and RTI/LRTIs in 
infants. Continuous monthly monitoring throughout the study will allow for ad-hoc data 
review meetings if deemed necessary by the IDMC.  
In addition, there will be 5 planned IDMC data review meetings: 
• 
The first planned meeting will take place once 75 maternal subjects have been dosed; 
• 
Additional meetings will occur to coincide with release of results from each of the 
analyses described in Section 9.5.1.  
For each review, the IDMC will be provided with unblinded safety data as described 
above. 
The IDMC will also review all safety data on infant subjects through 1 year of age. 
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As part of ongoing review, the IDMC will monitor the rates of pregnancy-related 
outcomes and pregnancy-related and neonatal AESIs. Observed rates of outcomes and of 
AESIs for active vaccine recipients that are higher than rates reported in the placebo 
group or expected in the general population may trigger enhanced scrutiny of the cases by 
the IDMC. Examples based on a 2-fold higher reporting rate in vaccine recipients as 
compared to the general population are listed in Table 19. For example, with 16 maternal 
infant pairs followed through delivery, no more than 2 cases of pre-term birth should be 
expected among the vaccinated group. If that number is 4 or greater, it could be an early 
indication that vaccination may be harmful and would prompt further scrutiny by the 
IDMC, including the possibility to hold further vaccination. Depending on the nature and 
severity of the outcome or AESI, enhanced scrutiny may be triggered even if there is a 
less than 2-fold increase in reporting rate in vaccine recipients compared to that expected 
in the general population or seen in the placebo group. 
Table 19 
Examples of rates for AESIs 
Event of Special Interest 
Reported Rate 
in general 
population  
Rate that could trigger additional safety concern (for the 
active vaccine groups combined) 
% of 
subjects 
Number of subjects 
in vaccinated groups 
at IDMC meeting 1  
Number of subjects in 
vaccinated groups at 
IDMC meeting 2 
Gestational hypertension 
8% 
16% 
3 
16 
Gestational diabetes 
6-7% 
14% 
3 
14 
Small for gestational age 
10% 
20% 
4 
20 
Non-reassuring fetal status 
15% 
30% 
5 
30 
Preterm Birth 
12% 
24% 
4 
24 
Low birth weight 
8% 
16% 
3 
16 
Respiratory distress/asphyxia 
10% 
20% 
4 
20 
Antenatal bleeding  
4-5% 
10% 
2 
10 
Intrauterine growth restriction 
3-7% 
14% 
3 
14 
Enhanced scrutiny of the cases by the IDMC can be triggered at any point during the 
study depending on the observed rate of an AESI or any other safety concern. 
8.2.3.4. 
Risk assessment 
Figure 5 illustrates the probability of not meeting holding rule 1 and 2 for 16 active 
vaccine recipients at the first planned IDMC meeting. 
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Figure 5 
Evaluations based on 16 active recipients - Risk assessment curve 
for one formulation based on the proposed safety holding rules 
across active groups 
 
Thus, with 16 active vaccine recipients across study groups: 
• 
Each holding rule 1a-1c has a more than 90% chance of not being met for 
vaccination with a true incidence rate below 1% and has a more than 80% chance of 
being met for vaccination with a true incidence rate above 10%. 
• 
Each holding rule 2a-2c has a more than 90% chance of not being met for 
vaccination with a true incidence rate below 10% and a more than 80% chance of 
being met for vaccination with a true incidence rate above 35%. 
The risk of ERD related to boosting pre-existing maternal antibody and transfer of 
vaccine-induced neutralizing antibodies from mother to infant, is considered negligible. 
However, as data evaluating this risk are expected before the vaccination of larger 
numbers of pregnant women, surveillance and evaluation of all RTIs in infants and 
medically attended-RTIs in mothers (Section 8.4) has been implemented. 
To assess the ability of the study to demonstrate with 90% power that the progression rate 
from RSV infection to severe disease or hospitalization is lower than the 80% rate seen in 
the historical formalin-inactivated vaccine, the accrual of at least 5 cases of RSV 
infection among infants will be needed. With a one-sided 5% type one error rate and 
assumption of a 10% rate of infection progressing to severe disease or hospitalization, 5 
infections can provide at least 90% statistical power to demonstrate the progression rate 
from RSV infection to severe disease or hospitalization is less than 80%. 
Table 20 shows examples of the rate of progression to more severe disease or 
hospitalization and their corresponding upper 95% confidence intervals when 5 or 10 
cases of RSV among infants are accrued. Where the upper limit of the 95% confidence 
interval is above 80%, this suggests a rate of severe disease that is equivalent to the 
historical formalin-inactivated vaccine. Where the upper limit is less than 80%, this 
would suggest that the current vaccine is not equivalent to the historical vaccine in terms 
of progression to more severe RSV disease. 
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Table 20 
Rates of progression to more severe RSV disease or RSV 
associated hospitalization 
 
Rate of hospitalization or severe disease 
Observed number of infected 
infant subjects 
Observed Number of 
hospitalizations or 
severe disease 
Actual 
Upper 95% CI 
5 
1 
20% 
71.6% 
5 
2 
40% 
85.3% 
10 
1 
10% 
45% 
10 
2 
20% 
56% 
10 
3 
30% 
65.2% 
10 
4 
40% 
73.8% 
10 
5 
50% 
81.3% 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
other events of interest 
8.3.1. 
Time period and frequency for collecting AE, SAE and other 
safety information 
Table 21 provides an overview of the protocol-required reporting periods for safety (as 
well as RTI) information. 
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Table 21 
Timeframes for collecting and reporting safety (and RTI) information 
 
Before Delivery* 
Delivery / Birth 
Post-Delivery*  
Timepoint 
D-28 
D1 
D7 
D8 
D31 
D61 
 
D 43 
D121 
D181 
D271 
12 months 
Maternal subject visits Pre-** 
V1 
 
V2 
V3 
V4 
V5 
V6 
V7 
V8  
 
 
Infant visits 
 
 
 
 
 
 
V1-NB 
V2-NB 
V3-NB 
V4-NB 
C1-NB 
V5-NB 
Event 
Administration site and systemic 
solicited events 
 
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
Subsequent Pregnancies*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M 
 
AEs/SAEs leading to 
Withdrawal from the study 
 
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
I 
SAEs and MAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
M  
 
 
 
 
 
 
 
I 
AESIs*****
 
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
 
 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medically attended RTII
 
M 
 
RTI/LRTII
 
 
 
 
 
 
I 
 
SAEs related to study participation
or concurrent GSK medication or vaccine
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Approximately monthly contacts pre- and post-delivery also occur within the timeframes described above and are described in Section 1.3. **i.e. consent obtained. Pre = pre-
vaccination; V=visit; C = contact; D= Day. *** if subsequent pregnancy occurs during the study, follow-up extends up to 8 weeks post birth of the infant If subsequent pregnancy occurs 
after Visit 8, report adverse pregnancy outcomes / other SAEs experienced by mother / infant, if known. ****AESIs include adverse pregnancy outcomes, pregnancy related AEs of 
special interest and neonatal AEs of special interest. Neonatal AEs of special interest identified after V2-NB (e.g., congenital anomalies) will continue to be reported as such 
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The investigator or designee will record and immediately report all SAEs (including RTIs 
associated with hospitalization of a maternal or infant subject and all adverse pregnancy 
outcomes), as well as all pregnancy related AESIs and neonatal AESIs to the sponsor or 
designee via the Expedited AE Reporting Form. This reporting should under no 
circumstances occur later than 24 hours after the investigator becomes aware of the event, 
as indicated in Section 10.3.10. The investigator will submit any updated data to the 
sponsor within 24 hours of it being available. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting periods defined in Table 21 . Investigators are not obligated to actively seek 
AEs or SAEs in former study subjects. However, if the investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study, and 
he/she considers the event to be reasonably related to the study vaccine(s)/product(s), the 
investigator will promptly notify the Study Contact for Reporting SAEs mentioned in 
Table 23. 
8.3.2. 
Method of detecting AEs, SAEs, other events of interest, and 
subsequent pregnancies  
Methods of detecting and recording AE/SAE/AESI/subsequent pregnancies are detailed 
in Section 10.3.8. The assessment of AE/SAE intensity, causality and outcome are 
provided in the Section 10.3.9.  
Open-ended and non-leading verbal questioning of the maternal subjects/infant subjects’ 
parent(s)/LAR(s) is the preferred method of acquiring information related to an 
AE/SAE/AESI/subsequent pregnancy.  
8.3.2.1. 
COVID-19 Infection 
COVID-19 cases identified within the existing framework of the study will be captured 
and reported using standard AE, medically-attended AE or SAE criteria, as outlined in 
Section 10.3. 
COVID-19 cases should be reported in the eCRF according to the WHO Case Definition 
[WHO, 2020] using one of the following terms:  
• 
Suspected COVID-19 infection 
• 
Probable COVID-19 infection 
• 
Confirmed COVID-19 infection 
8.3.2.2. 
Clinically significant abnormal laboratory findings 
The investigator must review the laboratory report, document that he/she did so, and 
record any clinically relevant changes occurring during the study in the AE Section of the 
eCRF. Clinically significant abnormal laboratory findings are those which are not 
associated with an underlying disease, unless judged by the investigator to be more 
severe than expected for the subject's condition. 
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• 
All clinically significant abnormal laboratory test values during the study or within 8 
days after the last dose of study intervention should be repeated until the values 
return to normal or baseline, or are no longer considered significantly abnormal by 
the investigator or LML. Refer to Section 10.3.6 for more information on clinically 
abnormal laboratory assessments that qualify as an AEs or SAE. 
• 
If such values do not return to normal/baseline after an interval judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
8.3.3. 
Regulatory reporting requirements for SAEs, subsequent 
pregnancies, and other events 
Once an investigator (or designee) becomes aware that a study subject has experienced an 
SAE/AESI/subsequent pregnancy, he/she must report it to GSK using the documentation 
and within the timeframes mentioned in Table 22. This is essential for meeting legal 
obligations and ethical responsibilities for the subject safety and the safety of a study 
intervention under clinical investigation. 
For SAEs/AESIs, the investigator will always provide an assessment of causality at the 
time of the initial report as defined in Section 10.3.9.2. 
Local regulatory requirements and sponsor policy for the preparation of an investigator 
safety report for Suspected Unexpected Serious Adverse Reactions (SUSAR) must be 
followed. These reports will be forwarded to investigators as necessary. 
The sponsor has a legal responsibility to notify local authorities and other regulatory 
agencies about the safety of a study intervention under clinical investigation. The sponsor 
will comply with country-specific regulatory requirements related to safety reporting to 
the regulatory authority, IRB/ IEC, and investigators. 
Please refer to Section 10.3.10 for further details regarding the reporting of 
SAEs/AESIs/subsequent pregnancies  
Table 22 
Timeframes for submitting serious adverse event, subsequent 
pregnancy and other event reports to GSK  
Type of Event 
Initial Reports 
Follow-up of Relevant Information 
on a Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs (including adverse 
protocol pregnancy outcomes) 
24 hours* ‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited 
Adverse Events Report 
AESIs 
24 hours** ‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited 
Adverse Events Report 
Maternal subjects: MA-RTIs 
Infant subjects: RTIs/LRTIs 
3 days* 
eCRF 
1 week 
eCRF 
Subsequent Pregnancies 
2 weeks* 
electronic pregnancy 
report 
2 weeks* 
electronic pregnancy 
report 
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff.  
**Timeframe allowed once investigator determines event meets protocol definition of an AESI.  
‡ The investigator will be required to confirm review of SAE/AESI causality by ticking the ‘reviewed’ box in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE/AESI  
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Study contact for questions regarding SAEs, 
AESIs, subsequent pregnancies  
Study contact for reporting of study 
holding rules  
Refer to the local study contact information 
document 
As soon as the investigator is aware that a 
holding rule is met, he/she must 
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Back-up study contact for reporting SAEs, 
AESIs, subsequent pregnancies  
Available 24/24 hours and 7/7 days: 
Back-up study contact for escalation of 
holding rules  
GSK Clinical Safety & Pharmacovigilance 
Refer to the local study contact information 
document. 
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Fax: 
 
Email address: 
 
US sites only: 
Fax: 
 
Canadian sites only: 
Fax: 
 
 
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Maternal subjects/ infant subjects’ parent(s)/LAR(s) must be instructed to keep these 
subject cards in his/her/their possession at all times throughout the study. 
In an emergency, the cards serve to inform the responsible attending physician that the 
maternal / infant subject is in a clinical study and that relevant information may be 
obtained by contacting the investigator. 
8.4. 
Respiratory tract illnesses (RTIs) 
The definitions provided in Sections 8.4.1.1 and 8.4.1.2 are for use by site personnel. 
They are designed to provide GSK Biologicals with the information needed to apply case 
definitions during data analyses. They are related but not identical to the case definitions 
themselves (Section 4.2.6). For additional details regarding maternal MA-RTI and infant 
RTI surveillance and assessment, refer to the SPM.  
8.4.1. 
Definitions 
8.4.1.1. 
Medically attended respiratory tract illnesses (MA-RTIs) in maternal 
subjects 
A maternal MA-RTI occurs when the maternal subject visits a healthcare professional 
(e.g., a General Practitioner) for any respiratory symptom, including (but not limited to) 
cough, sputum production and difficulty breathing. 
8.4.1.2. 
Respiratory tract illnesses (RTIs) in infant subjects 
RTI symptoms include: 
• 
Nasal discharge running freely out of the infant’s nose (runny nose),  
• 
Breathing through the mouth because the infant’s nose is blocked (blocked nose), 
• 
Regular bursts of cough,  
• 
Difficulty in breathing (fast breathing, poor feeding, working hard to breathe, or 
making unusual sounds when breathing), and 
• 
Wheezing (a whistling sound when the infant breathes out, and thus another sign of 
difficulty in breathing). 
Worsening means any clinically observed/diagnosed symptoms and signs that are 
reported during the same respiratory tract illness and reflect a deterioration in the infant’s 
respiratory tract functions. 
8.4.2. 
Surveillance (Amended 30-SEP-2020) 
MA-RTI surveillance begins when a maternal subject enters the study and ends 6 months 
after delivery (Visit 8). RTI surveillance in infant subjects begins at birth (Visit 1-NB) 
and ends 6 months after birth (Visit 4-NB).  
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An electronic Diary (e-Diary) device will be provided to the maternal subject/LAR at 
Visit 1.  
As noted in Section 10.3.8, maternal subjects/LARs will use the e-Diary to capture the 
occurrence of maternal medically attended RTIs and RTIs in infant subjects. Maternal 
subjects/LARs will also use the e-Diary to capture solicited administration site or 
systemic events, the occurrence of unsolicited adverse events 30 days post vaccination, 
and medically attended adverse events (additional to maternal medically attended RTIs).  
Maternal subjects/LARs will keep the e-Diary device until the last surveillance visit 
(Visit 8 for the maternal subject or Visit 4-NB for the infant subject), whichever comes 
last, has been completed.  
During surveillance, the maternal subject/LAR will:  
• 
Complete the eDiary daily, and 
• 
Contact site personnel if: 
− 
The maternal subject/LAR encounters any difficulty with eDiary entry, or  
− 
The maternal subject has respiratory symptoms for which she visits (or plans to 
visit) a healthcare professional, or for which she is hospitalized, or 
− 
The infant subject has any new or worsening RTI symptoms, or  
− 
The maternal subject/LAR intends to seek medical care because of concern 
about the infant’s respiratory tract illness, or general health in the context of the 
infant’s respiratory tract illness, or 
− 
The maternal subject experiences severe solicited administration site or systemic 
events in the 7 days post-vaccination, or 
− 
The maternal subject has any new symptoms or medical problems, whether 
related or unrelated to her pregnancy. 
• 
Site personnel will:  
− 
Review the e-Diary web portal on a regular basis, 
− 
Promptly follow up on any maternal subject/LAR initiated or e-Diary generated 
alert, 
− 
Initiate planned scripted contacts with the maternal subject/LAR as described in 
Table 2 and Table 4. During these contacts, site personnel will reinforce the 
maternal subject’s/LAR’s understanding of the eDiary, elicit information as 
described in Table 1 and Table 3, and determine whether the maternal 
subject/LAR has visited a healthcare provider not affiliated with the study (for 
the maternal or infant subject’s care).  
− 
In the event that ERT portal/ alerts are not functioning, the site should contact 
subjects at least weekly until Visit 8 (maternal subjects) / 4-NB (infant subjects) 
to complete surveillance questions and collect information about adverse events. 
Contact may be via telephone, SMS, email or other means (including 
videotelephony or telemedicine), depending on local best practice.  
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If the maternal subject visited / the infant subject was taken to a healthcare provider not 
affiliated with the study, site personnel should (if permitted by local regulation) contact 
that healthcare provider to obtain the medical record(s) for the visit.  
Three attempts should be made within the week of a scheduled contact. If these attempts 
are unsuccessful, that monthly contact is considered a missed contact. The next scheduled 
contact will be made the following month). Note, contacts may occur more often between 
Visit 5 and Visit 6 (See Table 2). 
Contact may be via phone call, SMS, email or other means, depending on local best 
practice. If the study site is the subject’s primary healthcare facility, contact with study 
personnel may also be made in the context of a visit for routine or event-driven care.  
8.4.3. 
Treatment of adverse events 
Any medication administered for the treatment of an SAE/AESI should be recorded in 
the Expedited Adverse Event Report of the subject’s eCRF screen (refer to Section 
10.3.10.1). 
8.4.4. 
When to conduct an assessment visit  
8.4.4.1. 
For a maternal MA-RTI  
Conduct an assessment visit (Section 8.4.5), ideally within 3 calendar days after a 
medically attended visit due to RTI symptoms occurs during the surveillance period. 
However, a visit may be conducted even if beyond this window if symptoms are ongoing. 
If a maternal subject informs the site that she has RTI symptoms and would see / have 
seen a physician for them if she was not already scheduled for a study visit, then the site 
should perform the MA-RTI assessment visit procedures (including nasal swab) during 
the already scheduled study visit. 
A decision tree is provided in Figure 6. Refer to the SPM for additional details regarding 
maternal MA-RTI surveillance. 
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Figure 6 
Decision Tree for site personnel – maternal surveillance and 
assessment  
 
RR: Respiratory rate: SpO2: Blood oxygen saturation by pulse oximetry. 
1Details regarding Surveillance are provided in Section 8.4.2 and the SPM. 
2Details regarding the RTI assessment visit are provided in Section 8.4.5 and the SPM. 
8.4.4.2. 
For an infant RTI  
Conduct an assessment visit, as described in Section 8.4.5, as soon as possible after at 
least one of the following has been reported during the surveillance period: 
• 
Cough, 
• 
Runny nose (if new), 
• 
Blocked nose, 
• 
Difficulty in breathing, 
• 
Wheezing. 
If reported symptoms include difficulty in breathing or wheezing, the visit should 
(ideally) take place within 24 hours; otherwise the visit should (ideally) take place within 
3 calendar days. However, a visit may be conducted even if beyond the specified ideal 
window provided symptoms are ongoing. 
e-Diary report or direct contact1
Yes
No
Perform assessment 2 visit within 3 days:
•
Document signs and symptoms
•
Record RR and SpO2 
•
Record health care utilization
•
Nasal swab
And (as applicable)
•
Document details from medical records
Any medicallyattended
RTI?
Remind to report any future 
medically attended RTIs by 
recording in e-Diary AND 
contacting site personnel
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After the first assessment visit, site personnel should use the RTI eDiary data and results 
of any unscheduled contacts to assess the development of new and worsening of 
previously reported symptoms.  
• 
Site personnel should conduct a follow-up assessment visit as soon as possible after 
learning: 
− 
that any symptom present at the first assessment visit has worsened, OR  
− 
that there are new symptoms, OR 
− 
that there is parental concern in the context of the respiratory tract illness. 
The timing of the follow-up visit should be consistent with the guidance given above; i.e., 
ideally within 24 hours if difficulty breathing or wheezing is reported; ideally within 3 
calendar days otherwise.  
A decision tree is provided in Figure 7. Refer to the SPM for additional details regarding 
infant RTI surveillance. 
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Figure 7 
Decision Tree for site personnel - infant surveillance and 
assessment  
 
RR: Respiratory rate: SpO2: Blood oxygen saturation by pulse oximetry. 
1Details regarding Surveillance are provided in Section 8.4.2 and the SPM. 
2Cough, runny nose, blocked nose, difficulty in breathing, wheezing are described in Section 8.4.4.2 
3Details regarding the RTI assessment visit are provided in Section 8.4.5 and the SPM. 
4 Post-visit follow up is described in Sections 8.4.7 and in the SPM. 
5If a follow-up assessment visit is conducted, collection of additional nasal swabs is as described in Table 12. 
6Parental concern in the context of an RTI 
e-Diary report or direct contact1
Yes
No
Yes
No
Perform assessment 3,4 visit within 3 
days:
•
Document signs and symptoms
•
Record RR and SpO2 
•
Record health care utilization
•
Nasal swab 5
And (as applicable)
•
Document details from medical records
Any RTI symptom
(e.g., cough, runny nose, 
blocked nose, difficulty in 
breathing, wheezing)2?
Remind to report any worsening 
of symptoms, any new 
symptoms, or parental concern 6
Remind to report any future 
symptoms
Worsening of 
symptoms, new 
symptoms or parental 
concern 6?
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8.4.5. 
Assessment visit procedures 
The purpose of each assessment visit is to objectively document signs and symptoms of a 
respiratory tract illness by an appropriately qualified person (i.e. medical or nursing), 
provide medical advice or referral as appropriate, and collect specimens for detection of 
RSV infection: 
An assessment visit may take place at the investigator’s clinical facility or another 
medical facility, or via a home visit by qualified site staff (or a designated third party), as 
appropriate per the judgment of the investigator (and as allowed by local law). 
Unless otherwise specified, assessment visit procedures will be the same for maternal 
subjects with MA-RTIs and for infant subjects with RTIs.  
Note that if the reported symptoms are severe enough to warrant urgent care, the 
subject / parent(s)/LAR(s) should be advised to seek such care (e.g. Emergency 
Room). 
8.4.5.1. 
Clinical evaluation  
At every assessment visit, the investigator/study staff/designated third party will evaluate 
the clinical signs and symptoms of the RTI. Data to be collected and recorded include 
(but are not limited to): 
For maternal subjects: 
• 
Temperature 
• 
Respiratory rate 
• 
Blood oxygen saturation measured by pulse oximetry (Section 8.2.1.2.2), in room 
air, if feasible 
• 
Results of chest auscultation 
• 
Signs of difficulty in breathing (wheezing and tachypnoea in maternal subjects) 
For infant subjects: 
• 
Temperature 
• 
Respiratory rate 
• 
Blood oxygen saturation (measured by pulse oximetry (Section 8.2.1.2.2), in room 
air, if feasible 
• 
Results of chest auscultation 
• 
Presence of cough, runny nose or blocked nose 
• 
Signs of difficulty in breathing (wheezing, tachypnoea, nasal flaring, chest in-
drawing and apnea)  
• 
Irritability/agitation 
• 
Lethargy/excessive sleepiness 
• 
Cyanosis 
• 
Feeding poorly 
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8.4.5.2. 
Nasal swab collection 
Refer to Table 11 (maternal subjects) and Table 12 (infant subjects). Additional details 
are provided in the SPM. 
8.4.5.3. 
Missed assessment visit 
If the criteria for an assessment visit have been met but the visit cannot take place while 
symptoms are ongoing, it is a missed assessment visit.  
If it is truly not possible to perform an assessment visit (for example, if the subject 
develops a MA-RTI or potential RTI/LRTI while the family is travelling, and all 
symptoms have resolved by the time the family returns), then the corresponding 
assessment visit page of the eCRF should be filled in as completely as possible using 
available medical history and medical records.  
8.4.6. 
RTI hospitalization during the surveillance interval  
Whenever a subject is admitted to hospital for observation or treatment of an acute 
respiratory illness during the surveillance interval for that subject, a nasal swab should be 
collected using GSK Biologicals -provided supplies, and sent to GSK Biologicals for 
analysis as described in Table 11 and Table 12.  
8.4.7. 
Follow-up of infant respiratory tract illnesses 
Any infant RTI documented as ongoing at a previous visit/contact will be reviewed at 
subsequent visits/contacts during the surveillance interval until (a) all symptoms have 
resolved (except runny nose, often chronic in infants), or (b) the subject completes Visit 
4-NB or (c) the subject is lost to follow up.  
8.5. 
Treatment of overdose 
Not applicable. 
8.6. 
Pharmacokinetics 
Not applicable. 
8.7. 
Pharmacodynamics 
Not applicable. 
8.8. 
Genetics 
Genetics are not evaluated in this study. 
8.9. 
Biomarkers  
Not applicable. 
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8.10. 
Health outcomes 
Not applicable. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical hypotheses 
All analyses will be descriptive. 
9.2. 
Sample size determination  
Up to 300 subjects will be randomised to achieve up to 270 evaluable subjects for an 
estimated total of up to 90 evaluable maternal subjects per study group. 
Assessments of both safety and immunogenicity data were considered when determining 
sample size for this study. 
Withdrawals will not be replaced. 
9.2.1. 
Safety 
A sample size of 50 maternal subjects per group will provide a probability of 78%, 92% 
or 99% to observe at least one AE, if the true AE rate is 3%, 5% or 10%, respectively. 
A sample size of 100 maternal subjects per group will provide a probability of 95%, 99% 
or >99.9% to observe at least one AE, if the true AE rate is 3%, 5% or 10%, respectively.  
Table 24 illustrates the precision one can expect on the percentage of subjects with 
symptoms following vaccination, considering sample sizes of 150 vaccinated women and 
300 vaccinated women (50 and 100, respectively, in the placebo control group; 50 and 
100, respectively, in each active vaccine group).  
There is 95% confidence that the true incident rate is within (0, 7.1%) if no AE is 
observed in a single vaccine group with 50 subjects. The true incident rate will be within 
(0, 3.6%) if no AE is observed across both active vaccine groups with 100 subjects.  
There is 95% confidence that the true incident rate is within (0, 3.6%) if no AE is 
observed in a single vaccine group with 100 subjects. The true incident rate will be within 
(0, 1.8%) if no AE is observed across both active vaccine groups with 200 subjects.  
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Table 24 
Exact 95% confidence interval on the percentage of subjects with 
adverse events following vaccination per group 
50 subjects in an RSV vaccine group 
100 subjects in an RSV vaccine group 
Number (%) of subjects 
with an AE 
Exact 95% Confidence Interval 
Number (%) of 
subjects with an 
AE 
Exact 95% Confidence Interval 
Lower Limit 
Upper Limit 
Lower Limit 
Upper Limit 
50 (100) 
92.9 
100.0 
100 (100) 
96.4 
100 
45 (90) 
78.2 
96.7 
90 (90) 
82.4 
95.1 
40 (80) 
66.3 
90 
80 (80) 
70.8 
87.3 
35 (70) 
55.4 
82.1 
70(70) 
60 
78.8 
30 (60) 
45.2 
73.6 
60 (60) 
49.7 
69.7 
25 (50) 
35.5 
64.5 
50 (50) 
39.8 
60.2 
20 (40) 
26.4 
54.8 
40 (40) 
30.3 
50.3 
15 (30) 
17.9 
44.6 
30 (30) 
21.2 
40 
10 (20) 
10 
33.7 
20 (20) 
12.7 
29.2 
5 (10) 
3.3 
21.8 
10 (10) 
4.9 
17.6 
0 (0) 
0.0 
7.1 
0 (0) 
0 
3.6 
Exact 95% CI computed based on Clopper/ Pearson formula 
9.2.2. 
Immune response  
Assuming a 10% rate of non-evaluable subjects, approximately 90 subjects per group will 
be evaluable for the analysis of RSV specific antibody titer/concentration. 
The two active vaccine groups will be compared at Day 31 using a one-sided two sample 
T-test with significance level of 5%. Table 25 includes the power to detect a fold change 
greater than 1 given that the alternative hypothesis of fold changes between 1.4- to 2.0 
between two vaccine groups is true, assuming the standard deviation of RSV-A 
neutralizing antibody titers of 0.25, 0.3, 0.35 and 0.4 on its log 10 scale. 
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Table 25 
Effect of dose: Power and fold increase in terms of RSV-A 
neutralizing antibody titers with sample sizes of 45 and 90 subjects 
per group at significance level of one- sided 5%  
Standard 
Deviation* 
Fold 
change 
No. of Subjects 
per group 
Power 
No. of Subjects 
per group 
Power 
0.25 
1.4 
45 
86.5 
90 
98.8 
1.5 
45 
95.2 
90 
99.9 
1.6 
45 
98.6 
90 
>99.9 
1.7 
45 
99.6 
90 
100 
1.8 
45 
99.9 
90 
100 
1.9 
45 
≥99.9 
90 
100 
2 
45 
≥99.9 
90 
100 
0.3 
1.4 
45 
74.1 
90 
94.6 
1.5 
45 
86.8 
90 
98.9 
1.6 
45 
94 
90 
99.8 
1.7 
45 
97.5 
90 
>99.9 
1.8 
45 
99.1 
90 
>99.9 
1.9 
45 
99.7 
90 
100 
2 
45 
99.9 
90 
100 
0.35 
1.4 
45 
62.5 
90 
87.3 
1.5 
45 
76.5 
90 
95.7 
1.6 
45 
86.4 
90 
98.8 
1.7 
45 
92.6 
90 
99.7 
1.8 
45 
96.3 
90 
>99.9 
1.9 
45 
98.2 
90 
>99.9 
2 
45 
99.2 
90 
>99.9 
0.4 
1.4 
45 
52.9 
90 
78.6 
1.5 
45 
66.5 
90 
90.2 
1.6 
45 
77.5 
90 
96.1 
1.7 
45 
85.6 
90 
98.6 
1.8 
45 
91.2 
90 
99.6 
1.9 
45 
94.9 
90 
99.9 
2 
45 
97.1 
90 
>99.9 
*Standard deviation on log10 transformed RSV-A neutralizing antibody titer based on previous studies on PreF2 
vaccine. **PASS: One sided two-Sample T-Test with alpha 5%  
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9.3. 
Populations for analyses  
For purposes of analysis, the following analysis sets are defined: 
9.3.1. 
Maternal Subjects  
 
