Clinical trial NCT04605159
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline
Start date: 2020-11-20; Completion date: 2023-06-14
Enrollment: 11194 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the ability of a single dose of the investigational RSV Maternal vaccine, administered intramuscularly (IM) to pregnant women aged 18-49 years, in good general maternal health, in preventing medically assessed RSV associated Lower Respiratory Tract Illnesses (LRTIs) in infants born to vaccinated mothers. The study also evaluated the safety of the investigational RSV Maternal vaccine both in vaccinated mothers and in their corresponding infant.

Following a recommendation from the Independent Data Monitoring Committee of NCT04605159 (RSV MAT 009), GSK made the decision to stop enrolment and vaccination in the study. Ongoing study participants at that time continued to be monitored as part of the study.

Detailed description:

Arms: arm 1: Maternal participants received a single dose of the RSV MAT vaccine administered at Day 1 in this study. arm 2: Maternal participants received a single dose of placebo administered at Day 1 in this study. arm 3: This group consisted of infants born to mothers (from RSV MAT Group - Mother) who received a single dose of RSV MAT vaccine during pregnancy. arm 4: This group consisted of infants born to mothers (from Placebo Group - Mother) who received a single dose of placebo during pregnancy.
Interventions: intervention 1: RSV MAT intervention 2: Placebo
Intervention descriptions: intervention 1: One dose of RSV MAT vaccine reconstituted with NaCl solution, administered intramuscularly in the non-dominant arm at Day 1. intervention 2: One dose of placebo (lyophilized sucrose reconstituted with NaCl solution) administered intramuscularly in the non-dominant arm at Day 1.

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 5
Study ID:  212171
Official Title of Study: A Phase III, randomized, double-blind, placebo-controlled 
multi-country study to demonstrate efficacy of a single dose of unadjuvanted RSV 
Maternal vaccine, administered IM to pregnant women 18 to 49 years of age, for 
prevention of RSV associated LRTI in their infants up to 6 months of age 
NCT number: NCT04605159
Date of Document: 03-Mar-2023


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212171 (RSV MAT-009) 
Protocol Amendment 5 Final 
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1 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’institut 89, 
1330 Rixensart, Belgium 
Primary Study 
vaccine/product and 
number(s) 
GlaxoSmithKline (GSK) Respiratory Syncytial Virus 
(RSV) Maternal (RSVPreF3) Vaccine 
(GSK3888550A) 
Other Study vaccine/product 
Placebo (Lyophilized sucrose reconstituted with 
saline [NaCl] solution)  
eTrack study number and 
abbreviated title 
212171 (RSV MAT-009) 
EudraCT number 
2020‐001355‐40 
Date of protocol 
Final: 26 June 2020 
Date of protocol amendment 
Amendment 5 Final: 23 February 2023 
Amendment 4 Final: 15 March 2022 
Amendment 3 Final: 10 February 2022 
Amendment 2 Final: 23 June 2021 
Amendment 1 Final: 5 October 2020 
Study Acronym 
GRACE 
InvestiGational RSV MAternal VaCcinE 
Title 
A Phase III, randomized, double-blind, placebo-
controlled multi-country study to demonstrate 
efficacy of a single dose of unadjuvanted RSV 
Maternal vaccine, administered IM to pregnant 
women 18 to 49 years of age, for prevention of RSV 
associated LRTI in their infants up to 6 months of 
age 
Short title 
A Phase III double-blind study to assess safety and 
efficacy of an RSV Maternal unadjuvanted vaccine, 
in pregnant women and infants born to vaccinated 
mothers 
Based on GSK Biologicals’ Protocol WS v17.0 
© 2020 GSK group of companies or its licensor. 


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PROTOCOL AMENDMENT 5 SPONSOR SIGNATORY APPROVAL  
eTrack study number and 
Abbreviated Title 
212171 (RSV MAT-009) 
EudraCT number 
2020‐001355‐40 
Date of protocol 
Final: 26 June 2020 
Date of protocol amendment 
Amendment 5 Final: 23 February 2023 
Title  
A Phase III, randomized, double-blind, placebo-
controlled multi-country study to demonstrate 
efficacy of a single dose of unadjuvanted RSV 
Maternal vaccine, administered IM to pregnant 
women 18 to 49 years of age, for prevention of RSV 
associated LRTI in their infants up to 6 months of 
age 
Sponsor signatory 
Joon Hyung Kim  
Clinical and Epidemiology Project Lead, RSV 
Maternal 
 
 
Signature 
 
 
 
Date 
 
 
 
Note: Not applicable if an alternative signature process (e.g. electronic signature or 
email approval) is used to get the sponsor approval. 


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PROTOCOL AMENDMENT 5 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 representatives 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 for the solely for the purpose of complying with regulatory 
requirements. 


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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. 


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eTrack study number and 
Abbreviated Title 
212171 (RSV MAT-009) 
EudraCT number 
2020‐001355‐40 
Date of protocol 
Final: 26 June 2020 
Date of protocol amendment 
Amendment 5 Final: 23 February 2023 
Title 
A Phase III, randomized, double-blind, placebo-
controlled multi-country study to demonstrate 
efficacy of a single dose of unadjuvanted RSV 
Maternal vaccine, administered IM to pregnant 
women 18 to 49 years of age, for prevention of RSV 
associated LRTI in their infants up to 6 months of 
age 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 


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SPONSOR INFORMATION  
1. Sponsor 
GlaxoSmithKline Biologicals SA  
2. Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
3. Sponsor Study Monitor 
Refer to the local study contact information document. 
4. Sponsor Study Contact for Reporting of a Serious Adverse Event 
GSK Central Back-up Study Contact for Reporting SAEs: refer to the 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 the protocol section 6.3.6.1. 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
Amendment 5 (23 February 2023): 
This amendment is considered substantial based on the criteria defined in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it significantly impacts the scientific value of the trial due to changes made to the 
secondary objectives of the study.  
Overall rationale for the current amendment:  
This protocol has been amended to reflect the following: 
 
The Benefit/Risk assessment has been updated to clarify that: 
 The observed numerical imbalance in neonatal deaths is not an independent 
safety signal but a consequence of the validated signal of preterm births. 
 Based on the evaluation of the Study Day 43 post-birth interim analysis,  
GSK concluded that preterm birth is an identified risk for the pregnant 
women population, for the RSV Maternal vaccine candidate. 
 GSK has discontinued the work on this RSV Maternal vaccine candidate and 
is closing out all ongoing vaccine trials. GSK will continue to monitor and 
follow-up the immunized participants in the trials for the duration specified in 
the respective protocols. 
 
For vaccine efficacy (VE) related objectives, the sensitivity and supportive analyses 
will be only conducted for primary efficacy endpoints, but the sensitivity analysis 
using the negative binomial model has been removed. 
 
The following changes have been made to the secondary efficacy endpoints: 
 For efficacy endpoint from birth to 7 months and above, only the efficacy 
endpoints of “From birth (Visit 1-NB) to 12 months (Visit 5-NB), 
occurrences of severe medically assessed, RSV-associated LRTIs” and 
“From birth (Visit 1-NB) to 12 months (Visit 5-NB), occurrences of any 
medically assessed, RSV-associated LRTIs” will be kept, and the analyses 
will be conducted by using Kaplan-Meier curves from birth to 12 month, so 
that the VE changes across time can be observed. 
 “From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences of any 
medically assessed, RSV-associated LRTIs by alternative case definitions” 
has been removed. 
 “From birth (Visit 1-NB) to 12 months (Visit 5-NB), time to the first 
occurrence of severe medically assessed, RSV-associated LRTIs according to 
the case definition” has been removed. 
 “From birth (Visit 1-NB) to 12 months (Visit 5-NB), time to the first 
occurrence of any medically assessed, RSV-associated LRTIs according to 
the case definition” has been removed. 


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 
Secondary efficacy endpoints on infant participants will only be assessed in the 
Modified Full Efficacy set (FAS) and Secondary efficacy endpoints on maternal 
participants will only be assessed in the Exposed Set (ES). 
 
Secondary immunogenicity endpoints will be assessed in a sub-cohort of maternal-
infant pairs including only those maternal-infant pairs from the per protocol set 
whose babies had blood collected for immunogenicity assessments at the allocated 
time-point.  
 
RSVPreF3 IgG antibody concentrations will be assessed only in maternal blood 
samples collected at delivery and cord blood (or blood samples collected from their 
respective infants within 72 hours after birth, if no cord blood available). 
 
RSV-B neutralizing antibody titers will no longer be assessed as part of the 
secondary immunogenicity endpoints.  
 
 
 
The following populations for analyses have been removed: 
 Maternal participants :- Full Analysis – Immunogenicity, Full Analysis – 
Efficacy 
 Infant participants:- Full analysis – Immunogenicity 
 
Country-specific requirements have been added in Appendix 10.6 for Spain and 
Argentina. 
Also, this amendment includes editorial changes to improve the consistency and 
typographical error corrections. 
List of main changes in the protocol and their rationale:  
Section # and title 
Description of change 
Brief rationale 
Section 2.3 Benefit/Risk 
assessment 
Updated to clarify the status of the 
safety signals after GSK’s signal 
validation process. 
Updated to reflect the changes in the 
benefit/risk profile. 
Section 3 Objectives and 
Endpoints 
Updated the objectives and 
endpoints plan. 
Immunogenicity testing, secondary 
efficacy and tertiary analyses are being 
limited as a consequence of the premature 
stop of enrollment. 
Section 4.2.4 Sub-cohorts, 
Section 6.3.2.1.1 Stage A, 
Section 8.1.3 Immunological 
read-outs  
Updated to note that secondary 
immunogenicity endpoints will be 
assessed only when blood 
samples from a maternal-infant 
pair are available.  
Secondary immunogenicity testing is being 
limited as a consequence of the premature 
stop of enrollment. 
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Section # and title 
Description of change 
Brief rationale 
Section 4.2.6.2/Table 9 
Alternative LRTI / Severe LRTI 
case definitions for data 
analysis in infants 
Added a note to indicate that the 
alternative case definitions will not 
be used for secondary efficacy 
analyses. 
The secondary efficacy objective using 
alternative case definitions has been 
removed. 
Section 8.1.2 Laboratory 
assays/Table 15, Section 8.1.3 
Immunological read-outs/Table 
16  
RSV-B neutralizing antibody 
assessment has been removed. 
Updated to indicate that 
RSVPreF3 IgG Ab concentrations 
will be assessed only in maternal 
blood samples collected at 
delivery, and cord blood. 
 
Secondary immunogenicity testing is being 
limited as a consequence of the premature 
stop of enrollment. 
 
 
 
 
Section 9.3 Populations for 
analyses /Table 22/Table 23  
Updated to reflect the changes to 
populations for analyses. 
Updated to reflect the change to study’s 
statistical analysis plan following the 
decision to stop further enrollment and 
vaccination. 
Section 9.4: Statistical analyses 
Updated to reflect changes to 
secondary efficacy endpoints. 
Updated to reflect changes to secondary 
efficacy endpoints. 
Section 10.6 Appendix 6: 
Country-specific requirements 
Updated to add country-specific 
requirements for Spain and 
Argentina. 
Updated to add country-specific 
requirements for Spain (regarding 
“COMPENSATION”) and Argentina 
(concerning “STUDY POPULATION”). 
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TABLE OF CONTENTS  
PAGE  
PROTOCOL AMENDMENT 5 SPONSOR SIGNATORY APPROVAL ............................. 2 
PROTOCOL AMENDMENT 5 INVESTIGATOR AGREEMENT ....................................... 3 
SPONSOR INFORMATION ............................................................................................ 6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 7 
Overall rationale for the current amendment: ............................................................ 7 
List of main changes in the protocol and their rationale: ........................................... 8 
1. 
PROTOCOL SUMMARY ........................................................................................ 20 
1.1. 
Synopsis ..................................................................................................... 20 
1.2. 
Schema ...................................................................................................... 21 
1.3. 
Schedules of Activities (SoAs) .................................................................... 22 
2. 
INTRODUCTION .................................................................................................... 35 
2.1. 
Study rationale (Amended 23 February 2023) ............................................ 35 
2.2. 
Background ................................................................................................ 36 
2.3. 
Benefit/Risk assessment ............................................................................. 36 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 38 
4. 
STUDY DESIGN .................................................................................................... 42 
4.1. 
Overall design ............................................................................................. 42 
4.2. 
Scientific rationale for study design ............................................................. 47 
4.2.1. 
Study population .......................................................................... 47 
4.2.2. 
Use of placebo ............................................................................. 47 
4.2.3. 
Randomization ratio ..................................................................... 47 
4.2.4. 
Sub-cohorts ................................................................................. 47 
4.2.4.1. 
Safety assessment in maternal participants ................ 47 
4.2.4.2. 
Blood sampling and immune response 
assessment (Amended 23 February 2023) ................. 47 
4.2.5. 
Adaptive design ........................................................................... 48 
4.2.6. 
Case definitions ........................................................................... 48 
4.2.6.1. 
Maternal, medically attended respiratory tract 
illness (MA-RTI) .......................................................... 48 
4.2.6.2. 
Respiratory tract illness (RTI) / Lower 
respiratory tract illness (LRTI) in infants ...................... 49 
4.2.6.3. 
RSV infection .............................................................. 50 
4.2.6.4. 
.................................................. 50 
4.3. 
Justification for dose ................................................................................... 51 
4.4. 
End of Study definition ................................................................................ 51 
5. 
STUDY POPULATION ........................................................................................... 51 
5.1. 
Inclusion criteria for enrolment .................................................................... 51 
5.1.1. 
Maternal participants.................................................................... 52 
5.1.2. 
Infant participants ........................................................................ 53 
5.2. 
Exclusion criteria for enrolment ................................................................... 53 
5.2.1. 
Maternal participants.................................................................... 53 
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5.2.1.1. 
Medical conditions ...................................................... 53 
5.2.1.2. 
Prior/Concomitant therapy .......................................... 56 
5.2.1.3. 
Prior/Concurrent clinical study experience .................. 57 
5.2.1.4. 
Other exclusions ......................................................... 57 
5.2.2. 
Infant participants ........................................................................ 57 
5.3. 
Lifestyle considerations ............................................................................... 57 
5.3.1. 
Demographic data ....................................................................... 57 
5.3.2. 
Lifestyle characteristics ................................................................ 58 
5.3.2.1. 
Maternal participants .................................................. 58 
5.3.2.2. 
Infant participants ....................................................... 58 
5.4. 
Screen failures ............................................................................................ 58 
6. 
STUDY INTERVENTION ........................................................................................ 58 
6.1. 
Study intervention(s) administered .............................................................. 59 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 59 
6.3. 
Measures to minimise bias: randomisation and blinding ............................. 59 
6.3.1. 
Participant identification ............................................................... 59 
6.3.2. 
Randomization to study intervention ............................................ 60 
6.3.2.1. 
Randomization to maternal study intervention 
group .......................................................................... 60 
6.3.2.1.1. 
Stage A (Amended 23 February 
2023) ...................................................... 60 
6.3.2.1.2. 
Stage B ................................................... 62 
6.3.3. 
Intervention allocation to the participant ....................................... 63 
6.3.4. 
Randomization of supplies ........................................................... 64 
6.3.5. 
Allocation of participants to assay subsets ................................... 64 
6.3.6. 
Blinding and unblinding ................................................................ 64 
6.3.6.1. 
Emergency unblinding ................................................ 65 
6.3.6.2. 
Emergency unblinding prior to regulatory 
reporting of SAEs ....................................................... 66 
6.4. 
Study intervention compliance .................................................................... 66 
6.5. 
Concomitant therapy ................................................................................... 66 
6.5.1. 
Maternal participants.................................................................... 66 
6.5.2. 
Infant participants ........................................................................ 67 
6.5.3. 
Maternal and Infant participants ................................................... 67 
6.6. 
Dose modification ....................................................................................... 68 
6.7. 
Intervention after the end of the study ......................................................... 68 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 68 
7.1. 
Discontinuation of study intervention ........................................................... 68 
7.1.1. 
Criteria for temporary delay for enrolment and/or 
vaccination ................................................................................... 68 
7.1.2. 
Contraindications to subsequent vaccine/product 
administration .............................................................................. 68 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 69 
7.3. 
Lost to follow-up .......................................................................................... 69 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 70 
8.1. 
Efficacy and/or immunogenicity assessments ............................................. 72 
8.1.1. 
Biological samples ....................................................................... 73 
8.1.2. 
Laboratory assays ....................................................................... 75 


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8.1.3. 
Immunological read-outs .............................................................. 76 
8.1.4. 
Immunological correlates of protection ......................................... 77 
8.2. 
Safety Assessments ................................................................................... 77 
8.2.1. 
Procedures for maternal participants ........................................... 77 
8.2.1.1. 
Medical/vaccination history ......................................... 77 
8.2.1.2. 
Physical examination (General and obstetric 
examination) ............................................................... 78 
8.2.1.2.1. 
Pulse oximetry ........................................ 79 
8.2.1.2.2. 
Monthly contacts ..................................... 80 
8.2.2. 
Procedures for infant participants................................................. 80 
8.2.2.1. 
Physical examination at Visits 1-NB through 5-
NB .............................................................................. 80 
8.2.3. 
Safety monitoring ......................................................................... 80 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and other 
events of interest ........................................................................................ 81 
8.3.1. 
Time period and frequency for collecting AE, SAE and 
other safety information ............................................................... 81 
8.3.2. 
Method of detecting AEs and SAEs, subsequent 
pregnancies and other events ...................................................... 83 
8.3.3. 
Regulatory reporting requirements for SAEs, subsequent 
pregnancies, and other events ..................................................... 83 
8.3.3.1. 
Contact information for reporting of SAEs, 
AESIs, subsequent pregnancies and study 
holding rules ............................................................... 84 
8.3.4. 
Additional Reporting Guidance for the Study Pregnancy .............. 84 
8.3.4.1. 
Labor and Delivery ..................................................... 84 
8.3.4.2. 
Pregnancy outcomes .................................................. 85 
8.3.5. 
Treatment of adverse events ....................................................... 86 
8.3.6. 
Participant cards .......................................................................... 86 
8.4. 
Respiratory tract illnesses (RTIs) ................................................................ 86 
8.4.1. 
Definitions .................................................................................... 87 
8.4.1.1. 
Medically attended respiratory tract illnesses 
(MA-RTIs) in maternal participants (Amended 
23 February 2023) ...................................................... 87 
8.4.1.2. 
Respiratory tract illnesses (RTIs) in infant 
participants ................................................................. 87 
8.4.2. 
Surveillance ................................................................................. 88 
8.4.2.1. 
Maternal participants .................................................. 88 
8.4.2.2. 
Infant participants ....................................................... 88 
8.4.2.2.1. 
RTI surveillance contacts ........................ 88 
8.4.2.2.2. 
RTI Diary cards ....................................... 89 
8.4.2.3. 
Maternal and infant participants .................................. 89 
8.4.3. 
When to conduct an assessment visit .......................................... 89 
8.4.3.1. 
For a maternal MA-RTI ............................................... 89 
8.4.3.2. 
For an infant RTI ........................................................ 91 
8.4.4. 
Assessment visit procedures ....................................................... 93 
8.4.4.1. 
Clinical evaluation....................................................... 93 
8.4.4.2. 
Nasal swab collection ................................................. 94 
8.4.4.3. 
Missed assessment visit ............................................. 94 
8.4.5. 
RTI hospitalization during the surveillance interval ....................... 94 
8.4.6. 
Follow-up of infant respiratory tract illnesses ............................... 94 
8.4.7. 
Covid-19 Infection ........................................................................ 94 


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8.5. 
Treatment of overdose ................................................................................ 95 
8.6. 
Pharmacokinetics ....................................................................................... 95 
8.7. 
Pharmacodynamics .................................................................................... 95 
8.8. 
Genetics ..................................................................................................... 95 
8.9. 
Biomarkers ................................................................................................. 95 
8.10. 
Health outcomes ......................................................................................... 95 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 95 
9.1. 
Statistical hypotheses ................................................................................. 95 
9.2. 
Sample size determination .......................................................................... 95 
9.3. 
Populations for analyses (Amended 23 February 2023) .............................. 96 
9.3.1. 
Criteria for elimination from analysis ............................................ 96 
9.3.1.1. 
Intercurrent medical conditions and 
concomitant medications / products / vaccines 
that may lead to elimination of a participant 
(maternal/infant) from per-protocol analyses 
(efficacy/immunogenicity) ........................................... 96 
9.3.1.1.1. 
Maternal participants .............................. 96 
9.3.1.1.2. 
Infant participants ................................... 97 
9.3.1.1.3. 
Maternal and Infant participants .............. 97 
9.3.1.2. 
Other situations that may lead to elimination of 
a participant (maternal / infant) from per-
protocol analyses (efficacy/immunogenicity) ............... 97 
9.4. 
Statistical analyses ..................................................................................... 97 
9.4.1. 
General considerations (Amended 23 February 2023) ................. 97 
9.4.2. 
Participants disposition ................................................................ 98 
9.4.3. 
Primary endpoints (Amended 23 February 2023) ......................... 98 
9.4.4. 
Secondary endpoints ................................................................. 100 
9.4.4.1. 
Efficacy (Amended 23 February 2023) ..................... 100 
9.4.4.2. 
Detailed Statistical Analysis Methods ....................... 102 
9.4.4.3. 
Immunogenicity (Amended 23 February 2023) ......... 102 
9.4.4.4. 
Safety ....................................................................... 103 
9.4.5. 
Tertiary/exploratory endpoint(s) ................................................. 105 
9.4.6. 
Other analyses........................................................................... 105 
9.4.6.1. 
Demography and baseline characteristics 
analyses ................................................................... 105 
9.4.6.2. 
Case accruals ........................................................... 106 
9.5. 
Interim analyses ........................................................................................ 106 
9.5.1. 
Sequence of analyses ................................................................ 106 
9.6. 
 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 107 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .......................................................................................... 107 
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10.1.1. 
Regulatory and ethical considerations ....................................... 107 
10.1.2. 
Financial disclosure ................................................................... 107 
10.1.3. 
Informed consent process .......................................................... 108 
10.1.4. 
Data protection .......................................................................... 108 
10.1.5. 
Committees structure ................................................................. 109 
10.1.6. 
Dissemination of clinical study data ........................................... 109 
10.1.7. 
Data quality assurance .............................................................. 110 
10.1.8. 
Source documents ..................................................................... 110 
10.1.9. 
Study and site start and closure ................................................. 111 
10.1.10. Publication policy ....................................................................... 111 
10.2. 
Appendix 2: Clinical laboratory tests ......................................................... 111 
10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting Definition of AE ................ 112 
10.3.1. 
Definition of an Adverse Event (AE) ........................................... 112 
10.3.1.1. Events Meeting the AE Definition ............................. 112 
10.3.1.2. Events NOT Meeting the AE Definition ..................... 113 
10.3.2. 
Definition of a Serious Adverse Event (SAE) ............................. 114 
10.3.3. 
Solicited events .......................................................................... 115 
10.3.4. 
Unsolicited adverse events ........................................................ 115 
10.3.5. 
Adverse events of special interest (AESIs) ................................ 116 
10.3.6. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as AEs or SAEs .................................... 117 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs ................... 117 
10.3.7.1. Subsequent Pregnancy ............................................ 117 
10.3.8. 
Recording and follow-up of AEs, SAEs, AESIs and 
subsequent pregnancies ............................................................ 118 
10.3.8.1. Time period for collecting and recording AEs, 
SAEs, AESIs and subsequent pregnancies .............. 118 
10.3.8.2. Where to record AEs, SAEs, AESIs, 
subsequent pregnancies and other events of 
interest ..................................................................... 118 
10.3.8.3. Follow-up of AEs, SAEs, AESIs, subsequent 
pregnancies or any other events of interest .............. 119 
10.3.8.3.1. Follow-up during the study .................... 119 
10.3.8.3.2. Follow-up after the participant is 
discharged from the study..................... 119 
10.3.8.3.3. Follow-up of subsequent 
pregnancies .......................................... 119 
10.3.8.4. Updating of SAE, AESI and subsequent 
pregnancy information after removal of write 
access to the participant’s eCRF .............................. 120 
10.3.9. 
Assessment of intensity and toxicity ........................................... 120 
10.3.9.1. Assessment of intensity ............................................ 120 
10.3.9.2. Assessment of causality ........................................... 121 
10.3.9.3. Medically attended visits ........................................... 122 
10.3.9.4. Assessment of outcomes .......................................... 122 
10.3.10. Reporting of SAEs, AESIs, subsequent pregnancies and 
other events ............................................................................... 123 
10.3.10.1. Events requiring expedited reporting to GSK ............ 123 
10.3.10.2. Back-up system in case facsimile or electronic 
reporting system does not work ................................ 123 


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10.4. 
Appendix 4: Contraceptive guidance and collection of subsequent 
pregnancy information .............................................................................. 123 
10.5. 
Appendix 5: Genetics ................................................................................ 123 
10.6. 
Appendix 6: Country-specific requirements (Amended 23 February 
2023) ........................................................................................................ 124 
10.6.1. 
France ....................................................................................... 124 
10.6.2. 
South Korea ............................................................................... 128 
10.6.3. 
Spain ......................................................................................... 128 
10.6.4. 
Argentina ................................................................................... 129 
10.7. 
Appendix 7: Abbreviations and glossary of terms ...................................... 130 
10.7.1. 
List of abbreviations ................................................................... 130 
10.7.2. 
Glossary of terms ....................................................................... 132 
10.8. 
Appendix 8: Gestational Age Assessment ................................................ 137 
10.8.1. 
GAIA gestational age assessment form ..................................... 137 
10.8.2. 
Methods of gestational age assessment and estimation of 
due date..................................................................................... 137 
10.9. 
Appendix 9: Definitions of maternal, fetal and neonatal events of 
interest as per GAIA.................................................................................. 138 
10.11. Appendix 11: Protocol Amendment history ............................................... 181 
11. REFERENCES ..................................................................................................... 309 
 
CCI


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LIST OF TABLES  
PAGE 
Table 1 
Schedule of activities for maternal participants ....................................... 24 
Table 2 
Schedule of activities for infant participants ............................................ 30 
Table 3 
Intervals between study visits and contacts ............................................ 33 
Table 4 
Study objectives and endpoints (Amended 23 February 2023) ............... 38 
Table 5 
Study groups, sub-cohorts, interventions, and blinding foreseen 
in the study: Stage A .............................................................................. 45 
Table 6 
Study groups, sub-cohorts, interventions, and blinding foreseen 
in the study: Stage B .............................................................................. 46 
Table 7 
MA-RTI case definitions for data analysis in maternal participants ......... 48 
Table 8 
RTI/LRTI case definitions for data analysis in infants ............................. 49 
Table 9 
Alternative LRTI / Severe LRTI case definitions for data analysis 
in infants................................................................................................. 50 
Table 10 
Study intervention(s) administered ......................................................... 59 
Table 11 
Contact information for emergency unblinding ....................................... 65 
Table 12 
Biological samples – maternal participants ............................................. 73 
Table 13 
Biological samples – Cord Blood ............................................................ 74 
Table 14 
Biological samples – infant participants .................................................. 74 
Table 15 
Laboratory assays .................................................................................. 75 
Table 16 
Immunological read-outs (Amended 23 February 2023) ......................... 76 
Table 17 
Molecular biology tests ........................................................................... 77 
Table 18 
Timeframes for collecting and reporting safety (and RTI) 
information ............................................................................................. 81 
Table 19 
Timeframes for submitting serious adverse event, subsequent 
pregnancy and other events reports to GSK ........................................... 84 
Table 20 
Contact information for reporting of SAEs, AESIs, subsequent 
pregnancies ........................................................................................... 84 
Table 21 
Reporting pregnancy outcomes with or without congenital 
anomalies as AESIs and/or SAEs .......................................................... 85 


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Table 22 
Maternal participants .............................................................................. 96 
Table 23 
Infant participants ................................................................................... 96 
Table 24 
Solicited administration site events ....................................................... 115 
Table 25 
Solicited systemic events ..................................................................... 115 
Table 26 
Intensity scales for solicited events in adults ........................................ 120 
Table 27 
Fetal death / Stillbirth............................................................................ 140 
Table 28 
Maternal Death..................................................................................... 143 
Table 29 
Hypertensive disorders of pregnancy (Gestational hypertension, 
Pre-eclampsia, Pre-eclampsia with severe features including 
eclampsia) ............................................................................................ 144 
Table 30 
Antenatal Bleeding ............................................................................... 146 
Table 31 
Postpartum hemorrhage ....................................................................... 148 
Table 32 
Fetal growth restriction ......................................................................... 149 
Table 33 
Gestational diabetes mellitus (pregnancy induced 
hyperglycemia) ..................................................................................... 150 
Table 34 
Non-reassuring fetal status .................................................................. 152 
Table 35 
Pathways to preterm birth .................................................................... 153 
Table 36 
Chorioamnionitis .................................................................................. 155 
Table 37 
Standard Definitions for Maternal Events of interest not defined 
as events in GAIA ................................................................................ 157 
Table 38 
Small for Gestational Age ..................................................................... 159 
Table 39 
Low Birth Weight (LBW) ....................................................................... 161 
Table 40 
Neonatal encephalopathy ..................................................................... 162 
Table 41 
Congenital Microcephaly ...................................................................... 163 
Table 42 
Major Congenital anomalies ................................................................. 166 
Table 43 
Neonatal Death .................................................................................... 169 
Table 44 
Neonatal Infections .............................................................................. 171 
Table 45 
Respiratory Distress in the Neonate ..................................................... 174 
Table 46 
Preterm Birth ........................................................................................ 175 


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Table 47 
Failure to Thrive ................................................................................... 176 
Table 48 
Standard Definitions for Neonatal Events of interest not defined 
as events in GAIA ................................................................................ 177 
Table 49 
Operating Characteristics with futility stopping, 200/month 
accrual, 1% severe LRTI, and 3% any-severity LRTI ........................... 178 
Table 50 
Operating Characteristics with futility stopping, 400/month 
accrual, 1% severe LRTI, and 3% any-severity LRTI ........................... 178 
Table 51 
Operating Characteristics with futility stopping, varying accrual 
rates, 1% severe LRTI, and 3% any-severity LRTI ............................... 178 
Table 52 
Operating Characteristics under 325/month accrual, 2% severe 
LRTI, and 6% any-severity LRTI .......................................................... 179 
Table 53 
Operating Characteristics under 325/month accrual, 0.5% severe 
LRTI, and 1.5% any-severity LRTI ........................................................ 179 
Table 54 
Operating Characteristics under varying accrual rates, 1% 
severe LRTI, and 3% any-severity LRTI) .............................................. 179 
Table 55 
Null scenario operating characteristics under different RSV 
attack rate scenarios, without futility stopping, 325/month accrual ........ 180 
Table 56 
Null scenario operating characteristics under different RSV 
attack rate scenarios, without futility stopping, 200/month accrual ........ 180 
 


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LIST OF FIGURES  
PAGE 
Figure 1 
Study design overview – maternal participants (Amended 23 
February 2023)....................................................................................... 43 
Figure 2 
Study design overview – infant participants ............................................ 44 
Figure 3 
Randomization Overview – Stage A ....................................................... 60 
Figure 4 
Stage A Sub-Cohort Distributions ........................................................... 62 
Figure 5 
Randomization Overview – Stage B ....................................................... 63 
Figure 6 
Decision Tree for site personnel – maternal surveillance and 
assessment ............................................................................................ 90 
Figure 7 
Decision Tree for site personnel - infant surveillance and 
assessment ............................................................................................ 92 
 


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1. 
PROTOCOL SUMMARY  
1.1. 
Synopsis  
Rationale: 
RSV MAT-009 will evaluate: 
 
The efficacy, safety, reactogenicity, and immunogenicity of the investigational RSV 
maternal vaccine when administered to pregnant women between 24 and 34 weeks 
gestational age (inclusive) and 
 
The effects of maternal immunization on the infants born to these vaccinated women. 
In the RSV maternal program to date, a Phase 1/2 study (RSV MAT-001; NCT 
03674177) in healthy non-pregnant women 18-45 years of age to determine the safety 
and immunogenicity of 3 dose levels of the RSV (RSVPreF3) maternal vaccine (30, 60 
and 120 µg) compared to placebo has been completed. No safety concerns have been 
identified.  
Based on preliminary results of RSV MAT-001, the 60 and 120 µg dose-levels were 
selected for further evaluation in the following 2 additional studies, which are ongoing:  
 
RSV-MAT 004 (NCT 04126213): A Phase II observer-blind study to assess safety, 
reactogenicity, and immunogenicity of GSK Biologicals’ investigational RSV 
Maternal unadjuvanted vaccine (GSK3888550A), in healthy pregnant women and 
infants born to vaccinated mothers 
 
RSV-MAT 011 (NCT 04138056): A Phase II study of 2 dose levels of an 
investigational RSV maternal vaccine, given alone or with Boostrix, to healthy non-
pregnant women to assess safety, reactogenicity, and immunogenicity.  
Based on the final results of RSV MAT-001, which are summarized in a clinical study 
report, and on the Day 31 results of RSV MAT-004 and -011, the 120 µg dose-level has 
been selected for evaluation in RSV MAT-009. 
RSV MAT-009 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-004 
and -011 studies.  
Note: Based on all available safety information following vaccination with the RSV 
MAT vaccine, there will be no further enrollment and vaccination of maternal 
participants. However, monitoring will continue for rest of the study. All planned 
objectives described in the latest protocol amendment will be assessed for the 
participants enrolled so far.  
Objectives and Endpoints are presented in Table 4. 


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1.2. 
Schema  
This is a multi-center, randomized, double-blinded, placebo-controlled study. Maternal 
participants 18 to 49 years of age (inclusive, at the time of the study intervention) will be 
assigned to one of 2 study groups and will receive a single intramuscular injection 
between 24 0/7 to 34 0/7 weeks of gestation (inclusive). 
Up to approximately 10 000 participants will be enrolled; it is expected that at least 20% 
of these participants will be enrolled at centers located in the U.S. 
Enrollment will occur in 2 sequential stages, A and B.  
In Stage A, approximately 4600 maternal participants will be enrolled as follows: 
 
RSV Maternal (RSVPreF3) vaccine, 120 µg (N ~ 3067),  
 
Control (Lyophilized sucrose placebo; N ~ 1533). 
In Stage B, an additional approximately 5,400 maternal participants will be enrolled: 
 
RSV Maternal (RSVPreF3) vaccine, 120 µg (N ~ 3600),  
 
Control (Lyophilized sucrose placebo; N ~ 1800). 
During both stages, maternal participants who receive the study intervention will be 
followed for safety for up to approximately 10 to 11 months (from screening until 6 
months after delivery). Infant participants will be evaluated for the occurrence of 
medically assessed, RSV-associated lower respiratory tract illnesses and safety for 12 
months after birth.  
In addition, during Stage A: 
 
All maternal participants will be evaluated for reactogenicity; 
 
A sub-cohort of approximately 1533 maternal participants will be evaluated for 
immune response, including maternal – infant RSV-specific antibody transfer 
(approximately 1020 study vaccine recipients; approximately 510 control recipients);  
 
Sub-cohorts of infant participants whose mothers were in the immunogenicity sub-
cohort referred to above, will be evaluated for RSV-specific antibody levels post-
birth (in total, approximately 1020 infants born to vaccine recipients evaluated for 
immune response and approximately 510 infants born to control recipients evaluated 
for immune response). 
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives, since sample collection in infants was discontinued 
following stop of enrollment. 
Section 4.1 provides an overview of the study design. 


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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.  
A firewall will be established to ensure that data are not inadvertently unblinded. Details 
are provided in a separate Firewall charter. 
* Due to the safety signal observed, the study was fully unblinded to ensure the safety of 
the participants. 
1.3. 
Schedules of Activities (SoAs)  
For maternal participants, Table 1 presents the Schedule of Activities (SoA). For infant 
participants, Table 2 presents the SoA. Table 3 describes the allowed study visit intervals 
for both maternal and infant participants.  
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 participants or their infants), participants 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 
 
Maternal participant visits at Screening / Visit 1 (Day 1) may take place at the study 
site or another medical facility.  
 
When a maternal participant completes Visit 1 (study intervention), and again at 
Visit 3 (delivery), site staff should, in so far as possible, 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 participant’s (approximate) date 
of delivery and potential enrolment of the neonate. 
 
Maternal participant Visits 2 and 4, infant participant Visits 1-NB, 2-NB, 3-NB, 4-
NB and 5-NB, and maternal and infant respiratory tract illness (RTI) assessment 
visits may take place at the investigator’s clinical facility, 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 site must have appropriate infrastructure and logistics to complete ALL study 
procedures if a visit is to be conducted at the participant’s home. Blood samples for 
immunogenicity collected during a home visit must be centrifuged within, at most, 
24 hours after collection. Cord blood samples must be centrifuged within, at most, 24 
hours after collection. 


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 
Contact may be via telephone, SMS, email, videotelephony/telemedicine or other 
means, depending on local best practice. If the study site is the participant’s primary 
healthcare facility, contact with study personnel may also be made in the context of a 
visit for routine or event-driven care. 


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Table 1 
Schedule of activities for maternal participants  
Visit / Contact 
Screening 
V1 
V2*  
Contacts 
(Monthly) 
V3 
V4  
C1 
Event Driven 
 
Gestational Age (GA) 
≤ 28 days 
before V1 
240/7 – 
340/7 
 
Until 
Delivery 
Delivery 
 
 
Additional 
contact(s)1 
Safety 
visit 
MA-
RTI 
visit 
For monthly contacts: 
Section 8.2.1.2.2.  
Additional contact(s) and/or 
safety visit(s) can be made 
between Visit-2 and the 
Delivery visit, if deemed 
necessary. 
Visit Day 
D-28 – D1 
before 
randomization 
D1 
D31 
 
D1PD 
D43 
PD 
D181 
PD 
V2-
Delivery 
 
 
Table 3 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
Section 10.1.3 
Check Inclusion/exclusion 
criteria  
● 
O 
 
 
 
 
 
 
 
 
Sections 5.1.1, 5.1.2 
Assign maternal participant 
study number  
● 
 
 
 
 
 
 
 
 
 
Section 6.3.1 
Register maternal 
participant in SBIR 
O 
 
 
 
 
 
 
 
 
 
Section 6.3.1 
Assign infant participant 
study number  
 
O 
 
 
 
 
 
 
 
 
Section 6.3.1 
Record Demographic data  
● 
 
 
 
 
 
 
 
 
 
Section 5.3 
Record lifestyle 
characteristics 
● 
 
 
 
 
 
 
 
 
 
Review & collect Medical 
and vaccination history 
O  
● 
 
 
 
 
 
 
 
 
 Section 8.2.1.1 
Record outcome of fetal 
morphology ultrasound 
scan 
● 
 
 
 
 
 
 
 
 
 
 


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Visit / Contact 
Screening 
V1 
V2*  
Contacts 
(Monthly) 
V3 
V4  
C1 
Event Driven 
 
Gestational Age (GA) 
≤ 28 days 
before V1 
240/7 – 
340/7 
 
Until 
Delivery 
Delivery 
 
 
Additional 
contact(s)1 
Safety 
visit 
MA-
RTI 
visit 
For monthly contacts: 
Section 8.2.1.2.2.  
Additional contact(s) and/or 
safety visit(s) can be made 
between Visit-2 and the 
Delivery visit, if deemed 
necessary. 
Visit Day 
D-28 – D1 
before 
randomization 
D1 
D31 
 
D1PD 
D43 
PD 
D181 
PD 
V2-
Delivery 
 
 
Table 3 
Record obstetric history 
from past and current 
pregnancies 
● 
(current 
pregnancy) 
●  
(past 
pregnancy/ 
ies) 
 
 
 
 
 
 
 
 
Record Travel history to or 
living in Zika virus endemic 
countries/regions  
● 
● 
● 
● 
● 
 
 
● 
 
 
During the current 
pregnancy only 
General and/or obstetrical 
examination  
● 
● 
● 
 
● 
● 
 
 
If 
needed 
If 
needed 
General and/or Obstetrical 
exam is symptom directed at 
V4, & 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. 
Blood sample  
(immunogenicity ~ 10 ml)  
 
● 
● 
 
Sub-
cohort 
● 
 
 
 
 
 
At V1 and V2, collected from 
all participants in both Stage 
A and Stage B. At V3, 
collected only from a sub-


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Visit / Contact 
Screening 
V1 
V2*  
Contacts 
(Monthly) 
V3 
V4  
C1 
Event Driven 
 
Gestational Age (GA) 
≤ 28 days 
before V1 
240/7 – 
340/7 
 
Until 
Delivery 
Delivery 
 
 
Additional 
contact(s)1 
Safety 
visit 
MA-
RTI 
visit 
For monthly contacts: 
Section 8.2.1.2.2.  
Additional contact(s) and/or 
safety visit(s) can be made 
between Visit-2 and the 
Delivery visit, if deemed 
necessary. 
Visit Day 
D-28 – D1 
before 
randomization 
D1 
D31 
 
D1PD 
D43 
PD 
D181 
PD 
V2-
Delivery 
 
 
Table 3 
cohort in Stage A. See 
Table 12 and Sections 8.1.1 
and 8.1.3 
As from protocol 
amendment 4 Blood sample 
at delivery to be collected 
from all participants. 
Cord blood (~ 5 to 10 ml) 
 
 
 
 
● 
 
 
 
 
 
Collected from all 
participants in both Stage A 
and Stage B. See Table 13 
and Sections 8.1.1 and 
8.1.3. 
Placenta sample 
 
 
 
 
● 
 
 
 
 
 
Collect from all participants, 
if feasible. 
Nasal swab  
 
 
 
 
 
 
 
 
 
● 
See Table 12 and Sections 
8.1.1, 8.1.3, and 8.4.4.  
Note: As from protocol 
amendment 4 nasal swab 
from maternal participants 
will no longer be collected 
and MA-RTI visit is no 
longer required. 
Check contraindications to 
and criteria for temporary 
delay for vaccination 
 
O 
 
 
 
 
 
 
 
 
Section 7.1 


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Visit / Contact 
Screening 
V1 
V2*  
Contacts 
(Monthly) 
V3 
V4  
C1 
Event Driven 
 
Gestational Age (GA) 
≤ 28 days 
before V1 
240/7 – 
340/7 
 
Until 
Delivery 
Delivery 
 
 
Additional 
contact(s)1 
Safety 
visit 
MA-
RTI 
visit 
For monthly contacts: 
Section 8.2.1.2.2.  
Additional contact(s) and/or 
safety visit(s) can be made 
between Visit-2 and the 
Delivery visit, if deemed 
necessary. 
Visit Day 
D-28 – D1 
before 
randomization 
D1 
D31 
 
D1PD 
D43 
PD 
D181 
PD 
V2-
Delivery 
 
 
Table 3 
Allocate maternal study 
group, intervention number 
 
O 
 
 
 
 
 
 
 
 
Sections 6.3.2, 6.3.3 
Recording will be done at 
Visit 1, upon maternal 
participant randomization 
but the eCRF entry will be 
done on the demography 
screen 
Record maternal sub-
cohort for immunogenicity 
assessment 
 
● 
 
 
 
 
 
 
 
 
Allocate infant sub-cohorts 
for immunogenicity 
assessment  
 
O 
 
 
 
 
 
 
 
 
Administer Study 
Intervention  
(study vaccine / placebo) 
 
● 
 
 
 
 
 
 
 
 
Sections 6.1, 6.2 
Record administered 
intervention number 
 
● 
 
 
 
 
 
 
 
 
Observe for 30 minutes 
post-dose 
 
O 
 
 
 
 
 
 
 
 
Distribute maternal 
participant card 
O 
O 
 
 
 
 
 
 
 
 
At screening or at Visit 1 as 
per local practice. Section 
8.3.6 
Record Labor / Delivery 
information  
 
 
 
 
● 
 
 
 
 
 
 
Record pregnancy / 
delivery outcomes  
 
 
 
 
● 
 
 
 
 
 
Submit Expedited AE report 
for an adverse pregnancy 
outcome (Section 8.3.3) 


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Visit / Contact 
Screening 
V1 
V2*  
Contacts 
(Monthly) 
V3 
V4  
C1 
Event Driven 
 
Gestational Age (GA) 
≤ 28 days 
before V1 
240/7 – 
340/7 
 
Until 
Delivery 
Delivery 
 
 
Additional 
contact(s)1 
Safety 
visit 
MA-
RTI 
visit 
For monthly contacts: 
Section 8.2.1.2.2.  
Additional contact(s) and/or 
safety visit(s) can be made 
between Visit-2 and the 
Delivery visit, if deemed 
necessary. 
Visit Day 
D-28 – D1 
before 
randomization 
D1 
D31 
 
D1PD 
D43 
PD 
D181 
PD 
V2-
Delivery 
 
 
Table 3 
Train maternal participant 
/LAR on use of electronic 
diary 
 
O 
Stage A 
 
 
 
 
 
 
 
 
Section 10.3.8  
 
 
 
 
 
Section 8.3.1 
Distribute electronic diary 
to maternal participant / 
LAR.  
 
O 
Stage A 
 
 
 
 
 
 
 
 
Review electronic diary 
entries 
 
 
O 
Stage 
A 
 
 
 
 
 
 
 
Return electronic diary 
 
 
O 
Stage 
A 
 
 
 
 
 
 
 
 
Concomitant medications / 
vaccinations. 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 6.5.1 and 6.5.3 
All unsolicited AEs (Days 1 
to 30)  
 
● 
● 
 
 
 
 
 
● 
● 
Sections 8.3.1, 10.3.4 and 
10.3.8 
Pregnancy-related AESIs  
 
● 
● 
● 
● 
● 
● 
● 
● 
 
Table 4, Sections 8.3.1, 
8.3.3, 8.3.4, and 10.3.5. 
Must submit an Expedited 
AE report. 
MAEs other than MA-RTIs 
 
● 
● 
● 
● 
● 
 
● 
● 
 
Medically attended RTIs to 
be reported up to C1. 
MA-RTI signs  
 
 
 
 
 
 
 
 
 
● 
Sections 8.3.1, 8.3.3, 8.4 
Note: As from protocol 
amendment 4 nasal swab 


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Visit / Contact 
Screening 
V1 
V2*  
Contacts 
(Monthly) 
V3 
V4  
C1 
Event Driven 
 
Gestational Age (GA) 
≤ 28 days 
before V1 
240/7 – 
340/7 
 
Until 
Delivery 
Delivery 
 
 
Additional 
contact(s)1 
Safety 
visit 
MA-
RTI 
visit 
For monthly contacts: 
Section 8.2.1.2.2.  
Additional contact(s) and/or 
safety visit(s) can be made 
between Visit-2 and the 
Delivery visit, if deemed 
necessary. 
Visit Day 
D-28 – D1 
before 
randomization 
D1 
D31 
 
D1PD 
D43 
PD 
D181 
PD 
V2-
Delivery 
 
 
Table 3 
from maternal participants 
will no longer be collected 
and MA-RTI visit is no 
longer required. 
SAEs, MA-RTI associated 
AEs and AEs leading to 
study withdrawal  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 7.2, 8.3.1 and 
10.3.8  
SAEs related to study 
participation or concurrent 
GSK medication/vaccine 
● 
● 
 
 
 
 
 
 
 
 
Sections 8.3.1 and 10.3.8 
Subsequent pregnancies 
 
 
 
 
 
● 
● 
 
● 
● 
Sections 8.3.1 and 10.3.8 
Record interest in joining 
future extension study 
O 
 
 
 
 
 
● 
 
 
 
Section 6.7 
Screening conclusion  
● 
 
 
 
 
 
 
 
 
 
 
Study conclusion 
 
 
 
 
 
 
● 
 
 
 
Section 4.4 
Investigator sign-off at 
study conclusion 
 
 
 
 
 
 
● 
 
 
 
 
The timing of an event-driven site visit (e.g., to further evaluate a potential AE or MA-RTI) cannot be defined with precision in the protocol. Event-driven visits may occur throughout the 
study. ● 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. 
* V2 may be replaced by V3, depending on delivery date. 
1 In addition to the monthly contacts between Visit-2 and the Delivery visit, additional not pre-specified visits and contacts (any desired frequency) can be made between Visit-2 and the 
Delivery visit, as per investigator’s or maternal participant’s discretion. 


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Table 2 
Schedule of activities for infant participants  
 Visit / Contact 
V1-
NB1  
Safety contact 
(recommended)1 
V2-NB 
C1-NB 
V3-NB  
V4-NB  
C2-NB  
V5-NB  
RTI Surveillance 
RTI Surveillance: Section 
8.4.2 
RTI Visit: Sections 8.4.3 
and 8.4.4 
Age of infant 
Birth 
8 days 
6 
weeks 
3 
months 
4 
months 
6 
months 
9 
months 
12 
months 
Contacts 
Visits 
 
Visit Day 
D 1-
21  
D8 (7 days post-
birth) 
D43 
D91 
D121 
D181 
D271 
D366 
Birth – D366 
See Table 3 for intervals 
between visits, contacts. 
Check Inclusion / 
exclusion criteria  
● 
 
 
 
 
 
 
 
 
 
Sections 5.1.2 and 5.2.2 
Re-consent / Consent for 
infant participation if 
required by local 
regulations  
● 
 
 
 
 
 
 
 
 
 
 
Record infant participant 
study number  
● 
 
 
 
 
 
 
 
 
 
 
Record sub-cohort for 
immunogenicity 
assessment, if applicable 
● 
 
 
 
 
 
 
 
 
 
Section 6.3.2.1.2 
Distribute infant’s 
participant card  
O 
 
 
 
 
 
 
 
 
 
Section 8.3.6 
Distribute infant RTI-
diary card  
O 
O 
O 
O 
O 
O 
O 
 
 
O 
Distribute at V1-NB: 
Distribute additional RTI-
diary cards as needed. 
Section 8.4.2.2 and SPM 
Review infant RTI-diary 
card  
 
O 
O 
O 
O 
O 
O 
O 
 
O 
 
Collect infant RTI-diary 
card 
 
O 
O 
O 
O 
O 
O 
O 
 
O 
Collect RTI-diary cards that 
are fully filled out. Section 
8.4.2.2 and SPM 
Transcribe applicable 
infant RTI-diary card 
data to eCRF  
 
● 
● 
● 
● 
● 
● 
● 
 
● 
 


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 Visit / Contact 
V1-
NB1  
Safety contact 
(recommended)1 
V2-NB 
C1-NB 
V3-NB  
V4-NB  
C2-NB  
V5-NB  
RTI Surveillance 
RTI Surveillance: Section 
8.4.2 
RTI Visit: Sections 8.4.3 
and 8.4.4 
Age of infant 
Birth 
8 days 
6 
weeks 
3 
months 
4 
months 
6 
months 
9 
months 
12 
months 
Contacts 
Visits 
 
Visit Day 
D 1-
21  
D8 (7 days post-
birth) 
D43 
D91 
D121 
D181 
D271 
D366 
Birth – D366 
See Table 3 for intervals 
between visits, contacts. 
Demographic data  
● 
 
 
 
 
 
 
 
 
 
Section 5.3  
Record at Visit 1-NB and if 
changes in lifestyle 
characteristics thereafter 
Lifestyle characteristics 
● 
 
● 
● 
● 
● 
● 
● 
 
 
Apgar score  
● 
 
 
 
 
 
 
 
 
 
At 1, 5 and (if 
available/performed) at 10 
minutes,  
Weight, length, head 
circumference, physical 
examination  
● 
 
● 
 
● 
● 
 
● 
 
 
Section 8.2.2 
Blood sample if no cord 
blood  
~2.5 ml 
● 
 
 
 
 
 
 
 
 
 
Adjust volume if weight ≤ 
2.5 Kg. Refer to Table 14  
Blood sample 
(immunology, infants) 
~2.5 ml 
 
 
● 
Sub 
cohort 
1 
 
● 
Sub 
cohort 2 
●  
Sub 
cohort 3 
 
 
 
 
1 sample at one of these 
visits, as per infant’s 
assigned sub-cohort. Adjust 
volume if weight ≤ 2.5 Kg. 
Refer to Table 14 
As from protocol 
amendment 4, Blood 
samples will no longer be 
collected at V2-NB, V3-NB 
or V4-NB. 
Concomitant 
vaccinations 
● 
● 
● 
● 
● 
● 
 
 
 
 
 
Concomitant medications  ● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 6.5.2 and 6.5.3 
Neonatal AESIs  
● 
● 
● 
 
 
 
 
 
 
 
Table 4, Sections 8.3.1, 
8.3.3, 8.3.4, and 10.3.5. 


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 Visit / Contact 
V1-
NB1  
Safety contact 
(recommended)1 
V2-NB 
C1-NB 
V3-NB  
V4-NB  
C2-NB  
V5-NB  
RTI Surveillance 
RTI Surveillance: Section 
8.4.2 
RTI Visit: Sections 8.4.3 
and 8.4.4 
Age of infant 
Birth 
8 days 
6 
weeks 
3 
months 
4 
months 
6 
months 
9 
months 
12 
months 
Contacts 
Visits 
 
Visit Day 
D 1-
21  
D8 (7 days post-
birth) 
D43 
D91 
D121 
D181 
D271 
D366 
Birth – D366 
See Table 3 for intervals 
between visits, contacts. 
Must submit an Expedited 
AE report. 
An additional recommended 
safety contact may be 
performed ~8 days post-
birth if deemed necessary to 
closely monitor the newborn 
and support collection and 
reporting of any neonatal 
AESI(s). 
SAEs, MAEs and AEs 
leading to study 
withdrawal  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 7.2, 8.3.1, and 
10.3.8 
Symptom-directed 
physical examination 
(includes RTI signs, 
symptoms) 
 
 
 
 
 
 
 
 
 
● 
Section 8.4.4 
Nasal swab 
 
 
 
 
 
 
 
 
 
● 
Sections 8.1.1 , 8.4.4.2, 
Table 14 
Study conclusion  
 
 
 
 
 
 
 
● 
 
 
Section 4.4 
Investigator sign-off at 
study conclusion 
 
 
 
 
 
 
 
● 
 
 
 
The timing of an event-driven visit cannot be defined with precision in the protocol. ● 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. 
1 An additional optional but recommended safety contact may be performed on ~Day 8 (7 days post-birth) if deemed necessary by the investigator or by the parent/LAR(s). 


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Table 3 
Intervals between study visits and contacts  
Interval 
Optimal 
interval 
in Days 
Allowed 
interval 
in Days 
Additional Information 
Maternal participants 
Screening to 
V1  
0  
0– 28  
The screening interval extends from Day -28 to Day 1 before randomization. If all eligibility criteria can be confirmed on the day of screening 
and all required procedures can be performed, then, “Screening” and “Visit 1” may occur on the same day (refer to Section 8.2.1.2).  
Data from all screening procedures must be available and eligibility must be confirmed before the participant is randomized. 
If a participant is screened but not vaccinated within the allowed interval, a re-screening should be done to establish the participant’s 
eligibility. Please make sure the participant’s gestational age is still within the allowed range, refer to Section 10.8 for guidance on 
gestational age assessment. 
V1 to V2  
30  
20 - 45  
If this visit occurs before Day 25, the site must contact the participant to collect information about any additional unsolicited adverse events 
that may occur between the date of the visit and Day 31.   
Monthly 
contacts 
~ every 25 – 35  
Monthly beginning after Visit 2 until Delivery. Contacts are additional to and do not replace protocol specified Visits. 
Additional contact(s)/visit(s) can be made more often if deemed necessary by the investigator or the maternal participant. 
V3 (delivery)  
0  
1 day 
before to 
3 days 
after 
delivery  
For maternal participants in the Stage A immunogenicity sub-cohort: collect maternal blood sample at any point from the start of labor up to 
delivery. 
(NOTE: For participants for which a cesarean section is planned, the sample may be collected as soon as the participant arrives at the clinic 
and the intravenous line is inserted to prepare them for the cesarean section). 
If blood is not collected during delivery, collect maternal blood sample no later than 72 hours after delivery.  
For all participants in both Stage A and Stage B: A cord blood sample should be collected at the time of delivery. If cord blood cannot be 
collected at delivery, a blood sample should be collected from the infant participant as soon as possible and no later than 72 hours after 
birth. 
V3 to V4 
42  
30 – 60  
If this visit occurs before Day 43, the site must contact the participant to collect information about any additional AESIs that may have been 
identified or may have occurred between the date of the visit and Day 43.   
V3 to C1 
180  
165 – 
200 
 
Infant participants 
Birth to V1-NB 0  
0 – 21  
If no cord blood was collected, a blood sample must be collected within 72 hours after birth.  
Consent (if required) should be obtained before any infant study-specific procedures are performed  
If written consent cannot be readily provided by the parent(s)/LAR(s) post-birth, and in order to be able to comply with RTI surveillance and 
other protocol required procedures, verbal consent – if permitted per local regulation -- may be sought from the parent(s) / LAR(s) instead. 


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Interval 
Optimal 
interval 
in Days 
Allowed 
interval 
in Days 
Additional Information 
Verbal consent should be documented in the source data by the investigator or delegate. The parent(s) / LAR(s) will provide additional, 
written informed consent by (or before) (Visit 2-NB) 
Refer to the SPM for additional details. 
Infant participants 
Birth to 
recommended 
safety contact 
8 
 
Safety contact (recommended, in interval between Day 7 to Day 10 ) 
Birth to V2-NB  42  
30 - 60  
 
Birth to C1-
NB 
90  
83 – 97  
 
Birth to V3-NB  120  
110 - 140  Visit may coincide with infant participant’s routine vaccination visit if consistent with the participating country’s routine infant vaccination 
schedule 
Birth to V4-NB  180  
165 - 200  Visit may coincide with infant participant’s routine vaccination visit if consistent with the participating country’s routine infant vaccination 
schedule 
Birth to C2-
NB  
270  
256 – 
286  
 
Birth to V5-NB  365  
330 - 400  Visit may coincide with infant participant’s routine vaccination visit if consistent with the participating country’s routine infant vaccination 
schedule 
RTI surveillance contacts (Birth to V5-NB) * 
Seasonal 
RSV 
transmission 
Weekly during RSV season 
Monthly outside the RSV season 
Year-round 
RSV 
transmission  
Every 2 weeks year-round 
RTI = respiratory tract illness; V= Visit; C = Contact; NB=Newborn 
* In special circumstances, the frequency of active contacts may be temporarily adapted, refer to Section 8.4.2.2.1 for guidance 


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2. 
INTRODUCTION  
2.1. 
Study rationale (Amended 23 February 2023)  
GSK is developing an investigational Respiratory Syncytial Virus (RSV) vaccine for 
administration to pregnant women, with the aim of preventing medically assessed, RSV-
associated lower respiratory tract illnesses (LRTIs) in their infants by transfer of maternal 
antibodies. The vaccine candidate is an engineered version of the RSV fusion (F) surface 
glycoprotein, stabilized in the pre-fusion conformation.  
In the RSV maternal program to date, a Phase 1/2 study (RSV MAT-001; NCT 
03674177) in healthy non-pregnant women 18-45 years of age to determine the safety 
and immunogenicity of 3 dose levels of RSV (RSVPreF3) maternal vaccine (30, 60 and 
120 µg) compared to placebo has been completed. No safety concerns have been 
identified.  
Based on preliminary results of RSV MAT-001, the 60 and 120 µg dose-levels were 
selected for further evaluation in the following 2 additional studies, which are ongoing:  
 
RSV-MAT 004 (NCT 04126213): A Phase II observer-blind study to assess safety, 
reactogenicity, and immunogenicity of GSK Biologicals’ investigational RSV 
Maternal unadjuvanted vaccine (GSK3888550A), in healthy pregnant women and 
infants born to vaccinated mothers 
 
RSV-MAT 011 (NCT 04138056): A Phase II study of 2 dose levels of an 
investigational RSV maternal vaccine, given alone or with Boostrix, to healthy non-
pregnant women to assess safety, reactogenicity, and immunogenicity.  
Based on the final results of RSV MAT-001, which are summarized in [GSK Study 
Report 208068/001], and on the Day 31 results of RSV MAT-004 and -011, the 120 µg 
dose-level has been selected for evaluation in RSV MAT-009. 
Participants will be vaccinated year-round and will not be limited to seasonal enrollment. 
Reactogenicity and safety of the candidate vaccine will be evaluated in maternal 
participants for up to 6 months after delivery. Safety in infants will be evaluated for up to 
12 months after birth. Safety evaluation  will include assessment of medically attended 
adverse events, serious adverse events, pregnancy outcomes, and pregnancy-related and 
neonatal adverse events of special interest (AESIs). 
Immunogenicity of the candidate vaccine will be evaluated in maternal participants 
through delivery. The transfer of RSV-specific antibodies from vaccinated maternal 
participants to infant participants will be evaluated at delivery. RSV-specific antibody 
levels will be evaluated in infant participants for up to 6 months after birth. 
The study will also evaluate the incidence of medically attended RSV-associated 
respiratory tract illnesses (MA-RTI) in maternal participants for up to 6 months after 


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delivery, and the incidence of medically assessed, RSV-associated respiratory tract / 
lower respiratory tract illnesses (RTI/LRTI) in infants for up to 12 months after birth.  
Note: Due to the stop on study enrollment and vaccination, nasal swabs from maternal 
participants will not be collected and no MA-RTI assessment visit will be performed. 
Assessment of incidence of MA-RTI in maternal participants will be limited to cases 
where a nasal swab was collected before study enrollment stop. 
2.2. 
Background  
Please refer to the current Investigator’s Brochure (IB) for background information on 
RSV infection, the rationale for the maternal immunization approach described in this 
protocol, and information regarding pre-clinical and clinical studies of the RSV Maternal 
(RSVPreF3) vaccine. 
2.3. 
Benefit/Risk assessment  
GSK has included provisions in this trial to ensure participant’s safety. Safety monitoring 
has been and will be conducted throughout this study by an unblinded Independent Data 
Monitoring Committee (IDMC) and by the Sponsor. The study includes the establishment 
of a surveillance system which may facilitate detection of respiratory tract infections, in 
particular lower respiratory tract illness (LRTIs) in infants enrolled in the study. 
Measures to suspend the study should a potential safety issue be identified are described 
in Section 8.2.3. 
In February 2022, the Independent Data Monitoring Committee (IDMC) for the RSV 
MAT-009 study observed an imbalance in the proportion of preterm births in the active 
versus the placebo group and recommended that study enrollment be paused. As a 
result, GSK voluntarily paused the enrollment, randomization, and vaccination of 
participants in its active pregnant women studies to investigate this safety signal.  
 
Following a review of additional unblinded data from the RSV MAT-009 study, the 
imbalance in preterm births was noted to persist across a range of risk factors. A 
higher proportion of neonatal deaths reported in the active group compared to the 
placebo group was also observed. GSK then decided to stop enrollment and vaccination 
in all ongoing trials of RSV Maternal Vaccine (RSVPreF3) as a precautionary 
measure. 
 
The observed numerical imbalance in neonatal deaths is not an independent safety 
signal but a consequence of the validated signal of preterm birth. No numerical 
imbalance in neonatal deaths was observed in the cohort of infants born at term. An 
in-depth qualitative review of the clinical information available for each neonatal 
death concluded that the events leading to neonatal death (e.g., very low or low birth 
weight, sepsis, necrotizing colitis, pneumonia, respiratory distress syndrome, hypoxic-
ischemic injury) are commonly observed in preterm-born infants, particularly those 
who are extremely and very preterm, and there is no consistent temporal pattern of 
events from birth or from maternal vaccination.  
 


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In January 2023, following assessment of the Study Day 43 post-birth interim analysis 
(DLP 04 October 2022) with data from 5328 maternal participants (3557 in the active 
group) and 5235 infant participants (3496 in the active group), the imbalance in 
preterm birth remains statistically significant (RR 1.38 (95% CI 1.08, 1.75); p value: 
0.0090) and persists across a range of risk factors. The overall incidence of preterm 
birth in the study is low in both groups and remains below the preterm birth 
background rates for the majority of the participating countries. The imbalance in 
preterm births was observed more with low and middle-income countries (RR: 1.57, 
95% CI: 1.17–2.10) than high-income countries (RR: 1.04, 95% CI: 0.68–1.58). In low 
and middle-income countries, the preterm birth imbalance peaked from August to 
December 2021 and was not observed consistently from January 2022 onward.  
 
GSK concluded that preterm birth is an identified risk for the pregnant women 
population, for the RSV Maternal vaccine candidate. GSK has discontinued the work 
on this RSV maternal candidate vaccine and is closing out all ongoing trials. 
Additionally, GSK continues to monitor and follow up those participants immunized in 
the trials. Another study (RSV MAT-015) has been initiated to describe the safety of 
study participants who received RSVPreF3 maternal vaccination (any dose) or control 
in previous RSV MAT studies, including the RSV MAT-009 study, during any 
pregnancy conceived post-vaccination or post-control. 
 


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3. 
OBJECTIVES AND ENDPOINTS  
Table 4 
Study objectives and endpoints (Amended 23 February 2023)  
Primary objectives 
Primary endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe LRTIs in their infant3 
participants up to 6 months of age 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of medically assessed 1, RSV-associated severe  LRTIs 
according to the case definitions2.  
 
OR 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant3 participants up to 6 months of age 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs according 
to the case definitions2. 
AND 
To evaluate the safety of the RSV Maternal 
vaccine in infants born to mothers who were 
vaccinated with a single IM dose of study vaccine, 
up to 12 months after birth. 
Occurrence of SAEs, AEs leading to study termination and 
medically attended AEs from birth up to 6 months after birth5. 
Occurrence of SAEs, AEs leading to study termination and 
medically attended AEs from birth up to 12 months after birth5. 
Secondary efficacy objectives 
Secondary efficacy endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing RSV-associated 
hospitalization in their infant3 participants up to 6 
months of age. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of RSV-associated hospitalizations according to the case 
definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant3 
participants up to 6 months of age, all cause 
LRTI. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause LRTI. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant3 
participants up to 6 months of age, all cause LRTI 
with hospitalization.  
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause LRTI with hospitalization. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe LRTIs in their infant3 
participants up to 12 months of age. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), occurrences 
of medically assessed, RSV-associated severe LRTIs 
according to the case definitions2. 


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Secondary efficacy objectives 
Secondary efficacy endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant3 participants up to 12 months of age. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), occurrences 
of any medically assessed, RSV-associated LRTIs according 
to the case definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing severe medically 
assessed1, RSV-associated LRTIs for each RSV 
subtype (A and B) separately in their infant3 
participants up to 6 months of age. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of severe medically assessed1, RSV-associated LRTIs 
according to the case definition2, for RSV subtype A and RSV 
subtype B separately. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity, for each 
RSV subtype (A and B) separately in their infant3 
participants up to 6 months of age. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs according 
to the case definition2, for RSV subtype A and RSV subtype B 
separately. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe LRTIs in their infant3 
participants up to 4 months of age. 
From birth (Visit 1-NB) to 4 months (Visit 3-NB), occurrences 
of severe medically assessed1, RSV-associated LRTIs 
according to the case definitions2.  
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant3 participants up to 4 months of age. 
From birth (Visit 1-NB) to 4 months (Visit 3-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs according 
to the case definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant3 
participants up to 6 months of age, all cause 
pneumonia. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause pneumonia.  
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing RSV-associated 
hospitalization in their infant3 participants up to 12 
months of age. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), occurrences 
of RSV-associated hospitalizations according to the case 
definitions2. 
To assess the efficacy of a single dose of RSV 
Maternal vaccine administrated to maternal 
participants in preventing, in all vaccinated 
maternal participants up to 6 months post-
delivery, RSV associated medically attended RTIs 
(MA-RTIs). 
From study intervention administration (Visit 1) to 6 months 
post-delivery (Contact 1), occurrence of RSV-associated 
medically attended RTIs (RSV-MA-RTIs)2. 


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Secondary immunogenicity objectives 
Secondary immunogenicity endpoints 
To evaluate the immunogenicity of the RSV 
Maternal vaccine in a sub-cohort of maternal 
participants 30 days after the study intervention, 
and at delivery. 
 
Neutralizing antibody titers against RSV-A  
Measured on blood samples collected at Day 1 before the 
study intervention (Visit 1), at Day 31 (Visit 2), and at delivery 
(Visit 3). 
To evaluate the immunogenicity of the RSV 
Maternal vaccine in a sub-cohort of infants in 
Stage A, at birth and up to 6 months after birth. 
 
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 72 hours 
after birth (if no cord blood sample can be obtained). 
Measured on a blood sample collected at Day 43 (Visit 2-NB), 
Day 121 (Visit 3-NB), or Day 181 (Visit 4-NB) after birth in 3 
sub-cohorts of infants. 
Infants born to women in the immunogenicity sub-cohort will 
be randomly assigned (1:1:1) to sample collection at 1 of the 3 
timepoints noted. 
To evaluate the transfer of RSV-specific 
antibodies from a sub-cohort of maternal 
participants vaccinated with a single IM dose of 
the RSV Maternal vaccine to their infants at the 
time of delivery. 
RSVPreF3 IgG-specific antibody concentration measured 
on blood samples collected at Delivery and cord blood* 
The ratio between cord blood* and maternal RSVPreF3 IgG-
specific antibody concentrations. 
* or an infant blood sample collected within 72 hours after birth 
(if no cord blood sample can be obtained). 
Secondary safety objectives 
Secondary safety endpoints 
To evaluate reactogenicity of a single IM dose of 
the RSV Maternal vaccine in stage A maternal 
participants, during a 7 day follow up period after 
the study intervention. 
Occurrence of solicited administration site and systemic 
events in stage A maternal participants, during a 7-day follow-
up period after the study intervention (i.e. the day of the 
intervention and 6 subsequent days). 
To evaluate the safety of a single IM dose of the 
RSV Maternal vaccine in all maternal participants, 
during a 30 day follow up period after the study 
intervention. 
Occurrence of unsolicited adverse events (AEs) in all maternal 
participants during a 30-day follow-up period after the study 
intervention (i.e. the day of the intervention and 29 subsequent 
days). 
To evaluate the safety of a single IM dose of the 
RSV Maternal vaccine in all maternal participants, 
from Visit 1 up to 6 months after delivery. 
Occurrence of serious adverse events (SAEs) 5, AEs leading 
to study termination, and medically attended RTIs in all 
maternal participants from Visit 1 (Day 1) up to 6 months after 
delivery. 
Occurrence of all other medically attended AEs in all maternal 
participants from Visit 1 (Day 1) up to Day 42 after delivery. 


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Secondary safety objectives 
Secondary safety endpoints 
To evaluate pregnancy outcomes and pregnancy-
related adverse events of special interest after a 
single IM dose of the RSV Maternal vaccine 
administered to maternal participants, from Visit 1 
up to 6 weeks after delivery (Visit 4). 
Pregnancy outcomes5 from Day 1 (Visit 1) up to 6 weeks after 
delivery (Day 43 post-delivery, Visit 4). These include live birth 
with no congenital anomalies, live birth with minor congenital 
anomaly(ies) only; live birth with at least one major congenital 
anomaly, fetal death/still birth (antepartum or intrapartum) with 
no congenital anomalies, fetal death/still birth (antepartum or 
intrapartum) with only minor congenital anomalies, fetal 
death/still birth (antepartum or intrapartum) with at least 1 
major congenital anomaly; elective/therapeutic termination 
with no congenital anomalies; elective/therapeutic termination 
with only minor congenital anomalies, and elective/therapeutic 
termination with at least 1 major congenital anomaly. 
 
Pregnancy-related adverse events (AEs) of special interest 
from Day 1 (Visit 1) up to 6 weeks after delivery (Day 43 post-
delivery, Visit 4). These include maternal death, hypertensive 
disorders of pregnancy (gestational hypertension, pre-
eclampsia, pre-eclampsia with severe features including 
eclampsia), fetal growth restriction, pathways to preterm birth 
(premature preterm rupture of membranes, preterm labor, 
provider-initiated preterm birth), gestational diabetes mellitus, 
chorioamnionitis4,5 . 
To evaluate the occurrence of neonatal AEs of 
special interest (reported up to 6 weeks after 
birth), in infants born to mothers who were 
vaccinated with a single IM dose of the RSV 
Maternal vaccine. 
The occurrence of neonatal AEs of special interest (reported 
up to 6 weeks after birth). These include small for gestational 
age, low birth weight including very low and extremely low 
birth weight (<2500 g, <1500g, <1000g), congenital anomalies 
(major external structural defects, internal structural defects, 
functional defects), neonatal death (in an extremely pre-term 
birth [22GA<28 weeks], in a preterm live birth [28GA<37 
weeks], or in a term live birth), preterm birth4,5. 
Tertiary objectives: 
CCI


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Tertiary objectives: 
 
1 By “medically assessed” it is meant that the infant was evaluated by a healthcare professional (physician, nurse, etc) 
for the lower respiratory tract illness. 
2Case definitions for RSV-associated medically attended RTIs (RSV-MA-RTIs), RSV associated LRTIs and 
surveillance for potential LRTIs are briefly summarized in Section 4.2.6.  
3An infant is defined as a child younger than 1 year of age; a neonate is defined as an infant 28 days old or less.  
4Maternal and neonatal AESI and pregnancy outcomes should be recorded in the eCRF along with assessment of level 
of diagnostic certainty by GAIA definitions when applicable. Of note, some events of 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. 
5The following adverse events are listed by GAIA as events of interest, but will not, for purposes of this study, be 
reported as AESIs. If any of these events meets the definition for an SAE, the event should be reported as such in the 
eCRF and the SAE narrative should contain enough information to permit assessment of level of diagnostic certainty 
by GAIA criteria: 
 
Pregnancy-related: antenatal bleeding (morbidly adherent placenta, placental abruption, cesarean scar 
pregnancy, uterine rupture), postpartum hemorrhage, non-reassuring fetal status, oligohydramnios, 
polyhydramnios, gestational liver disease (intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy), 
maternal sepsis.  
 
Neonatal: neonatal encephalopathy, congenital microcephaly (postnatally or prenatally diagnosed), neonatal 
infections (blood stream infections, meningitis, respiratory infection), respiratory distress in the neonate, failure to 
thrive, large for gestational age, macrosomia. 
4. 
STUDY DESIGN  
4.1. 
Overall design  
The study is a Phase III, double-blind, randomized, placebo controlled, multi-centric, 
multi-country study with 2 parallel groups. At least 20% of participants will be enrolled 
at centers in the U.S. 
The study design is adaptive, with recruitment and randomization occurring in 2 
sequential stages, A and B. Stage B may begin immediately after the last participant is 
randomized in Stage A.  
To encourage participation in the study and to achieve recruitment targets on time, the 
study sites will be encouraged to manage recruitment plans using methods that are 
acceptable within local regulations such as advertisements in news media and/or use of 
posters and fliers. All such recruitment materials will be approved by the local ethics 
committees. 
Following verification that inclusion/exclusion criteria are met, all maternal participants 
will be randomized 2:1 to receive either GSK Biologicals’ RSV Maternal (RSVPreF3) 
vaccine or the placebo control.  
Study procedures in Stage A differ from those in Stage B in 2 ways.  
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During Stage A only: 
 
All maternal participants will be asked to report solicited events during the 7 days 
post-dose, and  
 
Maternal and (as yet unborn) infant participants will be further randomized into sub-
cohorts for blood sample collection for the assessment of immune response.  
Figure 1 and Figure 2 provide overviews of the study design for maternal and infant 
participants, respectively.  
Section 1.3 provides Schedules of Activities (SoAs) for maternal and infant participants. 
Section 9.5.1 describes the sequence of analyses for maternal and infant participant data. 
Figure 1 
Study design overview – maternal participants (Amended 23 
February 2023) 
 
GA = Gestational age; I = immune response; (S)AE = (serious) adverse event; RTI = respiratory tract illness  
Visit 2 may be replaced by Visit 3 in case of premature delivery. 
All = all participants 
Refer to Section 6.3.2 for detailed description of Stage A and Stage B. Refer to Section 6.3.2.1.1 for additional 
description of the Stage A sub-cohort.  
Solicited events will be evaluated for all participants in Stage A only 
* Any pregnancy-related event of special interest identified after Visit 4 should also be reported. 
 
In addition to the monthy contacts between Visit-2 and the Delivery visit, additional not pre-specified visits and contacts 
(any desired frequency) can be made between Visit-2 and the Delivery visit, as per investigator’s or maternal 
participant’s discretion. 
As from protocol Amentment 4, blood samples will be collected at delivery from all maternal participants. Placental 
samples will be collected at delivery from all maternal participants, if feasible. 
Due to the stop on study enrollment and vaccination, nasal swab samples will no longer be collected from any 
maternal participant and no MA-RTI assessment visit will be performed, but the MAEs associated with an RTI 
will continue to be reported, as applicable. 


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Figure 2 
Study design overview – infant participants  
 
I = immune response; (S)AE = (serious) adverse event; RTI = respiratory tract illness  
Stage A + Stage B – all participants:  
*If cord-blood was not collected at delivery/birth, a blood sample should be collected from the infant within 72 hours 
post birth. Applies to all participants in Stage A and Stage B. 
**Any Neonatal AE of specific interest identified after Day 43 should also be reported. 
 
An additional recommended safety contact may be performed 8-days post-birth if deemed necessary by the 
investigator or by the parent/LAR(s). 
 
NOTE: Due to the stop on study enrollment and vaccination, blood samples will no longer be collected at V2-NB, V3-
NB or V4-NB.  
 
Study Type: self-contained 
 
Study Duration: Approximately 10 to 11 months (including the screening visit) for 
maternal participants; approximately 1 year after birth for infant participants.  
 
Blinding is as described in Table 5 and Table 6. 
 
Randomized intervention allocation is described in Table 5, Table 6, and Section 6.3. 
 
Study (intervention) groups are described in Table 5 and Table 6. 
 
Data collection: standardized Electronic Case Report Form (eCRF) e-Diaries will be 
used to collect solicited event data (Stage A mothers only). Unsolicited Adverse 
event data will be collected through questioning at study visits/contacts and reported 
into the eCRF, as appropriate. Parent(s) / LAR(s) will use a Paper Diary to record 
RTI symptoms experienced by infant participants; these data will be transcribed into 
the eCRF as appropriate.  
 
Safety monitoring will be conducted by an unblinded Independent Data Monitoring 
Committee (IDMC) and by an unblinded Safety Review Team* (Section 8.2.3). 
* Due to the safety signal observed, the study was fully unblinded to ensure the 
safety of the participants. 


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Table 5 
Study groups, sub-cohorts, interventions, and blinding foreseen in the study: Stage A  
Approximately 4600 maternal participants will be randomized during Stage A. 
 
 
 
 
Blinding 
Study 
groups 
Maternal participants (M) 
Infant participants (I) 
Study Groups 
for 
Randomization 
M only 
M + I 
I only 
 
~Number 
Age in 
Years 
(Min/Max) 
Intervention 
name 
Maternal Blood Sampling 
Sub-cohorts 
Infant Blood Sampling sub-
cohorts 
(Allocation 
12:2:2:2:6:1:1:1) 
Screen
-ing 
Up to 
D181 
post 
delivery/
birth 
D271, 
D366 
post 
delivery/
birth 
 
 
 
 
Name 
~Number 
Name 
~Number 
 
- 
Double 
blind 
Double 
blind 
RSV_MAT 
~3067 
18-49 
RSV_MAT 
RSV_MAT_0 
~2040 
RSV_MAT_0 
~2040 
RSVMAT_0 
● 
● 
● 
18-49 
RSV_MAT 
RSV_MAT_I 
~1020 
RSV_MAT_BS1 
~340 
RSVMAT_BS1 
● 
 
 
 
 
RSV_MAT_BS2 
~340 
RSVMAT_BS2 
● 
 
 
 
 
RSV_MAT_BS3 
~340 
RSVMAT_BS3 
● 
Control 
~1533 
18-49 
Control 
Control_0 
~1020 
Control_0 
~1020 
Control_0 
● 
● 
● 
18-49 
Control 
Control_I 
~510 
Control_BS1 
~170 
Control_BS1 
● 
 
 
 
 
Control_BS2 
~170 
Control_BS2 
● 
 
 
 
 
Control_BS3 
~170 
Control_BS3 
● 
Control = Placebo; Infant sub-cohorts are abbreviated “BS1;” “BS2;” BS3” and correspond to visits 2-NB (Day 43), 3-NB (Day 121) and 4-NB (Day 181), respectively. 
RSVMAT_0 and Control_0 = maternal and infant participants who are not in a sub-cohort for immune response assessment.  
RSVMAT_I and Control_I = maternal sub-cohorts for immune response assessment.  
RSVMAT_BS1, _BS2, _BS3 = infants born to women in the RSVMAT_I sub-cohort and evaluated for immune response at the designated timepoint (D43, D121 or D181).  
Control_BS1, _BS2, _BS3 = infants born to women in the Control_I sub-cohort evaluated for immune response at the designated timepoint (D43, D121 or D181).  


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Table 6 
Study groups, sub-cohorts, interventions, and blinding foreseen in the study: Stage B  
Stage B will only start after the last participant is randomized in Stage A.  
Study groups  
Number of 
maternal 
participants 
Age of maternal 
participant at enrolment 
(Min/Max) 
Intervention name 
Study groups for 
randomization 
(Allocation 2:1) 
Blinding 
Maternal 
participants 
Only 
(Screening) 
Maternal 
participants 
V1-C1 
Infant participants 
V1-NB – V4NB 
(double-blind) 
Infant participants 
only 
Contact 2-NB – V5-
NB  
(double blind) 
RSV_MAT  
~3600 
18 – 49 years 
RSV_MAT 
RSV_MAT 
● 
● 
● 
Control 
~1800 
18 – 49 years 
Control 
Control 
● 
● 
● 
 


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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: pregnant women between 
240/7 and 340/7 weeks gestational age (inclusive).  
4.2.2. 
Use of placebo  
The placebo group serves as a control for safety, reactogenicity, immunogenicity and 
efficacy assessments. No licensed vaccine against RSV is currently available. 
4.2.3. 
Randomization ratio  
A 2:1 randomization ratio was chosen to permit efficient evaluation of vaccine safety and 
efficacy without compromising statistical rigor. Ratios greater than 1:1 for vaccinated vs. 
placebo recipients increase the likelihood that reported events may occur among vaccine 
recipients. It is possible that a higher number of reported events among vaccine recipients 
may be attributed to the greater randomization ratio, the vaccine itself, or due to chance. 
GSK plans to mitigate the potential risk associated with the increased randomization of 
vaccinated to placebo participants by: a) improving standardization of reporting of 
predefined pregnancy related and neonatal AESI using GAIA definitions; b) conducting 
both epidemiological database studies and observational natural history studies to 
determine background rates for these events in different countries; and c) establishing 
processes for continuous review of blinded safety data by the SRT* and unblinded safety 
data by the IDMC. 
* Due to the safety signal observed, the study was fully unblinded to ensure the safety of 
the participants. 
4.2.4. 
Sub-cohorts  
4.2.4.1. 
Safety assessment in maternal participants  
Assessment of vaccine reactogenicity (solicited events) in the 7 days post dose has been 
limited to Stage A to reduce the burden for maternal participants while ensuring enough 
observations to support robust evaluation. 
4.2.4.2. 
Blood sampling and immune response assessment (Amended 
23 February 2023)  
A sub-cohort for maternal blood sampling and assessment (immune response at Day 1 
(Visit 1), Day 31 (Visit 2), and Delivery) has been defined to limit discomfort and risk 
while ensuring enough observations to support robust evaluation of secondary maternal 
immunogenicity objectives (see also Table 3).  


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Sub-cohorts for infant blood sampling have been defined to limit discomfort and risk 
while ensuring enough observations to support robust evaluation of immune response in 
maternal – infant pairs.  
Note however that blood samples for assessment of immune response at Day 1 (Visit 1), 
Day 31 (Visit 2), and delivery (Visit 3) will be collected from all maternal participants. 
Cord blood will also be collected from all participants. These samples may also be tested 
to support possible safety assessments, if necessary. 
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives and to assess antibody persistence in infants. 
4.2.5. 
Adaptive design  
This adaptive trial design will provide evidence for the efficacy of the RSV maternal 
vaccine in the prevention of medically assessed, RSV-associated LRTI of any severity 
and medically assessed, RSV-associated severe LRTI. The design has 90% power to 
detect the target vaccine efficacies of 70% and 50% on severe and any-severity LRTI, 
respectively. If the vaccine meets these target VE estimates, this design offers the 
opportunity to identify this benefit with an expected sample size of approximately 7598 
maternal participants, which may obviate the need to enroll the maximum sample size of 
10 000.  
Additional details are provided in Section 9. 
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 participants  
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 12. 
3 Hospitalization is defined as admission for observation or treatment based on the judgement of a health care 
provider. 


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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 4,5 
RSV-LRTI 
History of cough OR difficulty in breathing 1 
AND  
SpO2 < 95%2, OR RR increase 3 
AND  
Confirmed RSV infection 4,5 
RSV-severe LRTI 
Meeting the case definition of RSV-LRTI 
AND 
SpO2 < 93%2, OR lower chest wall in-drawing OR inability to feed OR failure to 
respond / unconscious 
RSV hospitalization 
Confirmed RSV infection 4,5 
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  
All-cause LRTI hospitalization 
Hospitalized due to all cause LRTI as defined above 
Definitions based on [Modjarrad, 2016] except that definitions for severe and very severe  RSV LRTI have been 
merged. RTI = respiratory tract illness; LRTI = lower respiratory tract illness; RR = respiratory rate; SpO2 = blood 
oxygen saturation by pulse oximetry. 
1Based 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.  
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 14. 
6 Hospitalization is defined as admission for observation or treatment based on the judgement of a health care 
provider. 


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Table 9 
Alternative LRTI / Severe LRTI case definitions for data analysis in 
infants  
To meet an alternative case definition, a participant must have at least one item from each 
column. 
Note: The alternative case definitions will no longer be considered for data analysis in 
infants. 
RSV confirmed 
Documented Physical 
Examination (PE) findings 
indicating lower respiratory 
tract involvement 
Objective measures of clinical severity 
Confirmed RSV infection 
as defined in Section 
4.2.6.3 
Rhonchi 
Increased respiratory rate (bpm) 
Crackles (Rales) 
 
≥ 60 for < 2 mo 
LRTI 
Wheeze 
 
≥ 50 for 2-6 mo 
 
Hypoxemia: 
 
 
SpO2 <95% at ≤1800 meters 
 
 
SpO2 <92% at > 1800 meters 
 
New onset apnea 
 
Nasal flaring 
 
Retractions 
 
Grunting 
 
 
Confirmed RSV infection 
as defined in Section 
4.2.6.3 
Rhonchi 
Hypoxemia 
Crackles (Rales) 
 
SpO2 <93% at ≤1800 meters 
Wheeze 
 
SpO2 <90% at > 1800 meters 
Severe LRTI 
 
Acute hypoxic or ventilatory failure 
 
Dehydration due to respiratory distress 
requiring nasogastric/IV hydration 
 
Failure to respond or unconscious 
 
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 12, Table 14 and Section 8.4. 
In the event the collection of a nasal swab for testing by the sponsor is impossible, results 
from locally collected samples, tested with locally approved tests, may also be considered 
for the determination of a case of RSV infection. 
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4.3. 
Justification for dose  
A single formulation of the investigational RSV maternal vaccine (containing 120µg of 
the RSVPreF3 antigen) is planned. Currently available data suggest that the 120 µg 
formulation has an acceptable safety profile and tends to elicit stronger immune 
responses in non-pregnant women (RSV MAT-001 and RSV MAT-011) and pregnant 
women (RSV MAT-004), which is likely to result in higher placental transfer of 
antibodies to the fetus than formulations containing 30 or 60 µg of the RSVPreF3 
antigen. Available results from these studies are included in the Investigator Brochure. 
Because re-infection with RSV occurs throughout an individual’s lifetime, it is extremely 
unlikely that an adult (in this case, a maternal participant) would not have been naturally 
infected with RSV before. Results of study RSV MAT-001 in non-pregnant women 
indicate that a single dose of the study vaccine is sufficient to boost the neutralizing 
antibodies induced by previous natural infections. 
The study vaccine will be administered between 240/7 and 340/7 weeks of gestation 
(inclusive). 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 
participants 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). 
4.4. 
End of Study definition  
A participant is considered to have completed the study if he/she returns for the last visit 
as described in the protocol. 
The Primary Completion Date (PCD) occurs on completion of the Month 12 post-
delivery visit (Contact 1 for the maternal participants and Visit 5-NB for the infant 
participants). 
End of Study (EoS) occurs with the date of last (infant) participant last visit (LSLV) or 
the last testing/reading released of the human biological samples related to primary and 
secondary endpoints, whichever comes last. EoS must be achieved no later than 8 months 
after LSLV. 
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 jeopardize the scientific integrity or 
regulatory acceptability of the study or participant safety. 


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5.1.1. 
Maternal participants  
Maternal participants must satisfy all the following criteria at study entry: 
 
Participants who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of diaries, return for follow-up visits).  
 
Participants 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 procedures are performed. The informed consent given at screening 
should (consistent with local regulations / guidelines) either:  
 
include consent for both the maternal participant’s participation and 
participation of the infant after the infant’s birth, or  
 
include consent for the maternal participant’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 49 years, inclusive, at the time of study intervention. 
 
Pre-pregnancy BMI (based on participant’s report) 17.0 to 39.9 kg/m2, inclusive. 
 
In good general maternal health as established by medical history and clinical 
examination before entering into the study. 
 
Singleton pregnancy (including instances where the singleton pregnancy derives 
from a vanishing twin syndrome). 
 
At 24 0/7 to 34 0/7 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) i.e. at or before 28 weeks of gestation.  
 
1st or 2nd trimester U/S only, if LMP is unknown/uncertain  
 
Certain LMP, corroborated by an U/S performed after 28 weeks of gestation is 
also acceptable.  
NOTES: If pregnancy resulted from assisted reproductive technologies, LMP date 
may be replaced by IUI (intrauterine insemination) or ET (embryo-transfer) date. 
If LMP (or IUI or ET) and U/S performed before 28 weeks of gestation, do not 
correlate, default to U/S gestational age assessment. 
If the first U/S is only performed after 28 weeks of gestation (i.e. 3rd trimester) and 
there is no other basis for estimating gestational age, or the only other basis is fundal 
height, then the GA calculation is uncertain and the woman should be excluded. 
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 10.8). 


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 
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 fetal anomaly ultrasound scan (also known as a level 2 
ultrasound or fetal morphology assessment) conducted at or beyond 18 weeks of 
gestation.  
 
Willing to provide cord blood. 
 
Who do not plan to give their child for adoption. 
 
Who plan to reside in the study area for at least one year after delivery.  
 
Willing to have the infant followed-up after delivery for a period of 12 months.  
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 participants  
Infant participants must satisfy all the following criteria at study entry: 
 
Live-born from the study pregnancy.  
 
If required per local regulations / guidelines, 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, before performing any 
study specific procedure. To comply with RTI surveillance and other protocol-
required procedures that begin immediately after birth: If written consent cannot be 
provided by the parent(s)/LAR(s) readily post-birth, verbal consent – if permitted per 
local regulation – may be sought from the parent(s) / LAR(s) instead. Verbal consent 
should be documented in the source data by the investigator or delegate. The 
parent(s) / LAR(s) will provide additional, written informed consent by (or before) 
Visit 2-NB. 
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 jeopardize the scientific integrity or 
regulatory acceptability of the study or safety of the participant. 
The following criteria should be checked at the time of study entry. The potential 
participant MUST NOT be included in the study if ANY exclusion criterion applies: 
5.2.1. 
Maternal participants  
5.2.1.1. 
Medical conditions  
 
History of allergic disease or reactions likely to be exacerbated by any component of 
the RSV vaccine. 


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 
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, 2019]. 
Women with gestational hypertension who maintain blood pressure in the 
normal range (<140 mmHg and <90 mmHg) through diet and/or on anti-
hypertensive medications would be eligible. 
 
Gestational diabetes which is not controlled by medication, diet and/or 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, 2019]. 
 
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, 2019]. 
 
Intrauterine Growth Restriction/Fetal Growth Restriction  defined as a fetus with 
a sonographic estimation of fetal weight below the tenth percentile for a given 
gestational age with increasing specificity for adverse perinatal outcome below 
the third percentile (see Table 32). 
 
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 (DPV) of > 8 cm or 
an amniotic fluid index (AFI) > 95th percentile for the corresponding gestational 
age) (see Table 37).  
 
Oligohydramnios (defined as an amniotic fluid index (AFI) < 8 cm or a deepest 
vertical pocket (DPV) < 2 cm in the presence of intact membranes without 
concern for fetal anomalies contributing to its etiology) (see Table 37). 
 
Preterm labour or history of preterm labour in the current pregnancy. 
 
Any intervention to prevent preterm delivery or medical treatment for suspected 
preterm delivery, including administration of systemic corticosteroids for fetal 
lung maturation.  


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Note: pregnant women under progesterone treatment beyond the 1st trimester of 
pregnancy, exclusively based on a prior pregnancy which resulted in preterm 
delivery/birth, but without any medical/clinical finding(s) which would lead to 
suspecting that there is a risk of preterm delivery in the current pregnancy (e.g. 
shortened cervical length, etc), would not be considered as meeting this 
exclusion criterion. 
 
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 participants in an investigational vaccine 
trial or might pose risk to the participant due to participation in the study. 
 
Significant (as per Investigator’s judgement) structural abnormalities of the uterus or 
cervix. 
 
History of 2 or more prior stillbirths or neonatal deaths, or history of multiple (2 or 
more) preterm births at ≤ 34 weeks gestation, or multiple (3 or more) consecutive 
spontaneous abortions.  
Note: Still births, pre-terms births and spontaneous abortions will be counted per 
pregnancy (i.e. regardless of the number of fetuses in the concerned pregnancy).  
 
Known HIV infection, as assessed by local standard of care serologic tests conducted 
during the current pregnancy and prior to enrolment. 
 
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. 
 
Current autoimmune disorder (based on medical history and physical examination; 
no laboratory testing required), for which the participant has received immune-
modifying therapy within 6 months before study vaccination, or plans administration 
through delivery.  
 
Lymphoproliferative disorder or malignancy within 5 years before study vaccination 
(excluding effectively treated non-melanoma skin cancer).  
 
Acute or chronic clinically significant abnormality or poorly controlled pre-existent 
co-morbidities or any other clinical conditions, as determined by physical 
examination or standard of care laboratory tests, that, in the opinion of the 
investigator, might pose additional risk to the participant due to participation in the 
study. 


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 
Any conditions that, in the investigator’s judgement, may interfere with participant’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. 
5.2.1.2. 
Prior/Concomitant therapy  
 
Prior receipt of an RSV vaccine in the current pregnancy. 
 
Use of any investigational or non-registered product other than the study 
vaccine/product as described below, or planned use during the study period:  
 
For a drug, vaccine or medical device: 29 days before the dose of study 
vaccine/product (Day -28 to Day 1). 
 
For immunoglobulins: 3 months before the dose of study vaccine/product. 
The exception to this is investigational products (drugs / vaccines / immunoglobulins) 
administered in the setting of a pandemic. Administration in this case should respect the 
same period outlined above prior to vaccination, but may be allowed following delivery.  
 
Planned administration/administration of any vaccine within 29 days before study 
vaccine administration (Day -28 to Day 1) or planned administration through 
delivery (Visit 3), except: 
 
Seasonal influenza vaccines, tetanus vaccines, dTpa/Tdap – alone vaccines, 
dTpa/Tdap vaccines that also contain other antigens  and Hepatitis B vaccines, 
all of 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. In that sense, COVID-19 vaccines will be allowed, when administered ≥ 15 
days before or after study vaccination. 
 
Administration of immunoglobulins (except anti-Rh0D IG, which may be 
administered at any time), blood products or plasma derivatives within 3 months 
before study vaccination or planned administration through delivery (Visit 3).  
 
Administration of immune-modifying therapy within 6 months before the study 
vaccination, 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. Inhaled. Intra-articular/intra-
bursal and topical steroids are allowed.  
 
Corticosteroids administered for fetal lung maturation. 


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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 participant 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, neglect of 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]). 
 
A local condition that in the opinion of the Investigator precludes injection of the 
study vaccine/product or precludes assessment of local (administration site) 
reactogenicity. 
 
Consanguinity of maternal participant and her partner (second degree cousins or 
closer) 
 
Any study personnel or their immediate dependents, family, or household members. 
5.2.2. 
Infant participants  
 
Concurrently participating in another clinical study, at any time during the study 
period, in which the participant has been or will be exposed to an investigational or a 
non-investigational vaccine/product (drug or medical device). 
 
Any condition which, in the investigator’s opinion, would increase the risks of study 
participation to the infant.  
 
Child in care 
Please refer to Section 10.7.2 for the definition of child in care.  
5.3. 
Lifestyle considerations  
5.3.1. 
Demographic data  
Demographic data for maternal and infant participants includes geographic ancestry 
(race)*, ethnicity*, month of birth (if allowed per local regulation) and year of birth.  
*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 study 
participants.  


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5.3.2. 
Lifestyle characteristics  
5.3.2.1. 
Maternal participants  
Lifestyle characteristics may include highest level of education, smoking 
status/exposures, household environment, and other factors that could place study 
participants at risk of adverse study outcomes.  
5.3.2.2. 
Infant participants  
Lifestyle characteristics may include 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. 
5.4. 
Screen failures  
Screen failures are maternal participants who consent to take part 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 
marketed product(s) or placebo intended to be administered to a participant during the 
study. 
Refer to the Study Procedures Manual (SPM) for additional details. 


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6.1. 
Study intervention(s) administered  
Table 10 
Study intervention(s) administered  
Study Intervention 
Name: 
RSV MAT 
Control 
Vaccine/product name 
RSVPreF3 
NaCl_solution 
Sucrose_Lyo 
NaCl_solution 
Presentation 
Powder for 
solution for 
injection, vial 
Solution for 
solution for 
injection; syringe 
Powder for solution 
for injection, vial 
Solution for 
solution for 
injection; syringe 
Vaccine/product 
formulation: 
RSVPreF3  
(120 µg) 
Sodium chloride 
(NaCl) (0.9%); 
Water for 
injections**  
Sucrose 
Sodium chloride 
(NaCl) (0.9%); 
Water for 
injections**  
Route of Administration 
Intramuscular use 
Intramuscular use 
Administration site: 
 
 
Location 
Deltoid  
Deltoid 
Laterality * 
Non-dominant  
Non-dominant  
Number of doses to be 
administered: 
1 
1 
Volume to be 
administered** 
Whole content 
Whole content 
Packaging and Labelling 
Refer to the SPM 
Refer to the SPM 
Manufacturer 
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 
** The entire contents of the pre-filled NaCl syringe will be transferred into the vial for reconstitution. The entire 
contents of the reconstituted vaccine/product will be withdrawn for administration. Refer to the SPM for additional 
information. 
Maternal participants must be observed closely for at least 30 minutes after the 
administration of the vaccine/product. Appropriate medical treatment must be readily 
available during the observation period in case of anaphylaxis and/or syncope. 
6.2. 
Preparation/Handling/Storage/Accountability  
The study vaccine/product 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/product. 
6.3. 
Measures to minimise bias: randomisation and blinding  
6.3.1. 
Participant identification  
Maternal identification numbers will be assigned sequentially to pregnant women who 
have consented to participate in the study, according to the range of participant 
identification numbers allocated to each study center. 