Description 
Analysis Set 
Maternal subjects 
Enrolled 
All maternal subjects who completed the informed consent process and signed the informed 
consent form. Refer to the glossary of terms for the definition of ‘enrolled’ 
Exposed 
All maternal subjects who received at least 1 dose of the study intervention. The allocation 
in a group is done in function of the administered intervention. 
Full Analysis 
All maternal subjects in the Exposed set who have post-vaccination immunogenicity data.  
Per Protocol 
All maternal subjects who received at least 1 dose of the study intervention to which they 
were randomised and have post-vaccination data (Full Analysis Set) minus subjects with 
protocol deviations that lead to exclusion.  
Unsolicited Safety 
All maternal subjects who received at least 1 dose of the study intervention (Exposed Set) 
that report unsolicited AEs/report not having unsolicited AEs 
Solicited Safety 
All maternal subjects in the Exposed Set who have solicited safety data 
9.3.2. 
Infant subjects 
 
Description 
Analysis Set 
 
Exposed 
Infants live-born to exposed maternal subjects, whose parents/LARs completed the 
informed consent process and signed the informed consent form 
Full Analysis 
All infant subjects in the Exposed set who have post-delivery/birth immunogenicity data. 
Per Protocol 
All infant subjects in the Full Analysis set minus those who (a) were born less than 4 weeks 
post- maternal subject vaccination and/ or (b) have protocol deviations that lead to 
exclusion. 
Unsolicited Safety 
All infants in the exposed set for whom unsolicited AEs /not having unsolicited AEs are 
reported 
9.3.3. 
Criteria for elimination from analysis 
The Statistical Analysis Plan (SAP) will provide a complete list of criteria for elimination 
from per protocol analyses. Criteria may include, but are not limited to, those in Section 
9.3.3.1 and 9.3.3.2.  
9.3.3.1. 
Intercurrent medical conditions and concomitant 
medications/products/vaccines that may lead to elimination of a 
subject from per-protocol analyses  
9.3.3.1.1. Maternal subjects  
• 
Any of the medications listed in Section 5.2.1.2 if administered up to Day 43 post-
delivery (Visit 6). 
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9.3.3.1.2. Infant subjects 
• 
Systemic immunosuppressants or other immune-modifying drugs administered 
chronically (i.e. for more than 14 consecutive days) up to Day 43 post birth (Visit 2-
NB), or Day 121 post birth (Visit 3-NB), or Day 181 post-birth (Visit 4-NB) 
depending on the relevant (visit-specific) sub-cohort for blood sampling.  
− 
For corticosteroids, this will mean prednisone or equivalent, ≥ 0.5 mg/kg/day. 
− 
Topical steroids are allowed.  
− 
Inhaled steroids are allowed if used in accordance with local labelling 
information (e.g. for budesonide). 
• 
Immunoglobulins and/or any blood or plasma derivatives administered up to Day 43 
post birth (Visit 2-NB), or Day 121 post birth (Visit 3-NB), or Day 181 post-birth 
(Visit 4-NB), depending on the infant’s assigned sub-cohort for blood sampling. 
9.3.3.1.3. Maternal and Infant subjects  
• 
Diagnosis during the study with an immunological disorder or occurrence during the 
study of a condition (other than the study pregnancy) capable of altering immune 
response. For evaluation of immunogenicity endpoints in maternal and infant 
subjects, this includes RSV infection confirmed either locally or by GSK Biologicals 
during the specified analysis interval. 
• 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine/product administered during the specified analysis interval.  
9.3.3.2. 
Other situations that may lead to elimination of a subject from per-
protocol analyses  
• 
Protocol violation(s) linked to the inclusion/ exclusion criteria, including age. 
• 
Study vaccine/product not administered as specified by the protocol. 
• 
Failure to comply with the post-vaccination immunogenicity blood sampling 
schedule at a given time-point (Table 2, Table 4). 
9.4. 
Statistical analyses 
9.4.1. 
General considerations 
The statistical analysis plan (SAP) will be finalized before database lock and will include 
a more technical and detailed description of the statistical analyses to be performed. This 
section summarizes planned statistical analyses of primary and secondary endpoints. 
The SAP describes how missing data will be handled during analyses. 
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9.4.1.1. 
Safety 
Safety analyses in maternal subjects will include summaries by study group and age 
category (18 - < 35 years of age; ≥35 years of age; overall) of hematology and 
biochemistry results by grade and per time point, solicited administration site and 
systemic events, unsolicited AEs, MAEs, SAEs, , MA-RTIs,, RSV-associated MA-RTIs, 
AEs leading to study withdrawal, pregnancy outcomes and pregnancy related AESIs. 
Safety analyses in infant subjects will include summaries by study group and gestational 
age at birth (> 37 weeks or ≤ 37 weeks) of neonatal AESIs, MAEs, SAEs, AEs leading to 
study withdrawal, and the occurrence of RSV-associated RTIs, LRTIs, severe LRTIs, very 
severe LRTIs and RSV-associated hospitalizations. Case definitions for RSV associated 
LRTIs are based on those described in [Modjarrad, 2016] and are described in Section 
4.2.6. 
All safety analyses will be performed on the Solicited Safety, Unsolicited Safety and 
Exposed sets. 
9.4.1.2. 
Immunogenicity 
The primary analysis will be based on the Per Protocol set for analysis of 
immunogenicity. If, in any study group and at any timepoint, the percentage of 
vaccinated subjects with serological results excluded from the Per Protocol set for 
analysis of immunogenicity is 5% or more, a second analysis based on the Full Analysis 
Set will be performed to complement the Per Protocol analysis. 
9.4.2. 
Subject disposition 
Number of screened, randomised, vaccinated and withdrawn maternal subjects in each 
group and overall will be described.  
Number of infants enrolled and withdrawn (by group and subcohort, and overall) will be 
described. Additional analyses by country and/or by site may be performed.  
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9.4.3. 
Primary endpoints 
9.4.3.1. 
Safety  
 
Primary Safety 
Endpoints  
Statistical Analysis Methods 
Maternal 
subjects 
Occurrence of Solicited 
administration site and 
systemic events during a 
7-day follow-up period 
after vaccination (i.e. the 
day of vaccination and 6 
subsequent days). 
The number and percentage with exact 95% CI of maternal subjects 
reporting each Solicited administration site event (any grade, each 
grade,) and solicited systemic event (any, each grade) during the 7-
day (days 1 to 7) follow-up period after vaccination will be tabulated by 
maximum intensity per subject for each study vaccine group.  
For fever during the 7-day follow-up period after vaccination, the 
number and percentage of maternal subjects reporting any fever (i.e., 
temperature ≥38 °C) and fever by half degree (°C) cumulative 
increments, any Grade 3 fevers, will be reported. In addition, the 
prevalence of any and Grade 3 fever will be presented graphically over 
time after vaccination. 
The number and percentage of maternal subjects with at least one 
administration site AE (solicited and unsolicited), with at least one 
systemic AE (solicited and unsolicited) and with any AE during the 
7-day follow-up period after vaccination will be tabulated with exact 
95% confidence interval (CI) by group. The same computations will be 
done for Grade 3 solicited and unsolicited AEs, for any AEs considered 
related to vaccination, for any Grade 3 AEs considered related to 
vaccination and for any AEs resulting in a medically attended visit (i.e., 
MAEs).  
Occurrence of any 
protocol-specified 
hematological or 
biochemical laboratory 
abnormality at baseline 
(up to 15 days before 
vaccination) and Day 8 
(Visit 2) 
The number and percentage of subjects with hematology and 
biochemistry results outside central laboratory normal ranges will be 
tabulated to show Day 8 versus baseline. The maximum grading as 
described in [Sheffield, 2013] and in the SPM from Screening up to Day 
8 will also be tabulated.  
 
Occurrence of unsolicited 
AEs that occur during a 
30-day follow-up period 
after vaccination (i.e. the 
day of vaccination and 29 
subsequent days). 
The number and percentage of maternal subjects with unsolicited 
symptoms within 30 days after vaccination with exact 95% CIs will be 
tabulated by group and by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term.  
Similar tabulations will be done for Grade 3 unsolicited symptoms, for 
any causally related unsolicited symptoms, for Grade 3 related 
unsolicited symptoms and for MAEs. 
 
The number and percentage of maternal subjects with at least one 
administration site AE (solicited and unsolicited), with at least one 
systemic AE (solicited and unsolicited) and with any AE during the 
30-day follow-up period after vaccination will be tabulated with exact 
95% confidence interval (CI) by group. The same computations will be 
done for Grade 3 solicited and unsolicited AEs, for any AEs considered 
related to vaccination, for any Grade 3 AEs considered related to 
vaccination and for MAEs.  
Occurrence of serious 
adverse events (SAEs), 
AEs leading to study 
withdrawal, and medically 
attended AEs from Visit 1 
The number and percentage of maternal subjects with  
• 
at least one SAE;  
• 
at least one MAE  
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Primary Safety 
Endpoints  
Statistical Analysis Methods 
(Day 1) up to 6 weeks 
after delivery (Day 43 
post-delivery, Visit 6). 
from Visit 1 (Day 1) up to 6 weeks after delivery with exact 95% CIs will 
be tabulated by group and by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  
By-subject listings of SAEs, AEs leading to study withdrawal, and 
MAEs will be prepared (but will not be released until the final, unblinded 
analysis has been completed). 
Pregnancy outcomes 
from Day 1 (Visit 1) up to 
6 weeks after delivery 
(Day 43 post-delivery, 
Visit 6). 
Outcomes are listed in 
Section 3. 
The number and percentage of maternal subjects with each pregnancy 
outcome will be tabulated with its exact 95% CI by group. 
By subject listings of adverse pregnancy outcomes will be prepared but 
will not be released until the final, unblinded analysis has been 
completed. 
Pregnancy-related AESIs 
from Day 1 (Visit 1) up to 
6 weeks after delivery 
(Day 43 post delivery; 
Visit 6). These events are 
listed in Section 3.  
The number and percentage of maternal subjects with each pregnancy-
related AESI will be tabulated with its exact 95% CI by group. 
By subject listings of pregnancy-related AESIs will be prepared but will 
not be released until the final, unblinded analysis has been completed.  
Infant 
subjects 
The occurrence of 
neonatal AESIs (reported 
up to 6 weeks after birth). 
These events are listed In 
Section 3. 
Occurrence of SAEs, AEs 
leading to study 
withdrawal and medically 
attended AEs from birth 
up to 6 weeks after birth.  
The number and percentage of infant subjects with each neonatal AESI 
will be tabulated with its exact 95% CI by group. 
By-subject listings of neonatal AESIs will be prepared, but will not be 
released until the final, unblinded analysis has been completed. 
The number and percentage of infant subjects with  
• 
at least one SAE; 
• 
at least one MAE  
from Visit 1 (Day 1) up to 6 weeks after delivery with exact 95% CIs will 
be tabulated by group and by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  
By-subject listings of SAEs, AEs leading to study withdrawal, and 
MAEs will be prepared (but will not be released until the final, unblinded 
analysis has been completed). 
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9.4.3.2. 
Immunogenicity 
 
Primary Immunogenicity 
Endpoints 
Statistical Analysis Methods 
Maternal 
subjects 
• 
RSVPreF3 IgG-
specific antibody 
concentration, and  
• 
Neutralizing 
antibody titers 
against RSV-A 
Measured on blood 
samples collected from 
vaccinated maternal 
subjects at Day 1 before 
vaccination (Visit 1), Day 
31 (Visit 3), and at 
Delivery (Visit 5). 
For each assay, at each timepoint and by study group and age category 
(18 - <35 years; ≥ 35 - years; overall):  
• 
Antibody titres/concentrations will be displayed using reverse 
cumulative curves. 
• 
Geometric Mean Titers (GMTs)/ Geometric Mean 
Concentrations(GMCs) will be tabulated with 95% CI and 
represented graphically. 
• 
Individual post-vaccination versus pre-vaccination results will be 
plotted using scatter plots. Results of the control group will be used 
as a reference. 
• 
Geometric mean of ratios of antibody titres/concentrations at each 
post-vaccination timepoint over pre-vaccination will be tabulated 
with 95% CI. 
• 
The distribution of antibody titres/concentration will be tabulated 
• 
Distribution of the fold increase of the antibody 
titres/concentrations (post- versus pre-vaccination) will be 
tabulated by pre-specified pre-vaccination titre category. 
Relationship between maternal RSVPreF3 IgG-specific antibody 
concentration and RSV-A neutralizing antibody at baseline, at day 31 
and at delivery will be explored using scatter plots of individual values. 
Between group evaluation of vaccine formulations in terms of RSVPreF3 
IgG-specific antibody concentrations and Neutralizing antibody titers 
against RSV-A will be performed at Day31 and at Delivery using a mixed 
effect model on the logarithm10 transformation of the 
concentrations/titers, and including the pre-vaccination logarithm10 
transformation of the concentrations/titers, the vaccine groups, 
gestational age at vaccination, and the interval between vaccination and 
delivery as covariates if needed. 
Cord 
blood/ 
placental 
transfer 
• 
RSVPreF3 IgG-
specific antibody 
concentration, and  
• 
Neutralizing 
antibody titers 
against RSV-A 
For each assay, the following analysis will be performed by study group 
• 
Antibody titres/concentrations will be displayed using reverse 
cumulative curves. 
• 
Geometric Mean Titers (GMTs)/ Geometric Mean 
Concentrations(GMCs) will be tabulated with 95% CI and 
represented graphically. 
• 
The distribution of RSV-A and RSVPreF3 IgG-specific antibody 
titres/concentration from cord blood will be tabulated  
• 
For each assay, relationship between maternal antibody titers and 
infant antibody titers at the time of delivery will be evaluated 
graphically using scatter plots of individual results. 
• 
The ratio between 
cord blood and 
maternal RSVPreF3 
IgG-specific 
antibody 
concentrations 
• 
Geometric mean of placental transfer will be tabulated with 95% CI 
by study group. 
• 
Percentage of infants with placental transfer ≥ 1 will be tabulated 
with exact 95 % CI by study group. 
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Primary Immunogenicity 
Endpoints 
Statistical Analysis Methods 
• 
All 3 endpoints 
measured on blood 
samples collected 
from maternal 
subjects at delivery 
and either cord 
blood, or (if cord 
blood cannot be 
collected) infant 
blood samples 
collected within 3 
days after birth 
Between group evaluation on vaccine formulations in terms of RSVPreF3 
IgG-specific antibody concentrations / neutralizing antibody titers will be 
performed on cord blood at Delivery using a mixed effect model on the 
logarithm10 transformation of the concentrations/titers, including the pre-
vaccination logarithm10 transformation of the concentrations/titers from 
maternal subjects, the vaccine groups, gestational age at vaccination, 
gestational age at birth (> 37 weeks; ≤ 37 weeks), and the interval 
between vaccination and delivery as covariates if appropriate. 
In addition, if cord blood samples are missing in 20% or more of infants 
in a single study group, and if the data permit: RSV antibody 
concentrations/titers and persistence of RSV antibody 
concentrations/titers in infants through time will be evaluated separately 
in infants with cord blood samples and in infants from whom, instead, a 
blood sample was obtained within 3 days after birth.  
The relationship between RSVPreF3 IgG-specific antibody concentration 
and RSV-A neutralizing antibody at delivery will be explored using 
scatter plots of individual values. 
9.4.4. 
Secondary endpoints 
9.4.4.1. 
Safety 
Secondary Safety Endpoints 
Statistical Analysis Methods 
Maternal 
subjects 
From Day 1 (Visit 1) through 6 
months after delivery (Visit 8), 
occurrences of SAEs, MAEs 
and AEs leading to study 
withdrawal. 
Occurrence of RSV-associated 
medically attended RTIs (RSV-
MA-RTIs) up to 6 months post-
delivery (Visit 8) 
The number and percentage of maternal subjects with at least one 
SAE, AE leading to study withdrawal, MAE from Day 1 up to 6 
months after delivery with exact 95% CIs will be tabulated by group 
and by Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term. 
By-subject listings of SAEs, AEs leading to study withdrawal and 
MAEs will be prepared (but will not be released until the final, 
unblinded, analysis has been completed). 
The number and proportion of subjects with at least one RSV-
associated MA- RTI (with 95 % CI) will be calculated and tabulated.  
Infant 
subjects 
From birth through 6 months 
(Visit 4-NB) after birth, 
occurrences of SAEs, AEs 
leading to study withdrawal, 
and medically attended AEs  
From birth through 1 year (Visit 
5-NB) after birth, occurrences 
of SAEs, AEs leading to study 
withdrawal, and MAEs 
For each category:  
• 
SAE,  
• 
AE leading to study withdrawal,  
• 
MAEs  
The number and proportion of infant subjects who experienced at 
least one event from birth up to 6 months after birth and the number 
and proportion of infant subjects who experienced at least one event 
from birth up to 1 year after birth will be tabulated with 95% CI by 
group.  
By-subject listings of SAEs, AEs leading to study withdrawal and 
MAEs will be prepared.  
From birth to 6 months (Visit 4-
NB), occurrences of RSV-
associated LRTI(s), Severe 
LRTI(s), very severe LRTIs 
and RSV-associated 
hospitalizations (according to 
the case definitions in Section 
4.2.6)  
For each category:  
• 
RSV-associated LRTI,  
• 
Severe LRTI,  
• 
Very severe LRTI 
• 
RSV-associated hospitalization  
The number and proportion (with 95% CI) of subjects with at least 
one event will be calculated and tabulated by group.  
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9.4.4.2. 
Immunogenicity 
 