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Maternal participants who have provided informed consent will be registered into an 
automated internet based system (SBIR) at the time of screening. SBIR will be further 
used to confirm eligibility to participate in the study, to randomize each maternal 
participant to an intervention, and to confirm that an intervention has been administered 
(see Section 6.3.3).  
The maternal participant’s (as yet unborn) infant will be assigned an identification 
number, according to the range of numbers allocated to each study center, AFTER the 
maternal participant has been randomized (and vaccinated) at Visit 1.  
Maternal and infant identification numbers will be linked. 
6.3.2. 
Randomization to study intervention  
6.3.2.1. 
Randomization to maternal study intervention group  
Up to (approximately) 10 000 pregnant women (maternal participants) will be randomly 
assigned (2:1) to receive the investigational vaccine or control (placebo) at Visit 1. 
Randomization will take place in 2 sequential stages, A and B. 
6.3.2.1.1. Stage A (Amended 23 February 2023)  
Stage A begins when the first maternal participant is randomized. 
Randomization to a study intervention 
Approximately 4600 maternal participants will be randomized to Stage A and dosed as 
shown in Figure 3. 
Figure 3 
Randomization Overview – Stage A  
 
All maternal participants in Stage A will: 
 
provide reactogenicity (solicited event) data for the first 7 days post-vaccination. 
 
have blood samples collected at Day 1 (Visit 1) and Day 31 (Visit 2) and Delivery 
(Visit 3).  


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At delivery, a cord blood sample will also be collected from all participants. (If it is not 
possible to collect cord blood, a blood sample will be collected from the neonate within 
72 hours post birth).  
All these samples may also be tested to support possible safety assessments, if necessary. 
Randomization to the immunogenicity subcohort:  
When they are randomized to a study intervention, maternal participants in Stage A (as 
well as their as yet unborn infants) will also be randomized either to participate in the 
immunogenicity sub-cohort (N ~ 1533) or to not participate (N ~ 3067).  
For the ~ 1533 maternal participants in the immunogenicity sub-cohort, an additional 
blood sample will be collected at delivery. 
For the ~ 1533 infant participants in the immunogenicity sub-cohort: 
 
Randomization will identify a single timepoint post-birth (Day 43 (Visit 2-NB), or 
Day 121 (Visit 3-NB), or Day 181 (Visit 4-NB)) at which each (as yet unborn) infant 
will have a blood sample collected. Thus, at each of the 3 post-birth immunogenicity 
timepoints, a sample will be collected from approximately one third of the infants in 
the sub-cohort (N ~510). 
Note that due to the stop on study enrollment and vaccination, there will no longer be 
collection of blood samples from the infants at V2-NB, V3-NB and V4-NB. 
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives and to assess antibody persistence in infants. 
Refer to Figure 4 and Table 5 for additional information. 


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Figure 4 
Stage A Sub-Cohort Distributions  
 
Note: As per Amendment 4, blood samples were to be collected from all maternal 
participants at Delivery (Visit 3). However, infant immunogenicity sub-cohort blood 
samples at Day 43 (V2-NB), Day 121 (V3-NB) or Day 181 (V4-NB) were no longer 
collected. 
6.3.2.1.2. Stage B  
Stage B will only start after the last participant is randomized in Stage A.  
Up to approximately 5400 maternal participants will be randomized and dosed as shown 
in Figure 5.  


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Figure 5 
Randomization Overview – Stage B  
 
All maternal participants in Stage B will have blood samples collected at Day 1 (Visit 1), 
Day 31 (Visit 2) and Delivery (Visit 3). Cord blood (or if not possible, neonatal blood 
within 72 hours from birth) will also be collected from all participants. These samples 
may also be tested to support possible safety assessments, if necessary. 
Reactogenicity (solicited events) will not be evaluated in Stage B. There will be no blood 
sampling sub-cohorts for maternal or infant participants. 
6.3.3. 
Intervention allocation to the participant  
An automated internet based system (SBIR) will be used. The system’s randomisation 
algorithm will use a minimisation procedure accounting for maternal age at the time of 
the study intervention (18-34, 35-39, ≥40 years of age), gestational age at the time of the 
study intervention (240/7-280/7; 28 1/7-340/7), and center. Minimisation factors will have 
equal weight in the minimisation algorithm. 
At Visit 1, site personnel will: 
 
Verify eligibility of the maternal participant.  
 
Access SBIR and  
 
Select the maternal participant’s identification number previously entered in the 
application (at the time of screening). 
 
Verify that the maternal participant’s calendar age and gestational age (GA) are 
correctly represented in SBIR. Entries in SBIR should reflect: calendar age at 
the time of V1/randomization, and GA based on LMP/IUI/ET and/or ultrasound 
results (as applicable). 
 
Proceed to intervention allocation 
The randomisation system will then determine the maternal participant’s study group and 
provide the intervention number to be used for the study intervention.  
Stage B
~3600
Pregnant 
Women
~ 1800 
Pregnant 
Women
~ 5400 
Pregnant 
Women
Receiving RSV MAT
Receiving Control


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In Stage A, the randomisation system will also determine: 
 
Whether or not the maternal participant and her (as yet unborn) infant are in the 
immunogenicity sub-cohort and 
 
For maternal and (as yet unborn) infant participants assigned to the immunogenicity 
sub-cohort, the post-birth timepoint at which blood sample will be collected from the 
infant. 
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. 
Randomization of supplies  
The randomisation of supplies within blocks will be performed at GSK, using MATerial 
Excellence (MatEx), a program developed for use in Statistical Analysis System (SAS) 
(Cary, NC, USA) by GSK. Entire blocks will be shipped to the study 
centres/warehouse(s). 
To allow GSK to take advantage of greater rates of recruitment in this multi-centre study 
and to thus reduce the overall study recruitment period, an over-randomisation of 
supplies will be prepared.  
6.3.5. 
Allocation of participants to assay subsets  
Not applicable. 
6.3.6. 
Blinding and unblinding  
To minimize the introduction of bias, this study will be double-blinded*. Participants will 
not have access to their randomization assignment, and investigators and their staff will 
be blinded to the participant’s assigned study intervention throughout the course of the 
study.  
The laboratory in charge of the sample testing will be blinded to the intervention 
assignment. Codes will be used to link the participant and study (without any link to the 
intervention attributed to the participant) to each sample. 
A firewall will be established to ensure that data are not inadvertently unblinded. Details 
are provided in a separate Firewall charter.  
* Following the decision to stop enrollment and vaccination, the study/site staff and 
maternal participants no longer stay blinded. Refer to Section 2.3 for details. 


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6.3.6.1. 
Emergency unblinding  
Unblinding a participant’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 participant. 
A participant may continue in the study even if that participant’s intervention assignment 
is unblinded. 
The emergency unblinding process enables the investigator to have unrestricted, 
immediate and direct access to the participant’s individual study intervention via an 
automated Internet-based system (SBIR). Investigators are cautioned not to share this 
knowledge with sponsor staff, or with study staff who do not need it, in order to ensure 
that other members of the study team remain blinded. 
As back up process, the investigator has the option of contacting a GSK Biologicals’ 
Helpdesk (refer to the Table 11) if he/she needs help performing the unblinding (i.e. 
he/she cannot access the automated Internet-based system). 
A non-investigator physician (e.g. physician from emergency room) or participant/care 
giver/family member may also request emergency unblinding either via the investigator 
(preferred option) or via the GSK Biologicals’ Helpdesk (back up process). The maternal 
and infant participant cards list contact information for both the investigator and GSK 
Biologicals’ Helpdesk. 
Table 11 
Contact information for emergency unblinding  
GSK Helpdesk 
Available 24/24 hours and 7/7 days 
The Helpdesk is available by phone, fax and email 
Phone :  
 
+32 2 656 68 04 
Fax :   
 
+32 2 401 25 75 
Email :  
 
rix.ugrdehelpdesk@gsk.com 
Toll-free numbers are available for the following countries.  
Country 
Toll free number 
Canada 
877.870.0019 or 1 833 541 0263 
United States and Puerto Rico 
877.870.0019 or 1 844 446 3133 
Australia 
0011 800 4344 1111 
Belgium, Estonia, France, Germany, Spain,  
00 800 4344 1111 
Italy 
800 879 197 
Finland 
999 800 4344 1111 
Philippines 
00 800 4344 1111, fixed line only 
Russia 
810 800 4344 1111 
South Korea, Thailand 
001 800 4344 1111 


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United Kingdom 
0 800 056 7221 
Brazil 
0 800 891 2906 
India 
000 800 919 0928 
Mexico 
800 123 3102 
South Africa 
0800 984 003 
6.3.6.2. 
Emergency unblinding prior to regulatory reporting of SAEs  
GSK policy (which incorporates ICH E2A guidance, the EU Clinical Trial Directive and 
US Federal Regulations) is to unblind the report of any unexpected SAE and which is 
attributable/suspected to be attributable to the study vaccine/product, prior to regulatory 
reporting. Vaccines Clinical Safety and Pharmacovigilance (VCSP) is responsible for 
unblinding the intervention assignment in accordance with the specified timeframes for 
expedited reporting of SAEs (refer to the Section 10.3.10.1).  
In addition, GSK VCSP staff may unblind the intervention assignment for any participant 
with a Suspected Unexpected Serious Adverse Reaction (SUSAR) or a Serious Adverse 
Event that is fatal or life threatening. If the SAE requires an expedited regulatory report 
be sent to 1 or more regulatory agencies, a copy of the report, identifying the participant’s 
intervention assignment, may be sent to investigators in accordance with local regulations 
and/or GSK policy. 
6.4. 
Study intervention compliance  
Before dosing, a qualified member of the study staff other than the person administering 
the dose will confirm that the intervention number is correct. The intervention number 
administered, and the administration date and time will be recorded in the source 
documents. 
6.5. 
Concomitant therapy  
At the timepoints indicated in the SoA, the investigator or delegate should question the 
maternal participant and/or the infant participant’s parent(s)/LAR(s) about any 
medications/products taken and vaccinations received by the participant. 
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 regarding 
concomitant or prior therapy. 
6.5.1. 
Maternal participants  
 
All folate and iron supplements beginning the month before the estimated date of 
conception and continuing through delivery (i.e., through Visit 3). These 
supplements should be reported when taken independently and/or when included in a 
multivitamin mineral supplement. 


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 
All antibiotics, antivirals, analgesics and anti-pyretics taken within 7 days before 
dose administration. 
 
All concomitant vaccines beginning the month before the estimated date of 
conception and throughout the study (i.e., through Contact 1). 
 
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 study vaccine, or to prevent 
re-occurrence of one or more post-vaccination AEs such as headache).  
 
Any concomitant medications/products given for pre-existing medical conditions, 
beginning at Visit 1 and ending at Contact 1 (Day 1 to Day 181). 
 
Any concomitant medications/products associated with a solicited event or with an 
unsolicited adverse event, beginning at Visit 1 and ending at Visit 2 (Day 1 to Day 
31). 
 
Any corticosteroids for fetal lung maturation administered prior to/during labour 
or delivery, as well as any antibiotics administered in the last week prior to delivery 
and/or during labor. Note: Standard of care medications/products administered 
routinely during labor/delivery (e.g., General/regional/local anesthetics, analgesics, 
etc) do not need to be reported. 
 
Any concomitant medications/products associated with a medically attended 
adverse event (MAE) other than an MA-RTI beginning at Visit 1 and ending at Visit 
4 (Day 1 to Day 43 post delivery). 
 
Any concomitant medications/products associated with an MA-RTI beginning at 
Visit 1 and ending at Contact 1 (Day 1 to Day 181 post delivery). 
6.5.2. 
Infant participants  
 
Vaccinations administered from Birth (Visit 1-NB) through the 6-month visit (Visit 
4-NB)  
 
Medications administered in relation to RTIs/LRTIs from Birth (Visit 1-NB) through 
the 12-month visit (Visit 5-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 participants  
 
Any concomitant medications/products/vaccines leading to a participant’s non-
eligibility (Sections 5.2.1 and 5.2.2) or potential non-evaluability (Section 9.3.1.1), 
or to a participant’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 also 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  
If a participant is not interested in taking part in the booster study, the reason for refusal 
will be documented, when available, in the participant’s eCRF. Refusal to participate in 
the extension study will not prevent participants from enrolling in the RSV MAT-009 
study.  
There will be no access to study intervention after the end of the study, because of the 
safety signal identified, leading to stopping of further enrolment and vaccination. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT 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 for enrolment and/or vaccination  
Vaccination must be postponed until transient circumstances cited below are resolved:  
 
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). 
Participants with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be vaccinated at the discretion of the investigator. 
 
Use of systemic antibiotic or antiviral treatment within 48 hours before study 
vaccination. 
Note: vaccination must be completed within the permitted time interval. If a participant is 
screened but not vaccinated within the allowed interval, a re-screening should be done to 
establish the participant’s eligibility. Please make sure the participant’s gestational age is 
still within the allowed range. 
Refer to SPM for further guidance. 
7.1.2. 
Contraindications to subsequent vaccine/product administration  
Not applicable. 


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7.2. 
Participant discontinuation/withdrawal from the study  
A participant 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 participant from the date of withdrawal/last contact. 
From an analysis perspective, a ‘withdrawal’ from the study refers to any participant 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 participants 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 
participant 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 10.3.10.1) 
 
Unsolicited non- serious adverse event 
 
Solicited adverse event (maternal participants) 
 
Protocol deviation 
 
Withdrawal by participant, not due to an adverse event* 
 
Migrated/Moved from the study area 
 
Lost to follow-up 
 
Sponsor study termination 
 
Other (specify) 
*If a participant is withdrawn from the study because she/the participant’s 
parent(s)/LAR(s) has withdrawn consent and provided the reason for the withdrawal, the 
investigator must document this reason in the eCRF. 
Participants who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigators will 
follow participants who are withdrawn from the study as a result of an SAE/AE until the 
event is resolved. (see Section 10.3.8.3). 
7.3. 
Lost to follow-up  
A maternal participant will be considered ‘lost to follow-up’ if she fails to return for 
scheduled visits and is unable to be contacted by the study site.  
An infant participant will be considered ‘lost to follow-up’ if his or her parent(s)/LAR(s) 
fail to return for scheduled visits and are unable to be contacted by the study site. 


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Please refer to the SPM for a description of the actions to be taken before considering the 
participant as lost to follow-up.  
8. 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarised in the SoAs (Section 1.3). 
Information not provided in the SoAs follows. 
As a reminder: study visits, assessments and procedures do not replace local standards of 
care, and that any adverse event / potential adverse event identified during a study visit or 
procedure should be treated according to local medical practice or by referral to an 
appropriate health care provider. 
Adherence to the protocol is 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 participants meet all eligibility criteria.  
The investigator will maintain a screening log of all participants 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, 
Ultrasounds, HIV testing, etc.) and obtained before the participant 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) and/or the eligibility criteria (Sections 5.1 and 
5.2). 
The SPM provides the investigator and site personnel with administrative and detailed 
technical information that does not impact participant safety. 
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.  
For guidance regarding the temporary delay of study intervention administration 
because of exposure to COVID-19, please refer to the SPM for details. 


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For the duration of such special circumstances: 
 
Enrolment of ADDITIONAL maternal participants 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 SMS, email, telephone, videotelephony or telemedicine. In 
such cases:  
 
Protocol-specified clinical data that  
 
cannot be collected by study staff during the contact (e.g., physical 
examination results; SpO2 results) BUT  
 
are available within the allowed interval (Table 3) in the 
participant’s medical records and can be obtained by site staff (as 
allowed by local law), may be recorded in the participant’s source 
document and entered into the eCRF.  
 
Whenever possible, as appropriate per the judgement of the 
investigator and as allowed by local law, arrangements should be 
made for qualified personnel to collect any protocol-specified 
biological samples at an alternate location within the visit interval 
(Table 3).  
 
Samples should not be collected if they cannot be processed in 
a timely manner and / or appropriately stored until the intended 
use.  
 
Nasal swabs for central testing must be collected using GSK-
provided supplies. (note: if collection at either the study site, 
participant’s home or an alternate location is not possible, 
participants may be instructed to collect nasal swab samples by 
themselves/for their infant. Collection will be done using GSK-
provided supplies and all the corresponding detailed 
instructions to allow such collection will be provided along 
with the nasal swab sampling kit) 
 
Blood / cord blood samples for assessment of immune response 
must be retrieved, processed and stored in accordance with the 
Investigator Laboratory Manual. 
 
“Medically attended visits” will include instances where, due to the special 
circumstances, the participant 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. 


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 
The frequency of RTI surveillance contacts by site personnel may be temporarily 
adapted. 
Impact on the analysis sets for efficacy and immunogenicity will be determined on a 
case by case basis. 
*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 for more details. 
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 participants 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 participant/infant participant’s parent(s)/LAR(s).  
Collected samples will be stored for a maximum of 20 years. This storage period begins 
when the last participant performed the last study visit, unless local rules, regulations or 
guidelines require different timeframes or procedures, which would then be in line with 
participant consent. These extra requirements need to be communicated formally to, and 
discussed and agreed with GSK. 


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8.1.1. 
Biological samples  
Table 12 
Biological samples – maternal participants  
Maternal 
Sample type 
Collected to 
Evaluate 
Minimum 
Quantity per 
participant 
Unit 
Time point 
Additional Information 
Whole blood  
Immune 
response 
~10 
ml 
Visit 1 (Day 1) pre dose 
Visit 1 and Visit 2: Applies to all participants, Stages A & B 
Visit 3: Applies to Stage A Immunogenicity sub-cohort only# 
Visit 2 (Day 31) 
Visit 3 (Delivery) 
 
~30 
ml 
Estimated TOTAL if assigned to the immunogenicity sub-cohort# 
~20 
ml 
Estimated TOTAL if NOT assigned to the immunogenicity sub-cohort 
Nasal Swab*  
Presence 
of:RSV A / B 
- 
- 
MA RTI Assessment 
Visit  
Collect a nasal swab from any maternal participant who reports a medically attended 
(MA) RTI 
 
 
- 
- 
RTI hospitalization 
Collect a nasal swab (if possible) from any maternal participant hospitalized with a RTI 
(or soon after discharge, as long as symptoms are ongoing).  
Volume of the blood sample collected for immune response assessment may be reduced to ~5 ml at investigator’s discretion. Refer to the laboratory manual for additional information. 
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 nasal swab specimens are collected and tested locally as per local standard of care, results will be recorded in the eCRF. In principle only the sponsor laboratory results will be 
used when applying the case definitions for data analysis in Section 4.2.6.3. Thus, where mandated by the protocol, every effort should be made to obtain nasal swab samples that can 
be analyzed by the sponsor (or sponsor-designated) laboratory. Results of locally tested samples, with locally approved tests may be used when applying case definitions only in the 
event the nasal swab for central testing was impossible to collect. 
* Due to the stop on study enrollment and vaccination, nasal swab samples will no longer be collected from any maternal participant and no MA-RTI assessment visit will be performed. 
# Following protocol amendment 4, blood samples will be collected at delivery from all maternal participants. Hence, even if not assigned to the immunogenicity sub-cohort, the 
estimated total volume of blood for all maternal participants will be ~30mL. In addition, placental samples will also be collected at delivery, whenever feasible. 


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Table 13 
Biological samples – Cord Blood  
Sample type 
Collected to Evaluate 
Minimum Quantity per participant 
Unit 
Time point 
Additional Information 
Cord blood  
Immune Response 
~5, up to ~10 
ml 
Visit 3 (Delivery) 
- 
Table 14 
Biological samples – infant participants  
Infant 
Sample 
type 
Collected to 
Evaluate 
Minimum 
Quantity per 
participant 
Unit 
Time point 
Additional Information 
Whole 
Blood 
Immune 
response - IF 
cord blood not 
collected 
~2.5 -  
Stages A and B 
ml 
Visit 1-NB  
(Within 3 days after 
birth) 
Volume must be reduced if weight ≤ 2.5 kg. 
[Trial-related blood loss for infant participants 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 and/or SPM for additional information. 
All minimum totals given below assume a body weight > 2.5 kg.  
 
Immune 
response – 
sub-cohort*# 
~2.5* - 
Stage A 
immunogenicity 
sub-cohort only 
ml 
Either 
Visit 2-NB (Day 43) or 
Visit 3-NB (Month 4) or 
Visit 4-NB (Month 6) 
 
 
~2.5 
ml 
Estimated TOTAL if cord blood NOT collected 
 
 
~2.5 
ml 
Estimated TOTAL if assigned to one of the three blood sampling sub-cohorts in Stage A 
 
 
~5.0 
ml 
Estimated TOTAL if assigned to a blood sampling sub-cohort in Stage A AND cord blood NOT collected 
Nasal 
swab 
Presence of 
RSV A / B 
- 
- 
LRTI Assessment Visit  
Collect at least one nasal swab for each potential LRTI reported. 
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 participant hospitalized with a RTI (or soon after release, as long as 
symptoms are ongoing). 
*Only from infant participants in the sample collection sub-cohort for the visit. Each infant is assigned to a single sub-cohort.  
# Due to the stop on study enrollment and vaccination, there will no longer be collection of blood samples from the infants at V2-NB, V3-NB and V4-NB  
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 nasal swab specimens are collected and tested locally as per local standard of care, results will be recorded in the eCRF. In principle only the sponsor laboratory results will be 
used when applying the case definitions for data analysis in Section 4.2.6.3. Thus, where mandated by the protocol, every effort should be made to obtain nasal swab samples that can 
be analyzed by the sponsor (or sponsor-designated) laboratory. Results of locally tested samples, with locally approved tests may be used when applying case definitions only in the 
event the nasal swab for central testing was impossible to collect.  


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8.1.2. 
Laboratory assays  
Table 15 
Laboratory assays  
Assay type 
System 
Component 
Method 
Laboratory* 
Humoral 
Immunity 
(Antibody 
determination) 
SERUM 
RSV-A NAb (RSV-A 
Neutralizing 
Antibody) 
NEUT 
GSK ** or GSK 
designated lab 
SERUM 
Respiratory Syncytial 
Virus PreF3 Ab.IgG 
(RSVPreF3 IgG 
antibody 
concentration) 
ELISA 
GSK ** or GSK 
designated lab 
Molecular 
Biology 
NASMUC 
(Nasal 
swab) 
Respiratory Syncytial 
Virus A RNA  
QRTPCR  
GSK ** or GSK 
designated lab 
 
NASMUC 
(Nasal 
swab) 
Respiratory Syncytial 
Virus B RNA  
QRTPCR 
GSK ** or GSK 
designated lab 
*Refer to the list of clinical laboratories for details. 
** GSK laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. CLS may 
delegate testing to GSK Research laboratories in Rixensart, Belgium; Rockville, USA; Sienna, Italy. 
ELISA = enzyme-linked immunosorbent assay; NEUT = Neutralization; 
RSV-A/B quantitative reverse transcription PCR will be performed on all specimens collected to evaluate RTI as 
specified in Section 8.4.4.  
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 16 
Immunological read-outs (Amended 23 February 2023)  
Approximately 1533 maternal participants (and their infant participants), in Stage A only, 
will be assigned to the immunogenicity sub-cohort.  
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives and to assess antibody persistence in infants. Therefore, 
maternal participants in the immunogenicity subcohort, who have blood samples 
collected from their respective infants, will have Visit 1 (Day 1), Visit 2 (Day 31), 
Delivery blood samples and cord blood samples tested for RSV-A NAb. In addition, 
their delivery and cord blood samples will be tested for RSVPreF3 IgG-specific 
antibody concentration.  
Blood sampling timepoint 
Approximate No. 
participants – 
Stage A 
Approximate No. 
participants – 
Stage B 
Component 
Type of 
contact and 
timepoint 
Sampling 
timepoint 
Maternal participants*  
V1 (Day 1) 
pre 
vaccination 
4600 
Up to 5400 
RSV-A NAb (neutralizing antibody) 
V2 (Day 31) 
post 
vaccination 
4600 
Up to 5400 
RSV-A NAb (neutralizing antibody) 
V3 (Delivery)# 
post-
vaccination  
venous blood: 1533 
Cord blood: 4600 
Venous blood: 0 
Cord blood: up to 
5400 
RSV-A NAb (neutralizing antibody) 
Respiratory Syncytial Virus PreF3 Ab.IgG 
(concentration) 
Infant participants** 
 
 
V1-NB (Birth)  
birth (only if 
cord blood 
cannot be 
collected) 
Event-driven 
Event-driven 
RSV-A NAb (neutralizing antibody) 
Respiratory Syncytial Virus PreF3 Ab.IgG 
(concentration) 
V2-NB (Day 
43)*** 
post birth 1  510 
0 
RSV-A NAb (neutralizing antibody) 
V3-NB (Day 
121)*** 
post birth 2  510 
0 
RSV-A NAb (neutralizing antibody) 
V4-NB (Day 
181)*** 
post birth 3  510 
0 
RSV-A NAb (neutralizing antibody) 
V = Visit; RSV-A/B: respiratory syncytial virus subtype A/B; NB: Newborn. IgG: immunoglobulin G;  
* Refer to Table 12, Table 13 
** Refer to Table 14  
***Due to the stop on study enrollment and vaccination, blood samples will no longer be collected from the infants at 
V2-NB, V3-NB or V4-NB. 
# As from Protocol Amendment 4 - Blood sample at delivery to be collected from all participants. Whenever feasible, 
placenta sample is expected to be collected from all participants. These samples may be tested to support 
possible safety assessments, if necessary. 


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Table 17 
Molecular biology tests  
Nasal swab sampling timepoint 
No. 
participants 
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 8.4.4 
# Due to the stop on study enrollment and vaccination, nasal swabs from maternal participants will not be collected and 
no MA-RTI assessment visit will be performed. 
8.1.4. 
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 the study, are AESIs, or that caused the participant to 
discontinue the study. 
Surveillance for / evaluation of respiratory tract illness is described in Section 8.4. 
8.2.1. 
Procedures for maternal participants  
Additional details are provided in the SPM. 
8.2.1.1. 
Medical/vaccination history  
Obtain the maternal participant’s medical/vaccination history by interviewing her and/or 
reviewing her medical records. Record any pre-existing maternal participant conditions, 
signs and/or symptoms present prior to the study vaccination in the eCRF. 
 
Record outcome of the fetal anomaly ultrasound (also known as a Level 2 ultrasound 
scan or fetal morphology assessment). Please see Section 10.7.2 for a description. If 
results are not available at screening, then the ultrasound can be performed as a study 
procedure under certain conditions and results confirming no significant 
abnormalities/congenital malformations should be available prior to participant’s 
study randomization and vaccination. Refer to the SPM for further details. If 
abnormal, participants will be referred, as/if applicable, per local standard of care. 
 
Information from additional routine standard of care antenatal / medical evaluations 
(external to study visits/procedures) are not to be reported in the CRF. If an 
unscheduled visit is performed post study vaccination, for safety reasons, results of 


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procedures performed, per investigators discretion (eg. hematology/biochemistry 
testing, urinalysis, etc) will be recorded in the “Unscheduled Safety visit” eCRF. 
 
Record number of past pregnancies, their outcome(s) and any pregnancy-related 
complications. 
 
For the current pregnancy, record: 
 
the participant’s pre-pregnancy BMI (i.e., BMI during the months before the 
participant became pregnant or at the very first maternal visit [if occurred early 
in the 1st pregnancy trimester]). This information can be obtained either via 
medical record review or participant interview. If BMI is not directly available, 
investigators will obtain participant’s pre-pregnancy weight (i.e. weight during 
the months before the participant became pregnant or are the very first maternal 
visit [if occurred early in the 1st trimester]) and calculate pre-pregnancy BMI 
from it, in order to report it in the eCRF. 
NOTE: in the exceptional circumstance where the pre-pregnancy weight/BMI is 
unknown and there is no maternal visit performed during the 1st trimester, the 
BMI calculated based on the weight at screening may be used for eligibility. In 
those cases, the investigator should carefully assess the nutritional status of the 
potential participant to exclude any signs of malnutrition, in conjunction with 
the other eligibility criteria. 
 
gestational age, along with GAIA level of certainty as defined in Section 10.8 
 
date of Last menstrual period date (LMP) or Embryo Transfer (ET) or 
Intrauterine insemination (IUI), as applicable  
 
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 and gestational age 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. 
 
Record all vaccination received by the maternal participant since the month 
prior to the estimated date of conception and before study vaccination 
8.2.1.2. 
Physical examination (General and obstetric examination)  
Screening and Visits 1 through 3 
 
Height (only at screening) 
 
Weight (at screening and Visits 1-2),  
 
Temperature at screening and Visits 1-3. At Visit 1, temperature need only be 
measured once, pre-vaccination. At visit 3 (delivery) temperature should be 
measured if/as per standard of care (SoC).  


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 
Systolic/diastolic blood pressure, heart rate and respiratory rate (after at least 10 
minutes rest) at screening and at Visits 1 and 2; and on admission for delivery at 
Visit 3. Respiratory rate should be measured at Visit 3 (delivery) if/as per SoC. 
 
Pulmonary examination including measurement of blood oxygen saturation and chest 
auscultation (at Visit 1). 
Obstetric examination should include: 
 
Fetal heart tones,  
 
Fetal movement and fundal height (at screening and visits 1 – 2). No specific test 
required for fetal movement, unless part of standard of care, information reported by 
the maternal participant while at the visit will be acceptable)  
 
Presence of edema (at screening and visits 1 – 2) 
 
Vaginal examination (manual and/or speculum) will be performed ONLY if 
warranted by participant's symptoms or as per investigator's clinical discretion. If 
done, results will be recorded (normal or abnormal; if abnormal, specify). 
If the Screening Visit and Visit 1/vaccination are performed on the same day: 
 
Physical examination (general and obstetrical) procedures required both at screening 
and at Visit 1/vaccination should be performed once; they do not need to be repeated. 
 
Temperature will only be measured once, but will need to be recorded twice in the 
eCRF.  
 
The Pulmonary examination foreseen at Visit 1 should be performed.  
Visit 4 
 
Vital signs (systolic/diastolic blood pressure, heart rate and respiratory rate after at 
least 10 minutes of rest) 
 
History and/or symptom directed physical and obstetrical exam as per standard of 
care (eg. check of c-section scar / episiotomy scar, any specific checks based on 
eventual complaints raised by the mother, etc. as applicable). Clinically significant 
abnormalities will be recorded 
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 participant assessments listed in Section 8.4.4.  
8.2.1.2.1. 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.  


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8.2.1.2.2. Monthly contacts  
At least 3 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.  
To ensure safety monitoring, in addition to the monthly contact between Visit-2 and the 
Delivery visit, additional not pre-specified visits and contacts (any desired frequency) can 
be made between Visit-2 and the Delivery visit, as per investigator’s or maternal 
participant’s discretion. 
8.2.2. 
Procedures for infant participants  
Additional details are provided in the SPM. 
8.2.2.1. 
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 assessment of the following: 
 
Weight, length, head circumference  
 
Temperature, heart rate and respiratory rate 
 
Age-appropriate organ system examination including: eyes, ears, musculoskeletal, 
reflexes (motor/visual/sound), pulmonary (chest auscultation), cardiovascular, 
neurological, skin and genitourinary. 
 
Presence of congenital anomalies. 
8.2.3. 
Safety monitoring  
Safety evaluations will include those performed by investigators, by a blinded SRT* 
composed of GSK RSV team members, and by an unblinded, independent data 
monitoring committee external to GSK (IDMC). Details regarding IDMC safety 
evaluations are provided in a separate IDMC charter. 
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). 
*Note: Due to the safety signal observed, the study has been fully unblinded to ensure 
safety monitoring for the participants. 


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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 18 
Timeframes for collecting and reporting safety (and RTI) information  
Applies to Stage A and Stage B unless otherwise noted below 
 
Before Delivery* 
Delivery/Birth 
Post-Delivery/Birth*  
Timepoint 
D-28 
D1 
D7 
D31 
 
D 43 
D91 
D121 
D181 
M9 
M12  
Maternal participant visits 
Pre-** 
V1 
 
V2 
V3 
V4 
 
 
C1  
 
 
Infant visits 
 
 
 
 
V1-NB 
V2-NB 
C1-NB 
V3-NB 
V4-NB 
C2-NB 
V5-NB  
Event 
Administration site and systemic solicited events - 
Stage A ONLY 
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
Unsolicited AEs that are neither SAEs, MAEs or 
AESIs 
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
Subsequent Pregnancies*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M 
 
AEs/SAEs leading to Withdrawal from the study 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
I 
SAEs  
 
 
 
 
 
 
 
 
 
 
 
M  
 
 
 
 
 
I 
 
 
 
 
 
 
 
 
 
 
 
 
MAEs 
 
M 
 
 
 
 
 
 
 
 
 
 
I 
 
 
 
 
 
AESIs**** 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medically attended RTIs (mothers)#;  
 
M 
 
 
RTI/LRTI (infants) 
 
 
 
 
I 
 
 
 
 
 
 
 
 
 


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Applies to Stage A and Stage B unless otherwise noted below 
 
Before Delivery* 
Delivery/Birth 
Post-Delivery/Birth*  
Timepoint 
D-28 
D1 
D7 
D31 
 
D 43 
D91 
D121 
D181 
M9 
M12  
Maternal participant visits 
Pre-** 
V1 
 
V2 
V3 
V4 
 
 
C1  
 
 
Infant visits 
 
 
 
 
V1-NB 
V2-NB 
C1-NB 
V3-NB 
V4-NB 
C2-NB 
V5-NB  
SAEs related to study participation or concurrent 
GSK medication or vaccine  
M 
 
 
 
 
 
 
 
Pre = pre-vaccination; V=visit; D: Day; M = Maternal participants; I= Infant participants. * Approximately monthly contacts pre- delivery also occur within the timeframes described 
above and are described in Section 1.2. **i.e. consent obtained. *** If subsequent pregnancy occurs during the study, follow-up may extend up to 8 weeks post birth of the infant from 
that subsequent pregnancy. ****AESIs include adverse pregnancy outcomes, pregnancy related AEs of special interest and neonatal AEs of special interest (for details refer to 
Section 10.3.5). Neonatal AEs of special interest identified after V2-NB (e.g., congenital anomalies) will continue to be reported as such. 
#Due to the stop on study enrollment and vaccination, MA-RTI surveillance of the maternal participants will no longer be performed. 


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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 participant 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 an 
SAE/AESI, as indicated in Section 10.3.10. and Table 19. The investigator will submit 
any updated SAE/AESI data to the sponsor within 24 hours of it being available. 
A post-study SAE is defined as any event that occurs after the end of the study. 
Investigators are not obligated to actively seek SAEs from former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study vaccine/product, the investigator will promptly notify the 
Study Contact for Reporting SAEs mentioned in the Table 20. 
8.3.2. 
Method of detecting AEs and SAEs, subsequent pregnancies and 
other events  
Methods of detecting and recording AE/SAE/AESI/subsequent pregnancies are detailed 
in the 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 participants/infant 
participants’ parent(s)/LAR(s) is the preferred method of acquiring information related to 
an AE/SAE/AESI/subsequent pregnancy. 
8.3.3. 
Regulatory reporting requirements for SAEs, subsequent 
pregnancies, and other events  
Once an investigator (or designee) becomes aware that a study participant has 
experienced an SAE/AESI/subsequent pregnancy, he/she must report it to GSK using the 
required documentation, and within the timeframes, mentioned in the Table 19. This is 
essential for meeting legal obligations and ethical responsibilities for participant 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 the 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. 


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Table 19 
Timeframes for submitting serious adverse event, subsequent 
pregnancy and other events reports to GSK  
Type of Event 
Initial Reports 
Follow-up of Relevant Information on 
a Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs (including adverse 
outcomes for the study 
pregnancy) 
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 participants: MA-
RTIs 
Infant participants: 
RTIs/LRTIs 
3 days* 
eCRF 
1 week 
eCRF 
Subsequent Pregnancies 
24 hours * 
electronic pregnancy 
report 
24 hours * 
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  
8.3.3.1. 
Contact information for reporting of SAEs, AESIs, subsequent 
pregnancies and study holding rules  
Table 20 
Contact information for reporting of SAEs, AESIs, subsequent 
pregnancies  
Study contact for questions regarding SAEs, AESIs, subsequent pregnancies  
Refer to the local study contact information document 
Back-up study contact for reporting SAEs, AESIs, subsequent pregnancies  
Available 24/24 hours and 7/7 days: 
GSK Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: ogm28723@gsk.com 
US sites only: 
Fax: 1-610-787-7053 
Canadian sites only: 
Fax: 1-866-903-4718 
8.3.4. 
Additional Reporting Guidance for the Study Pregnancy  
8.3.4.1. 
Labor and Delivery  
 
An uncomplicated vaginal delivery or planned cesarean section expected to occur in 
a hospital setting should NOT be reported as an AE, MAE or SAE. 
 
A medical complication that requires a cesarean section or an emergency induction 
may be reported as an SAE/AESI (as applicable), using the corresponding Expedited 
AE report form.  


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8.3.4.2. 
Pregnancy outcomes  
Table 21 summarizes the requirements for AESI/ SAE reporting of adverse pregnancy 
outcomes when congenital anomalies are / are not present  
Table 21 
Reporting pregnancy outcomes with or without congenital 
anomalies as AESIs and/or SAEs  
 
 
Fetal death 
Elective / Therapeutic 
Termination 
 
Live birth 
/stillbirth 
Congenital anomalies* 
AESI 
SAE 
AESI 
SAE 
AESI 
SAE 
None 
- 
- 
- 
X 
- 
X 
Major1  
X 
if reportable per 
MACDP3 
- 
X 
- 
X 
Minor2  
- 
if reportable per 
MACDP3 
- 
X 
- 
X 
* In the event of infant’s participation in the study, congenital anomalies are to be reported in the infant’s eCRF. 
However, when there is no live birth, or no signed informed consent for the infant or the congenital anomaly is being 
reported for a subsequent pregnancy, it will be encoded in the maternal participant’s eCRF.  
1Structural or functional defects that require surgical and/or medical treatment and that have serious adverse effects on 
health or development (functional) or have significant cosmetic impact. 
2Anatomic variants or defects that do not have serious medical, functional or cosmetic consequences for the child.  
3 Metropolitan Atlanta Congenital Defects Program (MACDP) 6-Digit Code Defect List 
Additional guidance when congenital anomalies are present follows: 
The term “congenital anomaly” is broad. GSK uses the case definitions provided in the 
Centers for disease Control and Prevention (CDC) Metropolitan Atlanta Congenital 
Defects Program guidelines, with specific reference to the MACDP 6-Digit Code Defect 
List [MACDP, 2021] to ensure that the collection and recording of these data is complete 
and consistent across studies and projects. 
To report a pregnancy outcome of live birth with congenital anomaly as an SAE per these 
guidelines, an infant must have a birth defect that is included in MACDP surveillance 
data per the MACDP 6-Digit Code Defect List. (Congenital anomalies that are not 
included in MACDP surveillance data may be reported as medically attended or serious 
adverse events, if appropriate). 
The characterization of major and minor congenital anomalies will follow CDC 
definitions [CDC, 2019]. Major congenital anomalies are structural or functional defects 
that require surgical and/or medical treatment and that have serious adverse effects on 
health or development (functional) or have significant cosmetic impact. They are always 
reported as AESIs, even if they are not reportable as SAEs.  
Minor congenital anomalies are anatomic variants or defects that do not have serious 
medical, functional or cosmetic consequences for the child. Minor congenital anomalies 
are not to be reported as AESIs, even if they are reportable as SAEs.  
If minor congenital anomalies are not reportable either as SAEs or MAEs, they may be 
recorded in the infant physical examination eCRF. 


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For example: 
 
Cleft palate is a major congenital anomaly and should be reported as an AESI. Per 
the MACDP 6 Digit Code Defect list, cleft palate is always included in MACDP 
surveillance data and should therefore also be reported as an SAE.  
 
If congenital aortic valve insufficiency or regurgitation meets the criteria for a major 
congenital anomaly, it is an AESI. Per the MACDP 6-digit code list, congenital 
aortic valve insufficiency or regurgitation is only included in MACDP surveillance 
data and should only be reported as an SAE if designated as moderate or severe, or 
(if the degree is not specified) if another heart defect is present. Other cases could be 
reported as medically attended or serious adverse events if the infant meets any other 
protocol criterion for a medically attended or serious AE because of the condition. 
 
Mongolian spots, in the absence of any associated findings represent a minor 
congenital anomaly. Per the MACDP 6-digit code list, they are never included in 
MACDP surveillance data. They are neither an AESI nor an SAE. They do not 
typically satisfy the criteria for a medically attended AE and so, in general, would 
only be recorded in the infant physical examination eCRF. 
Refer to the SPM for additional information and guidance. 
8.3.5. 
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 participant’s eCRF screen (refer to the 
Section 10.3.10.1). 
8.3.6. 
Participant cards  
The investigator (or designee) must provide the maternal participant/infant participant’s 
parent(s)/LAR(s) with a “participant card” containing information about the clinical 
study. One card will be provided to each maternal participant who enters the study. 
Another card will be provided for each infant participant who enters the study. 
Maternal participants/infant participant’s parent(s)/LAR(s) must be instructed to keep 
these participant cards in their possession at all times throughout the study. In an 
emergency, the cards serve to inform the responsible attending physician/LAR/care 
giver/family member that the maternal / infant participant 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 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. 


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8.4.1. 
Definitions  
8.4.1.1. 
Medically attended respiratory tract illnesses (MA-RTIs) in maternal 
participants (Amended 23 February 2023)  
A maternal MA-RTI occurs when the maternal participant visits a healthcare professional 
(e.g., a General Practitioner) for any respiratory symptom, including (but not limited to) 
cough, sore throat, sputum production and difficulty breathing. 
* Due to the stop on study enrollment and vaccination, MA-RTI surveillance of the 
maternal participants will no longer be performed. No nasal swab will be collected and 
no RTI assessment visit will be performed. However, any MAE related to RTI will still 
be reported (as applicable). 
8.4.1.2. 
Respiratory tract illnesses (RTIs) in infant participants  
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 
potential 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. 
A potential lower respiratory tract illness (LRTI) is one in which the infant’s RTI 
symptoms include at least one of the following: 
 
Difficulty in breathing (fast breathing, poor feeding, working hard to breathe, or 
making unusual sounds when breathing); 
 
Wheezing (a whistling sound when the infant breathes out); 
 
Parental concern (the parent(s)/LAR(s) or their designate(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). 


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8.4.2. 
Surveillance  
8.4.2.1. 
Maternal participants  
MA-RTI surveillance begins when a maternal participant enters the study and ends 6 
months after delivery (Contact 1). It will be accomplished via contacts initiated by 
maternal participants.  
At study entry, each maternal participant will be instructed to contact the site should 
she 
 
Visit (or plan to visit) a healthcare professional for any respiratory symptoms; 
 
Be hospitalized because of her respiratory symptoms. 
If the study site is the primary treating facility for the maternal participant, a “contact” 
may also be made by going directly to the study site. 
Site personnel will use a script to guide data collection once a contact has been made.  
Due to the stop on study enrollment and vaccination, MA-RTI surveillance for the 
maternal participants will no longer be performed. 
8.4.2.2. 
Infant participants  
RTI surveillance in infant participants begins at birth (Visit 1-NB) and ends 12 months 
after birth (Visit 5-NB).  
It will be accomplished via two types of contact and completion of diary cards 
8.4.2.2.1. RTI surveillance contacts  
 
In a Passive contact, the participant’s parent(s) / LAR(s) contact site personnel. Site 
personnel will use a script to guide data collection once a passive contact has been 
made. 
 
In an Active contact, site personnel contact the participant’s parent(s) / LAR(s). 
Active contacts will also be scripted.  
 
In regions where RSV transmission is seasonal, contacts should occur every 
week during the RSV season and every month outside the RSV season.  
 
In regions with year-round RSV transmission, contacts will occur every 2 
weeks. 
 
At least 3 attempts should be made within the week of a scheduled contact. If 
these attempts are unsuccessful, that active contact is considered a missed 
contact. The next active contact will be made according to schedule. 
In special circumstances, such as for example, in the event of a pandemic, social 
distancing and confinement measures may considerably impact the region’s usual RSV 


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seasonality. Hence, frequency of active contacts may be temporarily adapted (in 
agreement with GSK and subject to IEC/IRB approval, as needed) to avoid unnecessary 
burden (Refer to Section 8). 
Further details are provided in the SPM. 
Site staff will use information gathered during each active or passive surveillance contact 
to determine whether a visit to assess a potential LRTI (Section 8.4.4) should be 
scheduled.  
8.4.2.2.2. RTI Diary cards  
Infant RTI diary cards will be provided to the infant participant’s Parent(s)/LAR(s) as 
soon as possible after the infant’s birth (ideally, at Visit 1 NB). Parents will use the diary 
card to document symptoms of the RTI. 
Parent(s)/LAR(s) will be asked to bring any completed or partly completed diary cards 
with them to the infant participant’s study visits (including any RTI assessment visits).  
At each study visit/contact (including any assessment visits), RTI symptoms may have 
ended or may be ongoing. This will be evaluated in order to determine whether to retrieve 
the Diary Card and replenish the parent(s)/LAR(s)/designate(s) supply of blank cards as 
needed or, instruct them to continue collecting information until the corresponding 
symptom(s) have ended 
 
Completed RTI diary cards may be collected by study staff during a site visit, 
home visit, or via postal mail, whichever is most effective based on local 
practice.  
Refer to the SPM for additional details. 
8.4.2.3. 
Maternal and infant participants  
If the maternal participant visited / the infant participant 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.  
8.4.3. 
When to conduct an assessment visit  
8.4.3.1. 
For a maternal MA-RTI  
Due to the stop on study enrollment and vaccination, MA-RTI surveillance for the 
maternal participants will no longer be performed. 
Conduct an assessment visit (Section 8.4.4), 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 beyond this window if symptoms are ongoing. 


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If a maternal participant informs the site that she has RTI symptoms and (a) would seek / 
have sought medical advice for them and (b) is already scheduled for a study visit within 
the timeframes described above, 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. 
Figure 6 
Decision Tree for site personnel – maternal surveillance and 
assessment  
 
RR: Respiratory rate: SpO2: Blood oxygen saturation by pulse oximetry. 
1Includes cases where symptoms would have resulted in a medically attended visit if participant were not already 
scheduled for a study visit 
2Details regarding the RTI assessment visit are provided in Section 8.4.4 and the SPM. 
Participant notifies site that
she has RTI symptoms
Yes
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
Participant plans to 
seek medical care 
for the RTI1
Remind to report any future 
medically attended RTIs by 
contacting site personnel
Symptoms have 
already resulted in 
a medically
attended visit
No
No
Yes


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8.4.3.2. 
For an infant RTI  
Conduct an assessment visit, as described in Section 8.4.4, as soon as possible after at 
least one of the following has been reported during the surveillance period: 
 
Difficulty in breathing, 
 
Wheezing 
 
The maternal participant/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. 
The visit should take place as soon as possible; ideally within 3 calendar days. However, 
a visit may be conducted even beyond the specified ideal window if symptoms are 
ongoing. 
 
After the first assessment visit, site personnel should use results of additional 
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 of difficulty in breathing or wheezing, OR 
 
that there is new or increased 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.  
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 8.4.2.2 and the SPM. 
2Cough, runny nose, blocked nose, difficulty in breathing, wheezing are described in Section 8.4.1.2 
3Details regarding the RTI assessment visit are provided in Section 8.4.4 and the SPM. 
4 Post-visit follow up is described in Sections 8.4.6 and in the SPM. 
5If a follow-up assessment visit is conducted, collection of additional nasal swabs is as described in Table 14. 
6Parental concern in the context of an RTI 
Active or Passive surveillance 
contact 1
Yes
Yes
No
Yes
No
No
Perform assessment visit 3, 4 ideally
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
Difficulty in breathing OR 
wheezing OR parental 
concern? 2
Any RTI symptom
(Cough OR runny nose
OR blocked nose OR 
difficulty in breathing OR 
wheezing)? 2
Remind to report any worsening 
of symptoms, any new 
symptoms, or parental concern
Remind to report any future 
symptoms
Worsening of 
symptoms, new 
symptoms, or parental 
concern? 4


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8.4.4. 
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). 
Note that if the reported symptoms are severe enough to warrant urgent care, the 
participant / parent(s)/LAR(s) should be advised to seek such care (e.g. Emergency 
Room). 
8.4.4.1. 
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 participants: Due to the stop on MA-RTI surveillance for maternal 
participants, these checks will no longer be performed. 
 