Secondary Immunogenicity 
Endpoints 
Statistical Analysis Methods 
Maternal 
subjects 
• 
RSVPreF3 IgG-specific antibody 
concentration, and  
• 
Neutralizing antibody titers 
against RSV-A and 
• 
Neutralizing antibody titers 
against RSV B  
• 
For RSV-A: Measured on the 
blood sample collected Day 43 
post- delivery (Visit 6). 
• 
For RSV-B: Measured on blood 
samples collected from 
vaccinated maternal subjects at 
Day 1 before vaccination (Visit 
1), Day 31 (Visit 3), at Delivery 
(Visit 5) and at Day 43 post 
delivery (Visit 6). 
For each assay, at each timepoint and by study group and 
age category (18 - <35 years ;≥ 35 - years; overall): 
• 
Antibody titres/concentrations will be displayed using 
reverse cumulative curves. 
• 
GMTs/ GMCs will be tabulated with 95% CI and 
represented graphically. 
• 
Individual post-vaccination versus pre-vaccination 
results will be plotted using scatter plots. Results of the 
control group will be used as a reference. 
• 
Geometric mean of ratios of antibody 
titres/concentrations at each post-vaccination timepoint 
over pre-vaccination will be tabulated with 95% CI. 
• 
The distribution of antibody titres/concentration will be 
tabulated  
• 
Distribution of the fold increase of the antibody 
titres/concentrations (post- versus pre-vaccination) will 
be tabulated by pre-specified pre-vaccination titre 
category. 
Relationship between maternal RSVPreF3 IgG-specific 
antibody concentration and RSV-A neutralizing antibody, 
between RSV-A neutralizing antibody and RSV-B neutralizing 
antibody, and between RSV-B neutralizing antibody and 
RSVPreF3 IgG-specific antibody concentration at baseline, at 
day 31, at delivery and at day 43 post-delivery will be 
explored using scatter plots of individual values. 
In addition, between group evaluation of vaccine formulations 
in terms of RSVPreF3 IgG-specific antibody concentrations 
and Neutralizing antibody titers against RSV-A and RSV-B 
will be performed at Day31, , at Delivery and at Day 43 post-
delivery using a mixed effect model on the logarithm10 
transformation of the concentrations/titers, and including the 
pre-vaccination logarithm10 transformation of the 
concentrations/titers, the vaccine groups, gestational age at 
vaccination, and the interval between vaccination and delivery 
if available as covariates if needed. 
Infant 
subjects 
• 
RSVPreF3 IgG-specific antibody 
concentration  
• 
Neutralising antibody titres 
against RSV-A  
• 
Neutralising antibody titres 
against RSV-B  
For all 3 RSV-specific antibody 
assessments: measured in a 
subcohort of infants at Day 43 after 
birth (sub-cohort V2-NB), in a 
subcohort of infants at Day 121 (sub-
cohort V3-NB) after birth and in a 
subcohort of infants at D181 after birth 
(sub-cohort V4-NB). Each infant will 
For each assay, at each timepoint and by study group  
• 
Antibody titres/concentrations will be displayed using 
reverse cumulative curves. 
• 
GMTs/ GMCs will be tabulated with 95% CI and 
represented graphically. 
In addition, analyses will include exploratory evaluation of the 
persistence of RSV specific antibodies in infants through time, 
and half-life analysis modelling of logarithm transformed RSV 
antibody concentrations/titers over time.  
Between group evaluation on vaccine formulations in terms of 
RSVPreF3 IgG-specific antibody concentrations / neutralizing 
antibody titers will be performed on cord blood at Delivery, 
and on blood samples collected at 6 weeks, 3-4 months and 6 
months post-birth using a mixed effect model on the 
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Endpoints 
Statistical Analysis Methods 
be randomly assigned to 1 of these 3 
cohorts at the time of maternal 
randomization to intervention 
For neutralizing antibody titers against 
RSV-B only: measured on the cord 
blood sample collected at delivery, or 
on a blood sample collected from the 
infant within 3 days after birth (if no 
cord blood sample can be obtained). 
(Note: RSV-A neutralizing antibody at 
birth is a primary immunogenicity 
objective). 
logarithm10 transformation of the concentrations/titers, 
including the pre-vaccination logarithm10 transformation of the 
concentrations/titers from maternal subjects, the vaccine 
groups, gestational age at vaccination, gestational age at birth 
(> 37 weeks ; ≤ 37 weeks ), and the interval between 
vaccination and delivery as covariates if appropriate and 
needed. 
In addition, if cord blood samples are missing in 20% or more 
of infants in a single study group, and if the data permit: RSV 
antibody concentrations/titers and persistence of RSV 
antibody concentrations/titers in infants through time will be 
evaluated separately in infants with cord blood samples and 
in infants from whom, instead, a blood sample was obtained 
within 3 days after birth.  
The relationship between RSVPreF3 IgG-specific antibody 
concentration and RSV-A neutralizing antibody, between 
RSV-A neutralizing antibody and RSV-B neutralizing 
antibody, and between RSV-B neutralizing antibody and 
RSVPreF3 IgG-specific antibody concentration at delivery will 
be explored using scatter plots of individual values. 
9.4.5. 
Tertiary / exploratory endpoints 
9.4.5.1. 
Immunogenicity 
Tertiary Immunogenicity Endpoints 
Statistical Analysis 
Methods 
Tertiary endpoints for maternal and infant subjects may include: 
• 
Humoral immune response in terms of RSVpreF3 specific IgG subclasses, 
antibodies competing for binding to specific RSVpreF3 epitopes, and other 
exploratory endpoints 
• 
The presence of other respiratory viruses in nasal swabs (assessed via an Allplex 
Respiratory Viruses Panel or alternative; performed for RSV A/B-positive samples 
and if deemed necessary for RSV A/B-negative samples). 
To be described in a 
separate Statistical 
Analysis Plan.  
9.4.5.2. 
Exploratory endpoints 
Biomarker exploratory analyses and any other analysis (as applicable) will be described 
in a separate statistical analysis plan.  
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9.4.6. 
Other analyses 
9.4.6.1. 
Demography and baseline characteristics 
These analyses will be performed on the Exposed set and on the Per protocol set for 
immunogenicity. 
For all maternal subjects, demographic characteristics (e.g., age at vaccination (18 - <35; 
≥ 35 years), gestational age at vaccination (280/7 - 310/7, 311/7 - 336/7 weeks), geographic 
ancestry) will be summarized by group using descriptive statistics. The interval in days 
between maternal vaccination and delivery will be calculated and summarized by group 
using descriptive statistics. For their infants, demographic characteristics (e.g., gestational 
age at time of delivery (> 37 weeks; ≤ 37 weeks), sex, weight, length, head 
circumference, geographic ancestry, apgar score), and lifestyle characteristics (e.g., living 
environment, household composition, breastfeeding, passive smoking and and extent of 
contact with children less than 6 years of age) will be summarised by group, and for each 
immunogenicity sub-cohort within each group, using descriptive statistics. 
• 
Frequency tables will be generated for categorical variable such as geographic 
ancestry. 
• 
Mean, median, standard deviation and range will be provided for continuous data 
such as age. 
9.4.6.2. 
Dose Characterization 
The characterization of the doses and the choice of the dose to be carried over to 
subsequent studies will be based on the totality of safety, reactogenicity and 
immunogenicity data from the analyses above with a focus on maximizing cord blood 
titers. The vaccine dose that demonstrates the highest immunogenicity in pregnant 
women and in cord blood in terms of GMTs/GMCs at Day 31 and delivery, that is 
associated with an acceptable safety profile will be considered for subsequent trials. As 
variability in titers is expected to be lower at Day 31 than in the cord blood, power 
calculations for dose characterization are based on anticipated standard deviations at Day 
31. If immune response is similar in the active vaccination groups, additional analyses 
using a generalized ROC (Receiver Operating Characteristics) method [Yu, 2018] will be 
performed. 
Additional details will be provided in the SAP. 
9.4.6.3. 
Case accruals 
Rules for MA-RTI and RTI case accountability will be described in the Statistical 
Analysis Plan. 
9.5. 
Interim analyses 
No interim analyses are planned. However, analyses to evaluate objectives and endpoints 
will be performed in steps. The sequence of analyses is described below. 
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9.5.1. 
Sequence of analyses  
9.5.1.1. 
First analysis 
The first analysis will be conducted after approximately 75 maternal subjects have 
completed Visit 3 (Day 31) and approximately 24 maternal subjects and their infants 
have completed Visit 5 / Visit 1-NB (Delivery/Birth). 
By-study-group safety and immunogenicity analyses will be performed by an 
independent statistician not affiliated with the project (to preserve the observer blinding).  
Immunogenicity analyses will include all available test results at: 
• 
Visit 1 (Day 1) and Visit 3 (Day 31); 
• 
Visit 5 (delivery; maternal blood sample and cord blood).  If no cord blood was 
collected, test results for the infant blood sample collected within 3 days post birth 
(Visit 1-NB) will also be evaluated.  
Safety analyses will be performed by blinded treatment group, with the letters “A,” “B,” 
and “C” replacing treatment-specific group identifiers in all results summaries. Steps will 
be taken to minimize the risk of unblinding (e.g., events that happen in a single group 
will be masked by adding the same amount of counts to other groups). Although the risk 
of unblinding may be reduced with the proposed masking, this risk may not be avoidable 
in certain cases. 
Safety analyses will include all available data for:  
• 
Solicited events, unsolicited AEs for 30 days post-dose, MAEs, SAEs and AESIs. 
• 
RTI surveillance data (including nasal swab test results).  
A report summarizing these safety and immunogenicity results will be prepared but will 
not be made available to investigators. 
No individual (by-subject) data / data listings will be provided, except for SUSARs which 
will be reported to regulatory authorities in compliance with the regulations.  
9.5.1.2. 
Second analysis (Amended 30-SEP-2020) 
The second analysis will be performed after approximately 24 maternal subjects and 
their infants have completed Visit 7 / Visit 3-NB (Day 121 post-delivery / birth).  
By-study-group immunogenicity and by-study-group safety analyses will be performed 
by an independent statistician not affiliated with the project (to preserve the observer 
blinding).   
By-study-group immunogenicity analyses will include all available test results, at:  
• 
Visit 1 (Day 1) and Visit 3 (Day 31).  
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• 
Visit 5 (delivery; maternal blood sample and cord blood).  If no cord blood was 
collected, test results for the infant blood sample collected within 3 days post birth 
(Visit 1-NB) will also be evaluated.  
• 
Visit 6 / Visit 2-NB (Day 43 post delivery). 
• 
Visit 3-NB (Day 121 post-delivery). 
By-study-group safety analyses will include the following data from those subjects who 
have reached the Day 43 post-delivery visit: 
• 
Solicited events, unsolicited AEs for 30 days post-dose, MAEs, SAEs and AESIs. 
• 
RTI surveillance data (including nasal swab test results).  
Safety results that would lead to the unblinding of some subjects (e.g. a specific AE 
reported by one subject only) will be masked (i.e. the group in which this event occurred 
will not be identified). Although the risk of unblinding may be reduced with the proposed 
masking, this risk may not be avoidable in certain cases. 
Blinded SAE and AESI listings for all subjects will also be provided. 
The results will be summarized in an Investigator Brochure update. 
No individual (by-subject) data / data listings will be provided, except for SUSARs which 
will be reported to regulatory authorities in compliance with the regulations. 
9.5.1.3. 
Third analysis (Amended 30-SEP-2020) 
The third analysis will be performed after approximately 150 maternal and infant 
subjects have completed Visit 8/Visit 4-NB (Day 181 post-delivery/birth). 
By-study-group immunogenicity and by-study-group safety analyses will be performed 
by an independent statistician not affiliated with the project. 
By-study-group immunogenicity analyses will include all available test results at:  
• 
Visit 1 (Day 1) and Visit 3 (Day 31);  
• 
Visit 5 (delivery; maternal blood sample and cord blood).  If no cord blood was 
collected, test results for the infant blood sample collected within 3 days post birth 
(Visit 1-NB) will also be evaluated.  
• 
Visit 6 / Visit 2-NB (Day 43 post delivery);  
• 
Visit 3-NB (Day 121 post-delivery) 
• 
Visit 4-NB (Day 181 post-delivery) 
By-study-group safety analyses will include the following data from all vaccinated 
subjects who have reached the Day 43 post-delivery visit: 
• 
Solicited events, unsolicited AEs for 30 days post-dose, MAEs, SAEs and AESIs. 
• 
RTI surveillance data (including nasal swab test results). 
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Safety results that would lead to the unblinding of some subjects (e.g. a specific AE 
reported by one subject only) will be masked (i.e. the group in which this event occurred 
will not be identified). Although the risk of unblinding may be reduced with the proposed 
masking, this risk may not be avoidable in certain cases. In addition, blinded SAE and 
AESI listings for all subjects will be provided. 
The results will be summarized in an Investigator Brochure update. 
No individual (by-subject) data / data listings will be provided, except for SUSARs which 
will be reported to regulatory authorities in compliance with the regulations. 
9.5.1.4. 
Final analysis 
The final analysis will evaluate all data pertaining to primary and secondary safety and 
immunogenicity endpoints.  It will be performed by the GSK Biologicals biostatistics 
team when all primary and secondary endpoint data up to study end (last Visit 5-NB) are 
available.  
Results will be presented in a clinical study report.  This report will include results 
summarized by study group as well as individual (by subject) data / data listings and will 
be made available to investigators. 
If the data for tertiary endpoints become available at a later stage, (an) additional 
analysis/ analyses will be performed. These analyses will be documented in annex(es) to 
the clinical study report. 
9.5.2. 
Statistical considerations for interim analysis  
The first 3 analyses will be descriptive. Therefore, the conduct of these analyses has no 
impact on interpretation of study results. 
9.6. 
Data Monitoring Committee (DMC) 
An unblinded, independent data monitoring committee external to GSK (IDMC) will 
review the data for this study. Details concerning the IDMC’s structure and processes are 
provided in a separate IDMC charter. 
The analysis plan for IDMC reviews will be detailed in a separate SAP. These unblinded 
analyses will all be done by an independent statistician from an Independent Data 
Analysis Center (IDAC) outside GSK to maintain the study blind and will be documented 
in a statistical analysis report. 
Only the outcomes of the IDMC reviews will be communicated to the study team (no 
potentially unblinding safety signal details). 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, Informed Consent Form (ICF) or Informed 
Assent Form (IAF), Investigator Brochure, and other relevant documents (e.g. 
advertisements) must be submitted, to an IRB/IEC by the investigator for review and 
approval. These documents will be signed and dated by the investigator before the 
study is initiated.  
• 
Any protocol amendments will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects.  
• 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• 
The investigator will be responsible for the following: 
− 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. 
− 
Notifying the IRB/IEC of SAE(s) or other significant safety findings as required 
by IRB/IEC procedures. 
− 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
10.1.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing financial interest information prior initiation 
of the centre and at the end of the study. Investigators are responsible for providing a 
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Financial Disclosure update if their financial interests change at any point during their 
participation in a study and for 1 year after completion of the study.  
10.1.3. 
Informed consent process 
The investigator or his/her representative will explain the nature of the study to the 
subject / subject’s parent(s) or his/her LAR(s) and answer all questions regarding the 
study.  
Subjects/subjects’ parent(s)/LAR(s) must be informed that their participation is 
voluntary.  
Freely given and written/ witnessed/thumb printed informed consent must be obtained 
from each subject and/or each subject’s parent(s)/LAR(s)/witness as appropriate, prior to 
participation in the study.  
The content of informed consent form must meet the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 
The medical record must include a statement that written or witnessed/thumb printed 
informed consent was obtained before the subject was enrolled in the study and the date 
the consent was obtained. The authorised person obtaining the informed consent must 
also sign the ICF. 
Subjects / subjects parent(s) / LAR(s) must be re-consented to the most current version of 
the ICF(s) or an ICF addendum during their participation in the study.  
A copy of the ICF(s) must be provided to the subject or the subject’s parent(s)/LAR(s).  
Subjects who are rescreened are required to sign a new ICF. 
10.1.4. 
Data protection 
Subject will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject’s 
names or any information which would make the subject identifiable will not be 
transferred.  
The subject / subject’s parent(s)/LAR(s) must be informed that his/her personal study-
related data will be used by the sponsor in accordance with local data protection law.  
The subjects/subjects’ parent(s)/LAR(s) must be informed of their rights regarding the 
use of their personal data in accordance with the data privacy Section of the ICF. 
The subject / subject’s parent(s)/LAR(s) must be informed that his/her medical records 
may be examined by Clinical Quality Assurance auditors or other authorised personnel 
appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
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GSK will also ensure protection of the personal data of the investigator and site staff 
which will be collected within the framework and for the purpose of the study in 
accordance with the Data Privacy Notice that will be sent to the site staff.  
10.1.5. 
Committees structure 
Safety oversight will be provided by a blinded safety review team (SRT) composed of 
GSK RSV team members, and by an unblinded, independent data monitoring committee 
external to GSK (IDMC). Details regarding SRT and IDMC safety evaluations are 
provided in a separate IDMC charter. 
10.1.6. 
Dissemination of clinical study data 
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or the GSK Clinical Study Register in compliance with the 
applicable regulations/GSK policy. GSK will aim to register protocols summaries prior to 
study start and target results summaries submission within 12 months of primary/ study 
completion date. Where external regulations require earlier disclosure, GSK will follow 
those timelines.  
Where required by regulation, summaries will also be posted on applicable national or 
regional clinical trial registers. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK 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. 
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis. 
GSK intends to make anonymized patient-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance 
medical science or improve patient care. This helps ensure the data provided by trial 
subjects are used to maximum effect in the creation of knowledge and understanding. 
10.1.7. 
Data quality assurance 
The investigator should maintain a record of the location(s) of their respective essential 
documents including source documents. The storage system used during the trial and for 
archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval.  
Essential trial documents may be added or removed where justified (in advance of trial 
initiation) based on their importance and relevance to the trial. When a copy is used to 
replace an original document (e.g. source documents, CRF), the copy should fulfil the 
requirements for certified copies.  
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All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF.  
The investigator must maintain adequate and accurate source documents and trial records 
that include all pertinent observations on each of the site’s trial subjects (see Glossary of 
terms for the exact definition of source documents) that supports information entered in 
the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies.  
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data.  
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data should be traceable, should not 
obscure the original entry, and should be explained if necessary (e.g. via an audit trail). 
The safety and rights of subjects must be protected and study be conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
Trial records and source documents, including signed ICF, pertaining to the conduct of 
this study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.  
10.1.8. 
Source documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Investigator should maintain a record of the location(s) of 
their source documents.  
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
Definition of what constitutes source data and source documents can be found in the 
Glossary of terms. 
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10.1.9. 
Study and site start and closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK, provided there is sufficient notice given 
to account for patient’s safe exit from study participation. Study sites regular closure will 
occur upon study completion. A study site is considered closed when all required 
data/documents and study supplies have been collected and a study-site closure visit has 
been performed.  
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further study intervention development 
10.1.10. 
Publication policy 
GSK aims to submit for publication the results of these studies in searchable, peer 
reviewed scientific literature within 18 months from Last Subject Last Visit (LSLV) for 
interventional studies and follows the guidance from the International Committee of 
Medical Journal Editors. 
10.2. 
Appendix 2: Clinical laboratory tests 
Study-required laboratory assessments detailed in Table 26, except urinalysis, should be 
performed by a central laboratory. During special circumstances, hematocrit may be 
performed locally if it is not possible to collect a blood sample for central analysis using 
GSK-provided supplies (see Section 8). 
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Table 26 
Protocol-Required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Hematology 
Leukocytes (White Blood Cells)  
Lymphocytes 
Neutrophils 
Eosinophils 
Platelets  
Erythrocytes (Red Blood Cells)  
Hematocrit  
Hemoglobin 
Erythrocyte Mean Corpuscular Volume (MCV) 
Aspartate Aminotransferase (AST) / Serum Glutamic-
Oxaloacetic Transaminase (SGOT) 
Alanine Aminotransferase (ALT) / Serum Glutamic-
Pyruvic Transaminase (SGPT) 
Creatinine  
Urea nitrogen 
Urinalysis by dipstick 
Glucose 
Protein 
Assessment of eligibility and grading of laboratory parameters will be based on reference ranges described in 
[Sheffield, 2013] and the SPM for this study.   
10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting 
10.3.1. 
Definition of an Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical study subject, 
temporally associated with the use of a study intervention, whether or not considered 
related to the study intervention. 
NOTE: 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 study intervention. 
Events Meeting the AE Definition  
• 
Significant or unexpected worsening or exacerbation of the condition/indication 
under study. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study vaccine(s)/product(s) 
administration even though they may have been present prior to the start of the 
study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
vaccine(s)/product(s) or a concurrent medication (overdose per se should not be 
reported as an AE/SAE). 
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• 
Signs or symptoms temporally associated with study vaccine(s)/product(s) 
administration. 
• 
Signs, symptoms that require medical attention (e.g. hospital stays, physician visits 
and emergency room visits) 
• 
Pre- or post- intervention events that occur as a result of protocol-mandated 
procedures (i.e. invasive procedures, modification of participant’s previous 
therapeutic regimen). 
• 
Clinically significant abnormal laboratory findings or other abnormal assessments 
that are present at baseline and significantly worsen following the start of the study 
will also be reported as AEs or SAEs. 
• 
AEs to be recorded as solicited AEs are described in the Section 10.3.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
Events NOT Meeting the AE Definition 
• 
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 participant prior to 
the study vaccination. These events will be recorded in the medical history Section 
of the eCRF.  
• 
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline. 
• 
Clinically significant abnormal laboratory findings or other abnormal assessments 
that are associated with the disease being studied, unless judged by the investigator 
as more severe than expected for the participant’s condition, or that are present or 
detected at the start of the study and do not worsen. 
• 
Disease-related events (DRE), typically associated with the disease under study. 
These events will be recorded in the participant’s eCRF and will be monitored by 
the IDMC on a routine basis. 
However, if 1 or both of the following conditions apply, then the event should be 
reported promptly to GSK as an SAE (see Section 10.3.8): 
• 
The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, or 
• 
The investigator considers that there is a reasonable possibility that the event was 
related to the administration of the study vaccine/product 
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10.3.2. 
Definition of a Serious Adverse Event (SAE) 
An 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 participant 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 participant 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 as 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. 
d. Results in disability/incapacity  
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 participant  
f. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy). 
g. Other situations 
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 participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These should also 
be considered serious. Examples of such events are invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalisation. 
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10.3.3. 
Solicited events 
a. Solicited administration site events 
The following administration site events will be solicited: 
Table 27 
Solicited administration site events 
All age groups 
Pain  
Redness  
Swelling  
b. Solicited systemic events 
The following systemic events will be solicited: 
Table 28 
Solicited systemic events 
Adult/Child (≥6 years) 
Fatigue 
Fever 
Nausea  
Vomiting 
Diarrhea 
Abdominal pain 
Headache 
Note: maternal subjects will be instructed to measure and record the (preferably) oral 
temperature at least once each day, at approximately the same time each day. Should 
additional temperature measurements be performed at other times of day, subjects will be 
instructed to record the highest temperature in the electronic Subject Diary (e-Diary). 
10.3.4. 
Unsolicited adverse events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a maternal subject/infant subjects’ 
parent(s)/LAR(s) who has/have signed the informed consent. Unsolicited AEs include 
serious and non-serious AEs. 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalisation, or emergency room visit, or visit to/by a health care provider). 
The subject’s/ subject’s parent(s)/LAR(s) will be instructed to contact the site as soon as 
possible to report medically attended event(s), as well as any events that, though not 
medically attended, are of subject/ parental /LAR’s concern. Detailed information about 
reported unsolicited AEs will be collected by qualified site personnel and documented in 
the subject’s records. 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
maternal subject/infant subject’s parent(s)/LAR(s) will be collected during interview with 
the maternal subjects/ infant subjects’ parent(s)/LAR(s) and by review of available 
medical records at the next visit. 
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10.3.5. 
Adverse events of special interest (AESIs) 
AESIs include adverse pregnancy outcomes, pregnancy-related adverse events of special 
interest (newly occurring or worsening of existing condition), and neonatal adverse 
events of special interest. Refer to Section 10.8 for additional details. 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as an AESI. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as AESIs until the 
final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely.  
10.3.6. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as AEs or SAEs 
In the absence of a diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments the investigator considers 
clinically significant will be recorded as an AE or SAE if they meet the definition of an 
AE or SAE (refer to Sections 10.3.1 and 10.3.2).  
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. 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs 
10.3.7.1. 
Subsequent Pregnancy 
All maternal subjects will be in the third trimester of pregnancy at enrolment and are 
expected to deliver while participating in the study. Maternal subjects who become 
pregnant again after completing the study pregnancy may continue the study at the 
discretion of the investigator. 
While subsequent pregnancy itself is not considered an AE or SAE, any abnormal 
subsequent pregnancy outcome or complication or elective termination of a subsequent 
pregnancy for medical reasons will be recorded and reported as an AE or a SAE. Please 
refer to the Section 10.3.2 for the definition of a SAE.  
10.3.8. 
Recording and follow-up of AEs, SAEs, AESIs and subsequent 
pregnancies (Amended 30-SEP-2020) 
The maternal subjects/infant subjects’ parent(s)/LAR(s) will be instructed to contact the 
investigator immediately should the subjects manifest any signs or symptoms they/their 
parent(s) / LAR(s) perceive as serious.  
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
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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 maternal and infant 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. 
An Electronic Diary (eDiary) hereafter referred to as the Subject Diary will be used in 
this study to capture solicited administration site or systemic events, as well as the 
occurrence of unsolicited adverse events 30 days post vaccination, medically attended 
adverse events (including medically attended RTIs in maternal subjects), and RTIs in 
infant subjects. The maternal subject should be trained on how and when to complete 
each field of the Subject Diary. In case ERT portal/ alerts are not functioning, contacts 
will be conducted at least weekly until NB4/V8. Contact may be via telephone, SMS, 
email or other means (including videotelephony or telemedicine), depending on local 
laws and best practice. 
Any individual(s) who will perform the measurements of administration site or systemic 
events and who will enter the information into the Subject Diary should be trained on the 
use of the Diary. This training must be documented in the maternal subject’s source 
record. If any individual other than the maternal subject is making entries in the Subject 
Diary, their identity should be documented in the Subject Diary/maternal subject’s source 
record. 
Refer to the SPM for more information regarding the use of eDiaries. 
10.3.8.1. 
Time period for collecting and recording AEs, SAEs, AESIs, and 
subsequent pregnancies and other events of interest 
Refer to Section 8.3.1. 
10.3.8.2. 
Where to record AEs, SAEs, AESIs, subsequent pregnancies and other 
events of interest  
All solicited AEs that occur during the 7 days following administration of the study 
vaccine/product (Day 1 to Day 7) must be recorded into the eDiary, irrespective of 
intensity or whether or not they are considered vaccination-related.  
Details regarding all other AEs should be recorded into the appropriate section of the 
eCRF, irrespective of intensity or whether or not they are considered vaccination-related. 
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10.3.8.3. 
Follow-up of AEs, SAEs, AESIs, subsequent pregnancies and other 
events of interest  
10.3.8.3.1. Follow-up during the study 
After the initial AE/SA/AESI/subsequent pregnancy or any other event of interest for the 
study, the investigator is required to proactively follow each subject at subsequent 
visits/contacts. 
The investigator will follow participants with SAEs/AESIs (serious or non-serious) 
subsequent pregnancy or subjects withdrawn from the study because of an AE, until the 
event has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or until the participant is lost to follow-up.  
Non-serious medically attended AEs must be followed until recovered / resolved, or until 
the subject’s last study visit, or until the subject is lost to follow-up. 
Other non-serious AEs (maternal subjects) must be followed until 30 days after study 
vaccine/product administration or until the subject is lost to follow-up (if this occurs 
before Visit 3 (Day 31)). 
If a maternal or infant 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. 
10.3.8.3.2. Follow-up after the subject is discharged from the study 
The investigator will provide any new or updated relevant information on previously 
reported SAEs, AESIs, subjects withdrawn from the study because of an AE and 
subsequent pregnancies to GSK using a paper/electronic Expedited Adverse Events 
Report and/or pregnancy report as applicable. The investigator is obliged to perform or 
arrange for the conduct of supplemental clinical examinations/tests and/or evaluations to 
elucidate the nature and/or causality of the AE or SAE as fully as possible.  
10.3.8.3.3. Follow-up of subsequent pregnancies 
Maternal subjects who became pregnant again while participating in the study will be 
followed to determine the outcome of the subsequent 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 electronic pregnancy report and the Expedited 
Adverse Events Report if applicable. Generally, the follow-up period doesn’t need to be 
longer than 6 to 8 weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs for this study, if the subsequent pregnancy 
outcome is a SAE, it should always be reported as a SAE 
Furthermore, if the investigator becomes aware of any SAE occurring as a result of a 
post-study pregnancy AND this is considered by the investigator to be reasonably related 
to the study vaccine(s)/product(s), he/she has to report this information to GSK as 
described in Section 10.3.10. 
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10.3.8.4. 
Updating of SAE, AESI and subsequent pregnancy information after 
removal of write access to the subject’s eCRF 
When additional SAE, AESI or subsequent pregnancy information is received after 
removal of 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 Table 23) or to the GSK Clinical Safety and Pharmacovigilance 
department within the defined reporting time frames specified in Table 22). 
10.3.9. 
Assessment of intensity and toxicity  
10.3.9.1. 
Assessment of intensity 
The intensity of the following solicited events will be assessed as described: 
Table 29 
Intensity scales for solicited symptoms in adults  
Adults/Child (≥6 years)  
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 
Temperature* 
 
Record temperature in °C/°F (with 1 decimal) 
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 
 
 
Fatigue 
0 
Normal 
Nausea 
1 
Mild: Easily tolerated 
Vomiting 
2 
Moderate: Interferes with normal activity 
Diarrhea 
3 
Severe: Prevents normal activity 
Abdominal pain 
 