Temperature 
 
Respiratory rate 
 
Blood oxygen saturation measured by pulse oximetry (in room air, if feasible), see 
further details in Section 8.2.1.2.1 
 
Results of chest auscultation 
 
Signs of difficulty in breathing (wheezing and tachypnoea in maternal participants) 
For infant participants: 
 
Temperature 
 
Respiratory rate 
 
Blood oxygen saturation measured by pulse oximetry (in room air, if feasible), see 
further details in Section 8.2.1.2.1 
 
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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8.4.4.2. 
Nasal swab collection  
Refer to Table 12 (maternal participants) and Table 14 (infant participants). Additional 
details are provided in the SPM. 
8.4.4.3. 
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 participant 
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.  
* Due to the stop on study enrollment and vaccination, MA-RTI surveillance for the 
maternal participants will no longer be performed. 
8.4.5. 
RTI hospitalization during the surveillance interval  
Whenever a participant is admitted to hospital for observation or treatment of an acute 
respiratory illness during the surveillance interval for that participant, a nasal swab 
should be collected using GSK-provided supplies and sent to GSK for analysis. as 
described in Table 12 and Table 14.  
8.4.6. 
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 participant completes 
Visit 5-NB or (c) the participant is lost to follow up.  
8.4.7. 
Covid-19 Infection  
Maternal and infant COVID-19 cases identified during the study (as per standard of care) 
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 


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8.5. 
Treatment of overdose  
Not applicable. 
8.6. 
Pharmacokinetics  
Not applicable. 
8.7. 
Pharmacodynamics  
Not applicable. 
8.8. 
Genetics  
Not applicable. 
8.9. 
Biomarkers  
Not applicable. 
8.10. 
Health outcomes  
Not applicable. 
9. 
STATISTICAL CONSIDERATIONS  
9.1. 
Statistical hypotheses  
There are no hypotheses test for vaccine efficacy endpoints. 
9.2. 
Sample size determination  
Note: A total of 5328 participants have been enrolled and vaccinated in the study so far, 
and there will be no new maternal participants vaccinated. Please refer to Section 2.3 for 
details. However, monitoring will continue for rest of the study period. All planned 
objectives will be assessed for the participants enrolled so far. 


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9.3. 
Populations for analyses (Amended 23 February 2023)  
Table 22 
Maternal participants  
 
Description 
Analysis Set 
Maternal participants 
Enrolled 
All maternal participants who completed the informed consent process and signed the informed 
consent form.  
Exposed 
All maternal participants who received the study intervention. The allocation in a group is done in 
function of the administered intervention. 
Per Protocol – 
Immunogenicity 
All maternal participants who received the study intervention to which they were randomised and 
have post-vaccination data minus participants with protocol deviations that lead to exclusion.  
Solicited Safety 
– Stage A only 
All maternal participants in the Exposed Set who have solicited safety data 
Table 23 
Infant participants  
Analysis Set 
Description 
Exposed 
Infants live-born to exposed maternal participants, whose parents/LARs completed the 
informed consent process and signed the informed consent form 
Per Protocol – 
Immunogenicity 
All infant participants in the Exposed set minus those who (a) were born less than 4 weeks 
post- maternal participant vaccination and/ or (b) have protocol deviations that lead to 
exclusion. 
Full Analysis – 
Efficacy  
All infant participants in the Exposed set. 
 
Modified Full 
Analysis – Efficacy 
All infant participants in the Exposed set who were born after at least 4 weeks of 
vaccination. 
Per Protocol – 
Efficacy 
All infant participants in the Modified Full Analysis – Efficacy set minus those who have 
protocol deviations that lead to exclusion. 
9.3.1. 
Criteria for elimination from analysis  
The Statistical Analysis Plan (SAP) will provide a complete list of criteria for elimination 
from the analysis sets. Criteria may include, but are not limited to, those in Sections 
9.3.1.1 and 9.3.1.2.  
9.3.1.1. 
Intercurrent medical conditions and concomitant medications / 
products / vaccines that may lead to elimination of a participant 
(maternal/infant) from per-protocol analyses (efficacy/immunogenicity)  
9.3.1.1.1. Maternal participants  
 
Any of the medications listed in Section 5.2.1.2 if administered up to Delivery 
(Visit 3), except corticosteroids for fetal lung maturation administered after 
study vaccination. 


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9.3.1.1.2. Infant participants  
 
For the efficacy analyses:  
 
Systemic immunosuppressants or other immune-modifying drugs administered 
chronically (i.e. for more than 14 consecutive days).  
 
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). 
 
RSV-specific immunoglobulins at any time during the study 
 
For the immunogenicity analyses: 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. 
9.3.1.1.3. Maternal and Infant participants  
 
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 
participants, 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. 
9.3.1.2. 
Other situations that may lead to elimination of a participant (maternal / 
infant) from per-protocol analyses (efficacy/immunogenicity)  
 
Protocol violation(s) linked to the inclusion/ exclusion criteria, including maternal 
age at Visit 1 (study intervention). 
 
Study intervention not administered as specified by the protocol. 
 
Failure to comply with the post-dose immunogenicity blood sampling schedule at a 
given time-point (Table 3).  
9.4. 
Statistical analyses  
9.4.1. 
General considerations (Amended 23 February 2023)  
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. 
If, during the trial, changes need to be made on primary objectives and statistical methods 
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objectives, along with the reason(s) for the changes, will be documented in the SAP and 
the Clinical Study Report. 
9.4.2. 
Participants disposition  
Number of screened, randomised, vaccinated and withdrawn maternal participants in 
each group and overall will be described.  
Number of infant participants enrolled and withdrawn (by group and sub-cohort, and 
overall) will be described.  
9.4.3. 
Primary endpoints (Amended 23 February 2023)  
The primary analysis of vaccine efficacy will be based on the modified full analysis 
efficacy set for infants (modified FAS-E). A secondary analysis based on the full analysis 
efficacy set (FAS-E) and the per protocol efficacy set for infants will be performed to 
complement the modified FAS-E analysis. 
Analyses of primary safety endpoint will be performed on the Exposed set. 
Primary Efficacy Endpoints – Infant 
participants 
Statistical Analysis Methods 
From birth to 6 months, occurrences of 
medically assessed, RSV-associated severe  
LRTIs according to the case definitions 
OR 
From birth to 6 months, occurrences of any 
medically assessed, RSV-associated LRTIs 
according to the case definitions. 
Primary Safety Endpoint – Infant 
Participants 
Statistical Analysis Methods  
Occurrence of SAEs, AEs leading to study 
termination and medically attended AEs from 
birth up to 12 months after birth. 
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9.4.3.1. 
Detailed Statistical Analysis Methods  
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9.4.4. 
Secondary endpoints  
9.4.4.1. 
Efficacy (Amended 23 February 2023)  
The primary analysis of vaccine efficacy on secondary efficacy endpoints in infants will 
be based on the modified full analysis set for efficacy (modified FAS-E).  
The analysis of vaccine efficacy in maternal participants will be based on the Exposed 
set. 
Secondary Efficacy 
Endpoints  
Statistical Analysis Methods 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of RSV-associated 
hospitalizations according to 
the case definitions. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause 
LRTIs.  
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause LRTIs 
with hospitalization.  
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definitions. 
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Secondary Efficacy 
Endpoints  
Statistical Analysis Methods 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definition, for RSV 
subtype A and RSV subtype B 
separately. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definition, for RSV subtype A 
and RSV subtype B separately. 
From birth (Visit 1-NB) to 4 
months (Visit 3-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definition. 
From birth (Visit 1-NB) to 4 
months (Visit 3-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definitions. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause 
pneumonia. 
From study intervention 
administration (Visit 1) to 6 
months post-delivery (Contact 
1), occurrence of RSV-
associated medically attended 
RTIs (RSV-MA-RTIs). 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of RSV-associated 
hospitalizations according to 
the case definitions. 
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9.4.4.2. 
Detailed Statistical Analysis Methods  
 
 
  
9.4.4.3. 
Immunogenicity (Amended 23 February 2023)  
All immunogenicity analyses in stage A will be based on the Per Protocol 
Immunogenicity set.  
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives and to assess antibody persistence in infants. 
Secondary Immunogenicity 
Endpoints – Maternal Participants 
Statistical Analysis Methods 
 
Neutralizing antibody titers 
against RSV-A  
Measured on blood samples collected 
at Day 1 before vaccination (Visit 1), 
at Day 31 (Visit 2), and at delivery 
(Visit 3). 
Secondary Immunogenicity 
Endpoints – Cord blood / placental 
transfer 
Statistical Analysis Methods 
 
RSVPreF3 IgG-specific 
antibody concentration 
measured on blood samples 
collected at Delivery and cord 
blood* 
 
The ratio between cord blood* 
and maternal RSVPreF3 IgG-
specific antibody concentrations  
* or an infant blood sample collected 
within 72 hours after birth (if no cord 
blood sample can be obtained) 
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Secondary Immunogenicity 
Endpoints – Infant Participants 
Statistical Analysis Methods 
 
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 72 hours after birth if no 
cord blood sample can be 
obtained) and at Day 43 (Visit 2-NB), 
Day 121 (Visit 3-NB), or Day 181 
(Visit 4-NB) after birth in 3 sub-
cohorts of infants. Infants born to 
women in the immunogenicity sub-
cohorts will be randomly assigned 
(1:1:1) to sample collection at 1 of the 
3 timepoints noted. 
9.4.4.4. 
Safety  
Analyses of solicited AEs will be performed on the Solicited Safety set (maternal 
participants only). Analyses of unsolicited AEs will be performed on the Exposed sets. 
Secondary Safety Endpoints – Maternal 
Participants 
Statistical Analysis Methods  
Occurrence of solicited injection site and 
systemic events in Stage A participants during 
a 7-day follow-up period after vaccination (i.e. 
the day of vaccination and 6 subsequent days). 
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Secondary Safety Endpoints – Maternal 
Participants 
Statistical Analysis Methods  
Occurrence of unsolicited adverse events (AEs) 
in all maternal participants during a 30-day 
follow-up period after vaccination (i.e. the day 
of vaccination and 29 subsequent days). 
Pregnancy outcomes from Day 1 (Visit 1) up to 
6 weeks after delivery (Day 43 post-delivery, 
Visit 4). These include live birth with no 
congenital anomalies, live birth with minor 
congenital anomaly(ies) only; live birth with at 
least one major congenital anomaly, fetal 
death/still birth (antepartum or intrapartum) with 
no congenital anomalies, fetal death/still birth 
(antepartum or intrapartum) with minor 
congenital anomalies only, fetal death/still birth 
(antepartum or intrapartum) with at least 1 
major congenital anomaly; elective/therapeutic 
termination with no congenital anomalies; 
elective/therapeutic termination with minor 
congenital anomalies only, and 
elective/therapeutic termination with at least 1 
major congenital anomaly. 
Pregnancy-related adverse events (AEs) of 
special interest from Day 1 (Visit 1) up to 6 
weeks after delivery (Day 43 post-delivery, Visit 
4). These include maternal death, hypertensive 
disorders of pregnancy (gestational 
hypertension, pre-eclampsia, pre-eclampsia 
with severe features including eclampsia), fetal 
growth restriction, pathways to preterm birth 
(premature preterm rupture of membranes, 
preterm labor, provider-initiated preterm birth), 
gestational diabetes mellitus, chorioamnionitis.  
Occurrence of serious adverse events (SAEs), 
AEs leading to study termination, and medically 
attended AEs in all maternal participants from 
Visit 1 (Day 1) up to 6 months after delivery. 
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Secondary Safety Endpoints – Infant 
Participants 
Statistical Analysis Methods  
The occurrence of neonatal AEs of special 
interest (reported up to 6 weeks after birth). 
These include small for gestational age, low 
birth weight including very low and extremely 
low birth weight (<2500 g, <1500g, <1000g), 
congenital anomalies (major external structural 
defects, internal structural defects, functional 
defects), neonatal death (in an extremely pre-
term birth (22GA<28 weeks), in a preterm live 
birth (28GA<37 weeks), or in a term live 
birth), preterm birth.  
Occurrence of SAEs, AEs leading to study 
termination and medically attended AEs from 
birth up to 6 months after birth. 
9.4.5. 
Tertiary/exploratory endpoint(s)  
 
 
  
9.4.6. 
Other analyses  
9.4.6.1. 
Demography and baseline characteristics analyses  
These analyses will be performed on the Exposed set and on the modified full analysis set 
for efficacy (modified FAS-E). 
For all maternal participants, demographic characteristics (e.g., age at vaccination (18-34, 
35-39, ≥40 years of age), gestational age at vaccination (240/7 - 280/7, 281/7 - 34 0/7weeks), 
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 extent of contact with children less than 
6 years of age) will be summarized 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. 
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9.4.6.2. 
Case accruals  
Rules for MA-RTI and RTI case accountability will be described in the Statistical 
Analysis Plan. 
9.5. 
Interim analyses  
Interim analyses may be performed, if deemed required.  
9.5.1. 
Sequence of analyses  
When all infant participants have completed Visit 5-NB (month 12, LSLV), a final 
analysis (for all maternal and infant participants in both Stage A and Stage B) will be 
performed. Analyses of any evaluated tertiary endpoints may also be performed. 
If the data for tertiary endpoints becomes available at a later stage, (an) additional 
analysis/analyses will be performed.  
9.5.2. 
Statistical considerations for interim analysis  
Not applicable. 
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 
individual listings or data with information that could unblind the study team to the 
intervention administered to a study participant will be disseminated). 


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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 participants.  
 
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/IEC. 
 
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 
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. 


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10.1.3. 
Informed consent process  
The investigator or his/her representative will explain the nature of the study to the 
participant/participants’ parent(s) or his/her LAR(s) and answer all questions regarding 
the study.  
Participants/participants’ 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 participant and/or each participant’s parent(s)/LAR(s)/witness, as appropriate, 
prior to participation in the study.  
The content of the 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 participant was enrolled in the study and the 
date the consent was obtained. The authorised person obtaining the informed consent 
must also sign the ICF.  
Participants 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 participants/participants’ parent(s)/LAR(s).  
Participants who are re-screened (because, for example, they could not meet the protocol 
allowed window between initial screening and V1/randomization/vaccination) are not 
required to sign a new ICF, unless the ICF was amended in the meantime. However, the 
investigator or his/her representative should ensure that there is documentation that the 
participant is still in agreement to participate in the study and be re-screened. This can be 
done on the initially signed ICF or, if applicable, on other study source/documentation (as 
per local practice/ regulations). 
10.1.4. 
Data protection  
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
The participants/participants’ 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 participants/participants’ 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 participants/participants’ parent(s)/LAR(s) must be informed that his/her medical 
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personnel appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities. 
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  
A firewall will be established to ensure that data are not inadvertently unblinded. Details 
are provided in a separate Firewall charter.  
Safety oversight will be provided by a blinded SRT* composed of GSK RSV team 
members, and by an unblinded, independent data monitoring committee external to GSK 
(IDMC). Details regarding IDMC safety evaluations are provided in a separate IDMC 
charter. 
* Due to the safety signal observed, the study was fully unblinded to ensure the safety of 
the participants. 
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 GSK Clinical Study register in compliance with the 
applicable regulations/GSK policy. GSK will aim to register the protocol summary prior 
to study start and target results summaries submission(s) 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 participants, as appropriate. 
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis. 
* Due to the safety signal observed, the study was fully unblinded to ensure the safety of 
the participants. Please refer to Section 2.3 for details. 
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 
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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.  
All participant data relating to the study will be recorded on a 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 participants [see Section 
10.7.2 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 authorized 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 participants must be protected and the study must 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 participant and substantiate 
the integrity of the data collected. The Investigator should maintain a record of the 
location(s) of their source documents.  


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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 Section 
10.7.2. 
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 participants by the investigator 
 
Discontinuation of further study intervention development 
10.1.10. 
Publication policy  
GSK aims to submit for publication the results of the study 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  
There is one assessment, hematocrit, which will be tested at Visits 1, 2 and 3, for all 
maternal participants in Stage A who are assigned to the immunogenicity sub-cohort, 
until the protocol amendment 2 is approved (unless IEC/IRB allows for immediate 
implementation of this measure to reduce participant’s burden, prior to full Amendment 2 
being approved) in the respective study country(ies). Testing will be performed by a 
central laboratory. Results will be used to help evaluate changes over time in antibody 
titers / concentrations that may be related to volumetric changes during pregnancy, if 
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Note that no clinical safety laboratory testing is mandated per protocol; thus, abnormal 
laboratory findings (if any) would be identified during tests performed per local standard 
of care. 
Laboratory assessments (pathology) may be performed on the placenta tissue samples 
collected from maternal participants at delivery visit to support possible safety 
assessments, if necessary. Additional assessments on the placental sample may be 
performed depending on local standard of practice, site capability and the investigator’s 
medical judgment. 
10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting Definition of 
AE  
10.3.1. 
Definition of an Adverse Event (AE)  
 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of 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 study intervention. 
10.3.1.1. 
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/product 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/product or a concurrent medication (overdose per se should not be 
reported as an AE/SAE). 
 
Signs or symptoms temporally associated with study vaccine/ 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 
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 
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. 
 
 “Lack of efficacy" or "vaccination failure of expected pharmacological action" per 
se will not be reported as an AE or SAE. Such instances will be captured in the 
efficacy assessments. However, the signs, symptoms, and/or clinical sequelae 
resulting from lack of efficacy will be reported as AE or SAE if they fulfil the 
definition of an AE or SAE.  
10.3.1.2. 
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 participant, or 
 
The investigator considers that there is a reasonable possibility that the event was 
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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  
Refer to Section 8.3.4.2 for additional information. 
f. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies*, ectopic pregnancy)  
*Refer to Section 8.3.4.2 for additional information. 
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 
jeopardize 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 for maternal participants in 
Stage A: 
Table 24 
Solicited administration site events  
All age groups 
Pain 
Redness 
Swelling 
b. Solicited systemic events 
The following systemic events will be solicited for maternal participants in Stage A: 
Table 25 
Solicited systemic events  
Adult 
Fatigue 
Fever 
Nausea 
Vomiting 
Diarrhea 
Abdominal pain 
Headache 
Note: maternal participants in Stage A 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, 
participants will be instructed to record the highest temperature in the diary. 
10.3.4. 
Unsolicited adverse events  
An unsolicited adverse event is an adverse event that was not solicited using a Participant 
Diary and that was spontaneously communicated by a maternal participant/infant 
participant’s 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 participants/ participant’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 participant/ parental /LAR’s concern. Detailed information 
about reported unsolicited AEs will be collected by qualified site personnel and 
documented in the participant’s records. 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant/participant’s parent(s)/LAR(s) will be collected during interview with the 


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participants/participant’s parent(s)/LAR(s) and by review of available medical records at 
the next visit. 
10.3.5. 
Adverse events of special interest (AESIs)  
AESIs include: 
 
The following pregnancy-related adverse events of special interest (newly 
occurring): 
 
maternal death, 
 
hypertensive disorders of pregnancy: 
o 
gestational hypertension,  
o 
pre-eclampsia,  
o 
pre-eclampsia with severe features including eclampsia, 
 
fetal growth restriction, 
 
pathways to preterm birth: 
o 
premature preterm rupture of membranes,  
o 
preterm labor,  
o 
provider-initiated preterm birth, 
 
gestational diabetes mellitus, and 
 
chorioamnionitis.  
 
The following neonatal adverse events of special interest: 
 
small for gestational age, 
 
low birth weight including very low and extremely low birth weight (<2500 g, 
<1500 g, <1000 g), 
 
congenital anomalies: 
o 
major external structural defects,  
o 
internal structural defects,  
o 
functional defects, 
 
neonatal death: 
o 
in an extremely pre-term birth [22GA<28 weeks],  
o 
in a preterm live birth [28GA<37 weeks], or  
o 
in a term live birth,  
and 
 
preterm birth.  


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Refer to Section 8.3.4 for additional information about categorizing and reporting 
congenital anomalies. 
Note: Worsening, post study vaccine administration, of pre-existing conditions already 
present at the time of enrolment. (eg. controlled gestational hypertension or controlled 
gestational diabetes) will be collected as (S)AEs and indicated as “worsening” or 
“aggravated” . These are not to be considered as AESIs. 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as AESI. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as AESI 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 the 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. 
Note that no clinical safety laboratory testing is mandated per protocol; thus, abnormal 
laboratory findings (if any) would be identified during tests performed per local standard 
of care. Follow-up of such findings should be consistent with local standard of care and 
the Investigator’s judgement 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs  
10.3.7.1. 
Subsequent Pregnancy  
All maternal participants will be in the second or third trimester of pregnancy at 
enrolment and are expected to deliver while participating in the study. Maternal 
participants 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 SAE. Please refer to 
the Section 10.3.2 for definition of SAE.  


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10.3.8. 
Recording and follow-up of AEs, SAEs, AESIs and subsequent 
pregnancies  
The maternal participants/infant participants’ parent(s)/LAR(s) will be instructed to 
contact the investigator immediately should the maternal or infant participants manifest 
any signs or symptoms they 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 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
participant’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 participant 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, hereafter referred to as the Participant Diary will be used in this 
study to capture solicited administration site or systemic events for participants in Stage 
A. The maternal participant should be trained on how and when to complete each field of 
the Participant Diary. 
Any individual(s) who performs the measurements of administration site or systemic 
events and who will enter the information into the Participant Diary should be trained on 
the use of the Diary. This training must be documented in the maternal participant’s 
source record. If any individual other than the maternal participant is making entries in 
the Participant Diary, their identity should be documented in the Participant 
Diary/maternal participant’s source record  
Refer to the SPM for more information regarding the use of the Diary. 
10.3.8.1. 
Time period for collecting and recording AEs, SAEs, AESIs and 
subsequent pregnancies  
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 events that occur during the 7 days following administration of the dose of 
study vaccine/product (Day 1 to Day 7) must be recorded into the electronic Diary, 
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 or any other 
events of interest  
10.3.8.3.1. Follow-up during the study  
After the initial AE/SAE/AESI/subsequent pregnancy or any other event of interest for 
the study, the investigator is required to proactively follow each participant at subsequent 
visits/contacts.  
The investigator will follow participants with SAEs/AESIs (serious or non-serious), 
participants withdrawn from the study because of an AE, until the event has resolved, 
stabilised, disappeared (if applicable), or until the event is otherwise explained, or the 
participant is lost to follow-up. The investigator will follow maternal participants with 
subsequent pregnancies as described in Section 10.3.8.3.3. 
Non-serious medically attended AEs must be followed until recovered / resolved, or until 
the participant’s last study visit, or until the participant is lost to follow-up. 
Other non-serious AEs (maternal participants) must be followed until 30 days after study 
vaccine/product administration or until the participant is lost to follow-up (if this occurs 
before Visit 3 (Day 31)). 
If a maternal or infant participant 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. Please refer to the SPM for more details. 
10.3.8.3.2. Follow-up after the participant is discharged from the study  
The investigator will provide any new or updated relevant information on previously 
reported SAEs, AESIs, participants 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 participants who become 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 the 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 an 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/product , 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 participant’s eCRF  
When additional SAE, AESI or subsequent pregnancy information is received after 
removal of write access to the participant’s eCRF, new or updated information should be 
recorded on the appropriate paper report, with all changes signed and dated by the 
investigator. The updated report should be faxed to the Study Contact for Reporting 
SAEs (refer to the Section 8.3.3.1) or to GSK Clinical Safety and Pharmacovigilance 
department, within the defined reporting time frames specified in the Table 19. 
10.3.9. 
Assessment of intensity and toxicity  
10.3.9.1. 
Assessment of intensity  
The intensity of the following solicited AEs will be assessed as described: 
Table 26 
Intensity scales for solicited events in adults  
Adults 
Event 
Intensity grade Parameter 
Pain at administration 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 administration site 
Record greatest surface diameter in mm 
Swelling at administration site 
Record greatest surface diameter in mm 
Temperature* 
 
Record temperature in °C/°F with 1 decimal 
Temperature will be analyzed 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 and swelling) will be scored at 
GSK Biologicals as follows: 
0: 
≤ 20 mm 
1: 
> 20 mm to ≤50 mm 
2: 
> 50 mm to ≤100 mm 
3: 
>100 mm 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement. 


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The intensity should be assigned to 1 of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the participant, 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 a young child, such an AE would, for example, prevent 
attendance at school/kindergarten/a day-care centre and would 
cause the parent(s)/LAR(s) to seek medical advice. 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 an 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 the 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 the Table 24 and Table 25.  
The investigator must assess the relationship between study vaccine/product 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/product 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/product 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/product 
contributed to the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine/product. There are other, more 
likely causes and administration of the study vaccine/product is not 
suspected to have contributed to the AE. 


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If an event meets the criteria to be determined as ‘serious’ (see Section 10.3.2), additional 
examinations/tests will be performed by the investigator to determine ALL possible 
contributing factors for each SAE. 
Possible contributing factors include: 
 
Medical history. 
 
Other medication. 
 
Protocol required procedure. 
 
Other procedure not required by the protocol. 
 
Lack of efficacy of the vaccine/product, 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 each solicited and unsolicited symptom the participant experiences, the 
participant/participant’s parent(s)/LAR(s) will be asked if he/she/the participant 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 participant, 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.  
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 WITHIN 24 HOURS. The investigator will always 
provide an assessment of causality at the time of the initial report. 
Refer to the Table 19 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 the 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 facsimile or electronic reporting system does 
not work  
In rare circumstances if the electronic reporting system does not work, the investigator 
(or designee) must fax completed, dated and signed paper Expedited Adverse Events 
Report to the Study Contact for Reporting SAEs (refer to the Sponsor Information) or to 
GSK Clinical Safety and Pharmacovigilance department within 24 hours.  
Investigator (or designee) must complete the electronic Expedited Adverse Events Report 
within 24 hours upon electronic reporting system is resumed. The 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.  
10.5. 
Appendix 5: Genetics  
Not applicable. 


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10.6. 
Appendix 6: Country-specific requirements (Amended 
23 February 2023)  
10.6.1. 
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. 
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. 
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. 
Concerning the “STUDY GOVERNANCE 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:  
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: 
 
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: 
French Patient Informed Consent Form is in duplicate (triplicate for minor subject). 
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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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). 
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. 
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 
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 updated, each of these people aforesaid has a right of access, correction 
and opposition on their own data through GlaxoSmithKline Laboratory (Clinical 
Operations Department). 
Ethnic Origin 
In accordance with the Data Protection French Law n° 78-17 of 6th January 1978 updated 
– article 4-3°, 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. 
Monitoring visits 
 
The Health Institution and the Investigator agree to receive on a regular basis a 
Clinical Research Assistant (CRA) of GLAXOSMITHKLINE or of a service 
provider designated by GLAXOSMITHKLINE. The Health Institution and the 
Investigator agree to be available for any phone call and to systematically answer to 
all correspondence regarding the Study from GLAXOSMITHKLINE or from a 
service provider designated by GLAXOSMITHKLINE. In addition, the Health 


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Institution and the Investigator agree that 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. 
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.  
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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Data Protection French Law of 6th January 1978 updated (CNIL) 
 
In accordance with the Data Protection French Law of 6 January 1978 updated, 
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. 
10.6.2. 
South Korea  
Concerning the “STUDY POPULATION – Exclusion criteria for enrolment – maternal 
participants”, the following will constitute an exclusion criterion in South Korea: 
 
Participation in a clinical trial targeting healthy people within the 6 months prior to 
enrolment/study vaccination. 
Concerning the “CRITERIA LEADING TO PAUSE OR EARLY TERMINATION OF 
THE STUDY”, the following clarification is made: 
 
No safety “holding rules” or criteria for pausing or early termination have been 
defined for this study. 
 
An Independent Data Monitoring Committee (IDMC) has been put in place and will 
be in charge of reviewing unblinded safety data on a regular basis (bi-monthly 
reviews are foreseen, but frequency may be adapted as the study progresses). It will 
be the IDMC discretion to recommend, if they deemed necessary, that the study 
recruitment is paused or terminated based on their unblinded data reviews. 
 
In addition to the IDMC reviews, GSK’s Safety Review Team (SRT) will perform 
regular reviews of blinded data and may request IDMC to perform ad-hoc unblinded 
reviews if any potential safety concern is suspected based on blinded data. 
10.6.3. 
Spain  
With regards to the “COMPENSATION” offered to the infant participants enrolled in 
the study, infant parents/LAR’s were offered the possibility to have the infant 
vaccinated with a commercially approved vaccine being part of the National Pediatric 
Immunization Calendar but, which costs are not financially covered by the health 
system in the corresponding Region/Autonomous Community: 
• 
Meningococcus B vaccine (Bexsero®) 
Or 
• 
Rotavirus vaccine (Rotarix®) 


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This compensation was put in place considering the recommendations laid out in ICH-
E11 (Clinical Investigation of Medicinal Products in the pediatric population) as well 
as in the “Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population”, developed by the ad-hoc group for the development of 
implementing guidelines for Directive 2001/20/EC relating to good clinical practice in 
the conduct of clinical trials on medicinal products for human use. 
Compensation was approved by the Spanish regulatory authority and Ethics 
Committee, and included in the country-specific Informed Consent. 
10.6.4. 
Argentina  
Concerning the “STUDY POPULATION – Exclusion criteria for enrolment – 
maternal participants” and, as per request from the Argentinean regulatory authorities 
(A.N.M.A.T - Administración Nacional de Alimentos, Medicamentos y Tecnología 
Médica), study recruitment in Argentina was limited to pregnant women aged 18 to 40 
years (inclusive), instead of 18 to 49 years (inclusive). 
This age limitation was initially expected to be temporal, and dependent on the 
availability of safety data coming from other countries on pregnant women > 40 years 
old, which was to be submitted to A.N.M.A.T for evaluation. However, further 
enrollment and vaccination in the study was stopped on 25th February 2022, before 
such safety data was submitted. 


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10.7. 
Appendix 7: Abbreviations and glossary of terms  
10.7.1. 
List of abbreviations  
AE 
Adverse Event 
AESI 
Adverse event of special interest 
BMI 
Body mass index 
CI 
Confidence Interval 
CLS 
Clinical Laboratory Sciences 
CoP: 
Correlate of Protection 
COVID-19 
Corona Virus Disease 2019 
eCRF 
electronic Case Report Form 
EoS 
End of Study 
FDA: 
Food and Drug Administration, United States of America 
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 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP: 
Investigational Medicinal Product 
IND: 
Investigational New Drug 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LAR 
Legally Acceptable Representative 


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LLOQ 
Lower Limit of Quantification 
LML 
Local Medical lead 
LMP 
Last Menstrual Period 
LRTI 
Lower Respiratory Tract illness 
LSLV 
Last Participant Last Visit 
MAE 
Medically attended adverse event 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralising antibody 
NB 
Newborn 
PCD 
Primary Completion Date 
PCR 
Polymerase Chain Reaction 
PP: 
Per protocol 
PRO: 
Patient Related Outcomes 
RR 
Respiratory Rate 
RSV 
Respiratory Syncytial Virus 
RTI 
Respiratory Tract Illness 
SAE 
Serious Adverse Event 
SARS-COV-2 
The corona virus that is the causative agent of COVID-19. 
SBIR: 
Source data Base for Internet Randomisation  
SDV: 
Source Document Verification 
SPM 
Study Procedures Manual 
SpO2 
Blood oxygen saturation as measured by pulse oximetry 
SRT 
Safety Review Team 
VE 
Vaccine efficacy 
WHO 
World Health Organization 


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10.7.2. 
Glossary of terms  
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation participant, temporally associated with the use of 
a medicinal product, whether or not considered related to the 
medicinal product. 
An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed 
medicinal products, this also 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.  
In an open-label study, no blind is used. Both the investigator 
and the participant know the identity of the intervention 
assigned.  
In a double-blind study, the participant, the investigator and 
sponsor staff who are involved in the treatment or clinical 
evaluation of the participants and the review or analysis of data 
are all unaware of the intervention assignment.  
In a single-blind study, the investigator and/or his staff are 
aware of the intervention assignment but the participant is not. 
Body Mass Index 
A key index for relating weight to height. Calculated as 
follows: Weight (kg) / (Height (m))2 
Caregiver 
A ‘caregiver’ is someone who  
 
lives in the close surroundings of a participant and has 
a continuous caring role or 
 
has substantial periods of contact with a participant 
and is engaged in his/her daily health care (e.g. a 
relative of the participant, a nurse who helps with daily 
activities in case of residence in a nursing home).  
In the context of a clinical study, a caregiver could include an 
individual appointed to oversee and support the participant's 
compliance with protocol specified procedures. 


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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, organization, 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)  
For studies with collection of human biologicals samples, EoS 
is defined as the date of LSLV or the last testing/reading 
released of the human biological samples related to primary and 
secondary endpoints, whichever comes last. EoS must be 
achieved no later than 8 months after LSLV.  
Enrolled 
‘Enrolled’ means a participant’s/parent’s/LAR’s agreement to 
participate in a clinical study following completion of the 
informed consent process. Potential participants 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. 
Essential 
documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of the data 
produced 
eTrack: 
GSK’s tracking tool for clinical trials. 
Evaluable: 
Meeting all eligibility criteria, complying with the procedures 
defined in the protocol, and, therefore, included in the per-
protocol analysis (see 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.  


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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 authorization 
when used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain further 
information about an approved use.  
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.  
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 authorized under 
applicable law to consent, on behalf of a prospective 
participant, to the participant's participation in the clinical trial. 
The terms legal representative or legally authorized 
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.  


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Local healthcare 
provider 
A healthcare provider who provides participants with medical 
care per local standards. This individual may or may not be a 
member of the study staff.  
Neonate (or 
Newborn) 
An infant 28 days old or younger. 
Neonatal adverse 
events of special 
interest 
Adverse events that occur from birth through 28 days of age 
and are to be reported as neonatal AESIs are listed in Table 4 
and Section 10.3.5. It is anticipated that most neonatal AESIs 
will be identified (and thus may be reported in the eCRF) by or 
before the Day 43 visit (V2-NB). However, as indicated in 
Table 18, any neonatal AESIs identified after V2-NB should 
also be reported in the eCRF. 
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 
Participant: 
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. 
Synonym: subject 
Participant 
number: 
A unique identification number assigned to each participant 
who consents to participate in the study. 
Pregnancy related 
adverse events of 
special interest  
Pregnancy related events that occur up to 42 days after delivery 
and are to be reported as AESIs are listed in Table 4 and 
Section 10.3.5.  
Primary 
completion date: 
The date that the final participant 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 Harmonization (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 participants, scope of the investigation, 
study design, or scientific integrity of the study. 
Randomization: 
Process of random attribution of study intervention to 
participants to reduce selection bias. 


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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 participant 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, participants' 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, participant 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 
authorized use of a vaccine/product/placebo as a reference or 
administered concomitantly, in a clinical trial that evaluates the 
use of an investigational vaccine/product. 
Study population: 
Sample of population of interest. 
Sub-cohort: 
A group of participants for whom specific study procedures are 
planned as compared to other participants or a group of 
participants who share a common characteristic (e.g. ages, 
vaccination schedule…) at the time of enrolment. 
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. 


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10.8. 
Appendix 8: Gestational Age Assessment  
10.8.1. 
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 immunization 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 1 
or 
1st trimester U/S 
Level 2A 
Certain LMP WITH 2nd trimester U/S 1 
or 
Certain LMP WITH 1st trimester physical examination2 
Level 2B 
Uncertain LMP WITH 2nd trimester U/S 1 
Level 3A 
Certain LMP WITH 3rd trimester U/S3,  
or 
Certain LMP WITH confirmatory 2nd trimester FH, 
or 
Certain LMP WITH birth weight, 
or 
Uncertain LMP WITH 1st trimester physical examination 
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 
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;  
Boldface = Applicable for enrollment in this study.  
1 If LMP and U/S do not correlate, default to U/S GA assessment 
2 For singleton pregnancies only. Unreliable if obesity, or uterine anomalies. 
3 May be enrolled provided  gestational age is within the limits specified for eligibility Refer to Section 5.1.1 for further 
details 
10.8.2. 
Methods of gestational age assessment and estimation of due 
date  
Adapted from: 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 700, May 2017 (accessed on-line on 05/Mar/2020 at: 
https://www.acog.org/clinical/clinical-guidance/committee-
opinion/articles/2017/05/methods-for-estimating-the-due-date). 


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Gestational age range* 
Method of measurement 
Discrepancy between U/S dating and LMP (or 
IUI or ET dating) prompting re-dating of EDD 
considering U/S 
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 
3rd trimester 
280//7 weeks and beyond 
BPD, HC, AC, FL 
> 21 days 
U/S: ultrasound examination; LMP: last menstrual period; IUI: intrauterine insemination; ET: embryo transfer; CRL: 
crown-rump length; BPD: biparietal diameter; HC: head circumference; AC: abdominal circumference; FL: femur 
length; , EDD: estimated date of delivery 
* Based on LMP (or, if applicable, IUI/ET date) 
Refer to the SPM for further details. 
10.9. 
Appendix 9: Definitions of maternal, fetal and neonatal 
events of interest as per GAIA  
 
IMPORTANT: NOT all the events that are listed below are AESIs for this study. 
Sections 3, 9.4.4 and 10.3.5 list events of interest per GAIA that must be reported as 
AESIs in this study. 
 
Other GAIA events of interest that meet the SAE definition (Section 10.3.2) should 
be reported with enough detail in the SAE narrative to permit level of diagnostic 
certainty assessment by GAIA criteria. 
 
Articles that discuss GAIA events of interest in detail 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. 


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Pregnancy Outcomes 
Fetal Death / Stillbirth 
Table 27 
Maternal Events of Interest 
Maternal Death – study defined pregnancy related AESI 
Table 28 
Hypertensive Disorders of Pregnancy – study defined pregnancy related AESIs 
Table 29 
Antenatal bleeding 
Table 30 
Postpartum hemorrhage 
Table 31 
Fetal Growth restriction – study defined pregnancy related AESI 
Table 32 
Gestational Diabetes Mellitus – study defined pregnancy related AESI 
Table 33 
Non-reassuring fetal status 
Table 34 
Pathways to Preterm Birth – study defined pregnancy related AESIs 
Table 35 
Chorioamnionitis - study defined pregnancy related AESI 
Table 36 
Standard definitions for events of interest not defined as such in GAIA (Oligohydramnios, 
Polyhydramnios, Intrahepatic Cholestasis of Pregnancy (ICP), Acute Fatty Liver of Pregnancy, 
Maternal Sepsis) 
Table 37 
Neonatal Events of Interest 
Small for Gestational Age – study defined neonatal AESI 
Table 38 
Low Birth Weight – study defined neonatal AESI 
Table 39 
Neonatal encephalopathy 
Table 40 
Congenital Microcephaly 
Table 41 
Congenital Anomalies – study defined neonatal AESIs 
Table 42 
Neonatal Death – study defined neonatal AESI 
Table 43 
Neonatal Infections 
Table 44 
Respiratory Distress in the Neonate 
Table 45 
Preterm Birth – study defined neonatal AESI 
Table 46 
Failure to thrive 
Table 47 
Standard definitions for events of interest not defined as such in GAIA (large for gestational age, 
macrosomia) 
Table 48 


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Table 27 
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  
1. 
Prenatal ultrasound examination documenting lack of fetal cardiac activity or movement before the 
onset of labor.  
OR 
2. 
Auscultation for fetal heart tones (using electronic devices or non-electronic devices) documenting 
lack of fetal heartbeat.  
AND 
3. 
Maternal report of lack of fetal movement for 24 h or more.  
OR 
4. 
Maternal physical examination confirming lack of fetal movement.  
OR 
5. 
Radiology findings consistent with intrauterine fetal death.  
AND 
6. 
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 
7. 
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 
1. 
Maternal report of lack of fetal movement for 24 h or more. 
OR 
2. 
Maternal physical examination confirming lack of fetal movement.  
OR 
3. 
Auscultation for fetal heart tones (using electronic or non-electronic devices) documenting lack of 
fetal heartbeat.  
AND 
4. 
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 
5. 
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 
1. 
Maternal report of lack of fetal movement for 24 h or more prior to delivery.  
OR 
2. 
Report of auscultation for fetal heart tones (using electronic or non-electronic devices) documenting 
lack of fetal heartbeat.  
AND 
3. 
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 
4. 
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. 


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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 
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: 
1. 
Ultrasound examination 
2. 
Fetal heart tones 
3. 
Positive serum or urine human chorionic gonadotropin pregnancy test 
4. 
Delivery of a neonate or other products of conception (abortus, stillborn)  
AND 
5. 
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: 
6. 
Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric complications, unanticipated complications  
7. 
Indirect: non obstetric complications  
8. 
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: 
1. 
LMP date 
2. 
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: 
3. 
Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric complications, unanticipated complications 
4. 
Indirect: non-obstetric complications  
5. 
Death during pregnancy, childbirth and the puerperium: other or coincidental 
6. 
Unspecified: unknown or undetermined 
3 
Absence of Level 1 or 2 criteria for establishing diagnosis of pregnancy and: 
1. 
Unsure LMP 
2. 
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: 
3. 
Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric com-plications, unanticipated complications 
4. 
Indirect: non-obstetric complications 
5. 
Death during pregnancy, childbirth and the puerperium: other or coincidental 
6. 
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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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:  
1. 
Systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110mmHg, which is confirmed 
after only minutes OR  
2. 
Development of severe, persistent headache OR 
3. 
Development of visual changes OR  
4. 
Eclampsia* OR  
5. 
New onset thrombocytopenia (platelets <100,000/L) OR 
6. 
New onset unremitting epigastric pain OR 
7. 
AST and ALT elevated to twice upper limit of normal OR 
8. 
Evidence of liver capsular hematoma or liver rupture (diagnosed on clinical exam or with imaging) 
OR 
9. 
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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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. 
Ultrasound evidence of placenta previa, 
AND  
hypervascularity at the site of the uteroplacental interface, diagnosed at laparotomy. 
OR 
1. 
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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Postpartum hemorrhage  
Genital tract bleeding after delivery (up to 42 days) of a fetus or infant that leads to an 
adverse clinical outcome, such as hypovolemia or anemia e.g. exertional dyspnea, 
postural presyncope, tiredness or reduced consciousness. At the furthest extreme 
uncorrected hypovolemic shock can lead to organ-dysfunction and maternal death. 
ICD-10 definition: “hemorrhage after delivery of a fetus 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 hemorrhage: 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.  


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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). 
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 above, 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.  


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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 10.8)  
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 10.8)  
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 
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. 


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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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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. 


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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)  
AND 
 
Documented membrane rupture by a diagnostic test (one of the below options): 
1. 
Positive intra-amniotic dye-injection method 
2. 
Positive result on amniotic fluid alpha-fetoprotein test kit  
3. 
Amniotic fluid pH measurement (nitrazine paper test) 
4. 
Amniotic fluid placental alpha macroglobulin-1 protein assay (PAMG-1) test (AmniSure test)  
5. 
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: 


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Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
 
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 
 
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. 


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Table 36 
Chorioamnionitis  
Chorioamnionitis encompasses a broad spectrum of disease during pregnancy that is 
characterized by inflammation and/or infection of intrauterine structures such as the 
placenta, the chorion and amnion.  
This case definition focusses on the infectious manifestation of chorioamnionitis, intra-
amniotic infection. Four definitions of chorioamnionitis have been developed based on 
systematic literature review, are summarized below, and must be considered when 
applying the case definitions.  
It is important to rule out other obvious sources of acute systemic infection (i.e. 
pyelonephritis) prior to chorioamnionitis diagnosis. 
Level 
Description 
All 
levels 
Clinical Definition A: 
Maternal fever ≥ 38 degrees Celsius on one occasion plus one or more of:  
 
Baseline fetal tachycardia (FHR > 160 bpm for 10 min or longer, excluding accelerations, 
decelerations and periods of marked variability or, where continuous monitoring is not available, an 
FHR exceeding 160 bpm during and after at least three consecutive contractions) 
 
Maternal WBC ≥ 15 000 per mm3 in the absence of corticosteroids. 
 
Definite purulent fluid from the cervical os. 
Clinical Definition B 
Maternal fever ≥ 38 degrees Celsius on one occasion plus two of:  
 
Maternal tachycardia (HR > 100 bpm) 
 
Baseline fetal tachycardia (FHR > 160 bpm for 10 min or longer, excluding accelerations, 
decelerations and periods of marked variability or, where continuous monitoring is not available, an 
FHR exceeding 160 bpm during and after at least three consecutive contractions 
 
Purulent fluid from the cervical os. 
 
Uterine tenderness 
 
Maternal WBC ≥ 15 000 per mm3 in the absence of corticosteroids 
Histologic diagnosis: 
 
Positive finding of invasion of maternal polymorphonuclear leukocytes into the placental plate, the 
chorion and/or amnion which meets criteria based on a widely accepted histopathologic staging and 
grading system [such as Blanc1 Redline2, or Salafia3 criteria]. 
Culture criteria: 
 
Positive culture of amniotic fluid (via amniocentesis), and/or 
 
Positive culture of placental membranes (between chorion/amnion) 
GAIA gestational age level 1–2 criteria denote higher gestational age certainty including a combination 
of certain last menstrual period (LMP), first or second trimester ultrasound or first trimester exam 
confirmation. Level 3 diagnostic certainty for gestational age has a lower accuracy compared to levels 1–
2. (see Section 10.8) 
1a 
Clinical Definition A 
AND 
Confirmation via histopathology or culture  
AND 
Gestational age ≥ 22–0/7 weeks by GAIA gestational age level 1–2 criteria  
1b 
Clinical Definition A 
AND 
Confirmation via histopathology or culture 
AND 
Gestational age ≥ 22–0/7 weeks by ANY GAIA gestational age criteria 


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Level 
Description 
2a 
Clinical Definition A  
OR 
Chorioamnionitis via histopathology or culture  
AND 
Gestational age ≥ 22–0/7 weeks by GAIA gestational age level 1–2 criteria  
2b 
Clinical Definition B  
AND 
Gestational age ≥ 22–0/7 weeks by GAIA gestational age level 1–2 criteria 
2c 
Clinical Definition A or B 
OR 
Chorioamnionitis via histopathology or culture  
AND 
Gestational age ≥22–0/7 weeks by any GAIA gestational age criteria 
3a 
Clinical definition A or B with report of fever or maternal feeling of ‘‘feverishness.” 
AND 
Gestational age ≥ 22–0/7 weeks by any GAIA gestational age criteria  
3b 
Clinical definition B without fever (documented or reported) 
AND 
Gestational age ≥ 22–0/7 weeks by any GAIA gestational age criteria 
1W.A. Blanc Pathology of the placenta, membranes, and umbilical cord in bacterial, fungal, and viral infections in man. 
Monogr Pathol, 22 (1981), pp. 67-132 
2R.W. Redline, O. Faye-Petersen, D. Heller, F. Qureshi, V. Savell, C. Vogler Amniotic infection syndrome: nosology 
and reproducibility of placental reaction patterns. Pediatric Dev Pathol: Off J Soc Pediatric Pathol Paediatric Pathol 
Soc, 6 (5) (2003), pp. 435-448 
3C.M. Salafia, C. Weigl, L. Silberman The prevalence and distribution of acute placental inflammation in uncomplicated 
term pregnancies. Obstet Gynecol, 73 (3 Pt 1) (1989), pp. 383-389 
Reference: Kachikis, A, Eckart L, Walker C et al. Chorioamnionitis: Case definition & guidelines for data collection, 
analysis, and presentation of immunization safety data. Vaccine. 2019; 7610–7622 


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Standard Definitions for Maternal Events of interest not defined as 
events in GAIA  
Event of 
Interest 
Definition 
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 pocket 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 
 
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 


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Event of 
Interest 
Definition 
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 consensus 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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Small for Gestational Age (continued) 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
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. 


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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  
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. 


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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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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 


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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Postnatally Diagnosed Microcephaly (continued) 
Level 
Description 
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 
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 


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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Prenatally Diagnosed Microcephaly (continued) 
Level 
Description 
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  
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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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)  


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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
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  
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) 


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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
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: 
 
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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Table 43 
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 


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Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
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) 
 
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 44 
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 


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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 
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 


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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 
 
Recognized virus identified using a validated assay from an upper respiratory sample  
OR 
 
Recognized 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 
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 immunization safety data. Vaccine. 2016;34 (49):6038-6046 


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Table 45 
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 
 
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. 


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Table 46 
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. 


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Table 47 
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. 
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 


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Level 
Description 
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 
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 48 
Standard Definitions for Neonatal Events of 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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10.10. 
Appendix 10: 
  
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10.11. 
Appendix 11: Protocol Amendment history  
The Protocol Amendment Summary of Changes Table for the current amendment 
is located directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Document 
Date of Issue 
Protocol 
26 June 2020 
Protocol Amendment 1 
5 October 2020 
Protocol Amendment 2 
23 June 2021 
Protocol Amendment 3 
10 February 2022 
Protocol Amendment 4 
15 March 2022 
Protocol Amendment 5 
23 February 2023 
Overall Rationale for the Protocol Amendment 5: 
This protocol has been amended to reflect the following: 
 
The Benefit/Risk assessment has been updated to clarify that: 
 The observed numerical imbalance in neonatal deaths is not an independent 
safety signal but a consequence of the validated signal of preterm births. 
 Based on the evaluation of the Study Day 43 post-birth interim analysis,  
GSK concluded that preterm birth is an identified risk for the pregnant 
women population, for the RSV Maternal vaccine candidate. 
 GSK has discontinued the work on this RSV Maternal vaccine candidate and 
is closing out all ongoing vaccine trials. GSK will continue to monitor and 
follow-up the immunized participants in the trials for the duration specified in 
the respective protocols. 
 
For vaccine efficacy (VE) related objectives, the sensitivity and supportive analyses 
will be only conducted for primary efficacy endpoints, but the sensitivity analysis 
using the negative binomial model has been removed. 
 
The following changes have been made to the secondary efficacy endpoints: 
 For efficacy endpoint from birth to 7 months and above, only the efficacy 
endpoints of “From birth (Visit 1-NB) to 12 months (Visit 5-NB), 
occurrences of severe medically assessed, RSV-associated LRTIs” and 
“From birth (Visit 1-NB) to 12 months (Visit 5-NB), occurrences of any 
medically assessed, RSV-associated LRTIs” will be kept, and the analyses 


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will be conducted by using Kaplan-Meier curves from birth to 12 month, so 
that the VE changes across time can be observed. 
 “From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences of any 
medically assessed, RSV-associated LRTIs by alternative case definitions” 
has been removed. 
 “From birth (Visit 1-NB) to 12 months (Visit 5-NB), time to the first 
occurrence of severe medically assessed, RSV-associated LRTIs according to 
the case definition” has been removed. 
 “From birth (Visit 1-NB) to 12 months (Visit 5-NB), time to the first 
occurrence of any medically assessed, RSV-associated LRTIs according to 
the case definition” has been removed. 
 
Secondary efficacy endpoints on infant participants will only be assessed in the 
Modified Full Efficacy set (FAS) and Secondary efficacy endpoints on maternal 
participants will only be assessed in the Exposed Set (ES). 
 
Secondary immunogenicity endpoints will be assessed in a sub-cohort of maternal-
infant pairs including only those maternal-infant pairs from the per protocol set 
whose babies had blood collected for immunogenicity assessments at the allocated 
time-point.  
 
RSVPreF3 IgG antibody concentrations will be assessed only in maternal blood 
samples collected at delivery, and cord blood (or blood samples collected from their 
respective infants within 72 hours after birth, if no cord blood available). 
 
RSV-B neutralizing antibody titers will no longer be assessed as part of the 
secondary immunogenicity endpoints.  
 
 
 
The following populations for analyses have been removed: 
 Maternal participants :- Full Analysis – Immunogenicity, Full Analysis – 
Efficacy 
 Infant participants:- Full analysis – Immunogenicity 
 
Country-specific requirements have been added in Appendix 10.6 for Spain and 
Argentina. 
Also, this amendment includes editorial changes to improve the consistency and 
typographical error corrections. 
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Detailed description of current Protocol Amendment (# 5) changes: 
In this section, deleted text is indicated in strikethrough and changed text in bold italics. 
 
Section 1.1:  
Note: Based on all available safety information following vaccination with the RSV 
MAT vaccine, there will be no further enrollment and vaccination of maternal 
participants. However, monitoring will continue for rest of the study. All planned 
objectives described in the latest protocol amendment will be assessed for the 
participants enrolled so far.  
 
Section 1.2 
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives, since sample collection in infants was discontinued 
following stop of enrollment. 
 
 
Section 2.1 
Note: Due to the stop on study enrollment and vaccination, nasal swabs from maternal 
participants will not be collected and no MA-RTI assessment visit will be performed. 
Assessment of incidence of MA-RTI in maternal participants and RTI/LRTI in infant 
participants will be limited to cases where a nasal swab was collected before study stop. 
 
Section 2.3 
In February 2022, the Independent Data Monitoring Committee (IDMC) for the RSV 
MAT-009 study observed an imbalance in the proportion of preterm births in the active 
versus the placebo group and recommended that study enrollment be paused. As a 
result, GSK voluntarily paused the enrollment, randomization, and vaccination of 
participants in its active pregnant women studies to investigate this safety signal.  
 
Following a review of additional unblinded data from the RSV MAT-009 study, the 
imbalance in preterm births was noted to persist across a range of risk factors. A 
higher proportion of neonatal deaths reported in the active group compared to the 
placebo group was also observed. GSK then decided to stop enrollment and vaccination 
in all ongoing trials of RSV Maternal Vaccine (RSVPreF3) as a precautionary 
measure. 
 
The observed numerical imbalance in neonatal deaths is not an independent safety 
signal but a consequence of the validated signal of preterm birth. No numerical 
imbalance in neonatal deaths was observed in the cohort of infants born at term. An 
in-depth qualitative review of the clinical information available for each neonatal 
death concluded that the events leading to neonatal death (e.g., very low or low birth 
weight, sepsis, necrotizing colitis, pneumonia, respiratory distress syndrome, hypoxic-


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ischemic injury) are commonly observed in preterm-born infants, particularly those 
who are extremely and very preterm, and there is no consistent temporal pattern of 
events from birth or from maternal vaccination.  
 
In January 2023, following assessment of the Study Day 43 post-birth interim analysis 
(DLP 04 October 2022) with data from 5328 maternal participants (3557 in the active 
group) and 5235 infant participants (3496 in the active group), the imbalance in 
preterm birth remains statistically significant (RR 1.38 (95% CI 1.08, 1.75); p value: 
0.0090) and persists across a range of risk factors. The overall incidence of preterm 
birth in the study is low in both groups and remains below the preterm birth 
background rates for the majority of the participating countries. The imbalance in 
preterm births was observed more with low and middle-income countries (RR: 1.57, 
95% CI: 1.17–2.10) than high-income countries (RR: 1.04, 95% CI: 0.68–1.58). In low 
and middle-income countries, the preterm birth imbalance peaked from August to 
December 2021 and was not observed consistently from January 2022 onward.  
 
GSK concluded that preterm birth is an identified risk for the pregnant women 
population, for the RSV Maternal vaccine candidate. GSK has discontinued the work 
on this RSV maternal candidate vaccine and is closing out all ongoing trials. 
Additionally, GSK continues to monitor and follow up those participants immunized in 
the trials. Another study (RSV MAT-015) has been initiated to describe the safety of 
study participants who received RSVPreF3 maternal vaccination (any dose) or control 
in previous RSV MAT studies, including the RSV MAT-009 study, during any 
pregnancy conceived post-vaccination or post-control. 
 
Following a recommendation from the IDMC, the Sponsor made the decision to pause 
the enrollment, randomization and vaccination of participants in our active pregnant 
women studies, including RSV MAT-009, based on an observation of imbalance in the 
proportion of preterm births between the vaccine group and the placebo group in the RSV 
MAT-009 study. This pause was to allow for an evaluation of the available data in RSV 
MAT-009 to better understand the safety signal observed. Following a review of 
additional unblinded data from this study in which a higher proportion of neonatal deaths 
reported in the treatment group compared to the placebo group was also observed, the 
Sponsor decided to STOP enrollment and vaccination in these studies. 
The safety signals are being investigated and, although at this time a cause has not been 
determined, GSK stopped active enrollment and further vaccination of participants in the 
RSV MAT studies enrolling pregnant women on February 25, 2022 as a precautionary 
measure. The study remains ongoing for safety follow-up. Participants already vaccinated 
and their infants will continue to be monitored until the end of the study. 
 
Section 3: Objectives and endpoints 
Secondary efficacy objectives 
Secondary efficacy endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
From birth (Visit 1-NB) to 7 months, birth to 8 months,birth to 9 
months (C2-NB), birth to 10 months, birth to 11 months, and 
birth to 12 months (Visit 5-NB), occurrences of medically 


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RSV-associated severe LRTIs in their infant43 
participants up to 7, 8, 9, 10, 11 and 12 months of 
age. 
assessed, RSV-associated severe LRTIs according to the 
case definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant43 participants up to 7, 8, 9, 10, 11 and 12 
months of age. 
From birth (Visit 1-NB) to 7 months, birth to 8 months,birth to 9 
months (C2-NB), birth to 10 months, birth to 11 months, and 
birth to 12 months (Visit 5-NB), occurrences of any medically 
assessed, RSV-associated LRTIs according to the case 
definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant4 
participants up to 6 months of age, medically 
assessed1 RSV LRTI by alternative case 
definitions2. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of medically assessed1 RSV LRTI by alternative case 
definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant43 
participants up to 6 months of age, all cause 
pneumonia. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause pneumonia.  
To assess the effect of administering a single 
dose of the RSV Maternal vaccine administered to 
maternal participants on time to first occurrence of 
any severe medically assessed1, RSV-associated 
LRTIs, in their infant4 participants up to 12 months 
of age, according to the case definition2. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), time to the 
first occurrence of severe medically assessed1, RSV-
associated LRTIs according to the case definition2. 
To assess the effect of administering a single 
dose of the RSV Maternal vaccine administered to 
maternal participants on time to first occurrence of 
any medically assessed, RSV-associated LRTIs 
in their infant4 participants up to 12 months of age, 
according to the case definition2. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), time to the 
first occurrence of any medically assessed, RSV-associated 
LRTIs according to the case definition2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing RSV-associated 
hospitalization in their infant3 participants up to 12 
months of age. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), occurrences 
of RSV-associated hospitalizations according to the case 
definitions2. 
To assess the efficacy of a single dose of RSV 
Maternal vaccine administrated to maternal 
participants in preventing, in all vaccinated 
maternal participants up to 6 months post-
delivery, RSV associated medically attended RTIs 
(MA-RTIs). 
From study intervention administration (Visit 1) to 6 months 
post-delivery (Contact 1), occurrence of RSV-associated 
medically attended RTIs (RSV-MA-RTIs)2. 
Secondary immunogenicity objectives 
Secondary immunogenicity endpoints 
To evaluate the immunogenicity of the RSV 
Maternal vaccine in a sub-cohort of maternal 
 
RSVPreF3 IgG-specific antibody concentration, and  
 
Neutralizing antibody titers against RSV-A and RSV-B 


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participants 30 days after the study intervention, 
and at delivery. 
Measured on blood samples collected at Day 1 before the 
study intervention (Visit 1), at Day 31 (Visit 2), and at delivery 
(Visit 3). 
To evaluate the immunogenicity of the RSV 
Maternal vaccine in a sub-cohort of infants in 
Stage A, at birth and up to 6 months after birth. 
 
RSVPreF3 IgG-specific antibody concentration, and  
 
Neutralizing antibody titers against RSV-A and RSV-B 
Measured on the cord blood sample collected at delivery, or 
on a blood sample collected from the infant within 72 hours 
after birth (if no cord blood sample can be obtained). 
Measured on a blood sample collected at Day 43 (Visit 2-NB), 
Day 121 (Visit 3-NB), or Day 181 (Visit 4-NB) after birth in 3 
sub-cohorts of infants. 
Infants born to women in the immunogenicity sub-cohort will 
be randomly assigned (1:1:1) to sample collection at 1 of the 3 
timepoints noted. 
To evaluate the transfer of RSV-specific 
antibodies from a sub-cohort of maternal 
participants vaccinated with a single IM dose of 
the RSV Maternal vaccine to their infants at the 
time of delivery. 
RSVPreF3 IgG-specific antibody concentration measured 
on blood samples collected at Delivery and cord blood* 
The ratio between cord blood* and maternal RSVPreF3 IgG-
specific antibody concentrations. 
* or an infant blood sample collected within 72 hours after birth 
(if no cord blood sample can be obtained). 
Secondary safety objectives 
Secondary safety endpoints 
To evaluate reactogenicity of a single IM dose of 
the RSV Maternal vaccine in stage A maternal 
participants, during a 7 day follow up period after 
the study intervention. 
Occurrence of solicited administration site and systemic 
events in stage A maternal participants, during a 7-day follow-
up period after the study intervention (i.e. the day of the 
intervention and 6 subsequent days). 
To evaluate the safety of a single IM dose of the 
RSV Maternal vaccine in all maternal participants, 
during a 30 day follow up period after the study 
intervention. 
Occurrence of unsolicited adverse events (AEs) in all maternal 
participants during a 30-day follow-up period after the study 
intervention (i.e. the day of the intervention and 29 subsequent 
days). 
To evaluate the safety of a single IM dose of the 
RSV Maternal vaccine in all maternal participants, 
from Visit 1 up to 6 months after delivery. 
Occurrence of serious adverse events (SAEs) 5, AEs leading 
to study termination, and medically attended RTIs in all 
maternal participants from Visit 1 (Day 1) up to 6 months after 
delivery. 
Occurrence of all other medically attended AEs in all maternal 
participants from Visit 1 (Day 1) up to Day 42 after delivery. 
To evaluate pregnancy outcomes and pregnancy-
related adverse events of special interest after a 
single IM dose of the RSV Maternal vaccine 
administered to maternal participants, from Visit 1 
up to 6 weeks after delivery (Visit 4). 
Pregnancy outcomes5 from Day 1 (Visit 1) up to 6 weeks after 
delivery (Day 43 post-delivery, Visit 4). These include live birth 
with no congenital anomalies, live birth with minor congenital 
anomaly(ies) only; live birth with at least one major congenital 
anomaly, fetal death/still birth (antepartum or intrapartum) with 
no congenital anomalies, fetal death/still birth (antepartum or 
intrapartum) with only minor congenital anomalies, fetal 
death/still birth (antepartum or intrapartum) with at least 1 
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with no congenital anomalies; elective/therapeutic termination 
with only minor congenital anomalies, and elective/therapeutic 
termination with at least 1 major congenital anomaly. 
 
Pregnancy-related adverse events (AEs) of special interest 
from Day 1 (Visit 1) up to 6 weeks after delivery (Day 43 post-
delivery, Visit 4). These include maternal death, hypertensive 
disorders of pregnancy (gestational hypertension, pre-
eclampsia, pre-eclampsia with severe features including 
eclampsia), fetal growth restriction, pathways to preterm birth 
(premature preterm rupture of membranes, preterm labor, 
provider-initiated preterm birth), gestational diabetes mellitus, 
chorioamnionitis4,5 . 
To evaluate the occurrence of neonatal AEs of 
special interest (reported up to 6 weeks after 
birth), in infants born to mothers who were 
vaccinated with a single IM dose of the RSV 
Maternal vaccine. 
The occurrence of neonatal AEs of special interest (reported 
up to 6 weeks after birth). These include small for gestational 
age, low birth weight including very low and extremely low 
birth weight (<2500 g, <1500g, <1000g), congenital anomalies 
(major external structural defects, internal structural defects, 
functional defects), neonatal death (in an extremely pre-term 
birth [22GA<28 weeks], in a preterm live birth [28GA<37 
weeks], or in a term live birth), preterm birth4,5. 
Tertiary objectives: 
2Case definitions for RSV-associated medically attended RTIs (RSV-MA-RTIs), RSV associated LRTIs and 
surveillance for potential LRTIs are briefly summarized in Section 4.2.6. 
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 
Section 4.1 
Figure 1 
Footnote modified to add: Due to the stop on study enrollment and vaccination, nasal 
swab samples will no longer be collected from any maternal participant and no MA-
RTI assessment visit will be performed, but the MAEs associated with an RTI will 
continue to be reported, as applicable. 
 
Section 4.2.4.2 
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives and to assess antibody persistence in infants. 
 
Section 6.3.2.1.1 
Samples collected from maternal and infant participants in the immunogenicity sub-
cohort will be used to evaluate secondary immunogenicity objectives and to assess 
antibody persistence in the infants. 
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives and to assess antibody persistence in infants. 
Note: As per Amendment 4, blood samples were collected from all maternal 
participants at Delivery (Visit 3). 
 
Section 8.1.2 
Table 15 
Assay type 
System 
Component 
Method 
Laboratory* 
Humoral 
Immunity 
(Antibody 
determination) 
SERUM 
RSV-A NAb (RSV-A 
Neutralizing 
Antibody) 
NEUT 
GSK ** or GSK 
designated lab 
SERUM 
RSV-B NAb (RSV-B 
Neutralizing 
Antibody)  
NEUT 
GSK ** or GSK 
designated lab 
SERUM 
Respiratory Syncytial 
Virus PreF3 Ab.IgG 
(RSVPreF3 IgG 
antibody 
concentration) 
ELISA 
GSK ** or GSK 
designated lab 
Molecular 
Biology 
NASMUC 
(Nasal 
swab) 
Respiratory Syncytial 
Virus A RNA  
QRTPCR  
GSK ** or GSK 
designated lab 
 
NASMUC 
(Nasal 
swab) 
Respiratory Syncytial 
Virus B RNA  
QRTPCR 
GSK ** or GSK 
designated lab 
*Refer to the list of clinical laboratories for details. 
** GSK laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. CLS may 
delegate testing to GSK Research laboratories in Rixensart, Belgium; Rockville, USA; Sienna, Italy. 
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RSV-A/B quantitative reverse transcription PCR will be performed on all specimens collected to evaluate RTI as 
specified in Section 8.4.4. 
 
 
Section 8.1.3 
Table 16 
All participating maternal participants will have Visit 1 (Day 1) and Visit 2 (Day 31) 
blood samples tested. All cord blood samples will also be tested. 
Approximately 1533 maternal participants (and their infant participants), in Stage A only, 
will be assigned to the immunogenicity sub-cohort.  
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives and to assess antibody persistence in infants. Therefore, 
maternal participants in the immunogenicity subcohort, who have blood samples 
collected from their respective infants, will have Visit 1 (Day 1), Visit 2 (Day 31), 
Delivery blood samples and cord blood samples tested for RSV-A NAb. In addition, 
their delivery and cord blood samples will be tested for RSVPreF3 IgG-specific 
antibody concentration.  
Blood sampling timepoint 
Approximate No. 
participants – 
Stage A 
Approximate No. 
participants – 
Stage B 
Component 
Type of 
contact and 
timepoint 
Sampling 
timepoint 
Maternal participants*  
V1 (Day 1) 
pre 
vaccination 
4600 
Up to 5400 
RSV-A NAb (neutralizing antibody) 
RSV-B NAb (neutralizing antibody) 
Respiratory Syncytial Virus PreF3 Ab.IgG 
(concentration) 
V2 (Day 31) 
post 
vaccination 
4600 
Up to 5400 
RSV-A NAb (neutralizing antibody) 
RSV-B NAb (neutralizing antibody) 
Respiratory Syncytial Virus PreF3 Ab.IgG 
(concentration) 
V3 (Delivery)# 
post-
vaccination  
venous blood: 1533 
Cord blood: 4600 
Venous blood: 0 
Cord blood: up to 
5400 
RSV-A NAb (neutralizing antibody) 
RSV-B NAb (neutralizing antibody) 
Respiratory Syncytial Virus PreF3 Ab.IgG 
(concentration) 
Infant participants** 
 
 
V1-NB (Birth)  
birth (only if 
cord blood 
cannot be 
collected) 
Event-driven 
Event-driven 
RSV-A NAb (neutralizing antibody) 
RSV-B NAb (neutralizing antibody) 
Respiratory Syncytial Virus PreF3 Ab.IgG 
(concentration) 
V2-NB (Day 
43)*** 
post birth 1  510 
0 
RSV-A NAb (neutralizing antibody) 
RSV-B NAb (neutralizing antibody) 
Respiratory Syncytial Virus PreF3 Ab.IgG 
(concentration) 
V3-NB (Day 
121)*** 
post birth 2  510 
0 
RSV-A NAb (neutralizing antibody) 
RSV-B NAb (neutralizing antibody) 
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Blood sampling timepoint 
Approximate No. 
participants – 
Stage A 
Approximate No. 
participants – 
Stage B 
Component 
Type of 
contact and 
timepoint 
Sampling 
timepoint 
Respiratory Syncytial Virus PreF3 Ab.IgG 
(concentration) 
V4-NB (Day 
181)*** 
post birth 3  510 
0 
RSV-A NAb (neutralizing antibody) 
RSV-B NAb (neutralizing antibody) 
Respiratory Syncytial Virus PreF3 Ab.IgG 
(concentration) 
 
Table 17 
Footnote modified: Quantitative reverse transcription PCR will be performed on all 
specimens collected to evaluate RTI as specified in Section 8.4.4. 
 
 
Section 8.4.1.1 
* Due to the stop on study enrollment and vaccination, MA-RTI surveillance of the 
maternal participants will no longer be performed. No nasal swab will be collected and 
no RTI assessment visit will be performed. However, any MAE related to RTI will still 
be reported (as applicable). 
 
Section 9.3 
Table 22 
 
Description 
Analysis Set 
Maternal participants 
Enrolled 
All maternal participants who completed the informed consent process and signed the informed 
consent form.  
Exposed 
All maternal participants who received the study intervention. The allocation in a group is done in 
function of the administered intervention. 
Full Analysis – 
Immunogenicity 
All maternal participants in the Exposed set who have post-vaccination immunogenicity data.  
Per Protocol – 
Immunogenicity 
All maternal participants who received the study intervention to which they were randomised and 
have post-vaccination data (Full Analysis Set) minus participants with protocol deviations that 
lead to exclusion.  
Full Analysis – 
Efficacy 
All maternal participants in the Exposed set. 
Solicited Safety 
– Stage A only 
All maternal participants in the Exposed Set who have solicited safety data 
 
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Table 23 
Analysis Set 
Description 
Exposed 
Infants live-born to exposed maternal participants, whose parents/LARs completed the 
informed consent process and signed the informed consent form 
Full Analysis – 
Immunogenicity 
All infant participants in the Exposed set who have post-delivery/birth immunogenicity data. 
Per Protocol – 
Immunogenicity 
All infant participants in the Full Analysis (Immunogenicity) Exposed set minus those who 
(a) were born less than 4 weeks post- maternal participant vaccination and/ or (b) have 
protocol deviations that lead to exclusion. 
Full Analysis – 
Efficacy  
All infant participants in the Exposed set. 
 
Modified Full 
Analysis – Efficacy 
All infant participants in the Exposed set who were born after at least 4 weeks of 
vaccination. 
Per Protocol – 
Efficacy 
All infant participants in the Modified Full Analysis – Efficacy set minus those who have 
protocol deviations that lead to exclusion. 
 
 
Section 9.4.1 
If, during the trial, changes need to be made on primary or secondary objectives and 
statistical methods related to those objectives, the protocol will be amended. Changes on 
secondary/tertiary objectives, along with the reason(s) for the changes, will be 
documented in the SAP and the Clinical Study Report. 
 
Section 9.4.3.1.2 
To evaluate how missing efficacy data (PCR confirmed RSV LRTI results ) can impact 
on the estimated VE from primary analysis, a tipping point analysis for binary data may 
be conducted. Sub-group analyses by regions and key demographic characteristics will 
also be explored, and the details will be included in the SAP. 
 
Section 9.4.4.1 
In general, The primary analysis of vaccine efficacy on secondary efficacy endpoints in 
infants will be based on the modified full analysis set for efficacy (modified FAS-E). A 
secondary analysis based on the full analysis set for efficacy and the per protocol set for 
efficacy will be performed to complement the modified FAS-E analysis. all secondary or 
tertiary efficacy analyses will be performed on the final data containing all participants 
enrolled and their follow up. 


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Secondary  Efficacy 
Endpoints  
Statistical Analysis Methods 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of RSV-associated 
hospitalizations according to 
the case definitions. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause 
LRTIs.  
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause LRTIs 
with hospitalization.  
From birth (Visit 1-NB) to 7 
months, occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 7 
months, occurrences of any 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 8 
months, occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 8 
months, occurrences of any 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
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Secondary  Efficacy 
Endpoints  
Statistical Analysis Methods 
From birth (Visit 1-NB) to 9 
months (C2-NB), occurrences 
of severe medically assessed, 
RSV-associated LRTIs 
according to the case 
definitions. 
From birth (Visit 1-NB) to 9 
months (C2-NB), occurrences 
of any medically assessed, 
RSV-associated LRTIs 
according to the case 
definitions. 
From birth (Visit 1-NB) to 10 
months, occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 10 
months, occurrences of any 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 11 
months, occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 11 
months, occurrences of any 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
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Secondary  Efficacy 
Endpoints  
Statistical Analysis Methods 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definitions. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definition, for RSV 
subtype A and RSV subtype B 
separately. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definition, for RSV subtype A 
and RSV subtype B separately. 
From birth (Visit 1-NB) to 4 
months (Visit 3-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definition. 
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Secondary  Efficacy 
Endpoints  
Statistical Analysis Methods 
From birth (Visit 1-NB) to 4 
months (Visit 3-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definitions. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs by alternative case 
definitions. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause 
pneumonia. 
From study intervention 
administration (Visit 1) to 6 
months post-delivery (Contact 
1), occurrence of RSV-
associated medically attended 
RTIs (RSV-MA-RTIs). 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), time to the 
first occurrence of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definition. 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), time to the 
first occurrence of any 
medically assessed, RSV-
associated LRTIs according to 
the case definition. 
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Secondary  Efficacy 
Endpoints  
Statistical Analysis Methods 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of RSV-associated 
hospitalizations according to 
the case definitions. 
 
Section 9.4.4.3 
All immunogenicity analyses in stage A will be based on the Per Protocol 
Immunogenicity set. If, in any study group and at any timepoint, the percentage of study 
intervention recipients 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 
Immunogenicity Set will be performed to complement the Per Protocol analysis. 
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives and to assess antibody persistence in infants. 
Secondary Immunogenicity 
Endpoints – Maternal 
Participants 
Statistical Analysis Methods 
 
RSVPreF3 IgG-specific 
antibody concentration, and  
 
Neutralizing antibody titers 
against RSV-A  
Measured on blood samples 
collected at Day 1 before 
vaccination (Visit 1), at Day 31 
(Visit 2), and at delivery (Visit 
3). 
Secondary Immunogenicity 
Endpoints – Cord blood / 
placental transfer 
 
RSVPreF3 IgG-specific 
antibody concentration 
measured on blood samples 
collected at Delivery and cord 
blood* 
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 
The ratio between cord blood* 
and maternal RSVPreF3 IgG-
specific antibody concentrations  
 
* or an infant blood sample collected 
within 72 hours after birth (if no 
cord blood sample can be 
obtained) 
Secondary Immunogenicity 
Endpoints – Infant 
Participants 
 
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 72 hours after birth 
(if no cord blood sample can be 
obtained). 
Measured on a blood sample 
collected on the cord blood 
sample collected at delivery 
(or on a blood sample 
collected from the infant 
within 72 hours after birth if 
no cord blood sample can be 
obtained) and at Day 43 (Visit 
2-NB), Day 121 (Visit 3-NB), or 
Day 181 (Visit 4-NB) after 
delivery birth in 3 sub-cohorts 
of infants. Infants born to 
women in the immunogenicity 
sub-cohorts will be randomly 
assigned (1:1:1) to sample 
collection at 1 of the 3 
timepoints noted. 
 
Section 10.6 
10.6.3. Spain 
With regards to the “COMPENSATION” offered to the infant participants enrolled in 
the study, infant parents/LAR’s were offered the possibility to have the infant 
vaccinated with a commercially approved vaccine being part of the National Pediatric 
Immunization Calendar but, which costs are not financially covered by the health 
system in the corresponding Region/Autonomous Community: 
• 
Meningococcus B vaccine (Bexsero®) 
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Or 
• 
Rotavirus vaccine (Rotarix®) 
This compensation was put in place considering the recommendations laid out in ICH-
E11 (Clinical Investigation of Medicinal Products in the pediatric population) as well 
as in the “Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population”, developed by the ad-hoc group for the development of 
implementing guidelines for Directive 2001/20/EC relating to good clinical practice in 
the conduct of clinical trials on medicinal products for human use. 
Compensation was approved by the Spanish regulatory authority and Ethics 
Committee, and included in the country-specific Informed Consent. 
10.6.4. Argentina 
Concerning the “STUDY POPULATION – Exclusion criteria for enrolment – 
maternal participants” and, as per request from the Argentinean regulatory authorities 
(A.N.M.A.T   Administración Nacional de Alimentos, Medicamentos y Tecnología 
Médica), study recruitment in Argentina was limited to pregnant women aged 18 to 40 
years (inclusive), instead of 18 to 49 years (inclusive). 
This age limitation was initially expected to be temporal, and dependent on the 
availability of safety data coming from other countries on pregnant women > 40 years 
old, which was to be submitted to A.N.M.A.T for evaluation. However, further 
enrollment and vaccination in the study was stopped on 25th February 2022, before 
such safety data was submitted. 
 
Section 10.7.1 
The following abbreviation was added: SRT – Safety Review Team 
Overall Rationale for the Protocol Amendment 4: 
This protocol has been amended to reflect the following: 
 
Following review of data collected so far from the study, safety signals have been 
identified: an imbalance in the proportion of preterm births and neonatal deaths has 
been observed in infants born to vaccinated mothers who received RSV maternal 
vaccine versus those who received a placebo. It is not known at this time whether 
this imbalance is related to the study participation or study vaccine. Based on the 
above observation, GSK has decided to stop enrolment and vaccination for all 
actively enrolling RSV MAT studies . 
 
There will be no new participants included in the ongoing studies. 
 
However, safety monitoring will continue, with additional monitoring measures 
implemented, for both maternal and infant participants during the rest of the study 
period. 
 
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 
Placental sample from all maternal participants at delivery will be collected, 
whenever feasible. 
 
No blood sample from the infants will be collected at V2-NB, V3-NB and V5-NB. 
 
Additional monitoring contact/s or visit/s for the maternal participants and infants 
have been included. 
 
Respiratory tract illness surveillance for maternal participants will not be performed. 
 
All planned objectives will be assessed for the participants enrolled so far. 
Also, this amendment includes editorial changes to improve the consistency and 
typographical error corrections. 


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Detailed description of Protocol Amendment (# 4) changes: 
In this section, deleted text is indicated in strikethrough and changed text in bold italics. 
 
Section 1.1:  
Note: Based on all available safety information following vaccination with the RSV 
MAT vaccine, there will be no further enrollment and vaccination of maternal 
participants. However, monitoring will continue for rest of the study. All planned 
objectives will be assessed for the participants enrolled so far.  
 
Section 1.2 
* Due to the safety signal observed, the study was fully unblinded to ensure the safety 
of the participants. 
 
Section 1.3 
Table 1: Schedule of activities for maternal participants 
Visit / Contact 
Screenin
g 
V1 
V2*  
Cont
acts 
(Mon
thly) 
V3 
V4  
C
1 
Event Driven 
 
Gestational 
Age (GA) 
≤ 28 
days 
before 
V1 
240/7 
– 
340/7 
 
Until 
Deliv
ery1 
Del
ive
ry 
 
 
Addition
al 
contact(
s)1 
Saf
ety 
visi
t 
MA
-
RT
I 
visi
t 
For monthly 
contacts: 
Section  8.4.2 
8.2.1.2.2. 
Additional 
contact(s) 
and/or safety 
visit(s) can be 
made between 
Visit-2 and the 
Delivery visit, 
if deemed 
necessary. 
Visit Day 
D-28 – 
D1 
before 
randomi
zation 
D1 
D31 
 
D1
PD 
D4
3 
PD 
D
18
1 
P
D 
V2-
Delivery 
 
 
Table 3 
Informed 
consent 
● 
 
 
 
 
 
 
 
 
 
Section 10.1.3 
Check 
Inclusion/exclu
sion criteria  
● 
O 
 
 
 
 
 
 
 
 
Sections 5.1.1, 
5.1.2 
Assign 
maternal 
participant 
study number  
● 
 
 
 
 
 
 
 
 
 
Section 6.3.1 


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Visit / Contact 
Screenin
g 
V1 
V2*  
Cont
acts 
(Mon
thly) 
V3 
V4  
C
1 
Event Driven 
 
Gestational 
Age (GA) 
≤ 28 
days 
before 
V1 
240/7 
– 
340/7 
 
Until 
Deliv
ery1 
Del
ive
ry 
 
 
Addition
al 
contact(
s)1 
Saf
ety 
visi
t 
MA
-
RT
I 
visi
t 
For monthly 
contacts: 
Section  8.4.2 
8.2.1.2.2. 
Additional 
contact(s) 
and/or safety 
visit(s) can be 
made between 
Visit-2 and the 
Delivery visit, 
if deemed 
necessary. 
Visit Day 
D-28 – 
D1 
before 
randomi
zation 
D1 
D31 
 
D1
PD 
D4
3 
PD 
D
18
1 
P
D 
V2-
Delivery 
 
 
Table 3 
Register 
maternal 
participant in 
SBIR 
O 
 
 
 
 
 
 
 
 
 
Section 6.3.1 
Assign infant 
participant 
study number  
 
O 
 
 
 
 
 
 
 
 
Section 6.3.1 
Record 
Demographic 
data  
● 
 
 
 
 
 
 
 
 
 
Section 5.3 
Record lifestyle 
characteristics 
● 
 
 
 
 
 
 
 
 
 
Review & 
collect Medical 
and 
vaccination 
history 
O  
● 
 
 
 
 
 
 
 
 
 Section 8.2.1.1 
Record 
outcome of 
fetal 
morphology 
ultrasound 
scan 
● 
 
 
 
 
 
 
 
 
 
 
Record 
obstetric 
history from 
past and 
current 
pregnancies 
● 
(current 
pregnan
cy) 
●  
(past 
preg
nanc
y/ 
ies) 
 
 
 
 
 
 
 
 
Record Travel 
history to or 
living in Zika 
virus endemic 
countries/regio
ns  
● 
● 
● 
● 
● 
 
 
● 
 
 
During the 
current 
pregnancy only 


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Visit / Contact 
Screenin
g 
V1 
V2*  
Cont
acts 
(Mon
thly) 
V3 
V4  
C
1 
Event Driven 
 
Gestational 
Age (GA) 
≤ 28 
days 
before 
V1 
240/7 
– 
340/7 
 
Until 
Deliv
ery1 
Del
ive
ry 
 
 
Addition
al 
contact(
s)1 
Saf
ety 
visi
t 
MA
-
RT
I 
visi
t 
For monthly 
contacts: 
Section  8.4.2 
8.2.1.2.2. 
Additional 
contact(s) 
and/or safety 
visit(s) can be 
made between 
Visit-2 and the 
Delivery visit, 
if deemed 
necessary. 
Visit Day 
D-28 – 
D1 
before 
randomi
zation 
D1 
D31 
 
D1
PD 
D4
3 
PD 
D
18
1 
P
D 
V2-
Delivery 
 
 
Table 3 
General and/or 
obstetrical 
examination  
● 
● 
● 
 
● 
● 
 
 
If 
ne
ed
ed 
If 
ne
ed
ed 
General and/or 
Obstetrical 
exam is 
symptom 
directed at V4, 
& 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. 
Blood sample  
(immunogenicit
y ~ 10 ml) 
 
● 
● 
 
Su
b-
co
hor
t 
● 
 
 
 
 
 
At V1 and V2, 
collected from 
all participants 
in both Stage A 
and Stage B. At 
V3, collected 
only from a sub-
cohort in Stage 
A. See Table 12 
and Sections 
8.1.1 and 8.1.3 
Blood sample 
at delivery to 


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Visit / Contact 
Screenin
g 
V1 
V2*  
Cont
acts 
(Mon
thly) 
V3 
V4  
C
1 
Event Driven 
 
Gestational 
Age (GA) 
≤ 28 
days 
before 
V1 
240/7 
– 
340/7 
 
Until 
Deliv
ery1 
Del
ive
ry 
 
 
Addition
al 
contact(
s)1 
Saf
ety 
visi
t 
MA
-
RT
I 
visi
t 
For monthly 
contacts: 
Section  8.4.2 
8.2.1.2.2. 
Additional 
contact(s) 
and/or safety 
visit(s) can be 
made between 
Visit-2 and the 
Delivery visit, 
if deemed 
necessary. 
Visit Day 
D-28 – 
D1 
before 
randomi
zation 
D1 
D31 
 
D1
PD 
D4
3 
PD 
D
18
1 
P
D 
V2-
Delivery 
 
 
Table 3 
be collected 
from all 
participants. 
Cord blood (~ 
5 to 10 ml) 
 
 
 
 
● 
 
 
 
 
 
Collected from 
all participants 
in both Stage A 
and Stage B. 
See Table 13 
and Sections 
8.1.1 and 8.1.3. 
Placenta 
sample 
 
 
 
 
● 
 
 
 
 
 
Collected from 
all participants 
in both Stage A 
and Stage B. 
See Table 13 
and Sections 
8.1.1 and 8.1.3. 
Collect from 
all 
participants, if 
feasible. 
Nasal swab 
 
 
 
 
 
 
 
 
 
● 
See Table 12 
and Sections 
8.1.1, 8.1.3, 
and 8.4.4. 
Note: nasal 
swab from 
maternal 
participants 
will no longer 
be collected 
and MA-RTI 
visit is no 
longer 
required. 


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Visit / Contact 
Screenin
g 
V1 
V2*  
Cont
acts 
(Mon
thly) 
V3 
V4  
C
1 
Event Driven 
 
Gestational 
Age (GA) 
≤ 28 
days 
before 
V1 
240/7 
– 
340/7 
 
Until 
Deliv
ery1 
Del
ive
ry 
 
 
Addition
al 
contact(
s)1 
Saf
ety 
visi
t 
MA
-
RT
I 
visi
t 
For monthly 
contacts: 
Section  8.4.2 
8.2.1.2.2. 
Additional 
contact(s) 
and/or safety 
visit(s) can be 
made between 
Visit-2 and the 
Delivery visit, 
if deemed 
necessary. 
Visit Day 
D-28 – 
D1 
before 
randomi
zation 
D1 
D31 
 
D1
PD 
D4
3 
PD 
D
18
1 
P
D 
V2-
Delivery 
 
 
Table 3 
Check 
contraindicatio
ns to and 
criteria for 
temporary 
delay for 
vaccination 
 
O 
 
 
 
 
 
 
 
 
Section 7.1 
Allocate 
maternal study 
group, 
intervention 
number 
 
O 
 
 
 
 
 
 
 
 
Sections 6.3.2, 
6.3.3 
Recording will 
be done at Visit 
1, upon 
maternal 
participant 
randomization 
but the eCRF 
entry will be 
done on the 
demography 
screen 
Record 
maternal sub-
cohort for 
immunogenicit
y assessment 
 
● 
 
 
 
 
 
 
 
 
Allocate infant 
sub-cohorts for 
immunogenicit
y assessment  
 
O 
 
 
 
 
 
 
 
 
Administer 
Study 
Intervention  
(study vaccine 
/ placebo) 
 
● 
 
 
 
 
 
 
 
 
Sections 6.1, 
6.2 
Record 
administered 
intervention 
number 
 
● 
 
 
 
 
 
 
 
 
Observe for 30 
minutes post-
dose 
 
O 
 
 
 
 
 
 
 
 


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Visit / Contact 
Screenin
g 
V1 
V2*  
Cont
acts 
(Mon
thly) 
V3 
V4  
C
1 
Event Driven 
 
Gestational 
Age (GA) 
≤ 28 
days 
before 
V1 
240/7 
– 
340/7 
 
Until 
Deliv
ery1 
Del
ive
ry 
 
 
Addition
al 
contact(
s)1 
Saf
ety 
visi
t 
MA
-
RT
I 
visi
t 
For monthly 
contacts: 
Section  8.4.2 
8.2.1.2.2. 
Additional 
contact(s) 
and/or safety 
visit(s) can be 
made between 
Visit-2 and the 
Delivery visit, 
if deemed 
necessary. 
Visit Day 
D-28 – 
D1 
before 
randomi
zation 
D1 
D31 
 
D1
PD 
D4
3 
PD 
D
18
1 
P
D 
V2-
Delivery 
 
 
Table 3 
Distribute 
maternal 
participant card 
O 
O 
 
 
 
 
 
 
 
 
At screening or 
at Visit 1 as per 
local practice. 
Section 8.3.6 
Record Labor / 
Delivery 
information  
 
 
 
 
● 
 
 
 
 
 
 
Record 
pregnancy / 
delivery 
outcomes  
 
 
 
 
● 
 
 
 
 
 
Submit 
Expedited AE 
report for an 
adverse 
pregnancy 
outcome 
(Section 8.3.3) 
Train maternal 
participant 
/LAR on use of 
electronic diary 
 
O 
Stag
e A 
 
 
 
 
 
 
 
 
Section 10.3.8  
 
 
 
 
 
Section 8.3.1 
Distribute 
electronic diary 
to maternal 
participant / 
LAR.  
 
O 
Stag
e A 
 
 
 
 
 
 
 
 
Review 
electronic diary 
entries 
 
 
O 
Sta
ge 
A 
 
 
 
 
 
 
 
Return 
electronic diary 
 
 
O 
Sta
ge 
A 
 
 
 
 
 
 
 
 
Concomitant 
medications / 
vaccinations. 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 6.5.1 
and 6.5.3 


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Visit / Contact 
Screenin
g 
V1 
V2*  
Cont
acts 
(Mon
thly) 
V3 
V4  
C
1 
Event Driven 
 
Gestational 
Age (GA) 
≤ 28 
days 
before 
V1 
240/7 
– 
340/7 
 
Until 
Deliv
ery1 
Del
ive
ry 
 
 
Addition
al 
contact(
s)1 
Saf
ety 
visi
t 
MA
-
RT
I 
visi
t 
For monthly 
contacts: 
Section  8.4.2 
8.2.1.2.2. 
Additional 
contact(s) 
and/or safety 
visit(s) can be 
made between 
Visit-2 and the 
Delivery visit, 
if deemed 
necessary. 
Visit Day 
D-28 – 
D1 
before 
randomi
zation 
D1 
D31 
 
D1
PD 
D4
3 
PD 
D
18
1 
P
D 
V2-
Delivery 
 
 
Table 3 
All unsolicited 
AEs (Days 1 to 
30)  
 
● 
● 
 
 
 
 
 
● 
● 
Sections 8.3.1, 
10.3.4 and 
10.3.8 
Pregnancy-
related AESIs  
 
● 
● 
● 
● 
● 
 
● 
● 
 
Table 4, 
Sections 8.3.1, 
8.3.3, 8.3.4, 
and 10.3.5. 
Must submit an 
Expedited AE 
report. 
MAEs other 
than MA-RTIs 
 
● 
● 
● 
● 
● 
 
● 
● 
 
Medically 
attended RTIs 
to be reported 
up to C1. 
MA-RTI signs  
 
 
 
 
 
 
 
 
 
● 
Sections 8.3.1, 
8.3.3, 8.4 
Note: nasal 
swab from 
maternal 
participants 
will no longer 
be collected 
and MA-RTI 
visit is no 
longer 
required. 
SAEs, MA-RTI 
associated AEs 
and AEs 
leading to 
study 
withdrawal  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 7.2, 
8.3.1 and 
10.3.8  
SAEs related 
to study 
participation or 
● 
● 
 
 
 
 
 
 
 
 
Sections 8.3.1 
and 10.3.8 


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Visit / Contact 
Screenin
g 
V1 
V2*  
Cont
acts 
(Mon
thly) 
V3 
V4  
C
1 
Event Driven 
 
Gestational 
Age (GA) 
≤ 28 
days 
before 
V1 
240/7 
– 
340/7 
 
Until 
Deliv
ery1 
Del
ive
ry 
 
 
Addition
al 
contact(
s)1 
Saf
ety 
visi
t 
MA
-
RT
I 
visi
t 
For monthly 
contacts: 
Section  8.4.2 
8.2.1.2.2. 
Additional 
contact(s) 
and/or safety 
visit(s) can be 
made between 
Visit-2 and the 
Delivery visit, 
if deemed 
necessary. 
Visit Day 
D-28 – 
D1 
before 
randomi
zation 
D1 
D31 
 
D1
PD 
D4
3 
PD 
D
18
1 
P
D 
V2-
Delivery 
 
 
Table 3 
concurrent 
GSK 
medication/vac
cine 
Subsequent 
pregnancies 
 
 
 
 
 
● 
● 
 
● 
● 
Section 8.3.1 
and 10.3.8 
Record interest 
in joining future 
extension 
study 
O 
 
 
 
 
 
● 
 
 
 
Section 6.7 
Screening 
conclusion  
● 
 
 
 
 
 
 
 
 
 
 
Study 
conclusion 
 
 
 
 
 
 
● 
 
 
 
Section 4.4 
Investigator 
sign-off at 
study 
conclusion 
 
 
 
 
 
 
● 
 
 
 
 
 
The timing of an event-driven site visit (e.g., to further evaluate a potential AE or MA-RTI) cannot be defined with 
precision in the protocol. Event-driven visits may occur throughout the study. ● 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. 
* V2 may be replaced by V3, depending on delivery date. 
1 In addition to the monthly contacts between Visit-2 and the Delivery visit, additional not pre-specified visits 
and contacts (any desired frequency) can be made between Visit-2 and the Delivery visit, as per investigator’s 
or maternal participant’s discretion. 


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Table 2 
Schedule of activities for infant participants  
 Visit / 
Contact 
V1
-
NB
1  
Safety 
contact 
(recommen
ded)1 
V2-
NB 
C1-
NB 
V3-
NB  
V4-
NB  
C2-
NB  
V5-
NB  
RTI 
Surveillance 
RTI 
Surveillance: 
Section 8.4.2 
RTI Visit: 
Sections 
8.4.3 and 
8.4.4 
Age of 
infant 
Bir
th 
8 days 
6 
wee
ks 
3 
mont
hs 
4 
mont
hs 
6 
mont
hs 
9 
mont
hs 
12 
mont
hs 
Conta
cts 
Visi
ts 
 
Visit Day 
D 
1-
21  
D8 (7 days 
post-birth) 
D43 
D91 
D12
1 
D18
1 
D27
1 
D36
6 
Birth – D366 
See Table 3 
for intervals 
between 
visits, 
contacts. 
Check 
Inclusion / 
exclusion 
criteria  
● 
 
 
 
 
 
 
 
 
 
Sections 
5.1.2 and 
5.2.2 
Re-
consent / 
Consent 
for infant 
participati
on if 
required 
by local 
regulation
s  
● 
 
 
 
 
 
 
 
 
 
 
Record 
infant 
participant 
study 
number  
● 
 
 
 
 
 
 
 
 
 
 
Record 
sub-cohort 
for 
immunoge
nicity 
assessme
nt, if 
applicable 
● 
 
 
 
 
 
 
 
 
 
Section 
6.3.2.1.2 
Distribute 
infant’s 
participant 
card  
O 
 
 
 
 
 
 
 
 
 
Section 8.3.6 
Distribute 
infant RTI-
diary card  
O 
O 
O 
O 
O 
O 
O 
 
 
O 
Distribute at 
V1-NB: 
Distribute 
additional 
RTI-diary 
cards as 
needed. 
Section 


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 Visit / 
Contact 
V1
-
NB
1  
Safety 
contact 
(recommen
ded)1 
V2-
NB 
C1-
NB 
V3-
NB  
V4-
NB  
C2-
NB  
V5-
NB  
RTI 
Surveillance 
RTI 
Surveillance: 
Section 8.4.2 
RTI Visit: 
Sections 
8.4.3 and 
8.4.4 
Age of 
infant 
Bir
th 
8 days 
6 
wee
ks 
3 
mont
hs 
4 
mont
hs 
6 
mont
hs 
9 
mont
hs 
12 
mont
hs 
Conta
cts 
Visi
ts 
 
Visit Day 
D 
1-
21  
D8 (7 days 
post-birth) 
D43 
D91 
D12
1 
D18
1 
D27
1 
D36
6 
Birth – D366 
See Table 3 
for intervals 
between 
visits, 
contacts. 
8.4.2.2 and 
SPM 
Review 
infant RTI-
diary card  
 
O 
O 
O 
O 
O 
O 
O 
 
O 
 
Collect 
infant RTI-
diary card 
 
 
O 
O 
O 
O 
O 
O 
 
O 
Collect RTI-
diary cards 
that are fully 
filled out. 
Section 
8.4.2.2 and 
SPM 
Transcribe 
applicable 
infant RTI-
diary card 
data to 
eCRF  
 
 
● 
● 
● 
● 
● 
● 
 
● 
 
Demograp
hic data  
● 
 
 
 
 
 
 
 
 
 
Section 5.3  
Record at 
Visit 1-NB 
and if 
changes in 
lifestyle 
characteristic
s thereafter 
Lifestyle 
characteri
stics 
● 
 
● 
● 
● 
● 
● 
● 
 
 
Apgar 
score  
● 
 
 
 
 
 
 
 
 
 
At 1, 5 and (if 
available/perf
ormed) at 10 
minutes,  
Weight, 
length, 
head 
circumfere
nce, 
physical 
examinati
on  
● 
 
● 
 
● 
● 
 
● 
 
 
Section 8.2.2 
Blood 
sample if 
no cord 
● 
 
 
 
 
 
 
 
 
 
Adjust volume 
if weight ≤ 2.5 
Kg. Refer to 
Table 14  


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 Visit / 
Contact 
V1
-
NB
1  
Safety 
contact 
(recommen
ded)1 
V2-
NB 
C1-
NB 
V3-
NB  
V4-
NB  
C2-
NB  
V5-
NB  
RTI 
Surveillance 
RTI 
Surveillance: 
Section 8.4.2 
RTI Visit: 
Sections 
8.4.3 and 
8.4.4 
Age of 
infant 
Bir
th 
8 days 
6 
wee
ks 
3 
mont
hs 
4 
mont
hs 
6 
mont
hs 
9 
mont
hs 
12 
mont
hs 
Conta
cts 
Visi
ts 
 
Visit Day 
D 
1-
21  
D8 (7 days 
post-birth) 
D43 
D91 
D12
1 
D18
1 
D27
1 
D36
6 
Birth – D366 
See Table 3 
for intervals 
between 
visits, 
contacts. 
blood  
~2.5 ml 
Blood 
sample 
(immunolo
gy, 
infants) 
~2.5 ml 
 
 
● 
Sub 
coh
ort 
1 
 
● 
Sub 
coho
rt 2 
●  
Sub 
coho
rt 3 
 
 
 
 
1 sample at 
one of these 
visits, as per 
infant’s 
assigned sub-
cohort. Adjust 
volume if 
weight ≤ 2.5 
Kg. Refer to 
Table 14 
Blood 
samples will 
no longer be 
collected  at 
V2-NB, V3-
NB or V4-NB. 
Concomita
nt 
vaccinatio
ns 
● 
● 
● 
● 
● 
● 
 
 
 
 
 
Concomita
nt 
medicatio
ns  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 
6.5.2 and 
6.5.3 
Neonatal 
AESIs  
● 
● 
● 
 
 
 
 
 
 
 
Table 4, 
Section 8.3.1, 
8.3.3, 8.3.4, 
and 10.3.5. 
Must submit 
an Expedited 
AE report. 
An 
additional 
recommende
d safety 
contact may 
be 
performed 
~8 days 
post-birth if 


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 Visit / 
Contact 
V1
-
NB
1  
Safety 
contact 
(recommen
ded)1 
V2-
NB 
C1-
NB 
V3-
NB  
V4-
NB  
C2-
NB  
V5-
NB  
RTI 
Surveillance 
RTI 
Surveillance: 
Section 8.4.2 
RTI Visit: 
Sections 
8.4.3 and 
8.4.4 
Age of 
infant 
Bir
th 
8 days 
6 
wee
ks 
3 
mont
hs 
4 
mont
hs 
6 
mont
hs 
9 
mont
hs 
12 
mont
hs 
Conta
cts 
Visi
ts 
 
Visit Day 
D 
1-
21  
D8 (7 days 
post-birth) 
D43 
D91 
D12
1 
D18
1 
D27
1 
D36
6 
Birth – D366 
See Table 3 
for intervals 
between 
visits, 
contacts. 
deemed 
necessary to 
closely 
monitor the 
newborn and 
support 
collection 
and 
reporting of 
any neonatal 
AESI(s). 
SAEs, 
MAEs and 
AEs 
leading to 
study 
withdrawal  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 7.2, 
8.3.1, and 
10.3.8 
Symptom-
directed 
physical 
examinati
on 
(includes 
RTI signs, 
symptoms
) 
 
 
 
 
 
 
 
 
 
● 
Section 8.4.4 
Nasal 
swab 
 
 
 
 
 
 
 
 
 
● 
Sections 
8.1.1 , 
8.4.4.2, Table 
14 
Study 
conclusion  
 
 
 
 
 
 
 
● 
 
 
Section 4.4 
Investigat
or sign-off 
at study 
conclusion 
 
 
 
 
 
 
 
● 
 
 
 
 
The timing of an event-driven visit cannot be defined with precision in the protocol. ● 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. 
1 An additional optional but recommended safety contact may be performed on  ~Day 8 (7 days post-birth) if 
deemed necessary by the investigator or by the parent/LAR(s). 