 
*Refer to the SoA for the definition of fever and the preferred location for temperature measurement. 
The maximum intensity of local injection site redness/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 1 of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities  
(In adults/adolescents, 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 1 of the pre-defined 
outcomes as described in Section 10.3.2. 
10.3.9.2. 
Assessment of causality 
All solicited administration site and systemic events will be considered causally related to 
vaccination. The complete list of these events is provided in Table 27 and Table 28. 
The investigator must assess the relationship between study vaccine(s)/product(s) and the 
occurrence of each unsolicited AE/SAE using clinical judgement. Where several different 
vaccines/products were administered, the investigator should specify, when possible, if 
the unsolicited AE/SAE could be causally related to a specific vaccine/product (i.e. 
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine(s)/product(s) cannot be determined, the investigator should indicate the 
unsolicited AE/SAE to be related to all products. 
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccine(s)/product(s) will be considered and investigated. The investigator will also 
consult the IB to determine his/her assessment. 
Causality should be assessed by the investigator using the following question: 
Is there a reasonable possibility that the unsolicited AE may have been caused by the 
study vaccine/product? 
YES 
: 
There is a reasonable possibility that the study vaccine(s)/product(s) 
contributed to the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine(s)/product(s). There are other, more 
likely causes and administration of the study vaccine(s)/product(s) is 
not suspected to have contributed to the AE. 
If an event meets the criteria to be determined as ‘serious’ (see Section 10.3.2), additional 
examinations/tests will be performed by the investigator to determine ALL possible 
contributing factors for each SAE. 
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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)/product(s), if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify). 
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important to 
record an assessment of causality for every event before submitting the Expedited 
Adverse Events Report to GSK.  
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. The investigator may change his/her opinion of causality after receiving 
additional information and update the SAE information accordingly. 
10.3.9.3. 
Medically attended visits 
For solicited and unsolicited symptoms the subject experiences, the subject/subject’s 
parent(s)/LAR(s) will be asked if he/she/the subject 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.  
10.3.9.4. 
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). 
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10.3.10. 
Reporting of SAEs, AESIs, subsequent pregnancies, and other 
events 
10.3.10.1. Events requiring expedited reporting to GSK 
Once an investigator becomes aware that an SAE has occurred in a study subject, the 
investigator (or designee) must complete 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. The report must then be dated and 
signed by the investigator (or designee).  
Even if the investigator does not have all information regarding an SAE, the report 
should still be completed within 24 hours. Once additional relevant information is 
received, the report should be updated GSK WITHIN 24 HOURS. The investigator will 
always provide an assessment of causality at the time of the initial report. 
Refer to Table 22 for the details on timeframes for reporting of SAEs/AESIs/subsequent 
pregnancies.  
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. 
Refer to Section 10.3.10.2 for the back-up system in case the electronic reporting system 
does not work. 
10.3.10.2. Back-up system in case the electronic reporting system does not work 
In rare circumstances if the electronic reporting system does not work, the investigator 
(or designee) must fax a completed, dated and signed paper Expedited Adverse Events 
Report to the Study Contact for Reporting SAEs (refer to the SPONSOR 
INFORMATION) or to the GSK Clinical Safety and Pharmacovigilance department 
within 24 hours.  
The Investigator (or designee) must complete the electronic Expedited Adverse Events 
Report within 24 hours once the electronic reporting system is working again. 
information reported through the electronic SAE reporting system will be considered 
valid for regulatory reporting purposes.  
10.4. 
Appendix 4: Contraceptive guidance and collection of 
subsequent pregnancy information  
Contraceptive guidance does not apply in this study. Refer to Sections 10.3.7, 10.3.8 and 
10.3.10 for further information on detection, recording, reporting and follow-up of 
subsequent pregnancies.  
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10.5. 
Appendix 5: Country-specific requirements 
10.5.1. 
France 
This appendix includes all applicable requirements of French Public Health Code / 
specific local GSK requirements and identifies, item per item, the mandatory 
modifications or additional information to the study protocol. 
10.5.1.1. 
Concerning the “SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA”  
• 
Subjects will be compensated for the inconvenience of participating in the study. The 
amount of compensation is stated in the Informed Consent Form. Subjects not 
completing the study for whatever reason could be compensated generally on a pro 
rata basis. 
• 
According to French Public Health Code law (L.1121-16 and R.1121-16), the 
following people must be registered in National File (“Fichier National”): 
− 
Healthy volunteer; 
− 
Subjects if the aim of the study is not linked to their disease; 
− 
Subjects on request of the Ethics Committee regarding study risks and 
constraints. 
• 
The following details will be described: 
− 
Reference of the study 
− 
Surname and first name 
− 
Date and place of birth 
− 
Gender 
− 
Dates of beginning and termination of the study 
− 
Exclusion period during which the subject cannot participate to another study 
(French Public Health Code law L.1121-12) 
− 
The total amount of compensation 
• 
The subjects’ registration in National File (“Fichier National”) should be 
documented in the source document - subject notes and monitored by the CRA. 
• 
The following vulnerable subject populations will be excluded: minors, protected 
subjects, adult subjects not in condition to express their consent, subjects deprived of 
liberty, subjects receiving psychiatric cares, subjects hospitalized in a Health and 
Social Establishment for other purpose than the participation to the study. 
• 
A subject will be eligible for inclusion in this study if he /she is either affiliated to or 
beneficiary of a social security category (French Public Health Code law L.1121-8-
1). (exception for a participant to a non-interventional study if authorised by the 
Ethics Committee). 
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• 
It is the investigator’s responsibility to ensure and to document (in the source 
document - subject notes) that the subject: 
− 
is either affiliated to or beneficiary of a social security category;  
− 
has got an authorisation by the Ethics Committee. 
10.5.1.2. 
Concerning the “STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES” and specially in the “SAMPLE SIZE ASSUMPTIONS” 
The expected number of subjects to be recruited in France is declared to the French 
regulatory authority. 
10.5.1.3. 
Concerning the “REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS” 
• 
In section “Regulatory and Ethical Considerations, including the Informed 
Consent Process” 
− 
Concerning the process for informing the subject and/or his/her legally 
authorized representative, the following text is added:  
o 
French Patient Informed Consent is a document which summarizes the main 
features of the study and allows collection of the subject and/or his/her 
legally authorized representative written consent. It also contains a 
reference to the authorisation of ANSM and the approval from the French 
Ethics Committee. 
− 
Concerning the process for obtaining subject informed consent: 
o 
if the subject is minor, the following text is added: 
The informed consent of the holders of parental authority must be obtained 
before the beginning of the study. The consent of the child will be also 
sought when he/she is old enough to express his/her opinion. His/her refusal 
or the revocation of his/her consent cannot be disregarded. If there is only 
one holder of parental authority, the investigator will ask the present person 
to file, date and sign the parental certificate indicating their situation 
regarding the parental authority. A copy of this parental certificate is joined 
to each consent form. 
If these directives are not followed, the subject inclusion could be 
considered as a protocol violation and the data of this case won't be taken 
into account. 
− 
Concerning the management of the Patient Informed Consent Forms, the 
following text is added: 
o 
French Patient Informed Consent Form is in duplicate (triplicate for minor 
subject). 
o 
The first page of the Patient Informed Consent Form is given to the 
investigator. The copy is kept by the patient or legally authorized 
representative. 
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10.5.1.4. 
NOTIFICATION TO THE HOSPITAL DIRECTOR 
In accordance with Article L1123-13 of the French Public Health Code, the Hospital 
Director is informed of the commitment to the trial in her/his establishment. The Hospital 
Director is supplied with the protocol and any information needed for the financial 
disposition, the name of the investigator(s), the number of sites involved in his 
establishment and the estimated time schedule of the trial (R.1123-69). 
10.5.1.5. 
INFORMATION TO THE HOSPITAL PHARMACIST 
In accordance with Article R.1123-70 of the French Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in her/his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows her/him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning the 
product(s) of the trial (e.g. included in the CIB), the name of the investigator(s), the 
number of sites involved in her/his establishment and the estimated time schedule of the 
trial. 
10.5.1.6. 
Concerning the “DATA MANAGEMENT” the following text is added: 
Within the framework of this clinical trial, data regarding the identity of the investigators 
and/or co-investigators and/or the pharmacists if applicable, involved in this clinical trial, 
and data regarding the subjects recruited in this clinical trial (subject number, treatment 
(intervention) number, subjects status with respect to the clinical trial, dates of visit, 
medical data) will be collected and computerized in GlaxoSmithKline data bases by 
GlaxoSmithKline Laboratory or on its behalf, for reasons of follow up, clinical trial 
management and using the results of said clinical trial. According to the Data Protection 
French Law n° 78-17 of 6th January 1978, each of these people aforesaid has a right of 
access, correction and opposition on their own data through GlaxoSmithKline Laboratory 
(Clinical Operations Department). 
DEMOGRAPHIC DATA 
In accordance with the Data Protection French Law n° 78-17 of 6th January 1978 – article 
8, the ethnic origin can only be collected if the collection of this data is strictly necessary 
and relevant for the purpose of the study. 
TESTING OF BIOLOGICAL SAMPLES 
In accordance with the French Public Health Code law – article L1211-2, a biological 
sample without identified purpose at the time of the sample and subject’s preliminary 
information is not authorized. 
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the CRA or the service provider designated by GLAXOSMITHKLINE have direct access 
to all the data concerning the Study (test results, medical record, etc …). This 
consultation of the information by GLAXOSMITHKLINE is required to validate the data 
registered in the electronic Case Report Form (eCRF), in particular by comparing them 
directly to the source data. In accordance with the legal and regulatory requirements, the 
strictest confidentiality will be respected. 
10.5.1.9. 
Data entry into the eCRF 
The Health Institution and the Investigator agree to meet deadlines, terms and conditions 
of the Study’s electronic Case Report Form (eCRF) use here below: 
The Health Institution and the Investigator undertake: 
1. That the Investigator and the staff of the investigator center make themselves 
available to attend the training concerning the computer system dedicated to the 
electronic Case Report Form (eCRF) of the Study provided by 
GLAXOSMITHKLINE or by a company designated by GLAXOSMITHKLINE. 
2. That the Investigator and the staff of the investigator center use the IT Equipment 
loaned and/or the access codes only for the purpose of which they are intended and 
for which they have been entrusted to them, namely for the Study achievement, to 
the exclusion of any other use. 
3. That the Investigator and the staff of the investigator center use the IT Equipment 
loaned according to the specifications and manufacturer’s recommendations which 
will have been provided by GLAXOSMITHKLINE. 
4. To keep the IT Equipment and/or access codes in a safe and secure place and to 
authorize only the use of this IT Equipment by investigator center staff designated by 
the principal investigator to enter the data of the Study. 
5. To be responsible for the installation and payment of the required Internet 
connections needed for the use of the IT Equipment, Computer systems and/or 
access codes. 
6. To return at the end of the Study the IT Equipment and/or access codes to 
GLAXOSMITHKLINE or to any company designated by GLAXOSMITHKLINE 
and any training material and documentation. The IT Equipment cannot under any 
circumstances be kept by the Health Institution or the Investigator for any reason 
whatsoever.  
10.5.1.10. CTR publication 
It is expressly specified that GLAXOSMITHKLINE and/or the Sponsor can make 
available to the public the results of the Study by the posting of the said results on a 
website of the GLAXOSMITHKLINE GROUP named Clinical Trial Registered (CTR) 
including the registration of all the clinical trials conducted by the 
GLAXOSMITHKLINE Group and this before or after the publication of such results by 
any other process. 
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10.5.1.11. Data Protection French Law of 6th January 1978 (CNIL) 
In accordance with the Data Protection French Law of 6 January 1978 updated the 20th of 
June 2018, personal data are processed in a manner that ensures appropriate security, 
including protection against unauthorized or unlawful processing and against accidental 
loss, destruction or damage, using appropriate technical or organizational measures. The 
processing is whether deemed to be compliant with one of the methodology of reference 
(MR-001) or has been the subject of a request for authorization to the CNIL. The 
Investigator has, regarding the processing data related to her/him, a right of access, of 
rectification, erasure and of opposition with GLAXOSMITHKLINE in accordance with 
the legal provisions. Personal information can be transferred or be accessed to/by other 
entities of GLAXOSMITHKLINE Group, what the Investigator agrees by the signature 
of the present Protocol. 
10.6. 
Appendix 6: Abbreviations and Glossary of terms  
10.6.1. 
List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
BMI 
Body mass index 
CI 
Confidence Interval 
CLS 
Clinical Laboratory Sciences 
eCRF 
electronic Case Report Form 
EoS 
End of Study 
FU 
Follow-Up 
GAIA 
Global Alignment of Immunization Safety Assessment in pregnancy 
GCP 
Good Clinical Practice 
GMC 
Geometric Mean Concentration 
GMT 
Geometric Mean Titer 
GSK 
GlaxoSmithKline 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LAR 
Legally Acceptable Representative 
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LLOQ 
Lower Limit of Quantification 
LMP 
Last Menstrual Period 
LRTI 
Lower Respiratory Tract illness 
LSLV 
Last Subject Last Visit 
MAE 
Medically attended adverse event 
NB 
Newborn 
PCD 
Primary Completion Date 
PCR 
Polymerase Chain Reaction 
RBC 
Red Blood Cell 
RR 
Respiratory Rate 
RSV 
Respiratory Syncytial Virus 
RTI 
Respiratory Tract Illness 
SAE 
Serious Adverse Event 
SPM 
Study Procedures Manual 
SpO2 
Blood oxygen saturation as measured by pulse oximetry 
WBC 
White Blood Cell 
WHO 
World Health Organization 
10.6.2. 
Glossary of terms  
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 1 or more parties to the trial are kept 
unaware of the intervention 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.  
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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 
intervention assignment.  
In a single-blind study, the investigator and/or his staff are 
aware of the intervention assignment but the subject is not. 
Body Mass Index 
A key index for relating weight to height. Calculated as 
follows: Weight (kg) / (Height (m))2 
Certified copy: 
A copy (irrespective of the type of media used) of the original 
record that has been verified (i.e. by a dated signature or by 
generation through a validated process) to have the same 
information, including data that describe the context, content, 
and structure, as the original. 
Child 
A young human being below the legal age of majority 
(generally < 18 years of age). 
Child in care: 
A child who has been placed under the control or protection of 
an agency, organisation, institution or entity by the courts, the 
government or a government body, acting in accordance with 
powers conferred on them by law or regulation. The definition 
of a child in care can include a child cared for by foster parents 
or living in a care home or institution, provided that the 
arrangement falls within the definition above. The definition of 
a child in care does not include a child who is adopted or has an 
appointed legal guardian. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
End of Study (EoS)  
(Synonym of End 
of Trial)  
EoS must be achieved no later than 8 months after the last 
infant subject last visit (LSLV; Visit 5-NB).  End of study 
(EoS) cannot be achieved BEFORE the last (infant) subject last 
visit (LSLV; Visit 5-NB). 
Enrolled 
‘Enrolled’ means a subject’s/parent’s/LAR’s agreement to 
participate in a clinical study following completion of the 
informed consent process. Potential subjects who are screened 
for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. Refer to Section 9.3 for the 
definition of ‘enrolled’ applicable to the study. 
Epoch: 
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomisation, study 
intervention, follow-up), which applies across all arms of a 
study. NOTE: Epoch is intended as a standardised term to 
replace: period, cycle, phase, stage.  
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Essential 
documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of the data 
produced 
eTrack: 
GSK Biologicals’ tracking tool for clinical trials. 
Evaluable: 
Meeting all eligibility criteria, complying with the procedures 
defined in the protocol, and, therefore, included in the per-
protocol analysis (see Section 9.3 for details on criteria for 
evaluability). 
GAIA 
Global Alignment of Immunization Safety Assessment in 
pregnancy. A project that aims to improve the quality of 
outcome data from clinical vaccine trials in pregnant women 
with a specific focus on the needs and requirements for safety 
monitoring in low to middle income countries.  
Gestational age: 
A measure of the age of a pregnancy where the origin is the first 
day of the woman's last normal menstrual period, or the 
corresponding age as estimated by other methods. Gestational 
age will be described in weeks of pregnancy completed + 
number of days completed of the following week. For example: 
28 0/7 means completed 28 weeks of pregnancy + 0 days of the 
29th week and 28 6/7 means completed 28 weeks of pregnancy 
+ 6 days of the 29th week. 
Immunological 
correlate of 
protection: 
A correlate of risk that has been validated to predict a certain 
level of protection from the targeted endpoint. 
Infant 
A child younger than 1 year of age  
Intervention 
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 participant. 
Intervention 
number: 
A number identifying an intervention to a participant, according 
to intervention allocation. 
Investigational 
vaccine/product: 
A pharmaceutical form of an active ingredient being tested 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.  
Synonym: Investigational Medicinal Product 
Investigator 
A person responsible for the conduct of the clinical trial at a 
trial site. If a trial is conducted by a team of individuals at a trial 
site, the investigator is the responsible leader of the team and 
may be called the principal investigator.  
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The investigator can delegate trial-related duties and functions 
conducted at the trial site to qualified individual or party to 
perform those trial-related duties and functions 
Legally acceptable 
representative 
An individual or juridical or other body authorised under 
applicable law to consent, on behalf of a prospective subject, to 
the subject's participation in the clinical trial. 
The terms legal representative or legally authorised 
representative are used in some settings. 
(Level 2 ultrasound 
also known as a 
fetal anomaly 
ultrasound scan or 
fetal morphology 
assessment)  
Comprehensive, detailed evaluation of fetal anatomy and 
development that is usually performed at approximately 20 
weeks of gestational age. In addition to standard ultrasound 
parameters such as fetal heart activity and gestational age 
estimation, a Level 2 ultrasound usually includes assessment of 
amniotic fluid levels; assessment of the condition of the 
placenta, cervix, and uterus; and detection of fetal anomalies.  
Local healthcare 
provider 
A healthcare provider who provides subjects with medical care 
per local standards. This individual may or may not be a 
member of the study staff.  
Neonatal adverse 
events of special 
interest  
Clinically significant events that occur from birth through 28 
days of age. They include but are not limited to preterm birth, 
neonatal death, congenital anomaly, low birth weight, small for 
gestational age, and neonatal infections, encephalopathy, sepsis, 
respiratory distress/asphyxia, and failure to thrive/growth 
deficiency.  
Neonate (or 
Newborn) 
An infant 28 days old or younger. 
Parental concern 
The parent(s) / Legally Acceptable Representative(s) are 
concerned about the infant’s respiratory tract illness (or general 
health in the context of the respiratory tract illness) and intend 
to seek medical care 
Pregnancy 
outcomes 
These include live birth with no congenital anomalies, live birth 
with congenital anomalies, fetal death/still birth with no 
congenital anomalies, fetal death/still birth with congenital 
anomalies, elective/therapeutic termination with no congenital 
anomalies and elective/therapeutic termination with congenital 
anomalies.  
Pregnancy related 
adverse events of 
special interest  
Clinically significant events that occur up to 42 days after 
delivery. They include but are not limited to the pregnancy 
related adverse events of special interest listed as primary safety 
endpoints in Table 5.  
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Primary 
completion date: 
The date that the final subject was examined or received an 
intervention for the purpose of final collection of data for all 
primary outcomes, whether the clinical trial/ pharmaco-
epidemiological study was concluded according to the pre-
specified protocol or was terminated. 
Protocol 
administrative 
change: 
A protocol administrative change addresses changes to only 
logistical or administrative aspects of the study.  
Protocol 
amendment: 
The International Council on Harmonisation (ICH) defines a 
protocol amendment as: ‘A written description of a change(s) to 
or formal clarification of a protocol.’ GSK Biologicals further 
details this to include a change to an approved protocol that 
affects the safety of subjects, scope of the investigation, study 
design, or scientific integrity of the study. 
Randomisation: 
Process of random attribution of study intervention to subjects 
to reduce selection bias. 
Self-contained 
study: 
Study with objectives not linked to the data of another study. 
Site Monitor: 
An individual assigned by the sponsor and responsible for 
assuring proper conduct of clinical studies at 1 or more 
investigational sites. 
Solicited event: 
Events to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a specified 
post-vaccination follow-up period. 
Source data: 
All information in original records and certified copies of 
original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). 
Source documents: 
Original legible documents, data, and records (e.g. hospital 
records, clinical and office charts, laboratory notes, memoranda, 
subjects' diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate 
copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories and at medico-technical 
departments involved in the clinical trial). 
Study 
vaccine/product: 
Any investigational vaccine/product being tested and/or any 
authorised use of a vaccine/product/placebo as a reference or 
administered concomitantly, in a clinical trial that evaluates the 
use of an investigational vaccine/product. 
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Study population: 
Sample of population of interest. 
Sub-cohort: 
A group of subjects for whom specific study procedures are 
planned as compared to other subjects or a group of subjects 
who share a common characteristic (e.g. ages, vaccination 
schedule…) at the time of enrolment. 
Subject: 
Term used throughout the protocol to denote an individual who 
has been contacted to participate or participates in the clinical 
study, either as a recipient of the vaccine/product or as a 
control. 
Subject number: 
A unique identification number assigned to each subject 
consenting to participate in the study. 
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. 
10.7. 
Appendix 7: Gestational Age Assessment 
10.7.1. 
GAIA Gestational Age Assessment Form 
Based on Quinn, JA, Munoz FM, Gonik B et al. Preterm birth: Case definition & 
guidelines for data collection, analysis, and presentation of immunisation safety data. 
Vaccine. 2016; 34: 6047 – 6056. 
LEVELS OF CERTAINTY OF GESTATIONAL AGE ASSESSMENT 
Level 
Description 
Level 1 
Highest level 
of certainty 
• 
Certain LMP or IUI date or ET WITH confirmatory 1st trimester 
U/S, 
or 
• 
1st trimester U/S 
Level 2A 
• 
Certain LMP WITH 2nd trimester U/S*, 
or 
• 
Certain LMP WITH 1st trimester physical examination** 
Level 2B 
Uncertain LMP WITH 2nd trimester U/S 
Level 3A 
• 
Certain LMP WITH 3rd trimester U/S***,  
or 
• 
Certain LMP WITH confirmatory 2nd trimester FH, 
or 
• 
Certain LMP WITH birth weight, 
or 
• 
Uncertain LMP WITH 1st trimester physical examination 
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Level 
Description 
Level 3B 
Lowest level 
of certainty 
• 
Uncertain LMP WITH FH, 
or 
• 
Uncertain LMP WITH neonatal physical assessment (New 
Ballard score), 
or 
• 
Uncertain LMP WITH birth weight 
grey highlights: applicable for enrollment in this study.  
1st trimester U/S: ≤136/7 weeks, 2nd trimester U/S: 140/7 to 276/7 weeks, 3rd trimester U/S: ≥280/7 weeks. 
GA: gestational age; U/S: ultrasound examination; LMP: last menstrual period; IUI: intrauterine insemination; ET: 
embryo transfer, FH: fundal height;  
* If LMP and U/S do not correlate, default to U/S GA assessment 
** For singleton pregnancies only. Unreliable if obesity, or uterine anomalies. 
*** Depending on gestational age at Screening Visit/ Visit 1 and depending on the local standard of care, this will be 
applicable for inclusion in the study. 
10.7.2. 
Methods Of Gestational Age Assessment 
Adapted from [ACOG, 2014]: The American College of Obstetricians and Gynecologists 
(ACOG) Committee on Obstetric Practice, American Institute of Ultrasound in Medicine 
and Society for Maternal-Fetal. Committee Opinions: Method for estimating Due Date. 
Number 611, October 2014 (accessed on-line on 13/Oct/2014 at: 
http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-
Obstetric-Practice/Method-for-Estimating-Due-Date). 
Gestational age range 
Method of measurement 
Discrepancy between U/S dating and LMP 
dating 
1st trimester   ≤136/7 weeks 
≤86/7 weeks 
90/7 to 136/7 weeks 
CRL 
> 5 days 
> 7 days 
2nd trimester   140/7 to 276/7 weeks 
140/7 to 156/7 weeks 
BPD, HC, AC, FL 
> 7 days 
160/7 to 216/7 weeks 
> 10 days 
220/7 to 276/7 weeks 
> 14 days 
U/S: ultrasound examination; LMP: last menstrual period; CRL: crown-rump length; BPD: biparietal diameter; HC: head 
circumference; AC: abdominal circumference; FL: femur length 
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10.8. 
Appendix 8: Definitions of maternal, fetal and neonatal 
adverse events of special interest as per GAIA  
The articles explaining these adverse events of special interest in detail and all 
corresponding information can be found in the following issues of Vaccine:  
Bauwens J, Bonhoeffer J, Chen RT, editors. Harmonising Immunisation Safety 
Assessment in Pregnancy. Vaccine. 2016. 34 (49): 5991 – 6110. 
Kochhar S, Bauwens J, Bonhoeffer J, editors. Harmonising Immunization Safety 
Assessment in Pregnancy – Part II. Vaccine. 2017. 35 (48): 6469-6582. 
Definitions and Levels of Diagnostic Certainty are presented in the following Tables. 
References specific to each event of interest are given at the end of the relevant Table. 
Pregnancy Outcomes 
Fetal Death / Stillbirth 
Table 30 
Maternal Adverse Events of Special Interest 
Maternal Death 
Table 31 
Hypertensive Disorders of Pregnancy 
Table 32 
Antenatal bleeding 
Table 33 
Postpartum hemorrhage 
Table 34 
Fetal Growth restriction 
Table 35 
Gestational Diabetes Mellitus 
Table 36 
Non-reassuring fetal status 
Table 37 
Pathways to Preterm Birth 
Table 38 
Standard definitions for events of interest not defined as such in GAIA (Chorioamnionitis, 
Oligohydramnios, Polyhydramnios, Intrahepatic Cholestasis of Pregnancy (ICP), Acute Fatty Liver 
of Pregnancy, Maternal Sepsis) 
Table 39 
Neonatal Adverse Events of Special Interest 
Small for Gestational Age 
Table 40 
Low Birth Weight 
Table 41 
Neonatal encephalopathy 
Table 42 
Congenital Microcephaly 
Table 43 
Congenital Anomalies 
Table 44 
Neonatal Death 
Table 45 
Neonatal Infections 
Table 46 
Respiratory Distress in the Neonate 
Table 47 
Preterm Birth 
Table 48 
Failure to thrive 
Table 49 
Standard definitions for adverse events of special interest not defined as such in GAIA (large for 
gestational age, macrosomia) 
Table 50 
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Table 30 
Fetal death / Stillbirth 
Fetal death occurring before birth after 20 to 28 weeks of gestation (variation due to 
country definitions). 
Antepartum Stillbirth (Fetal death occurs prior to the evidence of labor.) 
Level 
Description 
1 
Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical cord pulse, 
no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined by physical examination after 
delivery (with or without electronic monitoring of heart rate, respiratory rate, and pulse oximetry).  
AND  
• 
Prenatal ultrasound examination documenting lack of fetal cardiac activity or movement before the 
onset of labor.  
OR 
• 
Auscultation for fetal heart tones (using electronic devices or non-electronic devices) documenting 
lack of fetal heartbeat.  
AND 
• 
Maternal report of lack of fetal movement for 24 h or more.  
OR 
• 
Maternal physical examination confirming lack of fetal movement.  
OR 
• 
Radiology findings consistent with intrauterine fetal death.  
AND 
• 
Attended delivery followed by fetal physical examination afterbirth consistent with antepartum 
death, by obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, or pathologist. 
In the setting where access to a specialist is not feasible, diagnosis by a health care provider 
trained or experienced to make the diagnosis is acceptable (e.g. general practice physician, mid-
wife, nurse practitioner, a physician’s assistant or other qualified trained practitioner).  
OR 
• 
Fetal/placental pathology report consistent with antepartum death.  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level1 or 2 in GA assessment algorithm). 
2 
Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical cord pulse, 
no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined physical examination after 
delivery. 
AND 
• 
Maternal report of lack of fetal movement for 24 h or more. 
OR 
• 
Maternal physical examination confirming lack of fetal movement.  
OR 
• 
Auscultation for fetal heart tones (using electronic or non-electronic devices) documenting lack of 
fetal heartbeat.  
AND 
• 
Attended delivery followed by physical examination after birth consistent with antepartum death, by 
specialist or qualified trained practitioner appropriate to the health care setting.  
OR 
• 
Fetal/placental pathology report consistent with antepartum death.  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level1–2 in GA assessment algorithm). 
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Antepartum Stillbirth (Fetal death occurs prior to the evidence of labor.) (continued) 
Level 
Description 
3 
Delivery of an infant reported to have no of signs of life at birth (No spontaneous movements, no umbilical 
cord pulse, no heart-beat, no cry or spontaneous respirations, no chest movement, and whole body 
cyanosis). AND 
• 
Maternal report of lack of fetal movement for 24 h or more prior to delivery.  
OR 
• 
Report of auscultation for fetal heart tones (using electronic or non-electronic devices) documenting 
lack of fetal heartbeat.  
AND 
• 
Non-attended delivery followed by physical examination of the fetus after birth consistent with 
antepartum death by a healthcare professional appropriate to the level of standard of care in the 
health care setting.  
OR 
• 
Verbal history by a trained health care provider, non-medical witness or the mother of a fetus born 
with no signs of life or unresponsive to resuscitation efforts immediately after birth and with physical 
features consistent with antepartum death.  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level2–3 in GA assessment algorithm). 
4 
Report of stillbirth but fetus is not available for physical examination after birth (no objective assessment 
can be made) 
Maternal information insufficient to assess gestational age 
Intrapartum stillbirth (Fetal death occurs during labor and before delivery) 
Level 
Description 
1 
Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, no umbilical 
cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min 
Determination of the absence of signs of life is made by physical examination after delivery, with or 
without electronic monitoring of heart rate, respiratory rate, and pulse oximetry.  
AND 
Evidence of live fetus prior to onset of labor (documentation of fetal movement and of fetal heart tones by 
ultrasound prior to onset of labor) (Note: in the absence of evidence of a live fetus prior to the onset of 
labor, the fetal death should be reported as a stillbirth or an antepartum stillbirth). 
AND 
Attended delivery followed by physical examination afterbirth consistent with intrapartum death by 
obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, pathologist. In the setting 
where access to a specialist is not feasible, diagnosis by a health care provider trained or experienced to 
make the diagnosis is acceptable (e.g. general practice physician, midwife, or other qualified trained 
practitioner). 
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal-neonatal parameters (Level 1 in GA assessment algorithm) 
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Intrapartum stillbirth (Fetal death occurs during labor and before delivery) (continued) 
Level 
Description 
2 
Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, no umbilical 
cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min. 
Determination of the absence of signs of life is made by physical examination after delivery, with or 
without electronic monitoring of heart rate, respiratory rate, and pulse oximetry OR documentation of lack 
of response to resuscitation efforts.  
AND 
Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset of labor and 
documentation of fetal heart tones by auscultation or hand held Doppler) (Note: in the absence of 
evidence of a live fetus prior to the onset of labor, the fetal death should be reported as a stillbirth or an 
antepartum stillbirth).  
AND 
Attended delivery followed by physical examination after birth consistent with intrapartum death by a 
health care professional appropriate to the level of standard of care in the health care setting.  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level1–2 in GA assessment algorithm). 
3 
Delivery of an infant reported to have no of signs of life at birth, including: No spontaneous movements, 
no umbilical cord pulse, no heartbeat, no cry, no spontaneous respirations or chest movement, and whole 
body cyanosis. AND 
Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset of labor OR 
auscultation of fetal heart tones) (Note: in the absence of evidence of a live fetus prior to the onset of 
labor, the fetal death should be reported as a stillbirth or an antepartum stillbirth). AND 
Non-attended delivery followed by physical examination of the fetus after birth consistent with intrapartum 
death by a healthcare professional appropriate to the level of standard of care in the health care setting 
OR verbal history by a trained health care provider, non-medical witness or the mother of a fetus born 
with no signs of life or unresponsive to resuscitation efforts immediately after birth. AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level2–3 in GA assessment algorithm). 
4 
Report of stillbirth but fetus is not available for physical examination after birth (no objective assessment 
can be made). 
Maternal information insufficient to assess gestational age. 
Reference: DaSilva FT, Gonik B, McMillan M, et al. Stillbirth: Case definition and guidelines for data collection, 
analysis, and presentation of maternal immunisation safety data. Vaccine. 2016; 34(49):6057-6068. 
Table 31 
Maternal Death 
The death of a woman while pregnant or within 42 days of termination of pregnancy, 
irrespective of the duration and site of the pregnancy, from any cause related to or 
aggravated by the pregnancy or its management but not from accidental or incidental 
causes. (As ICD-10 terminology). 
In the context of immunization: “Death of a woman during pregnancy, childbirth and the 
puerperium that is closely related temporally to an immunization event of the mother 
which is likely the single or contributory cause 
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Levels of Diagnostic Certainty 
(Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Diagnosis of pregnancy established by any of the following documented criteria: 
• 
Ultrasound examination 
• 
Fetal heart tones 
• 
Positive serum or urine human chorionic gonadotropin pregnancy test 
• 
Delivery of a neonate or other products of conception (abortus, stillborn)  
AND 
Death of the mother while pregnant or within 42 days of termination of pregnancy, irrespective of the 
duration and site of the pregnancy  
AND 
Documentation of Cause of death as: 
• 
Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric complications, unanticipated complications  
• 
Indirect: non obstetric complications  
• 
Death during pregnancy, childbirth and the puerperium: other or coincidental 
2 
Diagnosis of pregnancy established by any of the following criteria in the absence of Level 1 criteria: 
• 
LMP date 
• 
Serial Symphysio Fundal Height examinations 
AND 
Death of the mother while pregnant or within 42 days of termination of pregnancy, irrespective of the 
duration and site of the pregnancy And  
Documentation of Cause of death as: 
• 
Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric complications, unanticipated complications 
• 
Indirect: non-obstetric complications  
• 
Death during pregnancy, childbirth and the puerperium: other or coincidental 
• 
Unspecified: unknown or undetermined 
3 
Absence of Level 1 or 2 criteria for establishing diagnosis of pregnancy and: 
• 
Unsure LMP 
• 
No clinical examination documented  
AND 
Death of the mother temporal to pregnancy, childbirth or the postpartum period when exact timing of 
death is unknown 
AND 
Documentation of cause of death as: 
• 
Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric com-plications, unanticipated complications 
• 
Indirect: non-obstetric complications 
• 
Death during pregnancy, childbirth and the puerperium: other or coincidental 
• 
Unspecified: unknown or undetermined. 
Reference: Patwardhan M, Eckert LO, Spiegel H, et al. Maternal death: Case definition and guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6077-6083. 
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Table 32 
Hypertensive disorders of pregnancy (Gestational hypertension, 
Pre-eclampsia, Pre-eclampsia with severe features including 
eclampsia) 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Gestational Hypertension  
Level 
Description 
All 
Clinical syndrome characterized by pregnancy ≥20 weeks 
AND 
New onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) 
sustained on two measurements over a minimum of 1 h 
WITHOUT severe features (see preeclampsia with severe features category) and WITHOUT proteinuria 
1 
No proteinuria (as defined by 24 h urine collection < 300 mg, spot protein:creatinine ratio <0.3) 
2 
No proteinuria (as defined by urine dipstick negative or trace)  
In Ev 
Blood pressure cannot be measured OR 
No proteinuria evaluation is available 
Preeclampsia has conventionally been defined as the development of gestational hypertension and proteinuria 
after 20 weeks gestation. Proteinuria can be quantified by: - 24 h urine collection, - a spot protein:creatinine ratio, or 
- with urinary dipstick. Proteinuria of ≥300 mg in a 24 h urine specimen (the gold standard for measurement of 
proteinuria), or ≥0.30 on a spot protein:creatinine ratio, or ≥1+ on a dipstick meets the criteria for preeclampsia. 
Level 
Description 
All 
Clinical syndrome characterized by pregnancy ≥20 weeks  
AND  
New onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) 
sustained on two measurements over a minimum of 1 h  
AND  
New onset proteinuria  
1 
Proteinuria diagnosed with ≥300 mg of protein on 24 h urine collection OR ≥0.3 on spot protein:creatinine 
ratio  
2 
Proteinuria diagnosed with ≥1+ protein on urine dipstick 
In Ev. 
Blood pressure cannot be measured  
OR  
no proteinuria evaluation is available (note diagnosis of preeclampsia with severe features does not 
require proteinuria, see definition below) 
In Ev = Insufficient Evidence 
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Hypertensive Disorders of Pregnancy Continued 
Preeclampsia with severe features NOTE :can be diagnosed in the presence or absence of proteinuria. 
Vascular: 
Severely elevated blood pressures, with systolic blood pressure≥160 mmHg and/or diastolic blood pressure ≥110 
mmHg, which is confirmed after only minutes (to facilitate timely anti-hypertensive treatment) 
Neurologic: 
Development of a severe headache (which can be diffuse, frontal, temporal or occipital) that generally does not 
improve with over the counter pain medications (such as acetaminophen/paracetamol) 
Eclampsia 
Development of visual changes (including photopsia, scotomata, cortical blindness) 
Hematologic: 
New onset thrombocytopenia, with platelet count <100,000/L 
Gastrointestinal: 
New onset of nausea, vomiting, epigastric pain 
Transaminitis (AST and ALT elevated to twice the upper limit of normal) 
Liver capsular hemorrhage or liver rupture 
Renal: 
Worsening renal function, as evidenced by serum creatinine level greater than 1.1 mg/dL or a doubling of the serum 
creatinine (absent other renal disease) 
Oliguria (urine output <500 mL/24 h) 
Respiratory: 
Pulmonary edema (confirmed on clinical exam or imaging) 
Level 
Description 
All 
Clinical syndrome characterized by pregnancy ≥20 weeks  
AND  
New onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) 
sustained on two measurements over a minimum of 1 h  
AND  
At least one of the criteria for severe disease: 
1 
At least one of the following:  
• 
Systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110mmHg, which is 
confirmed after only minutes OR  
• 
Development of severe, persistent headache OR 
• 
Development of visual changes OR  
• 
Eclampsia* OR  
• 
New onset thrombocytopenia (platelets <100,000/L) OR 
• 
New onset unremitting epigastric pain OR 
• 
AST and ALT elevated to twice upper limit of normal OR 
• 
Evidence of liver capsular hematoma or liver rupture (diagnosed on clinical exam or with imaging) 
OR 
• 
Worsening renal function, as evidenced by serum creatinine level greater than 1.1 mg/dL or a 
doubling of the serum creatinine (absent other renal disease) or oliguria (<500 cc/24 h) OR 
• 
Pulmonary edema (confirmed on imaging with chest X-ray, or on clinical exam) 
2 
New onset nausea and vomiting  
In Ev 
Blood pressure cannot be measured 
◦* ECLAMPSIA, or new-onset grand mal seizures in a patient with pre-eclampsia, without other provoking factors (such 
as evidence of cerebral malaria or pre-existing seizure disorder). Seizures are often preceded by headaches, visual 
changes or altered mental status: 
In Ev = Insufficient Evidence 
Reference: Rouse CE, Eckert LO, Wylie BJ, et al. Hypertensive disorders of pregnancy: Case definitions &amp; 
guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6069-6076 
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Table 33 
Antenatal Bleeding 
Antenatal bleeding is a clinical syndrome characterized by bleeding in the second or third 
trimester of pregnancy. Pathologic etiologies attributable to the pregnant state include 
placenta previa, vasa previa and intra-abdominal pregnancy (categories that are not 
applicable in this study, as women with these conditions are ineligible), and morbidly 
adherent placentation, placental abruption, cesarean scar pregnancy and uterine rupture. 
For both levels of diagnostic certainty for each etiology of antenatal bleeding: 
Bleeding is either documented vaginally or suspected to be occurring intrauterine, 
intraperitoneally, or (rarely) retroperitoneally, based on clinical signs and symptoms. 
In the case of ultrasound-based diagnosis, transvaginal ultrasound is more specific than 
transabdominal ultrasound, and transvaginal ultrasound is recommended where available. 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Morbidly adherent placenta 
Level 
Description 
1 
There are two definitions of equal specificity. 
1. 
Second- or third-trimester ultrasound or MRI evidence of placenta previa, 
AND  
One of the following ultrasound features:  
• 
Greyscale: loss of the retroplacental sonolucent zone, irregular retroplacental sonolucent 
zone, thinning or disruption of the hyperechoic serosa–bladder interface, presence of focal 
exophytic masses invading the urinary bladder, abnormal placental lacunae  
• 
Color Doppler: diffuse or focal lacunar flow, vascular lakes with turbulent flow (peak systolic 
velocity over 15 cm/s), hypervascularity of serosa–bladder interface, markedly dilated vessels 
over peripheral sub placental zone 
• 
3D Power Doppler: numerous coherent vessels involving the whole uterine serosa–bladder 
junction (basal view), hypervascularity (lateral view), inseparable cotyledonal and intervillous 
circulations, chaotic branching, detour vessels (lateral view) 
AND  
One of the risk factors: prior cesarean delivery, prior uterine surgery (including endometrial ablation 
or dilation and curettage) or cesarean scar pregnancy 
OR 
2. 
Morbidly adherent placentation found on histology in a hysterectomy or partial wedge resection 
specimen. 
2 
There are two definitions of equal specificity. 
1. 
Ultrasound evidence of placenta previa, 
AND  
hypervascularity at the site of the uteroplacental 
interface, diagnosed at laparotomy. 
OR 
2. 
Difficulty with placental separation after delivery of the infant, at either a vaginal or cesarean delivery 
with resultant hemorrhage due to partial separation. 
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Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Antenatal Bleeding continued 
Placental abruption 
Level 
Description 
1 
There are two definitions of equal specificity. 
1. 
In the absence of placenta previa on ultrasound, vaginal bleeding in the second or third trimester, 
AND one of the following: 
Either uterine irritability or labor, 
Or  
clinical signs of hypovolemic shock or coagulopathy. 
OR 
2. 
Placental pathology with histologic findings of a chronic abruption. 
2 
There are two definitions of equal specificity. 
1. 
Vaginal bleeding in the second or third trimester, 
AND  
uterine irritability or labor, without clinical signs of hypovolemic shock or coagulopathy 
OR 
2. 
Vaginal bleeding in the second or third trimester, 
AND  
Clinical evidence of retroplacental clot or visually evident placental infarcts at the time of delivery. 
Cesarean Scar Pregnancy 
Level 
Description 
1 
There are two definitions of equal specificity. 
1. 
Transvaginal ultrasound with the following characteristics: empty uterine cavity,  
AND  
Empty cervical canal, without contact with the gestational sac, AND  
Presence of gestational sac, +/- fetal pole, +/- cardiac activity, in the anterior uterine segment 
adjacent to the cesarean scar, AND  
Absence or defect in myometrium between bladder and gestational sac,  
AND  
Gestational sac well perfused on Doppler ultrasound (to differentiate from an expulsing, avascular 
gestational sac). 
OR 
2. 
Hysterectomy specimen with evidence of pregnancy implanted into the cesarean scar. 
2 
There is no Level 2 definition for this event. 
Uterine Rupture 
Level 
Description 
1 
Complete uterine disruption at the time of laparotomy in the context of vaginal or intra-abdominal bleeding. 
2 
There is no Level 2 definition for this event. 
Reference: Prabhu M, Eckert LO, Belfort M et al. Antenatal bleeding: Case definition and guidelines for data collection, 
analysis, and presentation of immunization safety data. Vaccine. 2017; 35: 6529-6537. 
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Table 34 
Postpartum hemorrhage 
Genital tract bleeding after delivery (up to 42 days) of a foetus or infant that leads to an 
adverse clinical outcome, such as hypovolemia or anaemia e.g. exertional dyspnoea, 
postural presyncope, tiredness or reduced consciousness. At the furthest extreme 
uncorrected hypovolaemic shock can lead to organ-dysfunction and maternal death. 
ICD-10 definition: “heamorrhage after delivery of a foetus or infant” 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Genital bleeding after delivery leading to severe maternal out-come (maternal death or maternal near 
miss) as defined by WHO1.  
2 
Genital bleeding after delivery with at least one of the following: measured abnormal bleeding (1000 ml or 
more), or any bleeding leading to hypotension or blood transfusion. 
3 
Genital bleeding after delivery estimated at 1000 ml or more 
Reference: Kerr R, Eckert LO, Winikoff B, et al. Postpartum haemorrhage: Case definition and guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6102-6109. 
1 Can be found in Kerr (op cit), Table 1.  
Table 35 
Fetal growth restriction 
A fetus with a sonographic estimation of fetal weight below the tenth percentile for a 
given gestational age with increasing specificity for adverse perinatal outcomes below the 
third percentile. 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
 
Fetal growth restriction is a sonographic finding characterized by: 
1a 
Level 1* evidence of pregnancy dating  
AND 
• 
Estimated fetal weight below 3% using locally-accepted growth curve  
OR 
• 
Estimated fetal weight below 10% using locally-accepted growth curve  
AND 
• 
Absent or reversed end-diastolic flow of the umbilical artery Doppler  
OR 
• 
Oligohydramnios as defined as amniotic fluid index (AFI) < 8 cm or deepest vertical pocket (DVP) < 
2 cm in the presence of intact membranes without concern for fetal anomalies contributing to its 
etiology 
1b 
Level 1* evidence of pregnancy dating  
AND 
Estimated fetal weight below 10%ile using locally-accepted growth curve  
AND 
Lack of absent or reversed end-diastolic flow of the umbilical artery or oligohydramnios (as defined above, 
cfr. Level 1a) 
2a  
Level 2 evidence of pregnancy dating  
AND 
• 
Estimated fetal weight below 3% using locally-accepted growth curve  
OR 
• 
Estimated fetal below 10% using locally-accepted growth curve  
AND 
• 
Absent or reversed end-diastolic flow of the umbilical artery Doppler.  
OR 
• 
Oligohydramnios (as defined above, cfr. Level 1a). 
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Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
2b 
• 
Level 2 evidence of pregnancy dating  
AND 
Estimated fetal weight below 10%ile using locally-accepted growth curve  
AND 
No findings of absent or reversed end-diastolic flow of the umbilical artery or oligohydramnios (as 
defined above, cfr Level 1a).  
OR 
• 
Level 1* evidence of pregnancy dating  
AND 
Estimated fetal weight below 10% using locally-accepted growth curve with no findings of 
oligohydramnios (as defined abopve, cfr. Level 1a) with inability to assess umbilical artery Doppler. 
In Ev 
Absence of ultrasound for use in assessment of estimated fetal weight. 
*Level 1 evidence of pregnancy dating as defined by the Preterm Birth Working Group of the Brighton Collaboration. 
Level 1 pregnancy dating depends on a confirmatory ultrasound performed ≤13 6/7 weeks gestation 
In Ev = Insufficient Evidence 
Reference: Easter SR, Eckert LO, Boghossian N, et al. Fetal growth restriction: Case definition & guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2017; 35: 6546-6554.  
Table 36 
Gestational diabetes mellitus (pregnancy induced hyperglycemia)  
Gestational diabetes mellitus (GDM) is a clinical syndrome characterized by the absence 
of pre-gestational diabetes diagnosis, defined by 
• 
Previous diagnosis of diabetes while not pregnant 
OR 
• 
First trimester hemoglobin A1c level of ≥ 6.5% (47.5 mmol/mol)  
OR 
• 
First trimester fasting blood glucose 126 mg/dL / ≥ 7mmol/L  
AND 
Identification of sustained hyperglycemia during pregnancy not due to other known 
causes (i.e. corticosteroids, beta-mimetics, etc.) 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Absence of pre-gestational diabetes mellitus diagnosis in the first trimester as defined above with level 1-
2 certainty for gestational age using GAIA definition for gestational age (Section 10.7)  
AND 
Diagnosis of gestational diabetes based on a positive internationally recognized oral glucose tolerance 
test (“major criteria” 1,2) using venous blood sample/samples 
2 
Absence of pre-gestational diabetes mellitus diagnosis in the first trimester as defined above with at least 
level 1-2 certainty for gestational age using GAIA definition for gestational age (Section 10.7)  
AND 
Diagnosis of gestational diabetes based on positive internationally recognized oral glucose tolerance test 
(“major criteria” 1,2) using capillary blood sample/samples 
3 
Absence of pre-gestational diabetes mellitus diagnosis in the first trimester as defined above with at least 
level 3 certainty for gestational age using GAIA definition for gestational age  
AND 
Diagnosis of gestational diabetes based on positive internationally recognized oral glucose tolerance test 
(see below ‘‘major criteria”1,2) using venous blood or capillary blood sample/samples 
OR 
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Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
Diagnosis of gestational diabetes based on fasting plasma glucose of 5.1-6.9 mmol/l (92-125 mg/dL) 
using venous or capillary blood samples. 
In Ev 
Blood glucose cannot be measured  
OR 
Elevated postprandial blood glucose level without confirmatory 
fasting venous blood or capillary glucose level 
OR 
Use of Hemoglobin A1c alone for the diagnosis of GDM without a diagnostic oral glucose tolerance test 
(OGTT) or elevated fasting plasma glucose level.  
OR 
Clinical and laboratory findings such as glucosuria, fundal height greater than dates, obesity, prior history 
of GDM or family history for the diagnosis of gestational diabetes mellitus without a diagnostic test. 
In Ev = Insufficient Evidence 
Reference(s): Kachikis A, Eckert LO, Walker C, et al. Gestational diabetes mellitus: Case definition & guidelines for 
data collection, analysis, and presentation of immunization safety data. Vaccine. 2017; 35:6555-6562. 
 
1 Major criteria (presented in Kachikis op cit) 
 
2 Further details regarding oral glucose tolerance tests presented in footnote 1 (Major Criteria); also presented in 
Kachikis (op cit) 
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Table 37 
Non-reassuring fetal status 
Indicator of underlying event resulting in temporary or permanent oxygen deprivation to 
the fetus which may lead to fetal hypoxia and metabolic acidosis 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Category III fetal heart rate tracings detected via continuous cardiotocography as defined by NICHD  
Absent baseline fetal heart rate variability AND any of the following: 
recurrent late decelerations 
recurrent variable deceleration 
bradycardia (<110 bpm)  
OR 
Sinusoidal pattern  
AND 
Umbilical cord blood analysis consistent with metabolic acidosis (pH < 7.0 and Base deficit >12 mmol/L) 
2 
Category III fetal heart rate tracings detected via continuous cardiotocography as defined by NICHD  
Absent baseline fetal heart rate variability AND any of the following: 
recurrent late decelerations 
recurrent variable deceleration 
bradycardia (<110 bpm) 
OR 
Sinusoidal pattern 
3 
Fetal heart pattern detected via intermittent auscultation suggestive of fetal hypoxia  
Baseline Fetal Heart rate (FHR) <110 bpm or >160 bpm 
Presence of repetitive or prolonged (>3 min) decelerations 
More than 5 contractions in a 10 min period 
Reference: Gravett C, Eckert LO, Gravett MG, et al. Non-reassuring fetal status: Case definition & guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6084-6092. 
Table 38 
Pathways to preterm birth 
Premature preterm rupture of membranes; Preterm labor; Insufficient cervix (not 
applicable to this study, as women with insufficient cervix are ineligible); Provider-
initiated preterm birth 
Preterm = Birth at less than 37 gestation-completed weeks (less than 259 days).  
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Preterm rupture of membranes 
Level 
Description 
All 
Patient is determined to be preterm as defined above.  
On presentation, patient is determined to not be in preterm labor, having ≤4 contractions per hour 
documented clinically or on tocodynometer, with <2 cm cervical dilation (greater than 4 contractions per 
hour would qualify the patient as having preterm labor)  
Fluid can be noted to be clear, blood-tinged, meconium-tinged (fetal stool), purulent-tinged (yellowish, 
suggesting infection) 
1 
Clinical history of rupture of membranes  
AND 
Visible leakage of fluid on vaginal speculum exam  
AND 
Visible arborization (ferning) on microscopy of amniotic fluid  
OR 
Ultrasound with oligohydramnios (AFI <5 or MVP <2)  
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Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Preterm rupture of membranes 
Level 
Description 
AND 
Documented membrane rupture by a diagnostic test (one of the below options): 
Positive intra-amniotic dye-injection method 
Positive result on amniotic fluid alpha-fetoprotein test kit  
Amniotic fluid pH measurement (nitrazine paper test) 
Amniotic fluid placental alpha macroglobulin-1 protein assay (PAMG-1) test (AmniSure test)  
Amniotic fluid insulin-like growth factor binding protein (IGFBP-1) test (Actim PROM test) 
2 
Clinical history of rupture of membranes  
AND 
Visible leakage of fluid on vaginal speculum examination  
AND 
Visible arborization (ferning) on microscopy of amniotic fluid  
OR 
Documented membrane rupture by a diagnostic test (one of those listed above)  
OR  
Ultrasound with oligohydramnios (AFI <5 or MVP <2) 
3 
Clinical history of rupture of membranes  
AND 
Visible leakage of presumed amniotic fluid; this may be on vaginal speculum examination (pooling in 
vagina), on inspection of the perineum (wet perineum due to leakage of fluid from the vagina), or fluid 
soaked cloth/clothes/sanitary pad. 
Preterm labor 
Level 
Description 
All 
Patient is determined to be have delivered preterm (at less than 37 gestation-completed weeks (less than 
259 days)).  
1 
On presentation, >4 documented uterine contractions per hour as determined by a tocodynometer  
AND 
Documented change in length or dilation of cervix by physical examination or transvaginal ultrasound 
over a two hour period, with clinical criteria for documenting cervical change by exam including: 
Cervical dilation 2 cm or greater at the internal os by digital examination  
Cervical length of 1 cm or less by digital examination 
50% or greater effacement by digital examination 
2 
Greater than 4 uterine contractions per hour as determined by a tocodynometer or clinical assessment  
AND 
Documented change in length or dilation of cervix by physical examination, with clinical criteria including:  
Cervical dilation 2 cm or greater at the internal os by digital examination 
Cervical length of 1 cm or less by digital examination 
50% or greater effacement by digital examination 
3 
Greater than 4 documented uterine contractions per hour determined by clinical assessment  
AND 
Documented change in cervical examination (change in dilation or effacement) over a two hour period 
Provider-initiated preterm birth 
Level 
Description 
All 
Patient is determined to be preterm (birth at less than 37 gestation-completed weeks (less than 259 
days).  
1 
Documentation in the healthcare record by a patient’s delivering provider that there were no signs or 
symptoms of the spontaneous onset of preterm labor  
AND 
Documentation in the healthcare record by a patient’s delivering provider that the patient needed to 
undergo induction of labor or cesarean delivery which led to the preterm delivery  
2 
From recall, delivering provider confirms that there was an absence of any signs or symptoms of the 
spontaneous onset of preterm labor  
AND 
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Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Preterm rupture of membranes 
Level 
Description 
Delivering provider reports from recall that he or she decided that the patient needed to undergo induction 
of labor or cesarean delivery 
3 
From recall, patient confirms that there was an absence of any signs or symptoms of the spontaneous 
onset of preterm labor  
AND 
Patient reports from recall that the healthcare provider indicated that she needed to undergo induction of 
labor or cesarean delivery 
Reference: Harrison MS, Eckert LO, Cutland C, et al. Pathways to preterm birth: Case definition and guidelines for 
data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6093-6101. 
Table 39 
Standard Definitions for Maternal Adverse Events of Special Interest 
not defined as events in GAIA  
Event of Interest 
Definition 
Chorioamnionitis 
Chorioamnionitis also known as intra-amniotic infection is an inflammation of the fetal 
membranes due to a bacterial infection. Clinical signs and symptoms of chorioamnionitis 
include the following: 
Fever (an intrapartum temperature >100.4ºF or >37.8ºC)  
Significant maternal tachycardia (>120 beats per minute [bpm])  
Fetal tachycardia (>160-180 bpm)  
Purulent or foul-smelling amniotic fluid or vaginal discharge  
Uterine tenderness  
Maternal leukocytosis (total blood leukocyte count >15,000-18,000 cells/μL)  
Of these criteria, intrapartum maternal fever appears to be the most frequent.  
When at least 2 of the aforementioned criteria are present, the risk of neonatal sepsis is 
increased. Each clinical sign and symptom of chorioamnionitis, however, is by itself of low 
predictive value 
Oligohydramnios 
Amniotic fluid index (AFI) < 8 cm or deepest vertical pocket (DVP) < 2 cm in the presence of 
intact membranes without concern for fetal anomalies contributing to its etiology 
Polyhydramnios 
Polyhydramnios is the presence of excess amniotic fluid in the uterus. By definition, 
polyhydramnios is diagnosed if the deepest vertical pool is more than 8 cm or amniotic fluid 
index (AFI) is more than 95th percentile for the corresponding gestational age 
Gestational liver 
disease 
(Intrahepatic 
Cholestasis of 
Pregnancy or 
ICP)1 
Intrahepatic cholestasis also called obstetric cholestasis should be suspected when pruritis 
develops during pregnancy in the absence of a rash. Lab evidence of cholestasis includes 
elevated bile acids (Glyco and Taurochenodeoxycholic Acid) (> 10 umol/L). Up to 60% of 
patients will have elevated transaminases and 20% of patients will have increased direct 
bilirubin levels. 
Jaundice may or may not be present. ICP typically is transient and resolves after delivery. 
Women that had ICP in previous pregnancy have higher risk to developing ICP in the following 
pregnancies or other hepatobiliary disorders in later life. ICP is associated with adverse fetal 
outcome like meconium-stained liquor, fetal asphyxia, spontaneous preterm delivery 
and intrauterine death.  
Gestational liver 
disease (Acute 
Fatty Liver of 
Pregnancy)2 
Acute fatty liver of pregnancy (AFLP) is a rare, potentially fatal complication that occurs in the 
third trimester or early postpartum period. AFLP is characterized by microvesicular fatty 
infiltration of hepatocytes without any inflammation or necrosis. Most frequent signs and 
symptoms are the following: 
Jaundice 
Abdominal Pain (usually right upper quadrat, midepigastric or radiating to back) 
Central nervous system (altered sensorium, confusion, disorientation, psychosis, restlessness, 
seizures or even coma) 
Disseminated intravascular coagulation 
Nausea and vomiting 
Gastrointestinal bleeding 
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Event of Interest 
Definition 
Acute renal failure 
Oliguria 
Tachycardia 
Late onset pyrexia 
Hypoglycemia 
ALT<500 U/L 
Hyperbilirubinemia, elevated ammonia, leukocytosis, hypofibrinogenemia 
Ultrasound examination and computed tomography may demonstrate fatty infiltration of the 
liver but are not sufficient for diagnosis 
Maternal Sepsis3 
Maternal sepsis is a life-threatening condition defined as organ dysfunction resulting from 
infection during pregnancy, child-birth, post-abortion, or post-partum period.  
Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points 
consequent to the infection. 
The baseline SOFA score can be assumed to be zero in patients not known to have preexisting 
organ dysfunction. 
A SOFA score ≥2 reflects an overall mortality risk of approximately 10% in a general hospital 
population with suspected infection. Even patients presenting with modest dysfunction can 
deteriorate further, emphasizing the seriousness of this condition and the need for prompt and 
appropriate intervention, if not already being instituted. 
 