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 
Table 3 
Maternal participants 
Monthly 
contacts 
~ every 25 – 
35  
Monthly beginning after Visit 2 until Delivery. Contacts are additional to and do not replace 
protocol specified Visits. 
Additional contact(s)/visit(s) can be made more often if deemed necessary by the 
investigator or the maternal participant. 
 
Infant participants 
Birth to 
recommended 
safety contact 
8 
 
Safety contact (recommended, in interval between Day 7 to Day 10) 
 
Section 2.3 
Detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of the RSV Maternal (RSVPreF3) vaccine can be found in the 
IB. 
GSK has included provisions in this trial to ensure participant’s safety. Maternal 
participants will remain under observation for 30 minutes after administration of the 
study intervention to ensure that immediate treatment may be provided in the event of a 
hypersensitivity reaction, or syncope. Safety monitoring has been and will be conducted 
throughout this study by an unblinded Independent Data Monitoring Committee (IDMC) 
and by blinded Safety Review Team.the Sponsor. The study includes the establishment 
of a surveillance system which may facilitate detection of respiratory tract infections, in 
particular lower respiratory tract infections (LRTIs) in women and infants enrolled in the 
study. Measures to suspend the study should a potential safety issue be identified are 
described in Section 8.2.3. 
Taking into account the measures to minimize potential risks for participants 
participating in this study, the potential or identified risks are justified by the potential 
benefits of enhanced surveillance for the participants, and by the potential future benefits 
an RSV vaccine for maternal immunization may provide in preventing LRTIs in the 
infants of vaccinated mothers.  
Based on ongoing systematic review of the safety data, the benefit-risk profile of the 
RSV Maternal Vaccine (RSVPreF3) continues to be favourable and justifies unaltered 
continuation of the development programme. 
Following a recommendation from the IDMC, the Sponsor made the decision to pause 
the enrollment, randomization and vaccination of subjects in our active pregnant 
women studies, including RSV MAT-009, based on an observation of imbalance in the 
proportion of preterm births between the vaccine group and the placebo group in the 
RSV MAT-009 study. This pause was to allow for an evaluation of the available data in 
RSV MAT-009 to better understand the safety signal observed. Following a review of 
additional unblinded data from this study in which a higher proportion of neonatal 
deaths reported in the treatment group compared to the placebo group was also 
observed, the Sponsor decided to STOP enrollment and vaccination in these studies. 


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The safety signals are being investigated and, although at this time a cause has not 
been determined, GSK stopped active enrollment and further vaccination of 
participants in the RSV MAT studies enrolling pregnant women on February 25, 2022 
as a precautionary measure. The study remains ongoing for safety follow-up. 
Participants already vaccinated and their infants will continue to be monitored until 
the end of the study. 
 
Section 3: Objectives and endpoints 
A secondary safety endpoint has been re-categorized as primary endpoint. 
Primary objectives 
Primary endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe LRTIs in their infant4 
participants up to 6 months of age 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of medically assessed 1, RSV-associated severe  LRTIs 
according to the case definitions2.  
 
OR 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant4 participants up to 6 months of age 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs according 
to the case definitions2. 
AND 
To evaluate the safety of the RSV Maternal 
vaccine in infants born to mothers who were 
vaccinated with a single IM dose of study 
vaccine, up to 12 months after birth. 
Occurrence of SAEs, AEs leading to study termination 
and medically attended AEs from birth up to 6 months 
after birth5. 
Occurrence of SAEs, AEs leading to study termination 
and medically attended AEs from birth up to 12 months 
after birth5. 
Mention of ‘confirmatory’ and ‘descriptive’ been deleted from this section. 
Footnote deleted: For analysis of secondary confirmatory efficacy objectives, overall 
type 1 error is controlled 
 
Figure 1 
Footnote added: 
In addition to the monthy contacts between Visit-2 and the Delivery visit, additional not pre-specified visits 
and contacts (any desired frequency) can be made between Visit-2 and the Delivery visit, as per investigator’s 
or maternal participant’s discretion. 
Blood samples will be collected at delivery from all maternal participants. Placental samples will be collected 
at delivery from all maternal participants, if feasible. 


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 
Figure 2: Study design overview- infant participants 
An additional recommended safety contact may be performed 8-days post-birth if deemed necessary by the 
investigator or by the parent/LAR(s). 
Due to the stop on study enrollment and vaccination, blood samples will no longer be collected.  
 
Across the document note included (in sections 4.1, 4.2.3, 10.1.5)  
* Due to the safety signal observed, the study was fully unblinded to ensure the safety 
of the participants. 
 
Across the document note included (in Sections 6.3.6) 
* Following the decision to stop enrollment and vaccination, the study/site staff and 
maternal participants no longer stay blinded. Refer to Section 2.3 for details. 
 
Table 18, Section 8.4.1.1, Section 8.4.2.1, Section 8.4.3.1, Section 8.4.4.3 
Note added: Due to the stop on study enrollment and vaccination, MA-RTI 
surveillance of the maternal participants will no longer be performed. 
 
Table 12 
Footnote added: 
* Due to the stop on study enrollment and vaccination, nasal swab samples will no longer be collected from 
any maternal participant and no MA-RTI assessment visit will be performed. 
# Blood samples will be collected at delivery from all maternal participants. Hence, even if not assigned to the 
immunogenicity sub-cohort, the estimated total volume of blood for all maternal participants wil be ~30mL. In 
addition placental samples will also be collected at delivery, whenever feasible. 
 
Table 14 
Footnote added: 
Due to the stop on study enrollment and vaccination, there will no longer be collection of blood samples from 
the infants at Visit-2-NB, Visit-3-NB and Visit-4-NB. 
 
Table 16 
Footnote added:  
***Due to the stop on study enrollment and vaccination, blood samples will no longer be collected from the 
infants at V2-NB, V3-NB or V4-NB. 
# Blood sample at delivery to be collected from all participants. Whenever feasible, placenta sample is 
expected to be collected from all participants. These samples may be tested to support possible safety 
assessments, if necessary. 
 
Table 17 
Footnote added:  
# Due to the stop on study enrollment and vaccination, nasal swabs from maternal participants will not be 
collected and no MA-RTI assessment visit will be performed. 


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 
Section 8.2.1.2.2 
To ensure safety monitoring, in addition to the monthly contact between Visit-2 and the 
Delivery visit, additional not pre-specified visits and contacts (any desired frequency) 
can be made between Visit-2 and the Delivery visit, as per investigator’s or  maternal 
participant’s discretion. 
 
Section 8.2.3 
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 
IDMC safety evaluations are provided in a separate IDMC charter. 
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). 
In addition, a firewall will be established to ensure that data are not inadvertently 
unblinded. Details are provided in a separate Firewall charter. 
Note: Due to the safety signal observed, the study has been fully unblinded to ensure 
safety monitoring for the participants. 
 
Section 6.7 
It is likely that the RSV antibodies elicited by the vaccine may wane during the period 
between pregnancies, therefore there may be a need to administer the vaccine during each 
pregnancy to achieve optimal anti-RSV antibody levels in the neonate. In order to assess 
whether a booster dose might induce a higher reactogenicity or immune-tolerance, RSV 
MAT-009 participants may be invited to take part in a booster study.  
The investigator will ask each participant, at the time of informed consent, if she is 
interested in taking part in a booster study and will document this in the source 
documents only. During the study conclusion visit/contact, the investigator will confirm 
the participant’s interest and report it in the eCRF.There will be no access to study 
intervention after the end of the study, because of the safety signal identified, leading to 
stopping of further enrolment and vaccination.  
 
Section 4.2.4 
Note however that blood samples for assessment of immune response at Day 1 (Visit 1) 
and, Day 31 (Visit 2) ), and delivery (Visit 3) will be collected from all maternal 
participants. Cord blood will also be collected from all participants. Analyses of 
theseThese samples willmay be usedtested to support possible future bridging 
studies.safety assessments, if necessary. 


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 
Section 6.3.2.1.1 
All maternal participants in Stage A will: 
 
provide reactogenicity (solicited event) data for the first 7 days post-vaccination. 
 
have blood samples collected at Day 1 (Visit 1) and Day 31 (Visit 2) and Delivery 
(Visit 3).  
The Day 1, Day 31 and cord blood (or neonatal blood) samples may be tested to support 
development of a sero-correlate for life cycle bridging. 
All these samples may also be tested to support possible safety assessments, if 
necessary. 
[….] 
For the ~ 1533 infant participants in the immunogenicity sub-cohort: 
 
Randomization will identify a single timepoint post-birth (Day 43 (Visit 2-NB), or 
Day 121 (Visit 3-NB), or Day 181 (Visit 4-NB)) at which each (as yet unborn) infant 
will have a blood sample collected. Thus, at each of the 3 post-birth immunogenicity 
timepoints, a sample will be collected from approximately one third of the infants in 
the sub-cohort (N ~510). 
Note that due to the stop on study enrollment and vaccination, there will no longer be 
collection of blood samples from the infants at V2-NB, V3-NB and V4-NB. 
 
Section 6.3.2.1,2 
All maternal participants in Stage B will have blood samples collected at Day 1 (Visit 1) 
and Day 31 (Visit 2).) and Delivery (Visit 3). Cord blood (or if not possible, neonatal 
blood within 72 hours from birth) will also be collected from all participants. These 
samples may also be tested to support development of a sero-correlate for life cycle 
bridgingpossible safety assessments, if necessary. 
 
Section 8.4.4 
Unless otherwise specified, assessment visit procedures will be the same for maternal 
participants with MA-RTIs and for infant participants with RTIs.  
 
Section 8.4.4.1 
For maternal participants: Due to the stop on MA-RTI surveillance for maternal 
participants, these checks will no longer be performed. 
 
Section 9.1: Statistical hypotheses 
The RSV vaccine arm will be compared to the control (placebo) arm in terms of the 
vaccine efficacy against any medically assessed RSV associated LRTI (VEany) and severe 
LRTI (VEsevere) in infants followed for 6 months after birth. The null hypothesis on any 
medically assessed RSV associated LRTI is that vaccine efficacy is less than or equal to 
20%. The null hypothesis on severe LRTI is that the vaccine efficacy is less than or equal 


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to 20%. The alternative hypothesis of interest is that either vaccine efficacy on any 
severity LRTI is above 20% or vaccine efficacy on severe LRTI is above 20%. That is:  
H10: VEany ≤ 20% vs H1a: VEany > 20%, and, H20: VEsevere ≤ 20%  vs H2a: VEsevere > 20% 
The study is considered a success if at least one null hypothesis is rejected. 
There are no hypotheses test for vaccine efficacy endpoints. 
 
Section 9.2: Sample size determination 
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 
Section 9.4.3: Primary endpoints 
The primary analysis of vaccine efficacy will be based on the modified full analysis 
efficacy set for infants (modified FAS-E). A secondary analysis based on the full analysis 
efficacy set (FAS-E) and the per protocol efficacy set for infants will be performed to 
complement the modified FAS-E analysis. 
Analyses of primary safety endpoipoint will be performed on the Exposed set. 
Primary Efficacy Endpoints – Infant 
participants 
Statistical Analysis Methods 
From birth to 6 months, occurrences of 
medically assessed, RSV-associated severe  
LRTIs according to the case definitions 
OR 
From birth to 6 months, occurrences of any 
medically assessed, RSV-associated LRTIs 
according to the case definitions. 
Primary Safety Endpoint – Infant 
Participants 
Statistical Analysis Methods  
Occurrence of SAEs, AEs leading to 
study termination and medically attended 
AEs from birth up to 12 months after 
birth. 
[…] 
Secondary Safety Endpoints – Infant 
Participants 
Statistical Analysis Methods  
The occurrence of neonatal AEs of special 
interest (reported up to 6 weeks after birth). 
These include small for gestational age, low 
birth weight including very low and extremely 
low birth weight (<2500 g, <1500g, <1000g), 
congenital anomalies (major external structural 
defects, internal structural defects, functional 
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Secondary Safety Endpoints – Infant 
Participants 
Statistical Analysis Methods  
defects), neonatal death (in an extremely pre-
term birth (22GA<28 weeks), in a preterm live 
birth (28GA<37 weeks), or in a term live 
birth), preterm birth.  
Occurrence of SAEs, AEs leading to study 
termination and medically attended AEs from 
birth up to 6 months after birth. 
Occurrence of SAEs, AEs leading to study 
termination and medically attended AEs from 
birth up to 12 months after birth. 
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 
Section9.4.4.2: Detailed Statistical Analysis Methods 
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Overall Rationale for the Protocol Amendment 3: 
This protocol has been amended to: 
 
Change the trigger point for interim analyses which could lead to claim VE(2, 3 and 
4) as there is a high chance of claiming VE earlier than initially anticipated. 
 
Add 2 new secondary descriptive efficacy objectives to assess VE against severe 
medically assessed LRTIs and any medically assessed LRTIs associated to RSV 
subtypes A and B separately in the infant participants from birth up to 6 months of 
age. 
 
Acquire further information on how the VE can be sustained up to 12 months post-
birth. 
 
Remove the distribution of antibody titers/concentrations and the scatter plots 
showing the individual post-vaccination versus pre-vaccination results, as well as 
scatter plots showing relationship between maternal and infant antibody titers. These 
analyses have been already described as part of previous completed RSV MAT 
studies and performing them in RSV MAT-009 (i.e. a larger sample size), is not 
expected to provide any additional critical information with regards to the study 
vaccine immunogenicity. 
 
Remove the section about predicted VE based on a surrogate endpoint due to the 
limitation of data from internal epidemological studies. Hence, the surrogate 
endpoint model cannot be robustly established and validated. 
Also, this amendment includes clarifications, editorial changes to improve the 
consistency and typographical error corrections. 
Detailed description of Protocol Amendment (# 3) changes: 
In this section, deleted text is indicated in strikethrough and changed text in bold italics. 
 
Section 3, Objectives and endpoints 
Table 4 
Study objectives and endpoints 
Secondary descriptive efficacy objectives 
Secondary descriptive efficacy endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to 
maternal participants in preventing severe 
medically assessed1, RSV-associated LRTIs 
for each RSV subtype (A and B) separately in 
their infant4 participants up to 6 months of 
age. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), 
occurrences of severe medically assessed1, RSV-
associated LRTIs according to the case definition2, for 
RSV subtype A and RSV subtype B separately. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to 
maternal participants in preventing medically 
assessed1, RSV-associated LRTIs of any 
severity, for each RSV subtype (A and B) 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), 
occurrences of any medically assessed1, RSV-associated 
LRTIs according to the case definition2, for RSV subtype 
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separately in their infant4 participants up to 6 
months of age. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe LRTIs in their infant4 
participants up to 4 months of age. 
From birth (Visit 1-NB) to 4 months (Visit 3-NB), occurrences 
of severe medically assessed1, RSV-associated LRTIs 
according to the case definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant4 participants up to 4 months of age. 
From birth (Visit 1-NB) to 4 months (Visit 3-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs according 
to the case definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant4 
participants up to 6 months of age, medically 
assessed1 RSV LRTI by alternative case 
definitions2. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of medically assessed1 RSV LRTI by alternative case 
definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant4 
participants up to 6 months of age, all cause 
pneumonia. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause pneumonia. 
Secondary descriptive efficacy objectives 
Secondary descriptive efficacy endpoints 
To assess the effect of administering a single 
dose of the RSV Maternal vaccine administered to 
maternal participants on time to first occurrence of 
any severe medically assessed1, RSV-associated 
LRTIs, in their infant4 participants up to 126 
months of age, according to the case definition2. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB)12 months 
(Visit 5-NB), time to the first occurrence of severe medically 
assessed1, RSV-associated LRTIs according to the case 
definition2. 
To assess the effect of administering a single 
dose of the RSV Maternal vaccine administered to 
maternal participants on time to first occurrence of 
any medically assessed, RSV-associated LRTIs 
in their infant4 participants up to 6 12 months of 
age, according to the case definition2. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB)12 months 
(Visit 5-NB), time to the first occurrence of any medically 
assessed, RSV-associated LRTIs according to the case 
definition2. 
 
Section 4.1, Overall design 
[…] 
The study design is adaptive, with recruitment and randomization occurring in 2 
sequential stages, A and B. Decisions regarding progression to Stage B are described in 
detail in Sections 9.2 and 9.5. If progression to Stage B occurs, it may begin immediately 
after the last participant is randomized in Stage A.  
Table 6 
Study groups, sub-cohorts, interventions, and blinding foreseen in the 
study: Stage B 


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Stage B will only start after the last participant is randomized in Stage A. Decisions 
regarding progression to Stage B are described in detail in Sections 9.2 and 9.5.  
 
Section 4.2.4.2, Blood sampling and immune response assessment 
[…] 
Note however that blood samples for assessment of immune response at Day 1 (Visit 1) 
and Day 31 (Visit 2) will be collected from all maternal participants. Cord blood will also 
be collected from all participants. Analyses of these samples will be used to support 
possible surrogate endpoint assessment as well as future bridging studies. 
 
Section 4.2.5, Adaptive Design 
This adaptive trial design will provide evidence for the efficacy of the RSV maternal 
vaccine in the prevention of medically assessed, RSV-associated LRTI of any severity 
and medically assessed, RSV-associated severe LRTI. The design has over 90% power to 
detect the target vaccine efficacies of 70% and 50% on severe and any-severity LRTI, 
respectively. If the vaccine meets these target VE estimates, this design offers the 
opportunity to identify this benefit with an expected sample size of approximately 7,598 
8,500 maternal participants, which may obviate the need to enroll the maximum sample 
size of 10,000. In addition to the analysis of observed vaccine efficacy, as described 
above, the study may also assess predicted vaccine efficacy through a surrogate endpoint 
(namely RSV neutralizing antibody) reasonably likely to predict clinical benefit.  
 
Section 5.2.1.1, Medical conditions 
 
[…] 
 
Any intervention to prevent preterm delivery or medical treatment for suspected 
preterm delivery, including administration of systemic corticosteroids for fetal 
lung maturation. 
Note: pregnant women under progesterone treatment beyond the 1st trimester 
of pregnancy, exclusively based on a prior pregnancy which resulted in preterm 
delivery/birth, but without any medical/clinical finding(s) which would lead to 
suspecting that there is a risk of preterm delivery in the current pregnancy (e.g. 
shortened cervical length, etc), would not be considered as meeting this 
exclusion criterion. 
 
Section 6.3.2.1.1, Stage A 
[…] 
The Day 1 and cord blood (or neonatal blood) samples will be tested to support surrogate 
endpoint analysis. The Day 1, Day 31 and cord blood (or neonatal blood) samples may 
also be tested to support development of a sero-correlate for life cycle bridging. 
 
Section 6.3.2.1.2, Stage B 
Stage B will only start after the last participant is randomized in Stage A. Decisions 
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 
Section 7.1.1, Criteria for temporary delay for enrolment and/or vaccination 
Vaccination may must be postponed within the permitted time interval until transient 
circumstances cited below are resolved:  
 
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). 
Participants with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be vaccinated at the discretion of the investigator. 
 
Use of systemic antibiotic or antiviral treatment within 48 hours before study 
vaccination. 
Note: vaccination must be completed within the permitted time interval. If a participant 
is screened but not vaccinated within the allowed interval, a re-screening should be 
done to establish the participant’s eligibility. Please make sure the participant’s 
gestational age is still within the allowed range. 
 
Section 8.1, Efficacy and/or immunogenicity assessments 
[…] 
Sample testing will be done in accordance with the recorded consent of the individual 
maternal participant/infant participant’s parent(s)/LAR(s).  
If additional testing is performed, the marker priority ranking given in the Section 8.1.3 
may be changed. 
 
Section 8.2.1.1, Medical/vaccination history 
 
For the current pregnancy, record: 
 
[…] 
 
number of prenatal visits attended up to the date of the study Screening visit, 
 
approximate date and gestational age of first prenatal visit, 
 
Section 8.4.4.1, Clinical evaluation 
For maternal participants: 
 
Temperature 
 
Respiratory rate 
 
Blood oxygen saturation measured by pulse oximetry (Section 8.2.1.2.1), in room 
air, if feasible), see further details in Section 8.2.1.2.1 
 
[…] 
For infant participants: 
 
Temperature 
 
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 
Blood oxygen saturation (measured by pulse oximetry (in room air, if feasible), see 
further details in Section 8.2.1.2.1 (Section 8.2.1.2.1), in room air, if feasible 
 
Section 9.2, Sample size determination 
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 
Section 9.3, Populations for analyses 
Table 24 
Maternal Participants 
 
Description 
Analysis Set 
Maternal participants 
Enrolled 
All maternal participants who completed the informed consent process and signed the informed 
consent form.  
Exposed 
All maternal participants who received the study intervention. The allocation in a group is done in 
function of the administered intervention. 
Full Analysis – 
Immunogenicity 
All maternal participants in the Exposed set who have post-vaccination immunogenicity data.  
Per Protocol – 
Immunogenicity 
All maternal participants who received the study intervention to which they were randomised and 
have post-vaccination data (Full Analysis Set) minus participants with protocol deviations that 
lead to exclusion.  
Full Analysis – 
Efficacy 
All maternal participants in the Exposed set.who either complete 6 months of follow-up after 
delivery or have a medically attended RTI (MA-RTI) case before completing the 6 month Contact. 
Solicited Safety 
– Stage A only 
All maternal participants in the Exposed Set who have solicited safety data 
Table 25 
Infant participants 
Analysis Set 
Description 
Exposed 
Infants live-born to exposed maternal participants, whose parents/LARs completed the 
informed consent process and signed the informed consent form 
Full Analysis – 
Immunogenicity 
All infant participants in the Exposed set who have post-delivery/birth immunogenicity data. 
Per Protocol – 
Immunogenicity 
All infant participants in the Full Analysis (Immunogenicity) set minus those who (a) were 
born less than 4 weeks post- maternal participant vaccination and/ or (b) have protocol 
deviations that lead to exclusion. 
Full Analysis - 
Efficacy  
All infant participants in the Exposed set. who either complete 6 months of follow-up or have 
a medically assessed RSV-associated LRTI case before completing the 6 month Visit (Visit 
4-NB). 
Modified Full 
Analysis - Efficacy 
All infant participants in the Exposed set who were born after at least 4 weeks of 
vaccination. AND either complete 6 months of follow-up or have a medically assessed RSV-
associated LRTI case before completing the 6 month Visit (Visit 4-NB) 
Per Protocol – 
Efficacy 
All infant participants in the Modified Full Analysis – Efficacy set Full analysis (efficacy) 
set minus those who have protocol deviations that lead to exclusion. 
 
Section 9.3.1.1.1, Maternal participants 
 
Any of the medications listed in Section 5.2.1.2 if administered up to Delivery 
(Visit 3), except corticosteroids for fetal lung maturation administered after 
study vaccination.if administered up to Delivery (Visit 3). 


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 
Section 9.4.3, Primary endpoints 
Primary Efficacy Endpoints – Infant 
participants 
Statistical Analysis Methods 
From birth to 6 months, occurrences of 
medically assessed, RSV-associated severe  
LRTIs according to the case definitions.  
OR 
From birth to 6 months, occurrences of any 
medically assessed, RSV-associated LRTIs 
according to the case definitions. 
 
Section 9.4.3.1, Detailed Statistical Analysis Methods 
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 
Section 9.4.4.1, Efficacy 
Secondary Descriptive Efficacy 
Endpoints 
Statistical Analysis Methods 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according 
to the case definition, for 
RSV subtype A and RSV 
subtype B separately. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definition, for RSV subtype A 
and RSV subtype B 
separately. 
[...] 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB) 6 months 
(Visit 4-NB), time to the first 
occurrence of severe medically 
assessed, RSV-associated 
LRTIs according to the case 
definition. 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB)6 months 
(Visit 4-NB), time to the first 
occurrence of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definition. 
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Figure 8 Secondary confirmatory endpoint hierarchy 
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 
Section 9.4.4.2, Detailed Statistical Analysis Methods: 
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 
Section 9.4.4.3, Immunogenicity 
Secondary Immunogenicity 
Endpoints – Maternal Participants 
Statistical Analysis Methods 
 
RSVPreF3 IgG-specific 
antibody concentration, and  
 
Neutralizing antibody titers 
against RSV-A and RSV-B 
Measured on blood samples 
collected at Day 1 before vaccination 
(Visit 1), at Day 31 (Visit 2), and at 
delivery (Visit 3). 
Secondary Immunogenicity 
Endpoints – Infant Participants 
Statistical Analysis Methods 
 
RSVPreF3 IgG-specific 
antibody concentration, and  
 
Neutralizing antibody titers 
against RSV-A and RSV-B. 
Measured on the cord blood sample 
collected at delivery, or on a blood 
sample collected from the infant 
within 72 hours after birth (if no cord 
blood sample can be obtained)  
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 
Measured on a blood sample 
collected at Day 43 (Visit 2-
NB), Day 121 (Visit 3-NB), or 
Day 181 (Visit 4-NB) after 
delivery in 3 sub-cohorts of 
infants. Infants born to women 
in the immunogenicity sub-
cohorts will be randomly 
assigned (1:1:1) to sample 
collection at 1 of the 3 
timepoints noted. 
 
Section 9.4.6.1, Demography and baseline characteristics analyses 
[…] 
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 extent of contact with children less than 
6 years of age) will be summarized by group, and for each immunogenicity sub-cohort 
within each group, using descriptive statistics. 
 
Section 9.4.6.3, Predicted VE based on surrogate endpoint (deleted) 
Surrogate endpoint analyses will be conducted at the same time as interim analysis #2 
when there are approximately 4,600 maternal participants with the opportunity to 
complete 6 months follow up post-delivery. If the lower bounds of the credible interval 
for the observed vaccine efficacy (VE) on either primary objective meet the pre-specified 
criteria, then the company will claim success based on the VE. However, if the pre-
specified lower bounds for the observed VE are not met for either primary objective, then 
the company plans to evaluate VE predicted by the surrogate endpoint model: 
The strategy can be summarized in 3 steps: 
1. Estimate the surrogate endpoint model using data from one or more GSK 
epidemiology studies. The model will be created based on the GSK RSV neutralizing 
antibody assay before the analysis of RSV MAT-009.  
2. Validate the model at interim analysis #2 (that is, validate whether the observed VE 
(when 4600 participants have had the opportunity to complete 6 months post-
delivery) is “similar to” the predicted VE). The validation of the model is done using 
an equivalence test (H0: δ < –Δ or δ > Δ) if feasible, where δ is the difference 
between the predicted VE and the observed VE, and Δ is an appropriate equivalence 
margin, or other methods for the validation of surrogate endpoints such as Principal 
stratification [Frangakis, 2002; Follmann, 2006; Gilbert, 2008]. 
3. Claim success based on predicted VE at the end of interim analysis #2. This will 
occur if the predicted VE for either primary endpoint meets the pre-specified success 
criteria based on a successfully validated surrogate endpoint model. RSV MAT-009 
will continue as designed. It is expected that the observed VE will meet the success 
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4. For more details, please refer to the separate statistical analysis plan “RSV Maternal 
Serocorrelate SAP.” 
 
Section 9.5, Interim analyses 
Interim analyses of vaccine efficacy for the two primary endpoints will be performed.  
In Stage A, tThe 1st interim analysis will be conducted when 4600 maternal participants 
are randomized, and the purpose of this analysis is to decide if further enrollment is 
needed and if the study can be stopped for futility. The number of completed participants 
and events at this interim will be based on the accrual rate and attack rate in the trial. 
Based on a blinded assessment of the overall accrual rate and attack rate in the trial, GSK 
may decide if this interim will be performed. If the accrual rate is faster than expected or 
the attack rate is lower than expected, GSK may decide to skip this interim. 
Interim analyses of vaccine efficacy for the two primary endpoints will be conducted 
when 3000, 4600, 6500, and 70008000 maternal participants have had the opportunity to 
complete 6 months follow-up post-delivery. The trial can claim success if either of the 
two primary endpoints meet success criteria at any of those three interim analyses. If 
there is a small number of events when interim analyses for efficacy are conducted, 
GSK may decide (blinded to treatment group) to skip those interim analyses. The alpha 
at skipped interim analyses will be considered not spent and the remaining alpha will 
be distributed according to the alpha spending function at the remaining interim and 
final analyses. 
Table 26 summarizes the interim analysis schedule and the decisions that may be made at 
each analysis. Decision rules are summarized in Section 9.2 and described in detail in the 
SAP and related documents. 
Table 26 Interim Analysis Schedule and Possible Decisions Made at each Analysis 
 
Section 9.5.1, Sequence of analyses 
In addition to the interim analyses of efficacy described above, full analyses will occur as 
described below: 
 
When an interim analysis of vaccine efficacy for the two primary endpoints shows 
that the trial can claim success (to evaluate primary efficacy endpoints, 
immunogenicity, reactogenicity and safety).  
Interim 
# 
Timing of analysis 
Can decide to 
stop accrual? 
Can stop for 
futility? 
Can claim 
success? 
Stage 
# 
Participants 
Participants triggering 
analysis 
1 
A 
4600 
Maternal participants 
randomized  
Yes 
Yes 
No 
2 
B 
30004600 
Maternal participants with 
the opportunity to complete 
6 months follow-up post-
delivery 
- 
Yes 
Yes 
3 
B 
46006500 
- 
Yes 
Yes 
4 
B 
70008000 
- 
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 
When 4600 maternal participants have had the opportunity to complete 6 months 
follow up post-delivery/birth (to evaluate primary and surrogate efficacy endpoints, 
immunogenicity, reactogenicity and safety if either primary (observed), or surrogate 
(predicted) vaccine efficacy endpoints meet success criteria). 
 
When all maternal and infant participants enrolled in both Stage A and Stage B 
complete 6 months follow-up post-delivery/birth (to evaluate primary and secondary 
efficacy endpoints, immunogenicity, reactogenicity and safety). 
 
Section 9.5.2, Statistical considerations for interim analysis 
 
Section 10.2, Appendix 2: Clinical laboratory tests 
There is one assessment, hematocrit, which will be tested at Visits 1, 2 and 3, for all 
maternal participants in Stage A who are assigned to the immunogenicity sub-cohort, 
until the current protocol amendment 2 is approved (unless IEC/IRB allows for 
immediate implementation of this measure to reduce participant’s burden, prior to full 
Amendment 2 being approved) in the respective study country(ies). Testing will be 
performed by a central laboratory. Results will be used to help evaluate changes over 
time in antibody titers / concentrations that may be related to volumetric changes during 
pregnancy, if deemed necessary. 
 
Section 10.7.1, List of abbreviations 
[…] 
 
VE 
Vaccine efficacy 
WHO 
World Health Organization 
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 
Section 10.10.1, 
 
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Overall Rationale for the Protocol Amendment 2: 
This protocol has been amended to: 
 
implement the changes discussed and agreed with Center for Biologics Evaluation 
and Research (CBER). 
 
extend the infant respiratory tract illness (RTI) surveillance to 12 months to ensure 
that this period will cover at least 1 full RSV season. 
 
remove the collection of hematocrit samples due to challenges (mostly due to the 
COVID-19 pandemic) faced in several countries preventing the samples from 
reaching  the central lab in adequate time for testing. 
 
define an additional population for analysis: Modified Full Analysis- Efficacy Set.  
Also, this amendment includes editorial changes to improve the consistency and 
applicable administrative changes. Typographical errors have been corrected. 
List of main changes: 
Section # and title 
Description of change 
Brief rationale 
Section 1.2 Schema, 
Section 1.3 Schedules of 
Activities (Table 2, Table 
3), Section 2 Schedule of 
activities for infant 
participants, Section 2.1 
Study rationale, Section 
3 Objective(s) and 
Endpoint(s), Section 4.1 
Overall design (Figure 2), 
Section 4.4 End of study 
definition, Section 8.3.1 
Time period and 
frequency for collecting 
AE, SAE and other 
safety information (Table 
18), Section 8.4.2.2 
Infant participants, 
Section 8.4.6 Follow-up 
of infant respiratory tract 
illnesses, Section 9.4.4.1 
Efficacy (Figure 8, Figure 
9), Section 9.5.1 
Sequence of analyses, 
Section 10.7.2 Glossary 
of terms 
Updated to extend the infant RTI 
surveillance to 12 months. 
Extended to ensure that infant RTI 
surveillance will cover at least 1 full RSV 
season. 
Section 1.3 Schedule of 
activities (Table 1), 
Section 4.1 Overall 
design (Figure 1), 
Section 4.2.4.2, Section 
6.3.2.1.1 Stage A (Figure 
4), Section 8 Study 
assessments and 
Updated to remove the collection of 
hematocrit samples 
Removed due to challenges (mostly due to 
the COVID-19 pandemic) faced in several 
countries preventing the samples from 
reaching the central lab in adequate time 
for testing. 
Samples collected until the current 
protocol amendment 2 is approved (unless 
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Section # and title 
Description of change 
Brief rationale 
procedures, Section 
8.1.1 Biological samples 
(Table 12), Section 8.1.2 
Laboratory assays (Table 
15, Table 17), Section 
10.2 Appendix 2: Clinical 
laboratory tests 
implementation of this measure to reduce 
participant’s burden, prior to full 
Amendment 2 being approved) will be still 
used, if required, as described in Section 
10.2. 
Section 1.3 Schedule of 
activities (Table 3) 
The interval between screening to Day 1 
visit has been updated from 0-29 days to 
0-28 days. 
The interval between screening and Day 1 
has been updated to ensure consistency 
(between Table 1 and Table 3). 
Section 4.2.6 Case 
defintions 
The case definitions for data analysis in 
infants have been updated to merge the 
severe and very severe LRTI case 
definitions. Therefore, across the 
document, mention of ‘including very 
severe’ has been deleted. 
The case definition has been updated 
based on the feedback received from 
CBER. 
Section 5.1.1 Inclusion 
criteria for enrolment- 
Maternal participants 
Change has been made to the allowed 
pre-pregnancy BMI range for enrolment 
(17.0-39.9 kg/m2 instead of 18.5-39.9 
kg/m2) 
The pre-pregnancy BMI range has been 
modified to allow enrolment of participants 
considered as mild underweight. Also, the 
BMI ranges may differ depending on the 
race and ethnicity (e.g. the average values 
in the Asian population are about 1-2 
points lower than the standard 
international chart). 
Section 5.2.1.1 Medical 
conditions 
Included a note to clarify that- still births, 
pre-terms births and spontaneous 
abortions will be counted per pregnancy 
(regardless of the number of fetuses in 
the concerned pregnancy) . 
The note is added to further clarify that the 
exclusion criteria on history of 2 or more 
prior stillbirths/preterm births ≤34 weeks or 
consecutive spontaneous abortions are to 
be counted/considered “per pregnancy” 
Thus, when any of those events occurs on 
multiple pregnancies (twin/triplet, etc.), it 
will be considered as a single case.  
Section 5.2.1.2 
Prior/concomitant 
therapy 
Addition of the specific allowed window 
for COVID-vaccines 
Following the implementation of Covid-19 
mass vaccination strategies in the different 
countries, incuding vaccination of pregnant 
women, the allowed window for the 
administration of these vaccines has been 
added. 
Section 6.5.1 Maternal 
participants 
Included “antivirals” to the list of 
concomitant medications to be recorded 
(in addition to antibiotics, analgesics and 
anti-pyretics). 
Text added to record all infection-related 
medications taken within 7 days- prior to 
the study vaccination. 
Section 8 Study 
assessment and 
procedures 
Text added to allow flexibility towards the 
conduct of RTI surveillance contact in the 
event of special circumstances. 
For the ease of study conduct in the event 
of a pandemic, social distancing, 
confinement measurements and 
considering the impact on the region’s 
usual RSV seasonality, the frequency of 
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Section # and title 
Description of change 
Brief rationale 
active contacts may be temporarily 
adapted. 
Section 8.2.1.1 
Medical/vaccination 
history 
Added guidance with regards to the pre-
pregnancy BMI in the exceptional 
circumstance when a pre-pregnancy 
weight/BMI (or weight/BMI in the 1st 
trimester of pregnancy) is not available. 
Addition made since there might be 
instances were the first maternal visit does 
not take place at the 1st pregnancy 
trimester but later. 
Section 8.3.3 Regulatory 
reporting requirements 
for SAE, subsequent 
pregnancies, and other 
events (Table 19) 
Timeframe for reporting subsequent 
pregnancy by the investigator/site staff 
after receipt or awareness, changed from 
2 weeks to 24 hours. 
This change is being made to correct 
inconsistencies between pregnancy 
reporting form and protocol template. 
Section 8.3.3.1 Contact 
information for reporting 
SAES, AESIs, 
subsequent pregnancies 
and other events 
Contact information updated for SAE 
reporting email address. 
The email address is changed to align to 
the most recent GSK template related 
recommendation. 
Section 8.3.4.2 
Pregnancy outcomes 
(Table 21), Section 
10.3.2 Definition of SAE 
Footnote added to clarify the reporting 
plan for congenital anomalies in the 
event of infant’s participation in the study, 
versus in the event that there is no live 
birth, or no signed informed consent for 
the infant or the congenital anomaly is 
being reported for a subsequent 
pregnancy 
Clarification made in order to prevent 
double reporting in both maternal 
participant and infant’s eCRF. Clarification 
has been added to the table as a footnote. 
Section 8.3.4.2 
Pregnancy outcomes, 
Section 11 References 
The reference of Metropolitan Atlanta 
Congenital Defects Program (MACDP) 
guidelines has been updated. 
To refer to the most updated version of 
MACDP guidelines. 
Section 9.3 Populations 
for analyses(Table 25) 
An additional analysis set for infant 
participants- ‘Modified Full Analysis- 
Efficacy Set’ has been added that 
excludes the infants born less than 4 
weeks post maternal participant’s 
vaccination  
The elimination of infants born less than 4 
weeks after the maternal participant’s 
vaccination from this population for 
analyses has been made to ensure that 
the analysis set takes into account the 
optimal timeframe for elicitation of immune 
response in the maternal participants and 
for antibody transfer to the babies prior to 
delivery. 
Section 9.4 Statistical 
analyses 
The analysis plan has been updated to 
include details about modified full 
analysis- efficacy set 
For consistency, the statistical analysis 
plan section has been updated. 
Section 10.3.5 Adverse 
events of special interest 
All AESIs are presented in list format. 
Also, the mention of ‘worsening of 
existing conditions’ has been deleted. A 
note has been added that worsening of 
existing AESI conditions are to be 
collected as (S)AEs (aggravated) but not 
as study-AESIs. 
For the ease of reading and presentation, 
all AESIs are presented in list format.  
As per the GAIA guidelines, AESIs to be 
reported will include only the new 
diagnoses made post study vaccine 
administration, and not the worsening of 
pre-existing events. 
Section 10.6 Appendix 6: 
Country specific 
requirements 
Section 10.6.2 has been added to include 
South Korea specific regulatory 
requirements for the study. 
The details have been added under 
country specific requirements, following 
consultation with South Korea regulatory 
authorities. 


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Section # and title 
Description of change 
Brief rationale 
Section 10.8 Appendix 8: 
Gestational age 
assessment 
A note is added to refer to SPM for 
details on estimation of the date of 
delivery/due date.  
Additional details and clarifications are 
added in SPM on accurate estimation of 
due date. Hence the note is added in the 
protocol. 
Section 10.9 Appendix 9: 
Definitions of maternal, 
fetal and neonatal events 
of interest as per GAIA 
Clarification note added in Appendix 9, 
that not all events listed in this section 
are AESIs in the RSV MAT-009 
(GRACE) study and to refer to Section 
10.3.5 for the list of AESIs. 
Also, all the events that are AESIs, have 
been flagged. 
As Appendix 9 contains all maternal, fetal 
and neonatal events of interest per GAIA 
definition as well as definitions for those 
events not (yet) defined per GAIA, of 
which only specific events are considered 
as AESIs in this study, The note is added 
to help in accurate categorization. 
Detailed description of Protocol Amendment (# 2) changes: 
In this section, deleted text is indicated in strikethrough and changed text in bold italics. 
 
Across the document mention of ‘very severe/including very severe’ has been 
deleted. 
 
Section 1.2, Schema 
During both stages, maternal participants who receive the study intervention will be 
followed for safety for up to approximately 10 to 11 months (from screening until 6 
months after delivery). Infant participants will be evaluated for the occurrence of 
medically assessed, RSV-associated lower respiratory tract infections and safety for 129 
months after birth and followed for safety for 12 months after birth.  
 
Section 1.3 Schedules of Activities (SoAs) 
Table 1 Schedule of activities for maternal participants 
Visit / Contact 
Screening 
V1 
V2*  
Cont
acts 
(Mon
thly) 
V3 
V4  
C1 
Event 
Driven 
 
Gestational Age 
(GA) 
≤ 28 days 
before V1 
240/7 – 
340/7 
 
Until 
Deliv
ery 
Deliv
ery 
 
 
Saf
ety 
visit 
MA-
RTI 
visit 
For monthly 
contacts: Section 
8.4.2. 
Visit Day 
D-28 – D1 
before 
randomiza
tion 
D1 
D31 
 
D1P
D 
D43 
PD 
D1
81 
PD 
 
 
Table 3 
Blood sample 
(hematocrit: ~ 3.0 
ml) 
 
Sub-
cohort  
● 
Sub-
coho
rt  
● 
 
Sub-
coho
rt  
● 
 
 
 
 
Collected only 
from a sub-cohort 
in Stage A. See 
Table 12 and 
Sections 8.1.1 
and 8.1.3. 
The timing of an event-driven site visit (e.g., to further evaluate a potential AE or MA-RTI) cannot be defined with 
precision in the protocol. Event-driven visits may occur throughout the study. ● 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. 
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Table 2 Schedule of activities for infant participants 
Visit / 
Contact 
V1-
NB  
V2-
NB 
C1-NB 
V3-NB  
V4-NB  
C2-NB  
V5-NB  
RTI Surveillance 
RTI 
Surveillance
: Section 
8.4.2 
RTI Visit: 
Sections 
8.4.3 and 
8.4.4 
Age of 
infant 
Birt
h 
6 
week
s 
3 
month
s 
4 
month
s 
6 
month
s 
9 
month
s 
12 
month
s 
Contact
s 
Visit
s 
 
Visit Day 
D 1-
21  
D43 
D91 
D121 
D181 
D271 
D366 
Birth – D366 
See Table 3 
for intervals 
between 
visits, 
contacts. 
Distribute 
infant 
RTI-diary 
card  
O 
O 
O 
O 
O 
O 
 
 
O 
Distribute at 
V1-NB: 
Distribute 
additional 
RTI-diary 
cards as 
needed. 
Section 
8.4.2.2 and 
SPM 
Review 
infant 
RTI-diary 
card  
 
O 
O 
O 
O 
O 
O 
 
O 
 
Collect 
infant 
RTI-diary 
card 
 
O 
O 
O 
O 
O 
O 
 
O 
Collect RTI-
diary cards 
that are fully 
filled out. 
Section 
8.4.2.2 and 
SPM 
Transcrib
e 
applicable 
infant 
RTI-diary 
card data 
to eCRF  
 
● 
● 
● 
● 
● 
● 
 
● 
 


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Table 3 Intervals between study visits and contacts 
Interval 
Optimal 
interval 
in Days 
Allowed 
interval 
in Days 
Additional Information 
Maternal participants 
Screening to 
V1  
0  
0– 
2829  
The screening interval extends from Day -28 to Day 1 before randomization. If all 
eligibility criteria can be confirmed on the day of screening and all required 
procedures can be performed, then, “Screening” and “Visit 1” may occur on the 
same day (refer to Section 8.2.1.2).  
Data from all screening procedures must be available and eligibility must be 
confirmed before the participant is randomized. 
If a participant is screened but not vaccinated within the allowed interval, a re-
screening should be done to establish the participant’s eligibility. Please make 
sure the participant’s gestational age is still within the allowed range, refer to 
Section 10.8 for guidance on gestational age assessment. 
V3 (delivery) 0  
1 day 
before 
to 3 
days 
after 
delivery  
For maternal participants in the Stage A immunogenicity sub-cohort: collect 
maternal blood sample at any point from the start of labour up to delivery. 
(NOTE: For participants for which a cesarean section is planned, the 
sample may be collected as soon as the participant arrives at the clinic and 
the intravenous line is inserted to prepare them for the cesarean section). 
If blood is not collected during delivery, collect maternal blood sample no later 
than 72 hours after delivery.  
For all participants in both Stage A and Stage B: A cord blood sample should be 
collected at the time of delivery. If cord blood cannot be collected at delivery, a 
blood sample should be collected from the infant participant as soon as possible 
and no later than 72 hours after birth. 
Infant participants 
RTI surveillance contacts (Birth to V5-NB Contact 2-NB)* 
* In special circumstances, the frequency of active contacts may be temporarily adapted, refer to Section 
8.4.2.2.1 for guidance 
 
Section 2, Study Rationale 
The study will also evaluate the incidence of medically attended RSV-associated 
respiratory tract illnesses (MA-RTI) in maternal participants for up to 6 months after 
delivery, and the incidence of medically assessed, RSV-associated respiratory tract / 
lower respiratory tract illnesses (RTI/LRTI) in infants for up to 129 months after birth. 
 
Section 3, Objectives and endpoints 
Secondary confirmatory3 efficacy objectives 
Secondary confirmatory3 efficacy endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe LRTIs in their infant4 
participants up to 7, 8, and 9, 10, 11 and 12 
months of age. 
From birth (Visit 1-NB) to 7 months, birth to 8 months, and 
birth to 9 months (C2-NB), birth to 10 months, birth to 11 
months, and birth to 12 months (Visit 5-NB), occurrences of 
medically assessed, RSV-associated severe LRTIs according 
to the case definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
From birth (Visit 1-NB) to 7 months, birth to 8 months, and 
birth to 9 months (C2-NB), birth to 10 months, birth to 11 
months, and birth to 12 months (Visit 5-NB), occurrences of 


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Secondary confirmatory3 efficacy objectives 
Secondary confirmatory3 efficacy endpoints 
infant4 participants 4 up to 7, 8, and 9, 10, 11 and 
12 months of age. 
any medically assessed, RSV-associated LRTIs according to 
the case definitions2. 
Secondary descriptive efficacy objectives 
Secondary descriptive efficacy endpoints 
To assess the effect of administering a single 
dose of the RSV Maternal vaccine administered to 
maternal participants on time to first occurrence of 
any severe medically assessed1, RSV-associated 
LRTIs, in their infant4 participants up to 6 
months of age, according to the case definition2. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), time to the 
first occurrence of severe medically assessed1, RSV-
associated LRTIs according to the case definition2 
To assess the effect of administering a single 
dose of the RSV Maternal vaccine administered to 
maternal participants on time to first occurrence of 
any medically assessed, RSV-associated LRTIs 
in their infant4 participants up to 6 months of 
age, according to the case definition2. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), time to the 
first occurrence of any medically assessed, RSV-associated 
LRTIs according to the case definition2  
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to 
maternal participants in preventing RSV-
associated hospitalization in their infant4 
participants up to 12 months of age. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), 
occurrences of RSV-associated hospitalizations 
according to the case definitions2. 
A footnote as not applicable has been deleted. Therefore, all the footnote numbers have 
been revised. 
3Note that as per the case definitions outlined in Table 8, which are based on the WHO 
case definitions, RSV-associated very severe LRTIs are a subset of RSV-associated 
LRTIs but not necessarily a subset of RSV-associated severe LRTIs. As such, an infant 
participant may meet the criteria for RSV-associated very severe LRTI without meeting 
that of RSV-associated severe LRTI. In this protocol, the primary endpoint related to 
medically assessed RSV-associated severe LRTI will include medically assessed RSV-
associated very severe LRTI. Similarly, medically assessed, RSV-associated LRTI 
endpoints will include RSV LRTI of any severity including cases that meet severe and 
very severe LRTI case definitions. 