 
MAP = mean arterial pressure; qSOFA = quick SOFA; SOFA = Sequential [Sepsis-related] 
Organ Failure Assessment 
References: 
1 Geenes V. Williamson C, Chappell L. Intrahepatic cholestasis of pregnancy. The Obstetrician and Gynecologist. 
2016; 18:273-81. 
2 Ko H, Yoshida E. Acute Fatty Liver of Pregnancy. Can J Gastroenterol. 2006; 20:25-30. 
3 Bonet M, Pileggi V, Rijken M et al. Towards a concensus definition of maternal sepsis: results of a systematic review 
and expert consultation. Reproductive Health. 2017; 14:67. 
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Small for Gestational Age 
Weight below 10th percentile for gestational age as assessed against a validated global, 
regional or local standard. 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
1 
Weight below 10th percentile for gestational age 
AND 
The following used in assessment of weight: 
Newborn weighed within 24 hours of birth 
Weight assessed using a calibrated electronic scale with 10 g resolution 
AND 
The following for assessment of gestational age: 
Certain LMP or IUI or embryo transfer date AND confirmatory ultrasound in first trimester  
OR 
First trimester ultrasound 
2a 
Weight below 10th percentile for gestational age  
AND 
The following used in assessment of weight:  
Newborn weighed within 24 hours of birth on any scale with a < 50 g resolution, tared to zero and 
calibrated  
AND 
The following for assessment of gestational age: 
Certain LMP with first or second trimester ultrasound  
OR 
Certain LMP with first trimester physical exam 
2b 
Weight below 10th percentile for gestational age  
AND 
The following used in assessment of weight:  
Newborn weighed within 24 hours of birth on any scale with a < 50 g resolution, tared to zero and 
calibrated  
AND 
The following assessment of gestational age:  
Uncertain LMP with second trimester ultrasound 
3a 
Weight below 10th percentile for gestational age  
AND 
The following used in assessment of weight: 
Infant weighed within the first 48 hours of life 
Newborn weighed on any scale with a < 50 g resolution, tared to zero and calibrated  
AND 
The following assessment of gestational age: 
Certain LMP with third trimester ultrasound  
OR 
Certain LMP with confirmatory 2nd trimester fundal height  
OR 
Certain LMP with birthweight  
OR 
Uncertain LMP with first trimester physical exam  
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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Small for Gestational Age (continued) 
Level 
Description 
3b 
Weight below 10th percentile for gestational age  
AND 
The following used in assessment of weight:  
Infant weighed within the first 48 hours of life 
Newborn weight assessed by measuring the difference between an adult holding the infant and the adult 
being weighed alone on any scale 
AND 
The following assessment of gestational age: 
Uncertain LMP with fundal height  
OR 
Uncertain LMP with newborn physical assessment  
OR 
Uncertain LMP with birthweight 
4 
Baby noted to be small, but no actual weight 
Baby with GA assessed only by infant examination 
Diagnosis extracted from billing codes or chart, with no documentation of actual birth weight or GA 
Reference: Schlaudecker EP, Munoz FM, Bardají A, et al. Small for gestational age: Case definition & guidelines for 
data collection, analysis, and presentation of maternal immunisation safety data. Vaccine. 2017; 35:6518-6528. 
Table 41 
Low Birth Weight (LBW) 
Regardless of gestational age:  
• 
Low birth weight (LBW): <2500 grams.  
• 
Very low birth weight (VLBW): <1500 grams  
• 
Extremely low birth weight (ELBW): <1000grams 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
1 
Newborn infant weighed within 24 hours of birth  
AND 
Use electronic scale which is graduated to 10 grams  
AND 
Scale is calibrated at least once a year  
AND 
Scale placed on level, hard surface  
AND 
Scale tared to zero grams  
AND 
Weight recorded as <2500 grams  
OR 
Birth weight recorded as <2500 grams  
AND 
Birth weight assessed as per health care facility’s standard operating procedure, which fulfills criteria 1 to 
5 above. 
2 
Newborn infant weighed within 24 hours of birth  
AND 
Scale (electronic/spring) is graduated to at least 50 grams  
AND 
Scale is calibrated at least once a year, or more often if moved  
AND 
Scale tared to zero grams or 0.00kg  
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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
AND 
Weight recorded as <2500 grams  
OR 
Birth weight recorded as <2500 grams AND 
Birth weight assessed as per health care facility’s standard operating procedure, which fulfills criteria 1 to 
4 above. 
(Scale used could be electronic or spring scale, including color-coded scale) 
3 
Newborn infant weighed on day 1 or 2 of life (first 48 hours of life)  
AND 
Weight measured using dial/spring/color-coded scale  
AND 
Weight assessed as <2500 grams 
4 
Newborn weight assessed between day 1 and 2 of life (first 48 hours)  
AND 
Proxy measure (newborn foot length, chest circumference, mid upper arm circumference) of birth weight 
used  
AND 
Weight CATEGORY assessed as <2500 grams 
Reference: Cutland CL, Lackritz EM, Mallett-Moore T, et al. Low birth weight: Case definition & guidelines for data 
collection, analysis, and presentation of maternal immunization safety data. Vaccine. 2017; 35:6492-6500. 
Table 42 
Neonatal encephalopathy 
Disease, malfunction of damage of the brain in a newborn (1–28 days) born at or beyond 
35 weeks of gestation, that may be due to a variety of etiologies including but not limited 
to hypoxia/ischemia, metabolic disturbance, infection and traumatic processes 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
1 
(Definite) 
Abnormal level of alertness or seizures AND 
Difficulty with initiating and maintaining respiration AND 
Depression of tone 
2 
(Probable) 
Abnormal level of alertness or seizures  
AND 
Difficulty with initiating and maintaining respiration OR Depression of tone 
3 
(Possible) 
Abnormal level of alertness or seizures without difficulty with initiating and maintaining respiration nor 
depression of tone 
Reference: Sell E, Munoz FM, Soe A, et al. Neonatal encephalopathy: Case definition & guidelines for data collection, 
analysis, and presentation of maternal immunisation safety data. Vaccine. 2017; 35: 6501-6505. 
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Table 43 
Congenital Microcephaly 
Congenital microcephaly, also referred to as primary microcephaly due to its presence in 
utero or at birth, is a descriptive term for a structural defect in which a fetus or infant’s 
head (cranium) circumference is smaller than expected when compared to other fetuses or 
infants of the same gestational age, sex and ethnic background 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Postnatally Diagnosed Microcephaly 
Level 
Description 
1 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of Gestational Age (GA)~  
AND  
Head Circumference (HC) 2 Standard Deviations (SD) below mean or <3rd percentile according to GA 
and gender, using appropriate standardized reference charts for the population (e.g., WHO growth 
reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
Measured between 24–36 hours after birth or end of pregnancy. 
~GA assessed based on certain Last Menstrual Period (LMP) with confirmatory 1st trimester or 2nd 
trimester ultrasound (US) scan, intrauterine insemination (IUI), or embryo transfer date 
2a 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA~  
AND  
HC 2 SD below mean or <3rd percentile according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA ≥37 weeks and Intergrowth-
21st reference charts for GA 24–36 weeks)  
AND  
Measured 
within the first 24 hours§ 
OR  
>36 hours and up to 6 weeks after birth or end of pregnancy with no apparent post-natal insult resulting in 
microcephaly  
~GA assessed based on certain LMP with confirmatory 1st trimester or 2nd trimester US scan, IUI, or 
embryo transfer date 
§Take into account the variability in this period based on molding of the head 
2b 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA~  
AND  
HC 2 SD below mean or <3rd percentile according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA ≥37 weeks and Intergrowth-
21st reference charts for GA 24–36 weeks)  
AND  
within the first 24 hours§ 
OR  
>36 hours and up to 6 weeks after birth or end of pregnancy with no apparent post-natal insult resulting in 
microcephaly  
~GA assessed based on uncertain LMP with 2nd trimester US scan 
§Take into account the variability in this period based on molding of the head 
3a 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA~_ 
AND  
HC 2 SD below mean or <3rd percentile according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA P37 weeks and Intergrowth-
21st reference charts for GA 24–36 weeks)  
AND 
Measured up to 6 weeks after birth or end of pregnancy with no apparent post-natal insult resulting in 
microcephaly 
~GA based on LMP without confirmatory 1st or 2nd trimester Ultrasound 
 
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Postnatally Diagnosed Microcephaly (continued) 
Level 
Description 
 
 
3b 
Live birth, stillbirth, or spontaneous or therapeutic abortion  
AND 
Case meets criteria for microcephaly using a validated algorithm: 1 inpatient diagnosis OR 2 outpatient 
diagnoses 
OR  
1 outpatient diagnosis AND death in first year using the following diagnostic codes ICD-9-CM code 742.1 
or ICD-10-CM code Q02 
4 
Live birth, stillbirth, or spontaneous or therapeutic abortion 
AND  
Diagnosis of congenital microcephaly based on: 
physical inspection without HC measurement  
OR  
ICD-9-CM or ICD-10-CM code that does not meet validated algorithm criteria above.  
Prenatally Diagnosed Microcephaly 
Level 
Description 
1a 
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 1st trimester (<14 weeks) or 2nd 
trimester US scan IUI, or embryo transfer date  
AND  
HC 2 SD below mean or <3rd percentile according to fetal ultrasound (US) examination using appropriate 
standardized reference charts according to GA and gender for the population (e.g. WHO growth 
reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3rd percentile) by: 
at least one additional US after 24 weeks and at least one week after first US  
OR 
HC measurement with standard tape measure at birth or autopsy  
1b 
Fetus of at least 24 weeks GA based on uncertain LMP with 2nd trimester US  
AND  
HC 2 SD below mean or <3rd percentile according to fetal ultrasound (US) examination using appropriate 
standardized reference charts according to GA and gender for the population (e.g. WHO growth 
reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3%) by:  
at least one additional US after 24 weeks and at least one week after first US  
OR  
HC measurement with standard tape measure at birth or autopsy 
2 
Fetus of at least 24 weeks GA based on certain or uncertain LMP with fundal height and no confirmatory 
1st or 2nd trimester US scan  
AND  
HC 2 SD below mean or <3rd percentile according to fetal US scan using appropriate standardized 
reference charts according to GA and gender for the population (e.g. WHO growth reference charts if GA 
≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks) with femur length and abdominal 
circumference concordant with GA assessment 
AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3%) by:  
at least one additional US scan after 24 weeks and at least one week after first US  
OR  
HC measurement with standard tape measure at birth or autopsy  
 
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Prenatally Diagnosed Microcephaly (continued) 
Level 
Description 
 
 
3a 
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 1st trimester or 2nd trimester US 
scan, uncertain LMP with 2nd trimester US, IUI, or embryo transfer date 
AND  
HC 2 SD below mean or <3rd percentile according to fetal US scan using appropriate standardized 
reference charts according to GA and gender for the population (e.g. WHO growth reference charts if GA 
≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks) with femur length and abdominal 
circumference concordant with GA assessment 
AND  
No additional data to confirm microcephaly (i.e., No additional prenatal US scan or confirmation of 
microcephaly with any additional US or by HC measurement at birth or autopsy at birth or autopsy) 
3b 
Fetus of at least 24 weeks GA based on certain or uncertain LMP with fundal height and no confirmatory 
1st or 2nd trimester US  
AND  
HC 2 SD below mean or <3 percentile according to fetal US scan using appropriate standardized 
reference charts according to GA and gender for the population (e.g., WHO growth reference charts if GA 
P37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks) with femur length and abdominal 
circumference concordant with GA assessment 
AND 
No additional data to confirm microcephaly (i.e., No additional prenatal US scan or confirmation of 
microcephaly by HC measurement at birth or autopsy) 
4 
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 1st trimester or 2nd trimester US 
scan, uncertain LMP with 2nd trimester US, IUI, embryo transfer date, or certain or uncertain LMP with 
fundal height and no confirmatory 1st or 2nd trimester US scan 
AND  
HC 2 SD below mean or <3% according to fetal US examination using appropriate standardized 
reference charts according to GA and gender for the population (e.g. WHO growth reference charts if GA 
≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
HC at birth or autopsy is in the normal range using appropriate standardized reference charts according 
to GA and gender for the population, which means that this is NOT a case of prenatally diagnosed 
congenital microcephaly 
Reference: DeSilva M, Munoz FM, Sell E, et al. Congenital microcephaly: Case definition & guidelines for data 
collection, analysis, and presentation of safety data after maternal immunisation. Vaccine. 35; 6472 – 6482. 
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Table 44 
Major Congenital anomalies 
Congenital anomalies, also commonly referred to as birth defects, congenital disorders, 
congenital malformations, or con-genital abnormalities. Major congenital anomalies are 
events of prenatal origin that a represent at birth, potentially impacting an infant’s health, 
development and/or survival. 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Major External Structural Defects 
Level 
Description 
1 
Alterations in external anatomy visible:  
at the time of live birth and persistent beyond the immediate peripartum period unless surgically repaired  
OR 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND 
Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing congenital 
anomalies and with the highest level of morphology training for the specific setting 
2 
Alterations in external anatomy visible:  
at the time of live birth and persistent beyond the immediate peripartum period unless surgically repaired  
OR 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND 
Confirmed by documentation of a diagnosis made by a clinician with some experience diagnosing 
congenital anomalies 
3 
Alterations in external anatomy visible: 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically repaired  
OR  
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND 
Confirmed: 
by documentation of a diagnosis made by a trained maternal or child health care provider with at least 
minimal experience diagnosing congenital anomalies  
OR 
For live births, by using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based 
algorithm, where the outcome (individual code or algorithm) has been validated 
4 
(Insufficient evidence to confirm) 
Alterations in external anatomy visible: 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically repaired  
OR 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND  
Confirmed: 
by medical record review  
OR 
in claims data (ICD-9/ICD-10 diagnoses)  
Internal Structural Defects 
Level 
Description 
1 
Alterations in internal anatomy present at the time of live birth and persistent beyond the immediate 
peripartum period unless surgically repaired 
AND 
Confirmed by definitive imaging study or intraoperative diagnosis  
OR  
Alterations in internal anatomy detected during autopsy for a stillbirth, spontaneous or therapeutic 
abortion confirmed by documentation by a pathologist or other relevant subspecialist  
2 
Alterations in internal anatomy present at the time of live birth and persistent beyond the immediate 
peripartum period unless surgically repaired  
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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
AND 
Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing congenital 
anomalies and with the highest level of morphology training for the specific setting without definitive 
imaging or intraoperative evaluation 
OR  
For stillbirth, spontaneous or therapeutic abortion, internal structural defect is visible by ultrasound or 
other imaging modality prenatally 
3 
Alterations in internal anatomy present at the time of live birth and persistent beyond the immediate 
peripartum period unless surgically repaired  
AND 
Confirmed: 
by documentation of a diagnosis made by a clinician with some experience diagnosing congenital 
anomalies  
OR 
using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based algorithm, where the 
outcome (individual code or algorithm) has been validated 
4 
(Insufficient evidence to confirm) 
Alterations in internal anatomy present: 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically repaired  
OR 
at time of stillbirth, spontaneous abortion, or induced abortion  
AND 
Confirmed: 
through medical record review, with the medical record demonstrating that the anomaly was present at 
the time of live birth or time of fetal demise, and that the anomaly was diagnosed by a trained maternal or 
child health care provider with minimal experience diagnosing congenital anomalies  
OR 
by claims data (ICD-9/ICD-10 diagnoses) 
Functional Defects 
Level 
Description 
1 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at the time of birth (or propensity to develop alteration present at live birth), and persistent 
beyond the immediate peripartum period, unless treated through gene therapy or stem cell 
transplantation  
OR  
For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND  
Confirmed by definitive diagnostic study 
2 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at livebirth (or propensity to develop alteration present at live birth), and persistent beyond 
the immediate peripartum period, unless treated through gene therapy or stem cell transplantation  
OR  
For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND  
Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing congenital 
anomalies and with the highest level of training in the diagnosis of functional defects for the specific 
setting 
3 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at livebirth (or propensity to develop alteration present at live birth), and persistent beyond 
the immediate peripartum period, unless treated through gene therapy or stem cell transplantation OR  
For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND 
Confirmed: 
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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
by documentation of a diagnosis made by a clinician with some experience diagnosing functional defects  
OR 
using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based algorithm, where the 
outcome (individual code or algorithm) has been validated 
4 
(Insufficient evidence to confirm) 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at the time of live birth (or propensity to develop alteration present at livebirth), and 
persistent beyond the immediate peripartum period, unless treated through gene therapy or stem cell 
transplantation  
OR 
For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND 
Confirmed: 
through medical record review, with the medical record demonstrating that the anomaly was present at 
the time of live birth or time of fetal demise, and that the anomaly was diagnosed by a trained maternal or 
child healthcare provider who is not a qualified geneticist, neonatologist, pathologist, subspecialist, 
pediatrician, obstetrician, or family medicine practitioner  
OR  
by claims data (ICD-9/ICD-10 diagnoses) 
Reference: DeSilva M, Munoz FM, Mcmillan M, et al. Congenital anomalies: Case definition and guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6015-6026.  
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Neonatal Death 
Death of a live born infant regardless of gestational age at birth, within the first 28 
completed days of life 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Neonatal death in a non-viable live birth 
Level 
Description 
1 
Live born infant  
AND 
Gestational age <22 weeks (GA level of certainty = 1)  
OR 
Birth weight <500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death 
2 
Live born infant  
AND 
Gestational age/size of newborn assessed as at least one of: 
Gestational age <22 weeks (GA Level of Certainty = 1 OR 2) 
Birth weight <500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
3 
Live born infant  
AND 
Gestational age <5 months according to parent/family member/delivery attendant (GA Level of Certainty 
= 2 OR 3)  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in an extremely preterm live birth 
Level 
Description 
1 
Live born infant  
AND 
Gestational age ≥22 and <28 weeks (GA Level of Certainty = 1)  
OR 
Birth weight ≥500 g but <1000 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death 
2 
Live born infant  
AND 
Gestational age/size of newborn assesses as one or more of: 
Gestational age ≥22 and <28 weeks (GA Level of Certainty = 1 OR 2)  
Birth weight ≥500 g but <1000 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Neonatal death in an extremely preterm live birth (continued) 
Level 
Description 
3 
Live born infant  
AND  
Gestational age ≥5 months but <7 months according to neonate’s parent (mother/father)/family 
member/delivery attendant (GA Level of Certainty = 2 OR 3)  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in a preterm live birth (gestational age ≥28to <37 weeks) 
Level 
Description 
1 
Live born infant  
AND 
Gestational age ≥28 and <37 weeks (Level of Certainty = 1) 
OR 
Birth weight ≥1000 g but <2500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death 
2 
Live born infant  
AND  
Gestational age/size of newborn assesses as one or more of: 
Gestational age ≥28 and <37 weeks (GA Level of Certainty = 1 OR 2)  
Birth weight ≥1000 g but <2500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
3 
(MAY apply to LMIC- or may be non-viable in LMIC) 
Live born infant  
AND 
Gestational age ≥7 months but <9 months according to parent/family member/delivery attendant (GA 
Level of Certainty = 2 OR 3)  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in a term live birth 
Level 
Description 
1 
Live born infant AND 
Gestational age ≥37 weeks (GA Level of Certainty = 1) AND 
Birth weight >2500 g  
OR  
Documented intra-uterine growth retardation if ≤2500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death 
Neonatal death in a term live birth (continued) 
Level 
Description 
2 
Live born infant  
AND 
Gestational age/size of newborn assesses as one or more of: 
Gestational age ≥37 weeks (GA Level of Certainty = 1 OR 2) 
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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Birth weight ≥2500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death which is confirmed by examination by (by 
at least) non-medically-trained attendant (e.g. undertaker, community member) 
3 
(apply to Lower Middle Income Countries) 
Live born infant AND 2. Gestational age ≥9 months according to parent/family member/delivery attendant 
(GA Level of Certainty = 2 OR 3) AND 
3. 
Death of infant in first 28 days of life  
AND 
4. 
Medically-confirmed death OR non-medically-confirmed death 
Reference: Pathirana J, Muñoz FM, Abbing-Karahagopian V, et al. Neonatal death: Case definition & guidelines for 
data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6027-6037. 
Table 46 
Neonatal Infections 
Neonatal bacteremia and sepsis (of early or late onset), meningitis, pneumonia and other 
respiratory infections such as bronchiolitis, caused by bacteria, parasites, viruses or fungi. 
Localized eye and ear infections, encephalitis, urinary tract infections and intestinal 
infections were excluded from these guidelines 
Neonatal invasive blood stream infections: bacterial/fungal/viral 
Level 
Description 
1 
Recognized pathogen identified using a validated method and from a normally sterile site. 
2 
Not meeting Level 1 of evidence  
AND  
Meeting 3 or more of the following criteria: 
Temperature ≥37.5 ◦C or <35.5 ◦C 
Tachycardia or new or more frequent episodes of bradycardia 
New or more frequent episodes of apnea or increased oxygen requirement or increased requirement for 
ventilatory support 
Lethargy or moving only when stimulated or hypotonia or irritability 
Difficulty in feeding or abdominal distention 
Pallor or poor perfusion or hypotension 
Abnormal White Cell Count or I/T ratio >0.2 
Abnormal platelet count  
Increased inflammatory markers (CRP, procalcitonin) 
Metabolic acidosis as defined by a base excess 
3 
Not meeting Level 1 or 2 of evidence  
AND 
Meeting 2 or more of the following criteria: 
Temperature ≥37.5 ◦C or <35.5 ◦C 
Tachypnea or severe chest in drawing or grunting or cyanosis 
Change in level of activity 
History of feeding difficulty 
History of convulsions 
Bacterial/fungal/viral meningitis 
Level 
Description 
1 
Recognized pathogen identified using a validated method from cerebrospinal fluid (CSF) 
2 
CSF pleocytosis OR positive IgM antibodies to a specific pathogen in the CSF  
AND 
Recognized pathogen identified using a validated method from a normally 
sterile site (other than CSF)  
AND 
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Temperature ≥37.5 ◦C or <35.5 ◦C  
AND 
1 or more criteria below: 
History of convulsions 
Lethargy or irritability 
Coma 
Apnea 
Bulging fontanel 
Neck stiffness 
3a 
CSF pleocytosis  
AND 
No pathogen identified using a validated method from a normally sterile site AND 
Temperature ≥37.5 ◦C or <35.5 ◦C  
AND 
3 or more criteria below: 
History of convulsions 
Lethargy or irritability 
Coma 
Apnea 
Bulging fontanel 
Neck stiffness 
3b 
No lumbar puncture done or no sample available  
AND 
Temperature ≥37.5 ◦C or <35.5 ◦C  
AND 
4 or more criteria below: 
History of convulsions 
Lethargy or irritability 
Coma 
Apnea 
Bulging fontanel 
Neck stiffness 
Respiratory bacterial/fungal/viral infection 
Level 
Description 
1 
New or progressive or persistent infiltrate or shadowing or fluid in the intrapleural cavity or interlobar 
fissure on chest X-ray  
AND 
Recognised virus identified using a validated assay from an upper respiratory sample  
OR 
Recognised pathogen identified using a validated method and from a normally sterile site  
AND  
3 or more criteria below: 
Temperature ≥37.5 ◦C or <35.5 ◦C 
Tachypnea or Nasal flaring or Chest in-drawing or Grunting 
Desaturations or increased oxygen requirements or increased ventilator requirements or oxygen 
saturation <95% 
Apneas 
Increased respiratory secretions or Increased suctioning requirements 
Cough or wheeze or crepitations 
Increased CRP or procalcitonin 
2 
New or progressive or persistent infiltrate or shadowing or fluid in the intrapleural cavity or interlobar 
fissure on chest X-ray  
AND  
4 or more criteria below: 
Temperature ≥37.5 ◦C or <35.5 ◦C 
Tachypnea or Nasal flaring or Chest in-drawing or Grunting 
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Desaturations or increased oxygen requirements or increased ventilator requirements or oxygen 
saturation <95% 
Apneas 
Increased respiratory secretions or Increased suctioning requirements 
Cough or wheeze or crepitations 
Increased CRP or procalcitonin 
3 
2 or more criteria below: 
Difficulty in breathing/Tachypnea 
Severe chest in-drawing 
Nasal flaring 
Grunting 
Wheezing 
Stridor 
Fever 
Reference: Vergnano S, Buttery J, Cailes B, et al. Neonatal infections: Case definition and guidelines for data 
collection, analysis, and presentation of immunisation safety data. Vaccine. 2016;34 (49):6038-6046 
Table 47 
Respiratory Distress in the Neonate 
Constellation of clinical findings that support the presence of breathing difficulty in the 
neonate (0-28 days of life), independent from etiology or severity, and independent from 
the infant’s gestational age or circumstances at the time of delivery 
Level 
Description 
1 
Newborn 0 to 28 days of life  
AND 
Abnormal respiratory rate: 
Measurement of number of breaths per minute consistent with: 
Tachypnea = respiratory rate of more than 60 breaths per minute OR  
Bradypnea = respiratory rate of less than 30 breaths per minute OR  
Apnea = cessation of respiratory effort (no breaths) for at least 20 seconds 
AND 
Clinical symptoms consistent with labored breathing: 
Nasal flaring (dilatation of alae nasi) OR 
Noisy respirations in the form of expiratory grunting, stridor, or wheeze OR  
Retractions or increased chest in-drawings on respiration (subcostal, intercostal, sternal, suprasternal 
notch) OR 
Central cyanosis (whole body, including lips and tongue) on room air OR  
Low Apgar Score (< 7 points) at 10 min, with respiration score <2  
AND 
Examination and documentation by qualified, trained, health care provider appropriate for the clinical 
setting. 
2 
Newborn 0 to 28 days of life  
AND 
Abnormal respiratory rate: 
Not measured, but reported as “rapid breathing”, “slow breathing”, having periods of “no breathing”, or 
“abnormal breathing”  
AND 
Clinical symptoms consistent with labored breathing: 
Nasal flaring (dilatation of alae nasi) OR 
Noisy respirations in the form of expiratory grunting, stridor, or wheeze OR 
Retractions or increased chest in-drawings on respiration (subcostal, intercostal, sternal, suprasternal 
notch) or seesaw respirations OR 
Central cyanosis (whole body, including lips and tongue) on room air OR 
Low Apgar Score (< 7 points) at 10 min, with respiration score <2 
AND 
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Level 
Description 
No medical record documentation, but reporting through either a non-medical observer (e.g. mother, 
father, community worker) or via standard census mechanisms (e.g. Demographic and Health 
Surveillance System) OR 
Collection of information from medical record review or billing codes. 
3 
No need for a level 3 per working group. 
4 
Not enough information to ascertain case of respiratory distress. 
5 
Not a case of respiratory distress in the neonate. 
Reference: Leigh R. Sweet, Cheryl Keech, Nicola P. Klein, et al. Respiratory distress in the neonate: Case definition & 
guidelines for data collection, analysis, and presentation of maternal immunization safety data. Vaccine. 2017; 35: 
6506-6517. 
Table 48 
Preterm Birth 
Birth in less than 37 gestation-completed weeks (less than 259 days).  
Prematurity and assessment of gestational age  
Level 
Description 
1 
Certain last menstrual period date (LMP) LMP or intrauterine insemination (IUI) date or embryo transfer 
(ET) date with confirmatory 1st trimester scan (≤13 6/7 weeks).  
OR 
1st trimester scan (≤13 6/7 weeks) 
2a 
Certain LMP* with 2nd trimester scan (14 0/7 weeks to 27 6/7weeks). 
Note: If LMP and U/S do not correlate, default to U/S GA assessment. 
OR 
Certain LMP* with 1st trimester physical examination. 
2b 
Uncertain LMP with 2nd trimester scan (14 0/7 weeks to 27 6/7 weeks). 
3a 
Certain LMP with 3rd trimester scan ≥ 28 0/7 weeks  
OR 
Certain LMP with confirmatory 2nd trimester Fundal Height (FH) 
OR 
Certain LMP with birth weight  
OR 
Uncertain LMP with 1st trimester physical examination. 
3b 
Uncertain LMP with FH.  
OR 
Uncertain LMP with newborn physical assessment.  
OR 
Uncertain LMP with Birth weight 
* 
Definitions of LMP, birth weight and physical assessment in referenced article. 
Reference: Quinn JA, Munoz FM, Gonik B, et al. Preterm birth: Case definition &amp; guidelines for data collection, 
analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6047-6056. 
Table 49 
Failure to Thrive  
Failure to Thrive (FTT) can be broadly defined as a faltering of growth from a previously 
established pattern of growth. It is universally established that a diagnosis of failure to 
thrive should be based on anthropometric data. However no consensus exits as to which 
measurements achieve the highest specificity and sensitivity. Weight is generally 
regarded is the indicator of choice, particularly a change in growth velocity, and as such 
has been selected as the standard for this case definition with a weight for age 
deceleration as the primary indicator of failure to thrive. The case definition should be 
applied when there is no clear alternative diagnosis for the reported event to account for 
the combination of symptoms. 
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Level 
Description 
1 
Infant age1 determined by a documented birth date 
AND 
Bare weights obtained using an appropriate electronic baby scale 
AND 
At least 2 such weights, measured at least 4 weeks apart 
AND 
Weight for age or weight for length/height falling by two major percentiles (percentile markers 95, 90, 75, 
50, 25, 10, and 5) over time 2,3,4 
2a 
Infant age determined by a documented birth date 
AND 
Weights obtained using a beam balance scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
growth chart 
OR 
Infants with an undocumented birth date, where age is determined 
based on Mothers recall to nearest month 
AND 
Weights obtained using electronic scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least two major percentiles (percentile markers 95, 90, 75, 50, 25, 
10, and 5) over time  
2b 
Infant age determined by a documented birth date 
AND 
Weights obtained using a spring balance scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
growth chart  
OR  
Weight measured using electronic scale or beam balance scale 
AND 
Length taken using Infantometer 
AND 
Weight for length less than or equal to the 3rd centile on the 
appropriate growth chart 
3a 
Infants with an undocumented birth date, where age is determined 
based on Mothers recall to nearest month 
AND 
Weight obtain using either beam balance or spring balance 
scale 
AND 
At least 2 weights, measured as least 4 weeks apart 
AND 
Weight for age deceleration through at least two major percentiles (percentile markers 95, 90, 75, 50, 25, 
10, and 5) over time  
3b 
Infants with no weight available 
AND 
Physical examination consistent with FTT5 
AND 
MUAC6 indicative of severe wasting 
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1This case definition is limited to infants up to 12 months of age. 
2Homan GJ, Failure to Thrive: A Practical Guide. Am Fam Physician. 2016; 94(4):295-9 
3 Weight should be documented on the appropriate growth chart at the time of assessment. A fall through 2 centile 
spaces may be demonstrated at any point in the first 12 months of life, using any two weights as long as they are taken 
at least 4 weeks apart. Details of use of the weight balances allowable under this case definition and use of the 
Infantometer for length assessment are presented in the reference given below. 
4 For infants born at 37 weeks gestation or above, the WHO growth charts should be applied. When using weight for 
age use the growth chart most accurate for the infants age. The birth to 6 months age range should be used where 
data is available for this range only, the birth to 2 years chart should be used where data is available beyond 6 months 
of life. When using weight for length, use the chart for birth to 2 years. For infants born less than 37 completed weeks 
gestation, the Intergrowth charts for postnatal growth standards in preterm infant should be used. All infants should be 
plotted on their respective growth chart using their corrected age. Links to relevant growth charts are presented in the 
reference given below. 
5 Physical examination with signs of Failure to Thrive (must include at least 2 findings, with at least one major finding) 
Major findings: Reduced subcutaneous fat stores; poor muscle mass; loose skin folds; prominent ribs; thin limbs. Other 
less specific signs include: sparse hair; rashes; pallor; miserable; lethargy/fatigue. 
6 Mid Upper Arm Circumference (MUAC): For infants 0–6 months, a MUAC of 6 110 mm is indicative of severe 
wasting. For infants 6–12 months, a MUAC of 6 115 mm is indicative of severe wasting. Instructions on performing 
MUAC are presented in the reference given below. 
Reference: Ross E, Munoz F, Edem B et al. Failure to thrive: case definition and guidelines for data collection, 
analysis, and presentation of maternal immunization safety data. Vaccine. 2017; 35:6483-6491. 
Table 50 
Standard Definitions for Neonatal Adverse Events of Special Interest 
not defined as events in GAIA   
Event of Interest 
Definition  
Large for gestational age 
Birth weight > 90% for newborns of same gestational age in same population (>4000g 
at term). 
Macrosomia 
BW >4000 g (8 lb, 13 oz). 
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10.9 
Appendix 9: Protocol Amendment/Administrative change 
history 
The Protocol Amendment/Administrative change Summary of Changes Table for the 
current amendment/administrative change is located directly before the Table of Contents 
(TOC). 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 3 
30-SEP-2020 
Amendment 2 
19-MAY-2020 
Amendment 1 
27-JAN-2020 
Administrative Change 1 
08-OCT-2019 
Original Protocol 
09-JUL-2019 
Amendments/Administrative changes summary of changes table: 
Document 
Date of 
issue 
Section # and Name 
Description of Change 
Brief Rationale 
Amend-
ment 1 
27-JAN-
2020 
Globally  
Number of maternal 
subjects has been 
increased from ~150 (i.e., 
~50 per group) to ~300 
(i.e, ~100 per group). 
Number of infant subjects 
has been increased from 
~150 (i.e., ~50 per group) 
to ~300 (i.e, ~100 per 
group). 
Number of infant subjects 
in each blood sampling 
subcohort has been 
increased from ~ 16 per 
timepoint per study group 
to ~ 33 per timepoint per 
study group.  
To provide 
additional safety 
and immune 
response data in 
support of 
subsequent studies 
 
 
Section 1.3, Table 2, Intervals 
between study visits – Maternal 
subjects 
The minimum interval 
between Visit 1 and Visit 
3 is 25 rather than 28 
days.  
To facilitate 
availability of 
immune response 
data at Visit 3.   
 
 
Section 1.3, Table 4, Intervals 
between study visits – Infant 
Subjects 
Language has been 
added to clarify that If 
consent is not obtained 
within the allowed 
interval, but the parent(s) 
/LAR(s) still wish the 
infant to participate, 
consent may be obtained 
at any time until the Day 
43 visit.  Refer to the 
SPM for additional 
details. 
To minimize infant 
subject attrition and 
enhance protocol 
compliance. 
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Document 
Date of 
issue 
Section # and Name 
Description of Change 
Brief Rationale 
 
 
Section 4.1, Data collection 
Reference to eDiary 
collection of maternal 
medically attended RTI 
data has been removed. 
The eDiary 
captures 
occurrences of 
maternal medically 
attended AEs but 
does not 
specifically query 
for occurrences of 
maternal medically 
attended RTIs. 
 
 
Section 4.2.5 
The second paragraph, 
indicating that after all 
safety data up to 6 
months post delivery/birth 
are available for all 
subjects and statistical 
analyses by group are 
performed by GSK 
Biologicals, the study can 
no longer be considered 
observer-blinded, has 
been removed. 
The schedule of 
analyses has 
changed and this 
analysis will no 
longer be 
performed. Refer to 
Section 9.5.1 for 
details of the 
current schedule of 
analyses. 
 
 
Section 4.4, End of study definition 
A paragraph equating 
End of Study with 
completion of assays 
needed to evaluate 
primary and secondary 
objectives has been 
removed.  
The paragraph is 
incorrect. 
 
 
Section 5.1.1, Inclusion criteria, 
maternal subjects 
“before performing any 
study specific 
procedures” has been 
replaced with “before any 
study specific procedures 
are performed.” 
Original language 
implies incorrectly 
that subjects 
perform these 
procedures.   
 
 
Section 5.2.1, Exclusion criteria, 
maternal subjects 
“ “Within 6 months before 
vaccination” has been 
removed from the 
following phrase: “Known 
or suspected impairment 
of the immune system or 
autoimmune disorder 
within 6 months before 
vaccination (based on 
medical history 
Prior receipt of an RSV 
vaccine” replaces 
“Previous participation in 
a clinical trial of an RSV 
vaccine””  
Presence of an 
autoimmune 
disorder or 
impairment of the 
immune system at 
screening is 
exclusionary, 
regardless of when 
the 
disorder/impairment 
first occurred.  
Revision better 
captures the intent 
of the exclusion 
criterion, since 
subjects who take 
part in clinical trials 
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Document 
Date of 
issue 
Section # and Name 
Description of Change 
Brief Rationale 
From the phrase 
“Planned administration 
of any vaccine within 29 
days before study vaccine 
administration (Day -28 to 
Day 1) and through Day 
43 post- delivery…..” Day 
43 has been removed; 
and “administration” has 
been added to “planned 
administration” (“planned 
administration / 
administration”).  
Consanguinity has been 
defined as second degree 
cousin or closer. 
of RSV vaccines 
may receive a 
placebo or other 
control preparation. 
Revision permits 
administration of 
MMR vaccine 
immediately post-
delivery and 
clarifies that 
exclusions pertain 
to both “planned 
administration’ and 
‘administration’ of 
vaccines during the 
specified interval. 
To improve clarity. 
 
 
Section 6.1, Study interventions 
administered 
Formulation information 
for sodium chloride has 
been updated 
Manufacturer has been 
updated, for both 
products, to “GSK 
Biologicals.” 
Formulation 
updated based on 
implementation of 
the IDMP ISO 
requirements 
To make clear that 
“manufacturer” 
should indicate the 
site where the 
vaccine/product is 
released.  
 
 
Section 6.4, Study intervention 
compliance 
Language modified to 
reflect the fact that the 
person administering the 
intervention may be 
unblinded. 
 “And in the eCRF” was 
removed from the phrase 
“intervention number 
administered, and the 
administration date and 
time will be recorded in 
the source documents 
and in the eCRF.” 
To ensure 
compliance while 
simplifying 
implementation at 
study sites. 
All of these 
parameters are 
recorded in the 
source document.  
Some but not all of 
them are also 
recorded in the 
eCRF.  
Administration time 
is not captured in 
the eCRF. 
 
 
Section 7.1.1 
Language adjusted to 
indicate that re-screening 
is allowed only for 
clinically significant Grade 
1 hematological / 
For consistency 
with maternal 
subject exclusion 
criteria 
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Document 
Date of 
issue 
Section # and Name 
Description of Change 
Brief Rationale 
biochemistry values that 
are expected to be 
transitory 
 
 
Section 8.1.3, Immunological 
Read-outs, Table 15 
Priority rank of RSV-B 
NAb (neutralizing 
antibody) assays has 
been corrected from “3” to 
“2.”  Priority rank of 
Respiratory Syncytial 
Virus PreF3 Ab.IgG 
(concentration) has been 
changed from “2” to “3.” 
Reflects the fact 
that a single aliquot 
will be prepared 
and used for both 
RSV-A and RSV-B 
Nab testing. 
 
 
Section 8.2.1.2.1, Physical 
Examination, Maternal subjects 
Language describing 
vaginal examinations has 
been modified.  
Modified to improve 
clarity. 
 
 
Section 8.2.2.2, Physical 
Examination, Infant subjects 
Protocol-required 
elements of physical 
examinations for infant 
subjects have been 
simplified 
Simplified to 
improve 
consistency with 
standard of care. 
 
 
Section 8.2.3.3.3, Overview of 
IDMC reviews 
Section has been 
adjusted to describe 5 
planned IDMC data 
reviews. 
Updated for 
consistency with 
additional 
enrolment and 
revised sequence 
of analyses. 
 
 
Section 8.4.3.1, when to conduct a 
maternal MA-RTI assessment visit 
Language to account for 
instances where ‘medical 
attendance‘ occurs in the 
context of a scheduled  
per-protocol study visit 
has been added 
Additions made to 
facilitate collection 
of MA-RTI data. 
 
 
Section 9.2.1 and 9.2.2, Sample 
size determinations for safety and 
immune response 
Data based on a sample 
size of 100 maternal 
subjects per group have 
been added. 
Reflects increase in 
overall enrolment 
from ~ 150 to ~ 300 
maternal subjects. 
 
 
Section 9.3, Populations for 
analyses 
Descriptions of maternal 
and infant subject 
populations for analyses 
have been presented 
separately. 
Descriptions of infant 
subject populations for 
analyses have been 
corrected.  
Adjusted to clarify 
differences in 
maternal / infant 
subject populations 
for analysis and 
corrected to 
remove 
inappropriate 
references to “post-
vaccination” status 
in infant subjects, 
who are not, 
themselves, 
vaccinated. 
 
 
Section 9.5.1, Sequence of 
Analyses 
A total of 4 rather than 5 
analyses will be 
performed. 
Updated for 
consistency with 
the increase in 
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Document 
Date of 
issue 
Section # and Name 
Description of Change 
Brief Rationale 
For the first 3 analyses, 
cutoff dates, number of 
subjects to be considered 
and parameters to be 
evaluated have been 
updated. 
enrolment from ~ 
150 to ~ 300 
maternal and infant 
subjects. 
 
 
Section 9.5.2, Statistical 
considerations for interim analysis 
The original reference to 
“final data” was incorrect 
and has been replaced. 
To more accurately 
reflect the 
sequence of 
analyses described 
in Section 9.5.1. 
Admin-
istrative 
Change 1 
08-OCT-
2019 
Facesheet 
List of contributing 
authors has been 
updated 
Persons serving as 
oversight data 
manager and study 
development lead 
have changed 
 
 
Section 4.4, End of Study 
Definition 
Typographical error 
corrected.  “V3-NB” 
should be “V2-NB” 
The Primary 
Completion Date 
(PCD) occurs on 
completion of the 
Day 43 post-
delivery visit in 
Epoch 002.  V2-NB, 
rather than V3-NB, 
is the correct label 
for the infant 
subject’s Day 43 
post-delivery visit. 
 
 
Section 6.3.5, Emergency 
Unblinding 
The fax number for North 
America and Puerto Rico 
has been removed.  
The emergency 
unblinding helpdesk 
fax number for 
North America and 
Puerto Rico was 
decommissioned. 
 
 
Section 10.6.2, Glossary of Terms, 
definition provided for pregnancy 
related adverse events of interest 
The specific list of 
pregnancy related 
adverse events of interest 
provided in the Glossary 
of Terms is inconsistent 
with the list of pregnancy 
related adverse events of 
interest presented in the 
body of the protocol (in 
Table 5).   
To avoid confusion, 
the specific list of 
pregnancy related 
adverse events of 
interest provided in 
the Glossary of 
terms has been 
replaced with a 
cross-reference to 
Table 5.   
 
 
Section 10.8, Appendix 8, 
Definitions of maternal, fetal and 
neonatal events of interest as per 
GAIA, Table 36, Gestational 
diabetes mellitus (pregnancy 
induced hyperglycemia) 
Cross References to the 
Gestational Age 
Assessment Tables were 
corrected.  
References to 
Appendix C were 
replaced with 
references to 
Section 10.7. 
 
 
Section 10.8, Appendix 8, 
Definitions of maternal, fetal and 
neonatal events of interest as per 
GAIA, Table 49, Failure to Thrive 
For the definitions of 
diagnostic certainty levels 
2a and 3a: The criterion 
pertaining to weight for 
The phrase 
“through at least 2 
centile spaces on 
growth chart” has 
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Date of 
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Section # and Name 
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95, 90, 75, 50, 25, 
10, and 5) over 
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209544 (RSV MAT-004) 
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• 
The visit location must have appropriate infrastructure and logistics to support 
completion of all study procedures.  Blood samples must be centrifuged within 1 
hour after collection if used to assess biochemistry, or within 2 hours of collection 
if used to assess hematology or immune response.   
• 
Contact may be via telephone, SMS, email or other means (including 
videotelephony or telemedicine), depending on local best practice. If the study site is 
the subject’s primary healthcare facility, contact with study personnel may also be 
made in the context of a visit for routine or event-driven care.   
Refer to Section 8 for information about special circumstances (e.g., the Covid 19 
pandemic) and their impact on study activities. 
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Table 1 
Visit / Contact 
Screening 
V1 
V2  
V3  
V4 
V5 
V6 
V7 
V8 
Monthly 
contacts  
Safety 
Visit  
MA-
RTI 
Visit  
For monthly 
contacts: Table 
2 & Section 
8.4.2. After 
delivery, 
maternal & 
infant monthly 
contacts 
coincide. 
 
Gestational Age 
(GA) 
 
28 0/7 - 
33 6/7 
29 0/7 - 34 6/7 
32 0/7 
- 37 6 
36 0/7 -
Delivery 
 
 
 
 
 
 
 
 
Blood sample 
(hematology / 
biochemistry, ~ 
5.5 ml) 
● 
● 
● 
 
 
 
 
 
 
 
● 
 
Table 11 
If screening 
sample ≤ 15 
days before V1, 
then V1 sample 
not required. 
During an 
event-driven 
safety visit, 
additional 
samples are per 
investigator’s 
discretion and 
standard of care 
and may to be 
tested locally. 
Pregnancy-
related AESIs  
 
● 
● 
● 
● 
● 
● 
 
 
● 
● 
● 
Sections 
8.3.3.2, 10.3.8 
Suspected, 
probable and 
confirmed 
cases of 
 
●  
●   
●   
●  
●  
●  
●  
●   
●   
●  
●  
Section 8.3.2.1 
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Visit / Contact 
Screening 
V1 
V2  
V3  
V4 
V5 
V6 
V7 
V8 
Monthly 
contacts  
Safety 
Visit  
MA-
RTI 
Visit  
For monthly 
contacts: Table 
2 & Section 
8.4.2. After 
delivery, 
maternal & 
infant monthly 
contacts 
coincide. 
 