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 
Section 4.1, Overall design 
Figure 1 Study design overview – maternal participants 
 
Deleted figure: 
 
GA = Gestational age; Hct = hematocrit; I = immune response; (S)AE = (serious) adverse event; RTI = respiratory tract 
illness  


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Figure 2 Study design overview – infant participants 
 
Deleted figure: 
 
 
Section 4.2.4.2 Blood sampling and immune response assessment 
A sub-cohort for maternal blood sampling and assessment (haematocrit plus immune 
response at Day 1 (Visit 1), Day 31 (Visit 2), and Delivery) has been defined to limit 
discomfort and risk while ensuring enough observations to support robust evaluation of 
secondary maternal immunogenicity objectives (see also Table 3).  
 
Section 4.2.5, Adaptive design 
Typographical error corrected: 
This adaptive trial design will provide evidence for the efficacy of the RSV maternal 
vaccine in the prevention of medically assessed, RSV-associated LRTI of any severity 
and medically assessed, RSV-associated severe LRTI. The design has  over 90% power 
to detect the target vaccine efficacies of 70% and 50% on severe and any-severity LRTI, 
respectively. If the vaccine meets these target VE estimates, this design offers the 
opportunity to identify this benefit with an expected sample size of approximately 
8,5007,000 maternal participants, which may obviate the need to enroll the maximum 
sample size of 10,000. In addition to the analysis of observed vaccine efficacy, as 
described above, the study may also assess predicted vaccine efficacy through a surrogate 
endpoint (namely RSV neutralizing antibody) reasonably likely to predict clinical benefit. 


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 
Section 4.2.6, Case definitions 
Table 8 RTI/LRTI case definitions for data analysis in infants  
RSV-RTI 
Runny nose, OR Blocked nose, OR Cough 
AND 
Confirmed RSV infection 5,6 4,5 
RSV-LRTI 
History of cough OR difficulty in breathing 1 2 
AND  
SpO2 < 95%23, OR RR increase 3 4 
AND  
Confirmed RSV infection 4,5 5,6 
RSV-severe LRTI 
Meeting the case definition of RSV-LRTI 
AND 
SpO2 < 93%23, OR lower chest wall in-drawing OR inability to feed OR failure 
to respond / unconscious 
RSV-very severe LRTI 
Meeting the case definition of RSV-LRTI  
AND  
SpO2 < 90%3, OR inability to feed OR failure to respond / unconscious 
RSV hospitalization 
Confirmed RSV infection 4,5 5,6 
AND 
Hospitalized for acute medical condition 6 7 
All-cause RTI 
Runny nose, OR Blocked nose, OR Cough 
All-cause LRTI 
History of cough OR difficulty in breathing 1 2  
AND  
SpO2 < 95% 2 3, OR RR increase 3 4 
All-cause LRTI hospitalization 
Hospitalized due to all cause LRTI as defined above 
Definitions based on [Modjarrad, 2016], except that severe and very severe (SpO2 < 90% OR inability to feed OR 
failure to respond/unconscious) RSV LRTI cases will be presented together. RTI = respiratory tract illness; LRTI 
= lower respiratory tract illness; RR = respiratory rate; SpO2 = blood oxygen saturation by pulse oximetry. 
1 Please note that per the above case definitions which are based on the WHO case definitions, “RSV-very 
severe LRTIs” are a subset of “RSV-LRTIs” but not necessarily a subset of the “RSV-severe LRTIs”. As such, 
an infant participant may meet the criteria for very severe LRTI without meeting that of severe LRTI 
12Based 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). 
23 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.  
34 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) 
45 Confirmed RSV infection defined in Section 4.2.6.3 
56 RSV (nasal swab) sampling and testing as specified in Table 14. 
67 Hospitalization is defined as admission for observation or treatment based on the judgement of a health care 
provider. 
 
Section 4.4, End of Study definition 
End of Study (EoS) occurs with the date of last (infant) participant last visit (LSLV) or 
the last testing/reading released of the human biological samples related to primary 
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and secondary endpoints, whichever comes last. EoS must be achieved no later than 8 
months after LSLV. 
 
Section 5.1.1, Maternal participants inclusion criteria 
Pre-pregnancy BMI (based on participant’s report) 17.0 18.5 to 39.9 kg/m2, 
inclusive. 
 
Section 5.2.1.1, Maternal participants exclusion criteria, Medical conditions 
History of 2 or more prior stillbirths or neonatal deaths, or history of multiple (2 or 
more) preterm births at ≤ 34 weeks gestation, or multiple (3 or more) consecutive 
spontaneous abortions.  
Note: Still births, pre-terms births and spontaneous abortions will be counted per 
pregnancy (i.e. regardless of the number of fetuses in the concerned pregnancy).  
 
Section 5.2.1.2, Maternal participants exclusion criteria, Prior/Concomitant 
therapy 
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. In that sense, COVID-19 vaccines will be allowed, when administered ≥ 
15 days before or after study vaccination. 
 
Section 6.3.2.1.1, Stage A 
Randomization to the immunogenicity subcohort: 
For the ~ 1533 maternal participants in the immunogenicity sub-cohort, : 
aAn additional blood sample will be collected at delivery. 
 
In order to assess the impact of fluid shifts on the antibody concentration/titer, 
hematocrit will be evaluated at all 3 blood sampling timepoints (Day 1, Day 31, and 
delivery).  


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Figure 4 Stage A Sub-Cohort Distributions 
 


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Deleted figure: 
 
 
Section 6.5.1, Maternal participants 
All antibiotics, antivirals, analgesics and anti-pyretics taken within 7 days before 
dose administration. 
 
Section 6.7, Intervention after the end of the study 
The investigator will ask each participant, at the time of informed consent, if she is 
interested in taking part in a booster study and will document this in the source 
documents only. During the study conclusion visit/contact, the investigator will confirm 
the participant’s interest and report it in the eCRF.  
 
Section 7.1.1, Criteria for temporary delay for enrolment and/or vaccination 
Use of systemic antibiotic or antiviral treatment within 48 hours before study 
vaccination. 
Refer to SPM for further guidance. 
 
Section 8, Study assessment and procedures 
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 guidance regarding the temporary delay of study intervention administration 
because of exposure to COVID-19, please refer to the SPM for details. 
For the duration of such special circumstances: 
 
Nasal swabs for central testing must be collected using GSK-
provided supplies. (note: if collection at either the study site, 
participant’s home or an alternate location is not possible, 
participants may be instructed to collect nasal swab samples by 
themselves/for their infant. Collection will be done using GSK-
provided supplies and all the corresponding detailed instructions to 
allow such collection will be provided along with the nasal swab 
sampling kit) 
 
Blood samples for central assessment of hematocrit must be 
collected using GSK provided supplies. 
 
Blood / cord blood samples for assessment of immune response 
must be retrieved, processed and stored in accordance with the 
Investigator Laboratory Manual. 
The frequency of RTI surveillance contacts by site personnel may be temporarily 
adapted. 
Impact on the analysis sets for efficacy and immunogenicity will be determined on a case 
by case basis. 
*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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 
Section 8.1.1, Biological samples 
Table 12, Biolgical samples- maternal participants 
Maternal 
Sample 
type 
Collected 
to 
Evaluate 
Minimum 
Quantity 
per 
participant 
Unit 
Time point 
Additional Information 
Whole 
blood  
Hematocrit  ~3  
ml 
Visit 1 (Day 
1) pre dose 
Applies to Stage A Immunogenicity sub-cohort only 
Visit 2 
(Day 31)  
Visit 3 
(Delivery)  
Immune 
response 
~10 
ml 
Visit 1 (Day 
1) pre dose 
Visit 1 and Visit 2: Applies to all participants, Stages A 
& B 
Visit 3: Applies to Stage A Immunogenicity sub-cohort 
only 
Visit 2 
(Day 31) 
Visit 3 
(Delivery) 
 
~3039 
ml 
Estimated TOTAL if assigned to the immunogenicity sub-cohort 
~20 
ml 
Estimated TOTAL if NOT assigned to the immunogenicity sub-cohort 
Table 14, Biolgical samples- infant participants 
Additional text to refer to SPM, added for clarification on blood collection volume.  
Infant 
Sample 
type 
Collected 
to 
Evaluate 
Minimum 
Quantity per 
participant 
Unit 
Time point 
Additional Information 
Whole 
Blood 
Immune 
response 
- IF cord 
blood not 
collected 
~2.5 -  
Stages A and B 
ml 
Visit 1-NB  
(Within 3 days 
after birth) 
Volume must be reduced if weight ≤ 2.5 kg. 
[Trial-related blood loss for infant participants 
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 and/or SPM for 
additional information. 
All minimum totals given below assume a body 
weight > 2.5 kg.  
 
Immune 
response 
– sub-
cohort* 
~2.5* - 
Stage A 
immunogenicity 
sub-cohort only 
ml 
Either 
Visit 2-NB 
(Day 43) or 
Visit 3-NB 
(Month 4) or 
Visit 4-NB 
(Month 6) 
 
 
~2.5 
ml 
Estimated TOTAL if cord blood NOT collected 
 
 
~2.5 
ml 
Estimated TOTAL if assigned to one of the three blood sampling 
sub-cohorts in Stage A 
 
 
~5.0 
ml 
Estimated TOTAL if assigned to a blood sampling sub-cohort in 
Stage A AND cord blood NOT collected 
Nasal 
swab 
Presence 
of RSV A 
/ B 
- 
- 
LRTI 
Assessment 
Visit  
Collect at least one nasal swab for each 
potential LRTI reported. 
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 participant 
hospitalized with a RTI (or soon after release, 
as long as symptoms are ongoing). 


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 
Section 8.1.2, Laboratory assays 
Table 15, Laboratory assays 
Assay type 
System 
Component 
Method 
Laboratory* 
Hematocrit 
Whole 
Blood 
Hematocrit 
Per Central 
Laboratory 
SOP 
Central Laboratory 
*Refer to the list of clinical laboratories for details. 
** GSK laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; Marburg, 
Germany. CLS may delegate testing to GSK Research laboratories in Rixensart, Belgium; Rockville, USA; Sienna, 
Italy. 
 
Section 8.1.2, Immunological read-outs 
Table 16, Immunological read-outs 
Infant participants** 
 
Footnote updated to refer to correcponding tables: V = Visit; RSV-A/B: respiratory syncytial virus subtype A/B; NB: 
Newborn. IgG: immunoglobulin G;  
* Refer to Table 12, Table 13 
** Refer to and Table 14 
Table 17, Hematocrit readouts – Stage A (deleted and subsequent tables have been 
renumbered accordingly) 
Hematocrit will only be performed for maternal participants in the Stage A 
immunogenicity subcohort. Data will be used exclusively to support evaluation of 
secondary immunogenicity objectives. 
Blood sampling timepoint 
Approximate No. 
participants 
Component 
Type of contact and 
timepoint 
Sampling timepoint 
Maternal participants 
V1 (Day 1) 
pre vaccination 
1,533 
Hematocrit 
V2 (Day 31) 
post vaccination 
1,533 
Hematocrit 
V3 (Delivery) 
delivery  
1,533 
Hematocrit 
 
Section 8.2.1.1, Medical/vaccination history 
 
the participant’s pre-pregnancy BMI (i.e., BMI during the months before the 
participant became pregnant or at the very first maternal visit [if occurred early 
in the 1st pregnancy trimester]). This information can be obtained either via 
medical record review or participant interview. If BMI is not directly available, 
investigators will obtain participant’s pre-pregnancy weight (i.e. weight during 
the months before the participant became pregnant or are the very first maternal 
visit [if occurred early in the 1st trimester]) and calculate pre-pregnancy BMI 
from it, in order to report it in the eCRF. 
NOTE: in the exceptional circumstance where the pre-pregnancy weight/BMI 
is unknown and there is no maternal visit performed during the 1st trimester. 
The BMI calculated based on the weight at screening may be used for 
eligibility. In those cases, the investigator should carefully assess the 


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nutritional status of the potential participant to exclude any signs of 
malnutrition, in conjunction with the other eligibility criteria. 
 
Section 8.3.1, Time period and frequency for collecting AE, SAE and other 
safety information 
Table 18, Timeframes for collecting and reporting safety (and RTI) information  
RTI/LRTI surveillance follow-up period (infant participants) extended to 12 months. 
Footnote added to add further clarification and to refer to relevant section for details:  
Pre = pre-vaccination; V=visit; D: Day; M = Maternal participants; I= Infant participants. * Approximately monthly 
contacts pre- delivery also occur within the timeframes described above and are described in Section 1.2. **i.e. 
consent obtained. *** If subsequent pregnancy occurs during the study, follow-up may extend up to 8 weeks post birth 
of the infant from that subsequent pregnancy. ****AESIs include adverse pregnancy outcomes, pregnancy related AEs 
of special interest and neonatal AEs of special interest (for details refer to Section 10.3.5). Neonatal AEs of special 
interest identified after V2-NB (e.g., congenital anomalies) will continue to be reported as such. 
A post-study SAE is defined as any event that occurs after the end of the study. 
Investigators are not obligated to actively seek SAEs from former study participants.A 
post-study AE/SAE is defined as any event that occurs outside of the AE/SAE reporting 
periods defined in Table 18. Investigators are not obligated to actively seek AEs or SAEs 
in former study participants.  
 
Section 8.3.3, Regulatory reporting requirements for SAEs, subsequent 
pregnancies, and other events 
Table 19, Timeframes for submitting serious adverse event, subsequent pregnancy and 
other events reports to GSK 
Type of Event 
Initial Reports 
Follow-up of Relevant 
Information on a Previous 
Report 
Timeframe 
Documents 
Timeframe 
Documents 
Subsequent Pregnancies 
24 hours * 
electronic pregnancy 
report 
24 hours * 
electronic 
pregnancy 
report 
Subsequent Pregnancies 
2 weeks24 hours * 
electronic pregnancy 
report 
2 weeks24 
hours * 
electronic 
pregnancy 
report 
Table 20, Contact information for reporting of SAEs, AESIs, subsequent pregnancies 
GSK Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: PV.ICSRManagementogm28723@gsk.com 


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 
Section 8.3.4.1, Labor and Delivery 
Spelling modified to align across the document. 
 
An uncomplicated vaginal delivery or planned cesarean caesarian section 
expected to occur in a hospital setting should NOT be reported as an AE, MAE 
or SAE. 
 
A medical complication that requires a cesarean caesarian section or an 
emergency induction may be reported as an SAE/AESI (as applicable), using the 
corresponding Expedited AE report form.  
 
Section 8.3.4.2, Pregnancy outcomes 
Table 21, Reporting pregnancy outcomes with or without congenital anomalies as AESIs 
and/or SAEs 
 
 
Fetal death 
Elective / Therapeutic 
Termination 
 
Live birth 
/stillbirth 
Congenital anomalies* 
AESI 
SAE 
AESI 
SAE 
AESI 
SAE 
None 
- 
- 
- 
X 
- 
X 
Major1  
X 
if reportable per 
MACDP3 
- 
X 
- 
X 
Minor2  
- 
if reportable per 
MACDP3 
- 
X 
- 
X 
* In the event of infant’s participation in the study, congenital anomalies are to be reported in the infant’s 
eCRF. However, when there is no live birth, or no signed informed consent for the infant or the congenital 
anomaly is being reported for a subsequent pregnancy, it will be encoded in the maternal participant’s eCRF.  
The term “congenital anomaly” is broad. GSK uses the case definitions provided in the 
Centers for disease Control and Prevention (CDC) Metropolitan Atlanta Congenital 
Defects Program guidelines, with specific reference to the MACDP 6-Digit Code Defect 
List [MACDP, 20212019] to ensure that the collection and recording of these data is 
complete and consistent across studies and projects. 
 
Section 8.4.2.2, Infant participants 
RTI surveillance in infant participants begins at birth (Visit 1-NB) and ends 129 months 
after birth (Visit 5Contact 1-NB).  
 
Section 8.4.2.2.1, RTI surveillance contacts 
Additional text added to allow modifiications to the frequency of planned RTI 
surveillance contacts. 
In special circumstances, such as for example, in the event of a pandemic, social 
distancing and confinement measures may considerably impact the region’s usual RSV 
seasonality. Hence, frequency of active contacts may be temporarily adapted (in 
agreement with GSK and subject to IEC/IRB approval, as needed) to avoid 
unnecessary burden (Refer to Section 8). 


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 
Section 8.4.2.2.2, RTI Diary cards 
At each study visit/contact (including any assessment visits), RTI symptoms may have 
ended or may be ongoing. This will be evaluated in order to determine whether to retrieve 
the Diary Card and replenish the parent(s)/LAR(s)/designate(s) supply of blank cards as 
needed or, instruct them to continue collecting information until the corresponding 
symptom(s) have ended 
 
Section 8.4.6, 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 participant completes 
Visit 5Contact 2-NB or (c) the participant is lost to follow up.  
 
Section 9.3, Populations for analyses 
Table 25, Infant participants 
Infant participants 
Analysis Set 
Description 
Exposed 
Infants live-born to exposed maternal participants, whose parents/LARs completed the 
informed consent process and signed the informed consent form 
Full Analysis – 
Immunogenicity 
All infant participants in the Exposed set who have post-delivery/birth immunogenicity data. 
Per Protocol – 
Immunogenicity 
All infant participants in the Full Analysis (Immunogenicity) set minus those who (a) were 
born less than 4 weeks post- maternal participant vaccination and/ or (b) have protocol 
deviations that lead to exclusion. 
Full Analysis - 
Efficacy  
All infant participants in the Exposed set who either complete 6 months of follow-up or have 
a medically assessed RSV-associated LRTI case before completing the 6 month Visit 
(Visit 4-NB). 
Modified Full 
Analysis - Efficacy 
All infant participants in the Exposed set who were born after at least 4 weeks of 
vaccination AND either complete 6 months of follow-up or have a medically assessed 
RSV-associated LRTI case before completing the 6 month Visit (Visit 4-NB) 
Per Protocol – 
Efficacy 
All infant participants in the Full analysis (efficacy) set minus those a) were born less than 4 
weeks post- maternal participant vaccination and/ or (b) who have protocol deviations that 
lead to exclusion. 
 
Section 9.4.3, Primary endpoints  
The primary analysis of vaccine efficacy will be based on the modified full analysis 
efficacy set for infants (modified FAS-E). A secondary analysis based on the full 
analysis efficacy set (FAS-E) and the per protocol efficacy set for infants will be 
performed to complement the modified FAS-E analysis.  
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 
Section 9.4.4.1, Secondary endpoints/Efficacy 
In general, the primary analysis of vaccine efficacy on secondary efficacy endpoints will 
be based on the modified full analysis set for efficacy (modified FAS-E). A secondary 
analysis based on the full analysis set for efficacy and the per protocol set for efficacy 
will be performed to complement the modified FAS-E analysis. However, if the trial is 
stopped for efficacy for primary endpoints at an interim analysis, all secondary or tertiary 
efficacy analyses will be performed on the final data containing all participants enrolled 
and their follow up.  
Secondary confirmatory 
Efficacy Endpoints – Block 2 
Statistical Analysis Methods 
From birth (Visit 1-NB) to 9 
months (C2-NB), occurrences 
of any medically assessed, 
RSV-associated LRTIs 
according to the case 
definitions. 
From birth (Visit 1-NB) to 10 
months, occurrences of 
severe medically assessed, 
RSV-associated LRTIs 
according to the case 
definitions. 
From birth (Visit 1-NB) to 10 
months, occurrences of any 
medically assessed, RSV-
associated LRTIs according 
to the case definitions. 
From birth (Visit 1-NB) to 11 
months, occurrences of 
severe medically assessed, 
RSV-associated LRTIs 
according to the case 
definitions. 
From birth (Visit 1-NB) to 11 
months, occurrences of any 
medically assessed, RSV-
associated LRTIs according 
to the case definitions. 
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From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according 
to the case definitions. 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definitions. 
Secondary Descriptive Efficacy 
Endpoints  
From birth (Visit 1-NB) to 4 
months (Visit 3-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definition. 
From birth (Visit 1-NB) to 4 
months (Visit 3-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definitions 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs by alternative case 
definitions. 
From study intervention 
administration (Visit 1) to 6 
months post-delivery 
(Contact 1), oOccurrence of  
RSV-associated medically 
attended RTIs (RSV-MA-RTIs) 
from vaccination up to 6 
months post-delivery (Visit 4) 
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From birth (Visit 1-NB) to 6 
months (Visit 4-NB), time to 
the first occurrence of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definition 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), time to 
the first occurrence of any 
medically assessed, RSV-
associated LRTIs according to 
the case definition  
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of RSV-
associated hospitalizations 
according to the case 
definitions. 
Strong control of type I error is applied for secondary confirmatory endpoints, and 
multiplicity will be controlled using a hierarchical, closed testing procedure. The 
secondary confirmatory endpoints will be grouped sequentially in two blocks. Block 1 
includes three endpoints: RSV-associated hospitalization, all cause LRTI, and all cause 
LRTI  hospitalization from birth to 6 months. Block 2 includes 12 six endpoints: severe 
medically assessed, RSV-associated LRTI and medically assessed, RSV-associated LRTI 
of any severity from birth to 7, 8, 9, 10, 11 and 912 months respectively (see Figure 8).  
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Figure 8, Secondary confirmatory endpoint hierarchy 
 
 
         
 
Block 1: RSV vaccine group versus placebo 
H21: From birth to 6 months, occurrences of RSV-associated hospitalizations 
H22: From birth to 6 months, occurrences of all-cause LRTI 
H23: From birth to 6 months, occurrences of all-cause LRTI with hospitalization 
Block 2: RSV vaccine group versus placebo 
H31: From birth to 7 months, occurrences of severe or very severe RSV-associated LRTIs 
H32: From birth to 8 months, occurrences of severe or very severe RSV-associated LRTIs 
H33: From birth to 9 months, occurrences of severe or very severe RSV-associated LRTIs 
H34: From birth to 10 months, occurrences of severe or very severe RSV-associated LRTIs 
H35: From birth to 11 months, occurrences of severe or very severe RSV-associated LRTIs 
H36: From birth to 12 months, occurrences of severe or very severe RSV-associated LRTIs 
H41: From birth to 7 months, occurrences of any RSV-associated LRTIs 
H42: From birth to 8 months, occurrences of any RSV-associated LRTIs 
H43: From birth to 9 months, occurrences of any RSV-associated LRTIs 
H44: From birth to 10 months, occurrences of any RSV-associated LRTIs 
H45: From birth to 11 months, occurrences of any RSV-associated LRTIs 
H46: From birth to 12 months, occurrences of any RSV-associated LRTIs 
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 
Section 10.2, Appendix 2: Clinical laboratory tests 
There is one assessment, hematocrit, which will be tested at Visits 1, 2 and 3, for all 
maternal participants in Stage A who are assigned to the immunogenicity sub-cohort, 
until the current protocol amendment 2 is approved (unless IEC/IRB allows for 
immediate implementation of this measure to reduce participant’s burden, prior to full 
Amendment 2 being approved) in the respective study country(ies). Testing will be 
performed by a central laboratory. Results will be used to help evaluate changes over 
time in antibody titers / concentrations that may be related to volumetric changes during 
pregnancy, if deemed necessary. 
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 
Section 10.3.2, Definition of a Serious Adverse Event (SAE) 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant  
Refer to Section 8.3.4.28.3.4 for additional information. 
f. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, 
congenital anomalies*, ectopic pregnancy)  
*Refer to Section 8.3.4.2 for additional information. 
 
Section 10.3.5, Adverse events of special interest (AESIs) 
In this section, all AESIs are presented in list format. 
AESIs include: 
 
The adverse pregnancy outcomes indicated in Table 21. 
 
The following pregnancy-related adverse events of special interest (newly occurring 
or worsening of existing conditions): 
 
maternal death, 
 
hypertensive disorders of pregnancy: 
o 
gestational hypertension,  
o 
pre-eclampsia,  
o 
pre-eclampsia with severe features including eclampsia, 
 
fetal growth restriction, 
 
pathways to preterm birth: 
o 
premature preterm rupture of membranes,  
o 
preterm labor,  
o 
provider-initiated preterm birth, 
 
gestational diabetes mellitus, and 
 
chorioamnionitis.  
 
The following neonatal adverse events of special interest: 
 
small for gestational age, 
 
low birth weight including very low and extremely low birth weight (<2500 g, 
<1500 g, <1000 g), 
 
congenital anomalies: 
o 
major external structural defects,  
o 
internal structural defects,  
o 
functional defects, 
 
neonatal death: 
o 
in an extremely pre-term birth [22GA<28 weeks],  


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o 
in a preterm live birth [28GA<37 weeks], or  
o 
in a term live birth),  
and 
 
preterm birth.  
Refer to Section 8.3.4 for additional information about categorizing and reporting 
congenital anomalies. 
Note: Worsening, post study vaccine administration, of pre-existingconditions already 
present at the time of enrolment. (eg. controlled gestational hypertension or controlled 
gestational diabetes) will be collected as (S)AEs and indicated as “worsening” or 
“aggravated” . These are not to be considered as AESIs. 
 
Section 10.3.8.2, Where to record AEs, SAEs, AESIs, subsequent pregnancies 
and other events of interest 
All solicited events that occur during the 7 days following administration of the dose of 
study vaccine/product (Day 1 to Day 7) must be recorded into the electronic Diary, 
irrespective of intensity or whether or not they are considered vaccination-related. 
 
Section 10.6, Appendix 6: Country specific requirements 
Section 10.6.2, South Korea 
Concerning the “STUDY POPULATION – Exclusion criteria for enrolment – 
maternal participants”, the following will constitute and exclusion criterion in South 
Korea: 
 
Participation in a clinical trial targeting healthy people within the 6 months prior 
to enrolment/study vaccination. 
Concerning the “CRITERIA LEADING TO PAUSE OR EARLY TERMINATION OF 
THE STUDY”, the following clarification is made: 
 
No safety “holding rules” or criteria for pausing or early termination have been 
defined for this study. 
 
An Independent Data Monitoring Committee (IDMC) has been put in place and 
will be in charge of reviewing unblinded safety data on a regular basis (bi-monthly 
reviews are foreseen, but frequency may be adapted as the study progresses). It will 
be the IDMC discretion to recommend, if they deemed necessary, that the study 
recruitment is paused or terminated based on their unblinded data reviews. 
 
In addition to the IDMC reviews, GSK’s Safety Review Team (SRT) will perform 
regular reviews of blinded data and may request IDMC to perform ad-hoc 
unblinded reviews if any potential safety concern is suspected based on blinded 
data. 


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 
Section 10.7.2, Glossary of terms 
End of Study (EoS)  
(Synonym of End of 
Trial)  
For studies with collection of human biologicals samples, EoS 
occurs withis defined as the date of last infant participant last 
visit (LSLV; Visit 5-NB) or the last testing/reading released of 
the human biological samples related to primary and 
secondary endpoints, whichever comes last. EoS must be 
achieved no later than 8 months after LSLV. 
 
Section 10.8, Appendix 8: Gestational age assessment 
A note has been added to Section 10.8.2: Refer to the SPM for further details. 
 
Section 10.8.2, METHODS OF GESTATIONAL AGE ASSESSMENT AND 
ESTIMATION OF DUE DATE 
Missing Asterix added against gestational age range: 
Gestational age range* 
Method of measurement 
Discrepancy between U/S dating and LMP (or IUI 
or ET dating) prompting re-dating of EDD 
considering U/S 
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 
3rd trimester 
280//7 weeks and beyond 
BPD, HC, AC, FL 
> 21 days 
Text added: Refer to the SPM for further details. 


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 
Section 10.9, Appendix 9: Definitions of maternal, fetal and neonatal events of 
interest as per GAIA 
 
IMPORTANT: NOT all the events that are listed below are AESIs for this study. 
Sections 3, 9.4.4 and 10.3.5 list events of interest per GAIA that must be reported as 
AESIs in this study.  
Pregnancy Outcomes 
Fetal Death / Stillbirth 
Table 30 
Maternal Events of Interest 
Maternal Death – study defined pregnancy-related AESI 
Table 31 
Hypertensive Disorders of Pregnancy – study defined pregnancy related AESIs 
Table 32 
Antenatal bleeding 
Table 33 
Postpartum hemorrhage 
Table 34 
Fetal Growth restriction – study defined pregnancy related AESI 
Table 35 
Gestational Diabetes Mellitus – study defined pregnancy related AESI 
Table 36 
Non-reassuring fetal status 
Table 37 
Pathways to Preterm Birth – study defined pregnancy related AESIs 
Table 38 
Chorioamnionitis - study defined pregnancy related AESI 
Table 39 
Standard definitions for events of interest not defined as such in GAIA (Oligohydramnios, 
Polyhydramnios, Intrahepatic Cholestasis of Pregnancy (ICP), Acute Fatty Liver of Pregnancy, 
Maternal Sepsis) 
Table 40 
Neonatal Events of Interest 
Small for Gestational Age – study defined neonatal AESI 
Table 41 
Low Birth Weight – study defined neonatal AESI 
Table 42 
Neonatal encephalopathy 
Table 43 
Congenital Microcephaly 
Table 44 
Congenital Anomalies – study defined neonatal AESIs 
Table 45 
Neonatal Death – study defined neonatal AESI 
Table 46 
Neonatal Infections 
Table 47 
Respiratory Distress in the Neonate 
Table 48 
Preterm Birth – study defined neonatal AESI 
Table 49 
Failure to thrive 
Table 50 
Standard definitions for events of interest not defined as such in GAIA (large for gestational age, 
macrosomia) 
Table 51 
 
Section 11, References 
Morgan WJ, et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up 
through adolescence. Am J Respir Crit Care Med. 2005;172(10):1253-8. 
Carbonell-Estrany X, Pérez-Yarza G E, Laura García Sanchez L, et al. Long-Term 
Burden and Respiratory Effects of Respiratory Syncytial Virus Hospitalization in 
Preterm Infants-The SPRING Study. PLoS One 2015; May 8;10(5):e0125422 
Fauroux B, Simo˜es A. F.E, Checchia A. P, et.alThe Burden and Long-term 
Respiratory Morbidity Associated with Respiratory Syncytial Virus Infection in Early 
Childhood. Infect Dis Ther 2017; 6:173–197 
Metropolitan Atlanta Congenital Defects Program (MACDP). 20212019. 
https://www.cdc.gov/ncbddd/birthdefects/documents/bpa-codes-rev2021-
508c.xlsxhttps://www.cdc.gov/ncbddd/birthdefects/macdp.html. Accessed 85 JuneMarch 
20212020. 


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Overall Rationale for the Protocol Amendment 1: 
Case definitions for lower respiratory tract illness have been modified to include the 
phrase “medically assessed."  In addition, the success criteria for the primary objective on 
any RSV-associated lower respiratory tract infection has been changed. Previously the 
lower bound of this primary endpoint was 10%; it has been increased to 20%. The timing 
of interim analyses have been modfied to make overall interim analyses operationally 
pragmatic.  In addition, the corresponding study design operational characteristics have 
been updated.   Editorial changes to improve internal consistency have been made. 
Typographical errors have been corrected. 
List of main changes: 
Section # and title 
Description of change 
Brief rationale 
Sections 1.2 (Schema), 2.1 (Study 
rationale), 3 (Endpoints and 
Objectives), 4.2.5 (Adaptive 
design), 4.2.6 (Case definitions), 
9.4.3 (Primary Endpoints), 9.4.4.1 
(Secondary efficacy endpoints), 
9.4.4.2 (Detailed statistical 
methods) 
The phrase “medically assessed” 
has been added to the phrase 
“RSV-associated lower respiratory 
tract infection.”  
To clarify that medical assessment is 
required to meet the case definition. 
Sections 3 (Endpoints and 
Objectives), 4.2.5 (Adaptive 
design), 4.2.6 (Case definitions), 9 
(Statistical considerations), 10.10 
(Operating characteristics)   
The phrases “severe / very severe” 
and “severe or very severe” LRTI 
have been replaced by the phrase 
“severe LRTI. 
To clarify that in this protocol, the 
primary endpoint related to medically 
assessed RSV-associated severe 
LRTI will not include medically 
assessed RSV-associated very 
severe LRTI. Similarly, medically 
assessed, RSV-associated LRTI 
endpoints will not include RSV LRTI 
of very severe LRTI case definitions. 
Section 2.1 (study rationale) 
Infant participants are to be 
evaluated for medically assessed 
RSV-associated lower respiratory 
tract infection for 9 months post 
birth. 
Evaluation of the infant occurs for 9 
months post-birth. An incorrect 
reference to “6 months” has been 
adjusted. 
Section 1.3 (Schedules of 
Activities), Table 1; row 35; Section 
8.3.1 (Time period and frequency 
for collecting AE, SAE and other 
safety information), Table 19, 
column 9 
References to maternal “Visit 5” 
have been replaced with references 
to maternal “contact 1.” 
Evaluation of the mother 6 months 
post-delivery occurs via contact.  A 
“visit” was referenced in these 2 
locations in error. 
Section 2.3 (Benefit/risk 
assessment) 
Language in the previous version of 
the protocol that presented risks 
information has been removed.  
More current and complete 
information is now available in Edition 
3 of the Investigator’s Brochure. 
Sections 1.2 (Schema) and  4.1 
(Overall design) 
Language has been added to 
indicate that at least 20% of 
participants will be enrolled at 
centers in the U.S. 
Addresses a regulatory request. 
Section 4.2.2 (Use of Placebo) 
The phrase “and efficacy” has been 
added  
The placebo serves as a control for 
safety, reactogenicity, 
immunogenicity and efficacy 
assessments. 


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Section # and title 
Description of change 
Brief rationale 
Section 5.2.1.2 (Prior / 
Concomitant Therapy) 
Has been re-written to remove a 
redundant reference to the phrase 
“planned use during the study 
period.” 
To improve clarity, a redundant 
reference to “planned use during the 
study period” has been removed. 
Sections 9.1 (Statistical 
hypotheses), 9.2 (Sample size 
determination), 9.4.3.1
 
 
, Section 10.10 
(Operating characteristics) 
The success criterion on lower 
bound of medically assessed RSV 
associated LRTI (VEany) has been 
changed to 20% and all the relevant 
design charicterristics have been 
updated 
Section 9 has been updated following 
changes to the success criteria for 
the primary objectives and in 
response to regulatory comments. 
 
 
Section 9.4.4.1 (Efficacy) 
Text describing the methods of type 
I error control on the analyses of the 
secondary confirmatory endpoints 
was updated. 
 
Section 9.4.6.3 (Predicted VE 
based on surrogate endpoint) 
The strategy for surrogate endpoint 
analyses was simplified. 
 
Section 9.5 (Interim analyses) 
The number of interim analyses has 
been reduced; the text was updated 
to reflect this and to further clarify 
the sequence of full analyses.  
 
Section 10.1.3 (Informed consent 
process) 
The discussion of consent for 
participants who are re-screened 
has been modified. 
For consistency with electronic data 
capture and study procedures. 
Detailed description of previous Protocol Amendment (#1) changes: 
In this section, deleted text is indicated in strikethrough and changed text in bold italics. 
Section 1.2, Schema 
Up to approximately 10,000 participants will be enrolled; it is expected that at least 
20% of these participants will be enrolled at centers located in the U.S. 
Infant participants will be evaluated for the occurrence of RSV-associated medically 
assessed, RSV-associated lower respiratory tract infections for 6 9 months after birth and 
followed for safety for 12 months after birth.  
CCI
CCI


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Table 1, Schedule of activities for maternal participants 
Visit / Contact 
Screening 
V1 
V2*  Contacts 
(Monthly) 
V3 
V4  C1 
Event 
Driven 
 
MAEs other 
than MA-RTIs 
 
● 
● 
● 
● 
● 
 
 
 
Medically 
attended RTIs to 
be reported up to 
V5 or C1. 
Pregnancy-
related AESIs  
 
● 
● 
● 
● 
● 
● 
● 
● 
Table 4, Sections 
8.3.1, 8.3.3, 8.3.4, 
and 10.3.5. Must 
submit an 
Expedited AE 
report. 
MAEs other 
than MA-RTIs 
 
● 
● 
● 
● 
● 
 
● 
 
Medically 
attended RTIs to 
be reported up to 
V5 or C1. 
SAEs, MA-RTI 
associated AEs, 
AESIs and AEs 
leading to study 
withdrawal  
 
● 
● 
● 
● 
● 
● 
● 
● 
Sections 7.2, 
8.3.1 and 10.3.8  
Table 3, Intervals between study visits and contacts 
Interval 
Optimal 
interval 
in Days 
Allowed 
interval 
in Days 
Additional Information 
Maternal participants 
Screening 
to V1  
0  
0– 29  
…Data from all screening procedures must be available and eligibility must be 
confirmed before the subjectparticipant is randomized…. 
Section 2.1, Study rationale 
GSK is developing an investigational Respiratory Syncytial Virus (RSV) vaccine for 
administration to pregnant women, with the aim of preventing RSV-associated medically 
assessed, RSV-associated lower respiratory tract illnesses (LRTIs) in their infants …  
SafetyReactogenicity and reactogenicitysafety of the candidate vaccine will be evaluated 
in maternal participants for up to 6 months after delivery; and.  Safety in infants will be 
evaluated for up to 12 months after birth. Safety evaluation  will include assessment of 
medically attended adverse events, serious adverse events, pregnancy outcomes, and 
pregnancy-related and neonatal adverse events of special interest (AESIs). 
The study will also evaluate the incidence of medically attended RSV-associated 
respiratory tract illnesses (MA-RTI) in maternal participants for up to 6 months after 
delivery, and the incidence of medically assessed, RSV-associated respiratory tract / 
lower respiratory tract illnesses (RTI/LRTI) in infants for up to 69 months after 
delivery/birth, and the incidence of medically attended and serious adverse events for up 
to 12 months, in infants born to vaccinated mothers.  


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Section 2.3, Benefit/Risk assessment 
One phase 1 clinical trial of the RSV investigational vaccine in non-pregnant women has 
been completed. Two phase 2 clinical trials – one in non-pregnant and one in pregnant 
women – are ongoing.As of the date of this protocol:  
 
The most commonly reported adverse events have been pain at the injection site, 
headache, and fatigue.  
 
Fever post-vaccination has been infrequent (about 1% of participants).  
 
Most adverse events have caused only limited discomfort, have not lasted long and 
have not prevented normal everyday activities.  
 
No serious adverse events attributed by the Investigator or by GSK to study vaccine 
administration have been reported in non-pregnant women, pregnant women, or their 
infants.  
Taking into account the measures to minimize potential risks for subjects participants 
participating in this study, the potential or identified risks are justified by the potential 
benefits of enhanced surveillance for the subjects participants…….  
Section 3, Objectives and Endpoints, Table 4 
Primary objectives 
Primary endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe or (including  very 
severe) LRTIs in their infant participants2 infant5 
participants up to 6 months of age 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of medically assessed 1, RSV-associated severe or 
(including very severeRSV-associated ) LRTIs according to 
the case definitions3 definitions2,3.  
 
OR 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant infant5 participants up to 6 months of age 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs 
according to the case definitions3 definitions2,3. 
Secondary confirmatory1 confirmatory4 
efficacy objectives 
Secondary confirmatory1 confirmatory4 efficacy endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing RSV-associated 
hospitalization in their infant infant5 participants up 
to 6 months of age. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of RSV-associated hospitalizations according to the case 
definitions3 definitions2,3. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant infant5 
participants up to 6 months of age, all cause LRTI  
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause LRTI3. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant infant5 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause LRTI with hospitalization3. 


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participants up to 6 months of age, all cause LRTI 
with hospitalization.  
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe (including very severe) 
LRTIs in their infant infant5 participants up to 7, 8 
and 9 months of age. 
From birth (Visit 1-NB) to 7 months, birth to 8 months, and 
birth to 9 months (C2-NB), occurrences of medically 
assessed, RSV-associated severe (including very 
severeRSV) LRTIs according to the case definitions3 
definitions2,3 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant participants 5 up to 7, 8 and 9 months of 
age. 
From birth (Visit 1-NB) to 7 months, birth to 8 months, and 
birth to 9 months (C2-NB), occurrences of any medically 
assessed, RSV-associated LRTIs according to the case 
definitions3 definitions2,3. 
Secondary descriptive efficacy objectives 
Secondary descriptive efficacy endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe (including very severe) 
LRTIs in their infant infant5 participants up to 4 
months of age 
From birth (Visit 1-NB) to 4 months (Visit 3-NB), occurrences 
of severe (including very severe) medically assessed1, 
RSV-associated LRTIs according to the case definitions3 
definitions2,3.  
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant infant5 participants up to 4 months of age 
From birth (Visit 1-NB) to 4 months (Visit 3-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs 
according to the case definitions3 definitions2,3 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infantinfant5 
participants up to 6 months of age, medically 
assessed1 RSV LRTI by alternative case 
definitions2. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of medically assessed1 RSV LRTI by alternative case 
definitions3definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infantinfant5 
participants up to 6 months of age, all cause 
pneumonia.  
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause pneumonia.  
To assess the effect of administering a single 
dose of the RSV Maternal vaccine administered to 
maternal participants on time to first occurrence of 
any severe or (including very severe) medically 
assessed1, RSV-associated LRTIs, in their 
infants infant5 participants, according to the case 
definition definition2,3. 
From birth to 6 months, time to the first occurrence of severe 
or (including very severe) medically assessed1, RSV-
associated LRTIs according to the case definitions3 
definitions2,3 
To assess the effect of administering a single 
dose of the RSV Maternal vaccine administered to 
maternal participants on time to first occurrence of 
any medically assessed, RSV-associated LRTIs 
in their infants infant5 participants, according to 
the case definition definition2. 
From birth to 6 months, time to the first occurrence of any 
medically assessed, RSV-associated LRTIs according to the 
case definition3definition2  


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To assess the efficacy of a single dose of RSV 
Maternal vaccine administrated to maternal 
participants in preventing, in all vaccinated 
maternal participants up to 6 months post-
delivery, RSV associated medically attended RTIs 
(MA-RTIs) 
From study intervention administration (Visit 1) to 6 months 
post-delivery (Contact 1), occurrence of RSV-associated 
medically attended RTIs (RSV-MA-RTIs) 3 2. 
Secondary safety objectives 
Secondary safety endpoints 
To evaluate the safety of a single IM dose of the 
RSV Maternal vaccine in all maternal participants, 
from Visit 1 up to 6 months after delivery 
Occurrence of serious adverse events (SAEs) 4 6, AEs leading 
to study termination, and medically attended RTIs in all 
maternal participants from Visit 1 (Day 1) up to 6 months after 
delivery. 
Occurrence of all other medically attended AEs in all maternal 
participants from Visit 1 (Day 1) up to Day 42 after delivery. 
To evaluate pregnancy outcomes and pregnancy-
related adverse events of special interest after a 
single IM dose of the RSV Maternal vaccine 
administered to maternal participants, from Visit 1 
up to 6 weeks after delivery (Visit 4). 
Pregnancy outcomes outcomes6 from Day 1 (Visit 1) up to 6 
weeks after delivery (Day 43 post-delivery, Visit 4). These 
include live birth with no congenital anomalies, live birth with 
minor congenital anomaly(ies) only; live birth with at least one 
major congenital anomaly, fetal death/still birth (antepartum or 
intrapartum) with no congenital anomalies, fetal death/still birth 
(antepartum or intrapartum) with only minor congenital 
anomalies, fetal death/still birth (antepartum or intrapartum) 
with at least 1 major congenital anomaly; elective/therapeutic 
termination with no congenital anomalies; elective/therapeutic 
termination with only minor congenital anomalies, and 
elective/therapeutic termination with at least 1 major 
congenital anomaly. 
 
Pregnancy-related adverse events (AEs) of special interest 
from Day 1 (Visit 1) up to 6 weeks after delivery (Day 43 post-
delivery, Visit 4). These include maternal death, hypertensive 
disorders of pregnancy (gestational hypertension, pre-
eclampsia, pre-eclampsia with severe features including 
eclampsia), fetal growth restriction, pathways to preterm birth 
(premature preterm rupture of membranes, preterm labor, 
provider-initiated preterm birth), gestational diabetes mellitus, 
chorioamnionitis.,4, 5. 6,7  
To evaluate the occurrence of neonatal AEs of 
special interest (reported up to 6 weeks after 
birth), in infants born to mothers who were 
vaccinated with a single IM dose of the RSV 
Maternal vaccine 
The occurrence of neonatal AEs of special interest (reported 
up to 6 weeks after birth). These include small for gestational 
age, low birth weight including very low and extremely low 
birth weight (<2500 g, <1500g, <1000g), congenital anomalies 
(major external structural defects, internal structural defects, 
functional defects), neonatal death (in an extremely pre-term 
birth [22GA<28 weeks], in a preterm live birth [28<GA<37 
weeks], or in a term live birth), preterm birth. 4, 5 6,7 
To evaluate the safety of the RSV Maternal 
vaccine in infants born to mothers who were 
vaccinated with a single IM dose of study vaccine, 
up to 12 months after birth 
Occurrence of SAEs, AEs leading to study termination and 
medically attended AEs from birth up to 6 months after birth. 4 6 
Occurrence of SAEs, AEs leading to study termination and 
medically attended AEs from birth up to 12 months after birth. 4 
6 


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Tertiary objectives: 
1For analysis of secondary confirmatory efficacy objectives, overall type 1 error is controlled 
2An infant is defined as a child younger than 1 year of age; a neonate is defined as an infant 28 days old or less.  
3Case1 By “medically assessed” it is meant that the infant was evaluated by a healthcare professional 
(physician, nurse, etc) for the lower respiratory tract illness. 
2Case definitions for RSV associated LRTIs and surveillance for potential LRTIs are briefly summarized in Section 
4.2.6. Alternative case definitions are briefly summarized in Section 4.2.6.2.   
3MaternalNote that as per the case definitions outlined in Table 8, which are based on the WHO case 
definitions, RSV-associated very severe LRTIs are a subset of RSV-associated LRTIs but not necessarily a 
subset of RSV-associated severe LRTIs. As such, an infant participant may meet the criteria for RSV-
associated very severe LRTI without meeting that of RSV-associated severe LRTI. In this protocol, the primary 
endpoint related to medically assessed RSV-associated severe LRTI will include medically assessed RSV-
associated very severe LRTI. Similarly, medically assessed, RSV-associated LRTI endpoints will include RSV 
LRTI of any severity including cases that meet severe and very severe LRTI case definitions. 
4For analysis of secondary confirmatory efficacy objectives, overall type 1 error is controlled 
5An infant is defined as a child younger than 1 year of age; a neonate is defined as an infant 28 days old or less.  
6Maternal and neonatal AESI and pregnancy outcomes should be recorded in the eCRF along with assessment of level 
of diagnostic certainty by GAIA definitions when applicable. Of note, some events of 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. 
5The7The following adverse events are listed by GAIA as events of interest, but will not, for purposes of this study, be 
reported as AESIs. If any of these events meets the definition for an SAE, the event should be reported as such in the 
eCRF and the SAE narrative should contain enough information to permit assessment of level of diagnostic certainty 
by GAIA criteria: 
Pregnancy-related: antenatal bleeding (morbidly adherent placenta, placental abruption, cesarean scar pregnancy, 
uterine rupture), postpartum hemorrhage, non-reassuring fetal status, oligohydramnios, polyhydramnios, gestational 
liver disease (intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy), maternal sepsis.  
Neonatal: neonatal encephalopathy, congenital microcephaly (postnatally or prenatally diagnosed), neonatal infections 
(blood stream infections, meningitis, respiratory infection), respiratory distress in the neonate, failure to thrive, large for 
gestational age, macrosomia. 
Section 4.1, Overall Design 
The study is a Phase III, double-blind, randomized, placebo controlled, multi-centric, 
multi-country study with 2 parallel groups. At least 20% of participants will be enrolled 
at centers in the U.S. 
Section 4.2.2, Use of placebo 
The placebo group serves as a control for safety, reactogenicity, and immunogenicity and  
efficacy assessments. No licensed vaccine against RSV is currently available. 
Section 4.2.3, Randomization ratio 
GSK plans to mitigate the potential risk associated with the increased randomization of 
vaccinated to placebo subjectparticipants by…  
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Section 4.2.4.2, Blood sampling and immune response assessment 
Note however that blood samples for assessment of immune response at Day 1 (Visit 1) 
and Day 31 (Visit 2) will be collected from all maternal participants. Cord blood will also 
be collected from all participants. Analyses of these samples will be used to support 
possible surrogate endpoint filing assessment as well as future bridging studies. 
Section 4.2.5, Adaptive Design 
This adaptive trial design will provide evidence for the efficacy of the RSV maternal 
vaccine in the prevention of medically assessed, RSV-associated LRTI of any severity 
and medically assessed, RSV-associated severe (including very severe) LRTI. The 
design has 93.7 over 90% power to detect the target vaccine efficacies of 70% and 50% 
on severe (including very severe) and any-severity LRTI, respectively. If the vaccine 
meets these target VE rates estimates, this design offers the opportunity to identify this 
benefit with an expected sample size of approximately 7,000 maternal participants, 
obviating which may obviate the need to enroll the maximum sample size of 10,000.  
Section 4.2.6.2, Table 8, RTI/LRTI case definitions for data analysis in infants, 
Footnotes: 
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 Based1 Please note that per the above case definitions which are based on the WHO case definitions, “RSV-
very severe LRTIs” are a subset of “RSV-LRTIs” but not necessarily a subset of the “RSV-severe LRTIs”. As 
such, an infant participant may meet the criteria for very severe LRTI without meeting that of severe LRTI 
2Based 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). 
3 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.  
4 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) 
5 Confirmed RSV infection defined in Section 4.2.6.3 
6 RSV (nasal swab) sampling and testing as specified in Table 14. 
7 Hospitalization is defined as admission for observation or treatment based on the judgement of a health care 
provider. 
Section 4.3, Justification for dose: 
A single formulation of the investigational RSV maternal vaccine (containing 120µg of 
the RSVPreF3 antigen) is planned. Currently available data suggest that the 120 µg 
formulation has an acceptable safety profile and tends to elicit stronger immune 
responses in non-pregnant women (RSV MAT-001 and RSV MAT-011) and pregnant 
women (RSV MAT-004), which is likely to result in higher placental transfer of 
antibodies to the fetus than formulations containing 30 or 60 µg of the RSVPreF3 
antigenHowever, this will be confirmed after review of additional safety and immune 
response data from RSV MAT-011, and RSV MAT-004. Available results from these 
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Section 5.2.1.2, Prior/Concomitant therapy 

Use of any investigational or non-registered product other than the study
vaccine/product during the period beginning as described below, or planned use
during the study period):
 
For a drug, vaccine or medical device: 29 days before the dose of study
vaccine/product (Day -28 to Day 1) or planned use during the study period.
 