Gestational Age 
(GA) 
 
28 0/7 - 
33 6/7 
29 0/7 - 34 6/7 
32 0/7 
- 37 6 
36 0/7 -
Delivery 
 
 
 
 
 
 
 
 
COVID-19 
infection 
MAEs 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Sections 8 and 
10.3.9.3 
Table 2: Intervals between study visits – maternal subjects 
Interval 
Optimal 
interval 
Allowed interval 
Additional Information 
V1 → V2  
7 days  
7 – 9 14 days  
 
V1 → V3  
30 days  
25 20 – 34 45 days  
 
V1 → V4 
60 days  
58 50–64 75 days  
 
V5 (delivery)  
0 days  
0 1 day before to 3 
days post delivery 
Collect maternal blood sample at any point from start of labor the day before  up to delivery. If blood is not 
collected during delivery, collect maternal blood sample no later than 3 days after delivery.  
A cord blood sample should be collected at the time of each delivery. If cord blood cannot be collected at 
delivery, a blood sample should be collected from the infant subject as soon as possible and no later than 3 days 
after birth. 
V5 → V6 
42 days  
40 – 46 60 days  
 
V5 → V7  
120 days  
116 110 – 130 140 
days  
Visit may coincide with infant subject’s routine vaccination visit if consistent with the participating country’s routine 
infant vaccination schedule) 
V5 → V8 
180 days  
165 – 195 200 days  
 
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Table 3: Schedule of activities for infants  
Visit / Contact 
 
To coincide with maternal 
visits 6, 7, 8  
 
Event-
Driven 
 
 
 
V1-NB 
V2-NB 
V3-NB  
V4-NB  
Monthly 
contacts  
RTI 
Visit  
 C1-NB 
V5-NB  
NB=Newborn 
Monthly Contacts coincide with maternal monthly 
contacts.  
RTI Visit: Sections 8.4.3 and 8.4.4. 
Demographic data and lifestyle 
characteristics 
● 
● 
● 
● 
 
 
● 
● 
Section 8.2.1.1.1 8.2.2.1, Record at Visit 1-NB 
and if changes in lifestyle characteristics 
thereafter 
Weight, length, head circumference, 
physical examination  
● 
● 
● 
● 
 
 
 
● 
Section 8.2.2 8.2.2.2 
Suspected, probable and 
confirmed cases of COVID-19 
infection 
● 
● 
● 
● 
● 
● 
● 
● 
 
MAEs  
● 
● 
● 
● 
● 
 
● 
● 
Sections 8 and 10.3.9.3 
Table 4: Intervals between study visits – infant subjects 
Interval 
Optimal 
interval 
Allowed interval 
Additional Information 
Birth → V1-NB 
0 days  
0 - 3 days (for 
blood sample 
collection) 
If no cord blood was obtained, a blood sample should be collected at this visit.  
If consent is not obtained within the allowed interval, but the parent(s) /LAR(s) still wish the infant to 
participate, consent may be obtained at any time until the Day 43 visit.  Refer to the SPM for additional details. 
Birth → V2-NB 
42 days  
28 – 60 40 – 46 
days  
 
Birth → V3-NB 
120 days  
110 -140 116 – 
130 days  
Visit may coincide with infant subject’s routine vaccination visit if consistent with the participating country’s 
routine infant vaccination schedule 
Birth → V4-NB 
180 days  
165 – 195 200 
days  
 
Birth →  C1-NB 
270 days  
256 – 286 days  
 
Birth → V5-NB  
365 days  
350 330 – 380 
400 days  
 
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Figure 1: Overall design – maternal subjects 
 
Table 6: Study groups, subcohorts, interventions, epochs and blinding foreseen in 
the study 
 
Epochs (Blinding) 
Study 
groups 
(Matern
al 
subject
s, 
allocat
ed 
1:1:1) 
Approxi
mate 
Number 
of 
materna
l 
subject
s 
Age of 
matern
al 
subject 
at 
enrolm
ent 
(Min/Ma
x) 
Interven
- 
tion 
name 
Blood sample 
subcohorts 
(infant 
subjects, 
allocated 1:1:1 
within each 
maternal study 
group) 
Approxim
ate 
Number 
of infant 
subjects 
Study 
groups for 
randomizat
ion 
(Allocation 
1:1:1:1:1:1:
1:1:1) 
Epoch 
001 
Mater
nal 
subjec
ts 
Only 
(Scree
ning) 
Epoch 002 
Maternal 
subjects 
V1-V8 
Infant 
subjects 
V1-NB – 
V4NB 
(observer-
blind) 
Epoch 003 
Infant 
subjects 
only 
Contact 1-
NB – V5-NB  
(single-
blind) 
RSV 
MAT 60 
Up to 
100 
18 – 40 
years 
RSVPre
F3_60  
BS1_60 
Up to 33 RSVMAT60
_BS1  
● 
●  
● 
BS2_60 
Up to 33 RSVMAT60
_BS2 
● 
BS3_60 
Up to 33 RSVMAT60
_BS3  
●  
RSV 
MAT 
120 
Up to 
100 
18 – 40 
years 
RSVPre
F3_120  
BS1_120 
Up to 33 RSVMAT12
0_BS1  
● 
●  
● 
BS2_120 
Up to 33 RSVMAT12
0_BS2  
●  
BS3_120 
Up to 33 RSVMAT12
0_BS3 
●  
Control Up to 
100 
18 – 40 
years 
Control 
BS1_C 
Up to 33 Control_BS
1 
● 
●  
● 
Section 4.4: End of study definition 
End of Study (EoS) must be achieved no later than 8 months after the last infant 
subjectlast visit (LSLV; Visit 5-NB). 
End of study (EoS) cannot be achieved before occurs with the last (infant) subject last 
visit (LSLV; Visit 5-NB). 
Section 5.2.1.2: Prior / Concomitant therapy 
• 
Prior receipt of a COVID-19 vaccine. 
Screening
Day - 28 to 
Day -1
VISIT 2
290/7-346/7
Day 8
VISIT 3
320/7-376/7
Day 31
VISIT 4
360/7-Delivery
Day 61
VISIT 5
Delivery
VISIT 7
Day 121
Post-
Delivery 
Visit 8
Day 181 
Post-
Delivery 
VISIT 6
Day 43 
Post-
Delivery
VISIT 1
280/7-336/7
Day 1
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Table 9: Study interventions administered  
Since the table was re-formatted, the prior and current versions are given in full.  
Current version: 
Study intervention 
name: 
RSVPreF3_60 
RSVPreF3_120 
Placebo 
Study intervention 
formulation: 
RSVPreF
3  
(60 µg) 
Sodium 
chloride (NaCl) 
(0.9%); Water 
for injections 
q.s, 0.5 mL 
RSVPreF
3  
(120 µg) 
Sodium 
chloride (NaCl) 
(0.9%); Water 
for injections 
q.s, 0.5 mL 
Sodium chloride 
(NaCl) (0.9%); 
Water for 
injections q.s, 
0.5 mL 
Presentation: 
Powder 
for 
suspensi
on for 
injection, 
vial 
Solution for 
injection; vial 
Powder 
for 
suspensi
on for 
injection, 
vial 
Solution for 
injection; vial 
Solution for 
injection; vial 
Route of 
administration: 
Intramuscular use 
Intramuscular use 
Intramuscular 
use 
Administration site: 
• 
Location 
Deltoid 
Deltoid 
Deltoid 
• 
Laterality * 
Non-Dominant 
Non-Dominant 
Non-Dominant 
Number of doses 
to be 
administered: 
1 
1 
1 
Volume to be 
administered: 
0.5 ml 
0.5 ml 
0.5 ml 
Packaging, 
labelling and TM: 
Refer to the SPM 
Refer to the SPM 
Refer to the 
SPM 
Manufacturer: 
GSK Biologicals 
GSK Biologicals 
GSK Biologicals 
Prior version: 
Study Intervention Name: 
RSVPreF3_60 
RSVPreF3_120 
Control 
Vaccine/product name * 
RSVPreF3 mid dose 
RSVPreF3 high dose  
- 
 
NaCl  
NaCl  
NaCl  
Presentation 
Vial 
Vial 
Vial 
Vaccine/product: 
RSVPreF3 (60µg)  
RSVPreF3(120µg)  
 
formulation 
Sodium Chloride (NaCl) 
water for injection q.s. 
0.5 mL 
Sodium Chloride (NaCl) 
water for injection q.s. 0.5 
mL 
Sodium Chloride (NaCl) 
water for injection q.s. 
0.5 mL 
Route of Administration 
IM injection 
IM injection 
IM injection 
Administration site: 
 
 
 
Location 
Deltoid  
Deltoid  
Deltoid 
Laterality ** 
Non-dominant  
Non-dominant  
Non-dominant  
Number of doses to be 
administered: 
1 
1 
1 
Volume to be administered 
0.5 ml 
0.5 ml 
0.5 ml 
Packaging and Labelling 
Refer to the SPM 
Refer to the SPM 
Refer to the SPM 
Manufacturer 
RSVPreF3 antigen: GSK 
Biologicals 
RSVPreF3 antigen: GSK 
Biologicals 
-  
 
NaCl: GSK Biologicals  
NaCl: GSK Biologicals  
NaCl: GSK Biologicals 
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Section 6.3.2, Randomization to study intervention 
Up to Aapproximately 300 eligible pregnant women will be randomly assigned to 3 study 
(intervention) groups in a 1:1:1 ratio and at the same time, their (as yet unborn) infants 
will be randomly assigned to 3 blood sampling subcohorts (also in a 1:1:1 ratio). This 
yields up to approximately 100 pregnant women per group and up to approximately 33 
infants per blood sampling subcohort within each group… 
Figures 3 and 4: 
The following footnote was added to each figure. 
*Numbers are approximate and represent maximum subject enrolment. 
Table 11: Biological samples – maternal subjects 
Maternal 
Sample 
type 
Collected to 
Evaluate 
Minimum 
Quantity 
per 
subject 
Unit 
Time 
point 
Additional Information 
Whole 
Blood  
Hematology, 
Biochemistry 
~5.5 
ml 
Screening 
As needed to achieve up to approximately 300 
eligible subjects at Visit 1. 
Urine  
Protein, 
Glucose 
Dipstick 
NA 
Screening 
As needed to achieve up to approximately 300 
eligible subjects at Visit 1. 
Table 12: Biological samples – infant subjects 
Infant 
Sample 
type 
Collected 
to 
Evaluate 
Minimum 
Quantity 
per 
subject 
Unit 
Time 
point 
Additional Information 
Blood 
Immune 
response 
~2.5  
ml 
Visit 1-NB 
(Within 3 
days after 
birth 
ONLY if 
cord blood 
cannot be 
collected.  
Volume must be reduced if weight ≤ 2.5 
kg. [Trial-related blood loss for infant 
subjects should be ≤ 1 % at each 
timepoint. Total blood volume is estimated 
at 80 to 90 ml/kg body weight, and 
venipuncture should not exceed ~ 1.6 ml 
for a 2kg baby or 2.0 ml for a 2.5 kg baby.] 
Refer to the Laboratory Manual for 
additional information. 
~2.5* 
ml 
Visit 2-NB 
(Day 43) 
 
~2.5* 
ml 
Visit 3-NB 
(Month 4) 
 
~2.5* 
ml 
Visit 4-NB 
(Month 6) 
 
~ 2.5 
 ~5.0 
ml 
Minimum TOTAL, assuming body weight > 2.5 kg and cord blood 
(Table 11) collected 
Minimum TOTAL, assuming body weight > 2.5 kg and cord blood NOT 
collected 
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Table 15: Immunological read-outs 
Blood sampling timepoint 
No. subjects 
Component 
Components 
priority rank  
Type of contact and 
timepoint 
Sampling 
timepoint 
Maternal subjects 
V1 (Day 1) 
pre 
vaccination 
up to 
approximately 
~300  
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V3 (Day 31) 
post 
vaccination 
up to 
approximately 
~300 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V5 (Delivery) 
(venous blood and 
cord blood)* 
delivery  
up to 
approximately 
~300 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V6 (Day 43 post-
Delivery 
post delivery  
up to 
approximately 
~300 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
Infant subjects 
V1-NB (Birth)* 
birth (only if 
cord blood 
cannot be 
collected) 
Event-driven 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V2-NB (Day 43) 
post birth 1  
up to 
approximately 
~100 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V3-NB (Day 121) 
post birth 2  
up to 
approximately 
~100 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
V4-NB (Day 181) 
post birth 3  
up to 
approximately 
~100 
RSV-A NAb (neutralizing antibody) 
1 
Respiratory Syncytial Virus PreF3 
Ab.IgG (concentration) 
3 
RSV-B NAb (neutralizing antibody) 
2 
Section 8: Study assessments and procedures 
Readers are reminded that study visits /contacts, assessments and procedures do not 
replace local standards of care, and that any adverse event / potential adverse event 
identified during a study visit/contact or procedure should be treated according to local 
medical practice or by referral to an appropriate health care provider. 
Study Procedures During Special Circumstances 
During special circumstances (e.g., the COVID-19 pandemic), the specific guidance 
from local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied.  
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For the duration of such special circumstances: 
• 
Enrolment of ADDITIONAL maternal subjects may be placed on hold.  Decisions 
on re-starting enrolment to achieve the planned sample size will be made in a 
manner consistent with guidance from public health and other competent 
authorities. 
• 
The following measures may be implemented for enrolled participants:  
− 
If it is not possible to conduct a protocol-specified, scheduled or event-driven 
visit as described in Section 1.3, the visit may be replaced with a contact 
conducted by telephone, videotelephony or telemedicine. SMS and email are 
not allowed.  
− 
Biological samples may be collected at a different location* other than the 
study site or the subject’s home. Biological samples should not be collected if 
they cannot be obtained within the visit interval (Table 2, Table 4), processed 
in a timely manner or appropriately stored until the intended use.  
o 
Nasal swabs and blood samples for assessment of immune response 
should only be collected using centrally provided supplies. 
o 
Hematocrit and dipstick urinalysis may be evaluated locally, using local 
supplies, if collection using centrally provided supplies is not feasible.  
− 
If hematocrit is evaluated locally, date, result and normal range should be 
recorded in the eCRF in the Comment section for the relevant visit. 
− 
If any other missing data were collected during a visit for standard care in the 
appropriate interval (Table 2 for maternal subjects; Table 4 for infant 
subjects), and if the medical records for this visit are accessible to site staff (as 
allowed by local law), then the data from the medical record may be recorded 
in the subject’s study source document and entered into the eCRF.  
• 
“Medically attended visits” will include actual visits to or from medical personnel 
and instances where, due to the special circumstances, the subject cannot seek 
medical advice for symptoms/an illness by visiting a medical facility or arranging 
for a home visit, and seeks this advice instead via telephone, SMS, email, 
videotelephony or telemedicine, or other means.  
• 
The eDiary device provided to the maternal subject may be returned to the site by 
conventional mail after Day 181 post-delivery/birth, if the Day 181 post- delivery / 
birth visits (Visit 8 / Visit 4-NB) cannot be performed. 
*It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH GCP requirements, such as 
adequate facilities to perform study procedures, appropriate training of the staff and 
documented delegation of responsibilities in this location. This alternate location 
should be covered by proper insurance for the conduct of study on participants by 
investigator and staff at a site other than the designated study site. Refer to EMA 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
pandemic (version 2, 27 March 2020) for more details. 
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The impact of measures taken during special circumstances on the per protocol set for 
immunogenicity will be determined on a case by case basis.  
Section 8.2.3.1: Limitation on number of doses administered per day (first 30 
maternal subjects) 
…..all (up to approximately 300) maternal subjects must be closely observed at the study 
site for at least 60 minutes….. 
Section 8.2.3.3.1: Holding rules assessed by the investigator 
The investigator is not permitted to start the administration of the next dose or enrol 
additional subjects until provided with written documentation of the favourable outcome 
of the safety evaluation, and written authorization to proceed. receipt of the favourable 
outcome of the safety evaluation, documented and provided in writing, authorising the 
investigator to proceed. Refer to Table 23 for contact information.  
The below flow of communication must be followed.  
• 
The central sponsor team ensures that SBIR is blocked, and all sites administering 
study vaccine/product are informed, and all country or region- specific regulatory 
authorities are informed. 
• 
Where required per local / regional regulation, the central sponsor team submits a 
substantial amendment to the local/regional authority requesting authorization to 
re-start the study.  
• 
When all required authorizations to re-start the study in a country / region have 
been provided, Tthe central sponsor team notifies provides written notification to 
local sponsor contactsof this decision; local sponsor contacts then provide written 
notification to notify study sites. 
Section 8.2.3.3.2: Holding rules assessed during IDMC evaluations 
If the study is placed on hold, the investigator must suspend enrolment and study 
vaccine/product administration. As noted in Section 8.3.3.3.1, the investigator is not 
permitted to start the administration of the next dose or enrol additional subjects until 
provided with written documentation of the favourable outcome of the IDMC 
evaluation, and written authorization to proceed. 
The below flow of communication must be followed. 
• 
IDMC Chair (or his/her representative) notifies the Clinical Research & 
Devevlopment Lead (CRDL).  
• 
The central sponsor team ensures that all country or region- specific regulatory 
authorities are informed. 
• 
Where required per local / regional regulation, the central sponsor team submits a 
substantial amendment to the local/regional authority requesting authorization to 
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re-start the study, and will not re-start the study until approval of the substantial 
amendment.  
• 
When all required authorizations to re-start the study have been provided, the 
CRDL / central sponsor team provides written notification to local sponsor contacts; 
local sponsor contacts then provide written notification to study sites. 
• 
The CRDL / central sponsor team notifies local sponsor contacts of this decision; 
local GSK sponsor contacts then notify study sites. 
Table 21: Timeframes for collecting and reporting safety (and RTI) information 
Footnote only: Pre = pre-vaccination; V=visit; C = contact; D= Day. 
Section 8.3.2.1: COVID-19 Infection 
COVID-19 cases identified within the existing framework of the study (e.g., MA-RTI in 
maternal subjects, suspected RTI assessments in infants) will be captured and reported 
using standard AE, medically-attended AE or SAE criteria, as outlined in Section 10.3. 
COVID-19 cases should be reported in the eCRF according to the WHO Case 
Definition [WHO, 2020] using one of the following terms:  
• 
Suspected COVID-19 infection 
• 
Probable COVID-19 infection 
• 
Confirmed COVID-19 infection 
Section 8.3.3.2: Additional Reporting Guidance for the Study Pregnancy 
A medical complication that requires an unplanned caesarian section or an emergency 
induction of vaginal delivery may be reported as an SAE/AESI (as applicable), using 
the corresponding Expedited AE report form.  
All congenital anomalies (minor and major) are to be reported as serious adverse 
events (SAEs).  To confirm if a medical condition is a congenital anomaly the 
WHO/CDC/ICBDSR birth defects surveillance manual [WHO/CDC/ICBDSR, 2014], 
available online, can be reviewed.  
Only major congenital anomalies meet the criteria for the GAIA case definition of 
neonatal AESI. To assess if a congenital anomaly is major and meets the criterion  for 
the AESI reporting the same website can be consulted. 
Section 8.4.3.1: For a maternal MA-RTI  
Conduct an assessment visit (Section 8.5.4 8.4.4),  
Figure 6: Decision Tree for Site Personnel – Maternal surveillance and assessment 
(footnotes only) 
1Details regarding Surveillance are provided in Section 8.5.2 8.4.2 and the SPM. 
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2Details regarding the RTI assessment visit are provided in Section 8.5.4 8.4.4  and the SPM. 
Section 8.4.3.1: For an infant RTI 
Conduct an assessment visit, as described in Section 8.5.4 8.4.4  
Figure 7: Decision Tree for site personnel - infant surveillance and assessment 
(Footnotes only) 
1Details regarding Surveillance are provided in Section 8.5.2 8.4.2 and the SPM. 
2Cough, runny nose, blocked nose, difficulty in breathing, wheezing are described in Section 
8.5.1.2 8.4.3.2 
3Details regarding the RTI assessment visit are provided in Section 8.5.4 8.4.4 and the SPM. 
4 Post-visit follow up is described in Sections 8.5.6 8.4.6 and in the SPM. 
Section 9.2: Sample size determination: 
Up to Approximately 300 subjects will be randomised to achieve up to approximately 
270 evaluable subjects for an estimated total of up to approximately 90 evaluable 
maternal subjects per study group. 
Section 9.5.1.1: First Analysis 
By-study-group safety and immunogenicity analyses will be performed by an 
independent statistician not affiliated with the project (to preserve the observer blinding).  
Immunogenicity These analyses will include all available test results at… 
Aggregate (blinded) safety analyses will be performed by the GSK Biologicals 
biostatistics team. TheseSafety analyses will be performed by blinded treatment group, 
with the letters “A,” “B,” and “C” replacing treatment-specific group identifiers in all 
results summaries. Steps will be taken to minimize the risk of unblinding (e.g., events 
that happen in a single group will be masked by adding the same amount of counts to 
other groups). Although the risk of unblinding may be reduced with the proposed 
masking, this risk may not be avoidable in certain cases. 
Safety analyses will include all available data for:  
• 
Solicited events, unsolicited AEs for 30 days post-dose, MAEs, SAEs and AESIs. 
• 
RTI surveillance data (including nasal swab test results).  
A report summarizing these safety and immunogenicity results will be prepared but will 
not be made available to investigators. 
Section 9.5.1.3: Third Analysis: 
By-study-group safety analyses will include the following data from all 300 vaccinated 
subjects who have reached the Day 43 post-delivery visit: 
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Section 10.2, Appendix 2: Clinical laboratory tests 
All study-required laboratory assessments detailed in Tabld 26 except urinalysis should 
will be performed by a central laboratory. The results of any test carried out locally must 
be entered into the eCRF. During special circumstances, hematocrit may be performed 
locally if it is not possible to collect a blood sample for central analysis using GSK-
provided supplies, with results entered into the eCRF (see Section 8). 
Section 11.0: REFERENCES 
World Health Organization / Centers for Disease Control/ International Clearinghouse 
for Birth Defects Surveillance and Research [ WHO/CDC/ICBDSR]. Birth defects 
surveillance: a manual for programme managers. Geneva: World Health 
Organization; 2014. Chapter 1. Available at¨ 
https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/chapters/chapter-
1/chapter1-4.html. Accessed 8 May 2020. 
World Health Organization [WHO]. Global Surveillance for COVID-19 caused by 
human infection with COVID-19 virus: Interim Guidance. March 2020. Available at: 
https://apps.who.int/iris/rest/bitstreams/1272502/retrieve.  Accessed 8 May 2020. 
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Detailed description of Protocol Amendment 3: 
Text that has been moved or added is presented in bold italics and deleted text in 
strikethrough. 
Table 6 
Study groups, subcohorts, interventions, epochs and blinding foreseen 
in the study  
 
Epochs (Blinding) 
Study 
groups 
(Matern
al 
subject
s, 
allocate
d 1:1:1) 
Approxi
mate 
Number 
of 
maternal 
subjects 
Age of 
materna
l subject 
at 
enrolme
nt 
(Min/Ma
x) 
Interven- 
tion name 
Blood sample 
subcohorts 
(infant 
subjects, 
allocated 1:1:1 
within each 
maternal study 
group) 
Approxim
ate 
Number of 
infant 
subjects 
Study 
groups for 
randomizati
on 
(Allocation 
1:1:1:1:1:1:
1:1:1) 
Epoch 
001 
Matern
al 
subject
s Only 
(Scree
ning) 
Epoch 002 
Maternal 
subjects 
V1-V8 
Infant 
subjects 
V1-NB – 
V4NB 
(observer-
blind) * 
Epoch 003 
Infant 
subjects 
only 
Contact 1-
NB – V5-NB  
(single-
blind) 
* After the second analysis, the study will not be considered observer blind as the investigator brochure will 
be updated to include safety information presented by treatment group. This could lead to inadvertent 
unblinding of investigators and site staff to some subjects’ treatment assignments. The subjects themselves 
will remain blinded throughout their participation in the study. 
4.2.5  Study blinding  
Therefore, double blinding is not feasible and the study will be conducted in an observer-
blinded manner until the second analysis is conducted, as described in Section 6.3.4. 
After the second analysis, the study will not be considered observer-blind as the 
investigator brochure will be updated to include safety information presented by 
treatment group. This could lead to inadvertent unblinding of investigators and site 
staff to some subjects’ treatment assignments. The subjects themselves will remain 
blinded throughout their participation in the study. 
6.3.4 Blinding and unblinding  
Investigators will remain blinded to each subject’s assigned study intervention until 
throughout the second analysis. After course of the second analysis, the investigator’s 
brochure will be updated to include safety information presented by treatment group. 
This could lead to inadvertent unblinding of investigators and site staff to some 
subjects’ treatment assignments. study.  
8.0 Study assessments and procedures  
Study Procedures During Special Circumstances: COVID-19 pandemic 
Study Procedures During Special Circumstance: E-diary failure 
• 
In case ERT portal/ alerts are not functioning, contacts will be conducted at least 
weekly until Visit 8 (maternal subjects) / 4-NB (infant subjects). Contact may be 
via telephone, SMS, email or other means (including videotelephony or 
telemedicine), depending on local laws and best practice. 
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8.4.2 Surveillance  
− 
In the event that ERT portal/ alerts are not functioning, the site should contact 
subjects at least weekly until Visit 8 (maternal subjects) / 4-NB (infant 
subjects) to complete surveillance questions and collect information about 
adverse events. Contact may be via telephone, SMS, email or other means 
(including videotelephony or telemedicine), depending on local best practice.  
9.5.1.2 Second analysis  
Safety results that would lead to the unblinding of some subjects (e.g. a specific AE 
reported by one subject only) will be masked (i.e. the group in which this event occurred 
will not be identified). Although the risk of unblinding may be reduced with the 
proposed masking, this risk may not be avoidable in certain cases. 
9.5.1.3 Third analysis  
By-study-group immunogenicity and by-study-group safety analyses will be performed 
by an independent statistician not affiliated with the project. (to preserve the observer 
blinding). 
Although the risk of unblinding may be reduced with the proposed masking, this risk 
may not be avoidable in certain cases. In addition, blinded SAE and AESI listings for all 
subjects will be provided. 
10.3.8 Recording and follow-up of AEs, SAEs, AESIs and subsequent pregnancies  
The maternal subject should be trained on how and when to complete each field of the 
Subject Diary. In case ERT portal/ alerts are not functioning, contacts will be 
conducted at least weekly until NB4/V8. Contact may be via telephone, SMS, email or 
other means (including videotelephony or telemedicine), depending on local laws and 
best practice. 
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11. 
REFERENCES  
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Obstetrics & Gynecology. 2019a; 133 (1) 211-214. 
ACOG. Practice Bulletin No. 204 Summary: Fetal Growth Restriction. Obstetrics & 
Gynecology. 2019b; 133 (2) 390-392. - Volume 133 - Issue 2 - p 390-392 
Dashe JL, Pressman EK, Hibbard JU. SMFM Consult Series #46: Evaluation and 
management of polyhydramnios, American Journal of Obstetrics and Gynecology, 2018; 
219 (4): B2-B8. 
Haralambieva IH, Ovsyannikova IG, Pankratz VS, Kennedy RB, Jacobson RM, Poland 
GA. The genetic basis for interindividual immune response variation to measles vaccine: 
new understanding and new vaccine approaches. Expert Rev Vaccines. 2013; 12(1):57–
70.  
Hasin DS, O’Brien CP, Auriacombe M, et al. DSM-5 Criteria for Substance Use 
Disorders: Recommendations and Rationale. The American journal of psychiatry. 
2013;170(8):834-851. 
Kachikis A, Eckert LO, Walker C, et al. Gestational diabetes mellitus: Case definition & 
guidelines for data collection, analysis, and presentation of immunization safety data. 
Vaccine. 2017; 35 (48): 6555-6562. 
Kollmann TR. Variation between Populations in the Innate Immune Response to Vaccine 
Adjuvants. Front Immunol. 2013; 4:81.  
Modjarrad K, Giersing B, Kaslow DC, Smith PG, Moorthy VS; WHO RSV Vaccine 
Consultation Expert Group. WHO consultation on Respiratory Syncytial Virus Vaccine 
Development Report from a World Health Organization Meeting held on 23-24 March 
2015. Vaccine. 2016;34(2):190-7.  
Pérez-Losada M, Posada D, Arenas M, et al. Ethnic differences in the adaptation rate of 
HIV gp120 from a vaccine trial. Retrovirology. 2009; 6:67.  
Reddy UM, Abuhamad AZ, Levine D, GR. Fetal imaging: Executive Summary of a Joint 
Eunice Kennedy Shriver National Institute of Child Health and Human Development, 
Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, 
American College of Obstetricians and Gynecologists, American College of Radiology, 
Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging 
Workshop. American Journal of Obstetrics and Gynecology. 2014; 210 (5): 387-397. 
Royal College of Obstetrics and Gynecology (RCOG). Obstetric Cholestasis. Guideline 
43. 2011 
Sheffield JS, Munoz FM, Beigi RH, et al. Research on vaccines during pregnancy: 
Reference values for vital signs and laboratory assessments. Vaccine 2013; 31: 4264-
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World Health Organization / Centers for Disease Control/ International Clearinghouse for 
Birth Defects Surveillance and Research [ WHO/CDC/ICBDSR]. Birth defects 
surveillance: a manual for programme managers.Geneva: World Health Organization; 
2014. Chapter 1. Available at¨ 
https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/chapters/chapter-
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World Health Organization [WHO]. Global Surveillance for COVID-19 caused by 
human infection with COVID-19 virus: Interim Guidance. March 2020. Available at: 
https://apps.who.int/iris/rest/bitstreams/1272502/retrieve.  Accessed 8 May 2020. 
Yu L, Esser M, Falloon J et. al. Generalized ROC methods for immunogenicity data 
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