For immunoglobulins: 3 months before the dose of study vaccine/product,
Or planned use during the study period.
Section 6.3.2.1.1, randomization to maternal study intervention group, Stage A 
The Day 1 and cord blood (or neonatal blood) samples will be tested to support surrogate 
endpoint filing analysis. The Day 1, Day 31 and cord blood (or neonatal blood) samples 
may also be tested to support development of a sero-correlate for life cycle bridging. 
Section 6.3.3, Intervention allocation to the participant 
Verify eligibility of the maternal subjectparticipant 
Section 8.0, Study procedures during special circumstances 

Enrolment of ADDITIONAL maternal subjectparticipants may be placed on hold.

“Medically attended visits” will include instances where, due to the special
circumstances, the subject participant cannot seek medical advice for……. 
Section 8.1.1, Biological samples, Table 12: 
Nasal 
Swab 
Presence 
of:RSV A 
/ B 
- 
- 
MA RTI 
Assessment 
Visit 
Collect a nasal swab from any maternal participant who 
reports a medically attended (MA) RTI 
- 
- 
RTI 
hospitalization 
Collect a nasal swab (if possible) from any maternal 
participant hospitalized with a RTI (or soon after 
discharge, as long as symptoms are ongoing). 
Section 8.1.2, Laboratory Assays, Table 15, Laboratory Assays, Footnote only 
The panel may include testing for SARS-COV-2 Please note that SARS-COV-2 testing is 
not intended to be diagnostic and results will not be provided to the investigator. Testing 
for SARS-COV-2 in any suspected infected subject participant should be performed as 
per the standard of care.  
Section 8.1.3, Immunological Readouts, Table 18, Molecular Biology Tests, Footnote 
only 
Testing for Covid-19 in any suspected infected subject participant should be performed 
as the standard of care. 
Section 8.2.1.2, Physical Examination (General and obstetric examination) 
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 
Vaginal examination (manual and/or speculum) will be performed ONLY if 
warranted by subjectparticipant's symptoms or as per investigator's clinical 
discretion. If done, results will be recorded (normal or abnormal; if abnormal, 
specify). 
Section 8.3.1, Table 19, Timeframes for collecting and reporting safety (and RTI) 
information 
Applies to Stage A and Stage B unless otherwise noted below 
 
Before Delivery* 
Delivery/Birth 
Post-Delivery/Birth*  
Timepoint 
D-
28 
D1 
D7 
D31 
 
D 
43 
D91 
D121 
D181 
M9 
M12  
Maternal participant visits 
Pre-
** 
V1 
 
V2 
V3 
V4 
 
 
V5 
C1  
 
 
Infant visits 
 
 
 
 
V1-NB 
V2-
NB 
C1-
NB 
V3-
NB 
V4-
NB 
C2-
NB 
V5-
NB  
Section 9.1, Statistical hypotheses 
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Section 9.4.1, Statistical analysis, general considerations: 
The SAP describes how missing data will be handled during analyses. 
If, during the trial, changes need to be made on primary or confirmatory secondary 
objectives and statistical methods related to those objectives prior to any unblinding, 
the protocol will be amended. Changes on other secondary objectives/tertiary 
objectives, along with the reason(s) for the changes, will be documented in the SAP 
and the Clinical Study Report. 
Section 9.4.2, Participants disposition 
Number of infant participants enrolled and withdrawn (by group and sub-cohort, and 
overall) will be described. Additional analyses by country and/or by site may be 
performed.  
Section 9.4.3, Primary objectives endpoints 
Primary Efficacy Endpoints – Infant 
participants 
Statistical Analysis Methods 
From birth to 6 months, occurrences of 
medically assessed, RSV-associated 
severe or (including very severeRSV-
associated) LRTIs according to the case 
definitions.  
OR 
From birth to 6 months, occurrences of any 
medically assessed, RSV-associated LRTIs 
according to the case definitions. 
Section 9.4.3.1, Detailed statistical analysis methods 
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Section 9.4.4.1 Secondary endpoints, efficacy 
……However, if the trial is 
stopped for efficacy for primary 
endpoints at an interim 
analysis, all secondary or 
tertiary efficacy analyses will be 
performed on the final data 
containing all 
subjectparticipants enrolled 
and their follow up. Secondary 
confirmatory Efficacy 
Endpoints – Block 2 
Statistical Analysis Methods 
From birth (Visit 1-NB) to 7 
months, occurrences of severe 
or(including very severe) 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 7 
months, occurrences of any 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
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From birth (Visit 1-NB) to 8 
months, occurrences of severe 
or(including very severe) 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 8 
months, occurrences of any 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 9 
months (C2-NB), occurrences 
of severe (including very 
severe) medically assessed, 
RSV-associated LRTIs 
according to the case 
definitions. 
From birth (Visit 1-NB) to 9 
months (C2-NB), occurrences 
of any medically assessed, 
RSV-associated LRTIs 
according to the case 
definitions. 
 
Secondary Descriptive 
Efficacy Endpoints  
Statistical Analysis Methods 
From birth to 4 months, 
occurrences of severe or very 
severe medically assessed, 
RSV-associated LRTIs 
according to the case 
definition. 
From birth to 4 months, 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definitions 
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Secondary Descriptive 
Efficacy Endpoints  
Statistical Analysis Methods 
From birth to 6 months, 
occurrences of any medically 
assessed, RSV-associated 
LRTIs by alternative case 
definitions. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause 
pneumonia. 
Occurrence of  RSV-associated 
medically attended RTIs (RSV-
MA-RTIs) from vaccination up 
to 6 months post-delivery (Visit 
4) 
From birth to 6 months, time to 
the first occurrence of severe 
(including very severe) 
medically assessed, RSV-
associated LRTIs according to 
the case definition 
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Section 9.4.4.2, Detailed Statistical Analysis Methods 
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Section 9.4.6.3, Predicted VE based on surrogate endpoint 
As a part of filing licensure strategy, Surrogate endpoint analyses will be conducted at 
the end of Stage A or at the same time as interim analysis #2 when there are 
approximately 4,600 maternal participants completing with the opportunity to complete 
6 months follow up in RSV MAT-009.post-delivery. If the lower bounds of the credible 
interval for the observed vaccine efficacy (VE) on either primary objective meet the pre-
specified criteria, then the company plans to submit a file will claim success  based on 
the VE. However, if the pre-specified lower bounds for the observed VE are not met for 
either primary objective, then the company plans to submit a file based on the evaluate 
VE predicted by the surrogate endpoint (predicted VE) based on the following two 
strategies model: 
Strategy 1 The strategy can be summarized in 3 steps: 
1. Estimate the surrogate endpoint model using data from one or more GSK 
epidemiology studies. The model will be created based on the GSK RSV 
neutralizing antibody assay before the analysis of RSV MAT-009.  
2. Validate the model at the end of RSV MAT-009-Stage A interim analysis #2  (that 
is, validate whether the observed VE at the end of Stage A (when 4600 participants 
have had the opportunity to complete 6 months post-delivery) is “similar to” the 
predicted VE). The validation of the model is done using an equivalence test (H0: δ 
< –Δ or δ > Δ) if feasible, where δ is the difference between the predicted VE and 
the observed VE, and Δ is an appropriate equivalence margin, or other methods 
for the validation of surrogate endpoints such as Principal stratification 
[Frangakis, 2002; Follmann, 2006; Gilbert, 2008]. 
3. File under Accelerated Approval Claim success based on predicted VE at the end of 
RSV MAT-009-Stage A interim analysis #2.  This will occur if the predicted VE 
for either primary endpoint meets the pre-specified success criteria based on a 
successfully validated surrogate endpoint model. RSV MAT-009 will continue as 
designed. It is expected that the observed VE will meet the success criteria as trial 
continues (during Stage B); The final results would be submitted to convert to 
traditional approval.). 
For more detailsfor strategy 1, please refer to the separate statistical analysis plan “RSV 
Maternal Serocorrelate SAP.” 
Strategy 2 will be implemented due to the impact of COVID 19. If RSV MAT-009 is 
conducted during COVID 19 and social distancing, the number of RSV cases may be 
much smaller than needed for the observed VE to meet the success criteria. In addition, 
the smaller number of RSV cases may make it impossible to validate the surrogate 
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endpoint model at the end of Stage A as outlined in step 2 above. As routine prevention 
of RSV LRTI remains an unmet medical need, Strategy 2 is proposed as an alternative 
should social distancing result in the number of RSV LRTI cases being too low to 
estimate observed vaccine efficacy.    
Strategy 2 to license based only on a surrogate endpoint can be summarized in the 
following steps 
1. Estimate the surrogate endpoint model using data from one or more GSK 
epidemiology study(ies). 
2. Evaluate the surrogate endpoint model based on Novavax study results (immune 
response and observed VE). A comparison of the Novavax predicted VE using the 
surrogate endpoint model vs. the actual efficacy observed in the Novavax trial could 
serve to validate the surrogate endpoint model. This would be done before the 
analysis of RSV MAT-009.  
3. File under Accelerated Approval at the end of RSV-MAT-009-Stage A if the 
predicted VE for either of primary endpoints meets pre-specified success criteria 
based on the above surrogate endpoint model.  
4. Demonstration of vaccine effectiveness post licensure. 
A detailed plan for surrogate endpoint licensure strategy due to the impact of COVID 19 
will be provided in a separate document. 
In the case of filing based on a surrogate endpoint, RSV MAT-009 will continue as 
designed and the interim/final analysis on observed vaccine efficacy will be included as 
supplemental evidence.  
Section 9.5, Interim analyses 
Interim analyses of vaccine efficacy for the two primary endpoints will be performed.  
In Stage A, these interim analyses will be timed according to the number of mother/infant 
pairs who have completed 6 months of follow-up post-delivery/birth. This coincides with 
maternal Contact 1 / infant Visit 4-NB (Day 181 Post-Delivery/Birth).  
In Stage B, interim analyses will be timed according to the number of maternal 
participants randomized in the trial. Interims begin when 6,000 maternal subjects have 
been randomized and will be conducted every 1,000 maternal subjects randomized 
thereafter, up to a maximum of 9,000 maternal subjects randomized.  
In Stage A, the interim analysis will be conducted when 4600 maternal participants are 
randomized, and the purpose of this analysis is to decide if further enrollment is 
needed and if the study can be stopped for futility. The number of completed 
participants and events at this interim will be based on the accrual rate and attack rate 
in the trial. Based on a blinded assessment of the overall accrual rate and attack rate in 
the trial, GSK may decide if this interim will be performed. If the accrual rate is faster 
than expected or the attack rate is lower than expected, GSK may decide to skip this 
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Interim analyses of vaccine efficacy for the two primary endpoints will be conducted 
when 4600, 6500, and 8000 maternal participants have had the opportunity to complete 
6 months follow-up post-delivery. The trial can  claim success if either of the two 
primary endpoints meet success criteria at any of those three interim analyses.  
Table 27, Interim Analysis Schedule and Possible Decisions Made at each Analysis 
Prior table: 
Interim # 
Stage 
Timing of analysis 
Can decide to begin 
accrual to Stage B? 
Can stop 
for futility? 
Can claim 
success? 
 
 
# 
Participants 
Participants triggering 
analysis 
 
 
 
1 
A* 
2,000** 
Maternal subjects with 
the opportunity to 
complete 6 months 
follow-up post-delivery 
Yes 
No 
No 
2 
A* 
2,800 
Yes 
Yes 
Yes, after 
Stage A 
follow-up 
3 
B 
6,000 
Maternal subjects 
randomized 
- 
Yes 
Yes 
4 
B 
7,000 
- 
Yes 
Yes 
5 
B 
8,000 
- 
Yes 
Yes 
6 
B 
9,000 
- 
Yes 
Yes 
* If randomization and dosing in Stage A are completed before the data needed for the 
first and/or second interim analysis(es) is/are available, GSK may choose to continue to 
Stage B while remaining blinded to the clinical endpoint data.  
**If both the first and second interim analyses in Stage A would occur only after stage B 
enrolment and randomization has started, then the first analysis will not be performed. 
Replaced by: 
If accrual to If the trial is not halted at any interim analysis, then accrual to the trial will 
continue to 10,000 maternal participants with the opportunity to complete 6 months 
follow-up post-delivery to evaluate vaccine efficacy for the primary endpoint(s).  
Interim 
# 
Timing of analysis 
Can decide to 
stop accrual? 
Can stop 
for futility? 
Can claim 
success? 
Stage 
# 
Participants 
Participants triggering 
analysis 
1 
A 
4600 
Maternal participants 
randomized  
Yes 
Yes 
No 
2 
B 
4600 
Maternal participants with 
the opportunity to 
complete 6 months 
follow-up post-delivery 
- 
Yes 
Yes 
3 
B 
6500 
- 
Yes 
Yes 
4 
B 
8000 
- 
Yes 
Yes 


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Section 9.5.1, Sequence of analyses 
In addition to the interim analyses of efficacy described above, full analyses will occur as 
described below: 
 
When all 4600 maternal and infant participants enrolled in Stage A complete 6 
months follow up post-delivery/birth (to evaluate primary and surrogate efficacy 
endpoints, immunogenicity, reactogenicity and safety if either primary (observed), 
or surrogate (predicted) vaccine efficacy endpoints meet success criteria.) 
 
When all maternal and infant participants enrolled in both Stage A and Stage B have 
the opportunity to complete 6 months follow-up post-delivery/birth (to evaluate 
primary and secondary efficacy endpoints, immunogenicity, reactogenicity and 
safety) 
Section 9.5.2, Statistical considerations for interim analysis 
Section 10.1.3, Informed consent process 
Participants who are rescreened are required to sign a new ICF. 
Participants who are re-screened (because, for example, they could not meet the 
protocol allowed window between initial screening and V1/randomization/vaccination) 
are not required to sign a new ICF, unless the ICF was amended in the meantime. 
However, the investigator or his/her representative should ensure that there is 
documentation that the participant is still in agreement to participate in the study and 
be re-screened. This can be done on the initially signed ICF or, if applicable, on other 
study source/documentation (as per local practice/ regulations). 
Section 10.10, 
 
Table 53, 
 
 
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11.
REFERENCES
ACOG. Practice Bulletin No. 202 Summary: Gestational Hypertension and Preeclampsia. 
Obstetrics & Gynecology. 2019; 133 (1) 211-214. 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine 2009; 28:586–604. 
Carbonell-Estrany X, Pérez-Yarza G E, Laura García Sanchez L, et al. Long-Term 
Burden and Respiratory Effects of Respiratory Syncytial Virus Hospitalization in Preterm 
Infants-The SPRING Study. PLoS One 2015; May 8;10(5):e0125422 
Centers for Disease Control and Prevention (CDC). Birth Defects Surveillance Toolkit. 
2019. https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/index.html. Accessed 
15 March 2022. 
Dmitrienko A, Tamhane A, Wiens B. General Multistage Gatekeeping Procedures. 2008; 
Biometrical Journal 50(5):667-677. 
Fauroux B, Simo˜es A. F.E, Checchia A. P, et.alThe Burden and Long-term Respiratory 
Morbidity Associated with Respiratory Syncytial Virus Infection in Early Childhood. 
Infect Dis Ther 2017; 6:173–197 
GSK Study Report 200150/001. A prospective, epidemiological, interventional, multi-
country based, cohort study to assess the disease burden of respiratory syncytial virus 
(RSV) associated, suspected lower respiratory tract infections (LRTIs) in newborns, from 
birth up to 2 years of age and population attributable risk percent of RSV LRTI on the 
development of wheeze and asthma from birth up to 6 years of age. 
GSK Study Report 208068/001. A Phase 1/2 randomized observer-blind placebo-
controlled study to evaluate the safety, reactogenicity and immunogenicity of different 
dose levels of GSK Biologicals’ investigational unadjuvanted RSV maternal vaccine 
(GSK3888550A) compared to placebo when administered to healthy non-pregnant 
women aged 18-45 years 
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. 


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Kollmann TR. Variation between Populations in the Innate Immune Response to Vaccine 
Adjuvants. Front Immunol. 2013; 4:81.  
Metropolitan Atlanta Congenital Defects Program (MACDP). 2021. 
https://www.cdc.gov/ncbddd/birthdefects/documents/bpa-codes-rev2021-508c.xlsx. 
Accessed 15 March 2022. 
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.  
Royal College of Obstetrics and Gynecology (RCOG). Obstetric Cholestasis. Guideline 
43. 2011 
Shi T, McAllister D, O’Brien K et. al. Global, regional, and national disease burden 
estimates of acute lower respiratory infections due to respiratory syncytial virus in young 
children in 2015: a systematic review and modelling study. Lancet. 2017; 390: 946-58. 
World Health Organization [WHO]. Global Surveillance for COVID-19 caused by 
human infection with COVID-19 virus: Interim Guidance. March 2020. Available at: 
https://www.who.int/docs/default-source/coronaviruse/2020-03-20-
surveillance.pdf?sfvrsn=e6be6ef1_2. Accessed 15 March 2022.  


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TRADEMARKS 
The following trademarked products are referenced in the present protocol. 
Trademarks of the GSK group of companies 
 
Generic description 
Boostrix 
 
Combined diphtheria, tetanus and acellular pertussis 
vaccine, adsorbed 
 


Signature Page for RPS-CLIN-049947 v1.0
Signature Page for RPS-CLIN-049947 v1.0
Approval
I am approving the content of this document and
authorize its issuance.
03-Mar-2023 14:04:47 GMT+0000
PPD

SAP_001.pdf: 
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Statistical Analysis Plan 
Title: 
A Phase III, randomized, double-blind, placebo-
controlled multi-country study to demonstrate efficacy 
of a single dose of unadjuvanted RSV Maternal 
vaccine, administered IM to pregnant women 18 to 49 
years of age, for prevention of RSV associated LRTI 
in their infants up to 6 months of age  
eTrack study number and 
Abbreviated Title 
212171 (RSV MAT-009) 
Scope: 
All analyses for the primary and secondary objectives 
of the study. Analysis details for tertiary objectives 
may be described in an SAP Amendment.  
Date of Statistical Analysis 
Plan 
Amendment 5 Final: 21 Sep 2023 
APP 9000058193 Statistical Analysis Plan Template V5 (Effective date: 1July2020) 


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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ............................................................................................. 7 
1. 
DOCUMENT HISTORY ............................................................................................ 8 
2. 
OBJECTIVES/ENDPOINTS ..................................................................................... 9 
3. 
STUDY DESIGN .................................................................................................... 13 
4. 
ANALYSIS SETS ................................................................................................... 18 
4.1. 
Definition..................................................................................................... 18 
4.2. 
Criteria for eliminating data from Analysis Sets ........................................... 24 
4.2.1. 
Elimination from Exposed Set (ES) .............................................. 24 
4.2.2. 
Elimination from Modified Full Analysis Set for Efficacy 
(modified FAS-E) ......................................................................... 24 
4.2.2.1. 
Excluded Infants from Modified Full Analysis 
Set for Efficacy ........................................................... 24 
4.2.3. 
Elimination from Full Analysis Set for Efficacy (FAS-E) ................ 24 
4.2.3.1. 
Excluded Infants from Full Analysis Set for 
Efficacy ....................................................................... 24 
4.2.4. 
Elimination from Per protocol analysis set for Efficacy 
(PPS-E) ....................................................................................... 25 
4.2.4.1. 
Excluded Infants from Per protocol analysis set 
for Efficacy (PPS-E) .................................................... 25 
4.2.5. 
Elimination from Per-protocol analysis Set for 
Immunogenicity (PPS-I) ............................................................... 26 
4.2.5.1. 
Excluded participants from Per-protocol 
analysis set for immunogenicity of maternal 
participants ................................................................. 26 
4.2.5.2. 
Excluded participants from Per-protocol 
immunogenicity (PPS-I) analysis set of infant 
participants ................................................................. 28 
4.2.6. 
Elimination from solicited safety set ............................................. 30 
4.2.6.1. 
Excluded participants from Solicited safety set ........... 30 
5. 
STATISTICAL ANALYSES ..................................................................................... 30 
5.1. 
Demography ............................................................................................... 30 
5.1.1. 
Analysis of demographics/baseline characteristics planned 
in the protocol .............................................................................. 30 
5.1.2. 
Additional considerations ............................................................. 31 
5.2. 
Efficacy ....................................................................................................... 31 
5.2.1. 
Analysis of primary efficacy endpoints planned in the 
protocol ........................................................................................ 31 
5.2.1.1. 
Sensitivity Analyses .................................................... 33 
5.2.2. 
Analysis of secondary efficacy endpoints planned in the 
protocol ........................................................................................ 33 
5.3. 
Immunogenicity........................................................................................... 36 
5.3.1. 
Analysis of immunogenicity planned in the protocol ..................... 36 
5.3.2. 
Additional considerations ............................................................. 37 
5.3.2.1. 
Sensitivity analysis ..................................................... 37 


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5.3.2.2. 
Between group analysis ............................................. 37 
5.4. 
Analysis of safety and reactogenicity .......................................................... 38 
5.4.1. 
Analysis of safety and reactogenicity planned in the 
protocol ........................................................................................ 38 
5.4.2. 
Additional considerations ............................................................. 41 
5.4.2.1. 
Analysis of solicited events ......................................... 41 
5.4.2.2. 
Exclusion of implausible solicited Event ...................... 42 
5.4.2.3. 
Analysis of Unsolicited Adverse Events ...................... 42 
5.4.2.4. 
Combined Solicited and Unsolicited Adverse 
Events ........................................................................ 42 
5.4.2.5. 
Other analysis ............................................................ 42 
6. 
ANALYSIS INTERPRETATION .............................................................................. 43 
7. 
CONDUCT OF ANALYSES .................................................................................... 43 
7.1. 
Sequence of analyses................................................................................. 43 
7.2. 
Statistical considerations for interim analyses ............................................. 44 
8. 
CHANGES FROM PLANNED ANALYSES ............................................................. 44 
9. 
NON-STANDARD DATA DERIVATION RULES AND STATISTICAL 
METHODS ............................................................................................................. 44 
9.1. 
Gestational age at vaccination .................................................................... 45 
9.2. 
Immunogenicity........................................................................................... 45 
9.2.1. 
Assay cut-offs .............................................................................. 45 
9.2.1.1. 
Assay cut-offs for serology results .............................. 45 
9.2.1.1.1. 
Assay cut-offs for central nasal 
swabs ..................................................... 45 
9.2.2. 
RTI and LRTI ............................................................................... 46 
9.2.2.1. 
Alternative LRTI / Severe LRTI case definitions 
for data analysis in infants .......................................... 47 
9.2.3. 
Hematology and Biochemistry parameters ................................... 47 
9.3. 
Statistical Method ....................................................................................... 48 
10. ANNEXES .............................................................................................................. 48 
10.1. 
Business rules for standard data derivations and statistical methods .......... 48 
10.1.1. 
Handling of missing data .............................................................. 48 
10.1.1.1. Dates .......................................................................... 48 
10.1.1.2. Laboratory data .......................................................... 49 
10.1.1.3. Daily recording of solicited adverse events ................. 49 
10.1.1.3.1. Studies with electronic diaries ................. 49 
10.1.1.4. Unsolicited adverse events ......................................... 49 
10.1.2. 
Data derivation ............................................................................ 49 
10.1.2.1. Age at vaccination in days .......................................... 49 
10.1.2.2. Age at vaccination in months ...................................... 49 
10.1.2.3. Age at vaccination in years ......................................... 49 
10.1.2.4. Weight ........................................................................ 50 
10.1.2.5. Height/Length ............................................................. 50 
10.1.2.6. Body mass index (BMI) .............................................. 50 
10.1.2.7. Temperature ............................................................... 50 
10.1.2.8. Numerical serology results ......................................... 50 


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10.1.2.9. Geometric mean titres (GMTs) and 
concentrations (GMCs) ............................................... 50 
10.1.2.10. Onset day ................................................................... 51 
10.1.2.11. Duration of events ...................................................... 51 
10.1.2.12. Counting rules for combining solicited and 
unsolicited adverse events ......................................... 51 
10.1.2.13. Counting rules for occurrences of solicited 
adverse events ........................................................... 51 
10.1.3. 
Display of decimals ...................................................................... 51 
10.1.3.1. Percentages ............................................................... 51 
10.1.3.2. Differences in percentages ......................................... 52 
10.1.3.3. Demographic/baseline characteristics statistics .......... 52 
10.1.3.4. Serological summary statistics ................................... 52 
10.1.4. 
Statistical methodology ................................................................ 53 
10.1.4.1. Exact confidence intervals around proportions ........... 53 
10.1.4.2. Standardized asymptotic confidence intervals 
around differences in proportions ............................... 53 
10.1.4.3. Adjusted GMT or GMC ratios ..................................... 53 
10.2. 
TFL TOC..................................................................................................... 53 
11. REFERENCES ....................................................................................................... 54 
 


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LIST OF TABLES 
PAGE 
Table 1 
Study objectives and endpoints ................................................................ 9 
Table 2 
Study groups, sub-cohorts, interventions, and blinding foreseen 
in the study: Stage A .............................................................................. 16 
Table 3 
Study groups, sub-cohorts, interventions, and blinding foreseen 
in the study: Stage B .............................................................................. 17 
Table 4 
Maternal Participants ............................................................................. 18 
Table 5 
Infant participants ................................................................................... 18 
Table 6 
Overview of analysis sets and exclusion codes ...................................... 19 
Table 7 
Elimination code and condition for maternal participants ........................ 26 
Table 8 
Elimination code and condition for infant participants ............................. 28 
Table 9 
Intensity scales for solicited symptoms in adults..................................... 41 
Table 10 
Implausible Solicited Events ................................................................... 42 
Table 11 
MA-RTI case definitions for data analysis in maternal participants ......... 46 
Table 12 
RTI/LRTI case definitions for data analysis in infants ............................. 46 
Table 13 
Alternative LRTI / Severe LRTI case definitions in infants ...................... 47 


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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview – maternal participants ....................................... 13 
Figure 2 
Study design overview – infant participants ............................................ 14 


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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse Events of Special Interest 
ANOVA 
Analysis of Variance 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTRS 
Clinical Trial Registry Summary 
eCRF 
Electronic Case Report Form 
ES 
Exposed Set 
FAS 
Full Analysis Set 
GMC 
Geometric mean antibody concentration 
GMT 
Geometric mean antibody titre 
GSK 
GlaxoSmithKline 
HIC 
High Income Countries 
IDMC 
Independent Data Monitoring Committee 
LL 
Lower Limit of the confidence interval 
LLOQ 
Lower Limit of Quantification 
LMIC 
Low-middle Income Countries 
LRTI 
Lower Respiratory Tract Illness 
MAE 
Medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not Applicable 
NB 
Newborn 
PD 
Protocol Deviation 
PPS 
Per-Protocol Set 
RTI 
Respiratory Tract Illness 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBIR 
GSK Biological’s Internet Randomization System 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 


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1. 
DOCUMENT HISTORY 
Date 
Description 
Protocol Version 
02 Nov 2020 
Final 
Amendment 1: 05 Oct 
2020 
01 Nov 2021 
Amendment 1 
Amendment 2: 23 
Jun 2021 
17 Nov.2022 
Amendment 2 
Amendment 4: 15 
Mar 2022 
03 Jan 2023 
Amendment 3 
Amendment 4: 15 
Mar 2022 
09 Mar 2023 
Amendment 4 
Amendment 5: 23 
Feb 2023 
21 Sep 2023 
Amendment 5 
Amendment 5: 23 
Feb 2023 


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2. 
OBJECTIVES/ENDPOINTS 
Table 1 
Study objectives and endpoints  
Primary objectives 
Primary endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe LRTIs in their infant3 
participants up to 6 months of age 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of medically assessed 1, RSV-associated severe LRTIs 
according to the case definitions2.  
 
OR 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant3 participants up to 6 months of age 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs according 
to the case definitions2. 
AND 
To evaluate the safety of the RSV Maternal 
vaccine in infants born to mothers who were 
vaccinated with a single IM dose of study vaccine, 
up to 12 months after birth.  
Occurrence of SAEs, AEs leading to study termination and 
medically attended AEs from birth up to 6 months after birth5.  
Occurrence of SAEs, AEs leading to study termination and 
medically attended AEs from birth up to 12 months after birth5.  
Secondary efficacy objectives 
Secondary efficacy endpoints 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing RSV-associated 
hospitalization in their infant3 participants up to 6 
months of age. 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of RSV-associated hospitalizations according to the case 
definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant3 
participants up to 6 months of age, all cause LRTI  
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause LRTI. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant3 
participants up to 6 months of age, all cause LRTI 
with hospitalization.  
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause LRTI with hospitalization. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe LRTIs in their infant3 
participants up to 12 months of age. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), occurrences 
of medically assessed, RSV-associated severe (including very 
severe) LRTIs according to the case definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant3 participants up to 12 months of age. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), occurrences 
of any medically assessed, RSV-associated LRTIs according 
to the case definitions2. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing severe medically 
assessed1, RSV-associated LRTIs for each RSV 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of severe medically assessed1, RSV-associated LRTIs 
according to the case definition2, for RSV subtype A and RSV 
subtype B separately. 


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subtype (A and B) separately in their infant3 
participants up to 6 months of age  
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing any medically 
assessed1, RSV-associated LRTIs for each RSV 
subtype (A and B) separately in their infant3 
participants up to 6 months of age 
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs according 
to the case definition2, for RSV subtype A and RSV subtype B 
separately. 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated severe LRTIs in their infant3 
participants up to 4 months of age 
From birth (Visit 1-NB) to 4 months (Visit 3-NB), occurrences 
of severe medically assessed1, RSV-associated LRTIs 
according to the case definitions2.  
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing medically assessed1, 
RSV-associated LRTIs of any severity in their 
infant3 participants up to 4 months of age 
From birth (Visit 1-NB) to 4 months (Visit 3-NB), occurrences 
of any medically assessed1, RSV-associated LRTIs according 
to the case definitions2 
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing, in their infant3 
participants up to 6 months of age, all cause 
pneumonia.  
From birth (Visit 1-NB) to 6 months (Visit 4-NB), occurrences 
of all-cause pneumonia.  
To assess the efficacy of a single dose of the 
RSV Maternal vaccine administered to maternal 
participants in preventing RSV-associated 
hospitalization in their infant3 participants up to 12 
months of age. 
From birth (Visit 1-NB) to 12 months (Visit 5-NB), occurrences 
of RSV-associated hospitalizations according to the case 
definitions2. 
To assess the efficacy of a single dose of RSV 
Maternal vaccine administrated to maternal 
participants in preventing, in all vaccinated 
maternal participants up to 6 months post-
delivery, RSV associated medically attended RTIs 
(MA-RTIs) 
From study intervention administration (Visit 1) to 6 months 
post-delivery (Contact 1), occurrence of RSV-associated 
medically attended RTIs (RSV-MA-RTIs) 2. 
Secondary immunogenicity objectives 
Secondary immunogenicity endpoints 
To evaluate the immunogenicity of the RSV 
Maternal vaccine in a sub-cohort of maternal 
participants 30 days after the study intervention, 
and at delivery. 
Neutralizing antibody titers against RSV-A  
Measured on blood samples collected at Day 1 before the 
study intervention (Visit 1), at Day 31 (Visit 2), and at delivery 
(Visit 3). 
To evaluate the immunogenicity of the RSV 
Maternal vaccine in a sub-cohort of infants in 
Stage A, at birth and up to 6 months after birth 
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 72 hours 
after birth (if no cord blood sample can be obtained)  
Measured on a blood sample collected at Day 43 (Visit 2-NB), 
Day 121 (Visit 3-NB), or Day 181 (Visit 4-NB) after birth in 3 
sub-cohorts of infants.  
Infants born to women in the immunogenicity sub-cohort will 
be randomly assigned (1:1:1) to sample collection at 1 of the 3 
timepoints noted. 


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To evaluate the transfer of RSV-specific 
antibodies from a sub-cohort of maternal 
participants vaccinated with a single IM dose of 
the RSV Maternal vaccine to their infants at the 
time of delivery. 
RSVPreF3 IgG-specific antibody concentration measured 
on blood samples collected at Delivery and cord blood* 
The ratio between cord blood* and maternal RSVPreF3 IgG-
specific antibody concentrations  
* or an infant blood sample collected within 72 hours after birth 
(if no cord blood sample can be obtained). 
Secondary safety objectives 
Secondary safety endpoints 
To evaluate reactogenicity of a single IM dose of 
the RSV Maternal vaccine in stage A maternal 
participants, during a 7 day follow up period after 
the study intervention. 
Occurrence of solicited administration site and systemic 
events in stage A maternal participants, during a 7-day follow-
up period after the study intervention (i.e. the day of the 
intervention and 6 subsequent days). 
To evaluate the safety of a single IM dose of the 
RSV Maternal vaccine in all maternal participants, 
during a 30 day follow up period after the study 
intervention. 
Occurrence of unsolicited adverse events (AEs) in all maternal 
participants during a 30-day follow-up period after the study 
intervention (i.e. the day of the intervention and 29 subsequent 
days).  
To evaluate the safety of a single IM dose of the 
RSV Maternal vaccine in all maternal participants, 
from Visit 1 up to 6 months after delivery 
Occurrence of serious adverse events (SAEs) 5, AEs leading 
to study termination, and medically attended RTIs in all 
maternal participants from Visit 1 (Day 1) up to 6 months after 
delivery. 
Occurrence of all other medically attended AEs in all maternal 
participants from Visit 1 (Day 1) up to Day 42 after delivery. 
To evaluate pregnancy outcomes and pregnancy-
related adverse events of special interest after a 
single IM dose of the RSV Maternal vaccine 
administered to maternal participants, from Visit 1 
up to 6 weeks after delivery (Visit 4). 
Pregnancy outcomes5 from Day 1 (Visit 1) up to 6 weeks after 
delivery (Day 43 post-delivery, Visit 4). These include live birth 
with no congenital anomalies, live birth with minor congenital 
anomaly(ies) only; live birth with at least one major congenital 
anomaly, fetal death/still birth (antepartum or intrapartum) with 
no congenital anomalies, fetal death/still birth (antepartum or 
intrapartum) with only minor congenital anomalies, fetal 
death/still birth (antepartum or intrapartum) with at least 1 
major congenital anomaly; elective/therapeutic termination 
with no congenital anomalies; elective/therapeutic termination 
with only minor congenital anomalies, and elective/therapeutic 
termination with at least 1 major congenital anomaly. 
 
Pregnancy-related adverse events (AEs) of special interest 
from Day 1 (Visit 1) up to 6 weeks after delivery (Day 43 post-
delivery, Visit 4). These include maternal death, hypertensive 
disorders of pregnancy (gestational hypertension, pre-
eclampsia, pre-eclampsia with severe features including 
eclampsia), fetal growth restriction, pathways to preterm birth 
(premature preterm rupture of membranes, preterm labor, 
provider-initiated preterm birth), gestational diabetes mellitus, 
chorioamnionitis. 4,5  
To evaluate the occurrence of neonatal AEs of 
special interest (reported up to 6 weeks after 
birth), in infants born to mothers who were 
vaccinated with a single IM dose of the RSV 
Maternal vaccine 
The occurrence of neonatal AEs of special interest (reported 
up to 6 weeks after birth). These include small for gestational 
age, low birth weight including very low and extremely low 
birth weight (<2500 g, <1500g, <1000g), congenital anomalies 
(major external structural defects, internal structural defects, 
functional defects), neonatal death (in an extremely preterm 
birth [22<GA<28 weeks], in a preterm live birth [28<GA<37 
weeks], or in a term live birth), preterm birth. 4,5 


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Tertiary objectives: 
1By “medically assessed” it is meant that the infant was evaluated by a healthcare professional (physician, nurse, etc) 
for the lower respiratory tract illness. 
2Case definitions for RSV-associated medically attended RTIs, RSV associated LRTIs, surveillance for potential 
LRTIs, are briefly summarized in Section 9.2.2. 
3An infant is defined as a child younger than 1 year of age; a neonate is defined as an infant 28 days old or less.  
4Maternal and neonatal AESI and pregnancy outcomes should be recorded in the eCRF along with assessment of level 
of diagnostic certainty by GAIA definitions when applicable. Of note, some events of interest fall under a single 
category but have multiple subcategories. For example, hypertensive disorder 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. 
5The following adverse events are listed by GAIA as events of interest, but will not, for purposes of this study, be 
reported as AESIs. If any of these events meets the definition for an SAE, the event should be reported as such in the 
eCRF and the SAE narrative should contain enough information to permit assessment of level of diagnostic certainty 
by GAIA criteria: 
• 
Pregnancy-related: antenatal bleeding (morbidly adherent placenta, placental abruption, cesarean scar 
pregnancy, uterine rupture), postpartum hemorrhage, non-reassuring fetal status, oligohydramnios, 
polyhydramnios, gestational liver disease (intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy), 
maternal sepsis.  
• 
Neonatal: neonatal encephalopathy, congenital microcephaly (postnatally or prenatally diagnosed), neonatal 
infections (blood stream infections, meningitis, respiratory infection), respiratory distress in the neonate, failure to 
thrive, large for gestational age, macrosomia. 
CCI


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3. 
STUDY DESIGN 
Figure 1 
Study design overview – maternal participants 
 
GA = Gestational age; I = immune response; (S)AE = (serious) adverse event; RTI = respiratory tract illness  
Visit 2 may be replaced by Visit 3 in case of premature delivery. 
All = all participants 
Refer to Protocol Amendment 5 Section 6.3.2 for detailed description of Stage A and Stage B. Refer to Protocol 
Amendment 5 Section 6.3.2.1.1 for additional description of the Stage A sub-cohort.  
Solicited events will be evaluated for all participants in Stage A only 
* Any pregnancy-related event of special interest identified after Visit 4 should also be reported. 
In addition to the monthly contacts between Visit-2 and the Delivery visit, additional not pre-specified visits and 
contacts (any desired frequency) can be made between Visit-2 and the Delivery visit, as per investigator’s or maternal 
participant’s discretion. 
As from protocol Amentment 4, blood samples will be collected at delivery from all maternal participants. Placental 
samples will be collected at delivery from all maternal participants, if feasible 
Due to the stop on study enrolment and vaccination, nasal swab samples will no longer be collected from any 
maternal participant and no MA-RTI assessment visit will be performed, but the MAEs associated with an RTI 
will continue to be reported, as applicable. 


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Figure 2 
Study design overview – infant participants 
 
I = immune response; (S)AE = (serious) adverse event; RTI = respiratory tract illness  
Stage A + Stage B – all participants:  
*If cord-blood was not collected at delivery/birth, a blood sample should be collected from the infant within 72 hours 
post birth. Applies to all participants in Stage A and Stage B. 
**Any Neonatal AE of specific interest identified after Day 43 should also be reported. 
An additional recommended safety contact may be performed 8-days post-birth if deemed necessary by the 
investigator or by the parent/LAR(s). 
Due to the stop on study enrolment and vaccination, blood samples will no longer be collected at V2-NB, V3-NB or V4-
NB. 
• 
Study Type: self-contained 
• 
Study Duration: Approximately 10 to 11 months (including the screening visit) for 
maternal participants; approximately 1 year after birth for infant participants.  
• 
Blinding is as described in Table 2 and Table 3. 
• 
Randomized intervention allocation: A minimum of 4600 and up to a maximum of 
10,000 pregnant women (maternal participants) will be randomly assigned (2:1) to 
receive the investigational vaccine or control (placebo) at Visit 1. Randomization 
will take place in 2 sequential stages, A and B. Approximately 4,600 maternal 
participants will be randomized into Stage A. Stage B will only start after the last 
participant is randomized in Stage A. Participants in stage A will be randomized 
(12:2:2:2:6:1:1:1 ratio) to be in the RSV group, in one of the 3 infant blood sampling 
sub-cohorts and receiving the investigational vaccine (RSVMAT_BS1 (Day 43), 
RSVMAT_BS2 (Day 121), RSVMAT_BS3 (Day 181)), in the Control group, or in 
one of the 3 infant blood sampling sub-cohorts receiving placebo (Control_BS1 (Day 
43), Control_BS2 (Day 121), Control_BS3 (Day 181)). Randomization will be via 
the automated internet-based system (SBIR). The system’s randomisation algorithm 
of maternal enrolment will use a minimisation procedure accounting for maternal age 
at the time of the study intervention (18-34, 35-39, ≥40 years of age), gestational age 
at the time of the study intervention (240/7-280/7; 28 1/7-340/7), and center. 
Minimisation factors will have equal weight in the minimisation algorithm. 
• 
Study (intervention) groups are described in Table 2 and Table 3 
• 
Data collection: standardized Electronic Case Report Form (eCRF). E-Diaries will be 
used to collect solicited event data. 


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• 
Safety monitoring will be conducted by an unblinded Independent Data Monitoring 
Committee (IDMC) and by an unblinded Safety Review Team*. The analyses for 
IDMC safety evaluations will be described in a separate SAP for IDMC.  
* Due to the safety signal observed, the study was fully unblinded to ensure the 
safety of the participants. 
 


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Table 2 
Study groups, sub-cohorts, interventions, and blinding foreseen in the study: Stage A 
Approximately 4,600 maternal participants will be randomized during Stage A. 
 
 
 
 
Blinding 
Study 
groups 
Maternal participants (M) 
Infant participants (I) 
Study Groups 
for 
Randomization 
M only 
M + I 
I only 
 
~Number 
Age in 
Years 
(Min/Max) 
Intervention 
name 
Maternal Blood 
Sampling Sub-cohorts 
Infant Blood Sampling 
sub-cohorts 
(Allocation 
12:2:2:2:6:1:1:1) 
Screen-
ing 
Up to D181 
post 
delivery/birth 
D271, D366 
post 
delivery/birth 
 
 
 
 
Name 
~Number 
Name 
~Number 
 
- 
Double blind 
Double blind 
RSV_MAT 
~3,067 
18-49 
RSV_MAT 
RSV_MAT_0 
~2,040 
RSV_MAT_0 
~2,040 
RSVMAT_0 
● 
● 
● 
18-49 
RSV_MAT 
RSV_MAT_I 
~1020 
RSV_MAT_BS1 
~340 
RSVMAT_BS1 
● 
 
 
 
 
RSV_MAT_BS2 
~340 
RSVMAT_BS2 
● 
 
 
 
 
RSV_MAT_BS3 
~340 
RSVMAT_BS3 
● 
Control 
~1,533 
18-49 
Control 
Control_0 
~1020 
Control_0 
~1020 
Control_0 
● 
● 
● 
18-49 
Control 
Control_I 
~510 
Control_BS1 
~170 
Control_BS1 
● 
 
 
 
 
Control_BS2 
~170 
Control_BS2 
● 
 
 
 
 
Control_BS3 
~170 
Control_BS3 
● 
Control = Placebo; Infant sub-cohorts are abbreviated “BS1;” “BS2;” BS3” and correspond to visits 2-NB (Day 43), 3-NB (Day 121) and 4-NB (Day 181), respectively. 
RSVMAT_0 and Control_0 = maternal and infant participants who are not in a sub-cohort for immune response assessment.  
RSVMAT_I and Control_I = maternal sub-cohorts for immune response assessment.  
RSVMAT_BS1, _BS2, _BS3 = infants born to women in the RSVMAT_I sub-cohort and evaluated for immune response at the designated timepoint (D43, D121 or D181).  
Control_BS1, _BS2, _BS3 = infants born to women in the Control_I sub-cohort evaluated for immune response at the designated timepoint (D43, D121 or D181).  


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Table 3 
Study groups, sub-cohorts, interventions, and blinding foreseen in the study: Stage B 
Approximately a maximum of 5,400 maternal participants may be randomized during Stage B. 
Stage B will only start after the last participant is randomized in Stage A.  
Study groups  
Number of 
maternal 
participants 
Age of maternal 
participant at enrolment 
(Min/Max) 
Intervention name 
Study groups for 
randomization 
(Allocation 2:1) 
Blinding 
Maternal 
participants 
Only 
(Screening) 
Maternal 
participants 
V1-C1 
Infant participants 
V1-NB – V4NB 
(double-blind) 
Infant participants 
only 
Contact 2-NB – V5-
NB  
(double blind) 
RSV_MAT  
~3,600 
18 – 49 years 
RSV_MAT 
RSV_MAT 
● 
● 
● 
Control 
~1,800 
18 – 49 years 
Control 
Control 
● 
● 
● 


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4. 
ANALYSIS SETS 
4.1. 
Definition 
For the purpose of the analysis the following analysis sets are defined. 
Table 4 
Maternal Participants  
Analysis Set 
Description 
Enrolled 
All maternal participants who completed the informed consent process and signed the 
informed consent form. 
Exposed 
All maternal participants who received the study intervention. The allocation in a group is 
done in function of the administered intervention. 
Per Protocol - 
Immunogenicity 
All maternal participants who received the study intervention to which they were randomised 
and have post-vaccination data minus participants with protocol deviations that lead to 
exclusion.  
Solicited Safety – 
Stage A only 
All maternal participants in the Exposed Set who have solicited safety data 
Table 5 
Infant participants 
Analysis Set 
Description 
Exposed 
Infants live-born to exposed maternal participants, whose parents/LARs completed the 
informed consent process and signed the informed consent form. 
Per Protocol - 
Immunogenicity 
All infant participants in the Exposed set minus those who (a) were born less than 4 weeks 
post- maternal participant vaccination and/ or (b) have protocol deviations that lead to 
exclusion. 
Full Analysis - 
Efficacy  
All infant participants in the Exposed set. 
Modified Full 
Analysis - Efficacy 
All infant participants in the Exposed set who were born after at least 4 weeks of 
vaccination.  
Per Protocol - 
Efficacy 
All infant participants in the Modified Full Analysis – Efficacy set minus those who have 
protocol deviations that lead to exclusion. 
 


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Table 6 
Overview of analysis sets and exclusion codes 
 
Code 
Description 
Maternal analysis set 
Infant analysis set 
Determined in 
mother or 
infant  
 
Enrolled 
Exposed  
Per Protocol - 
Immunogenicity 
Solicited Safety 
Exposed  
Per Protocol - 
Immunogenicity 
Modified Full 
Analysis - 
Efficacy 
Full Analysis - 
Efficacy 
Per Protocol - 
Efficacy 
Mother 
800, 800# 
Fraudulent Data 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Mother 
900, 900# 
Invalid informed consent 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Mother 
1030, 1030# 
Study vaccine not administered 
 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Mother 
1040.Vx+*, 
1040# 
Administration of concomitant 
vaccine(s) forbidden in the protocol 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
1050, 1050# 
Randomisation failure 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
1060, 1060# 
Randomisation code was brokena 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
1070, 1070# 
Mother got vaccinated with the 
correct vaccine but incorrect volume 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
1070, 1070# 
Vaccination not according to protocol 
(site of injection, route of 
administration, wrong replacement of 
study treatment administered) 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
1070, 1070# 
Study treatment not prepared as per 
protocol (e.g. reconstitution) 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
1070, 1070# 
Other deviations related to wrong 
study treatment/ administration/dose 
 
 
Y 
 
 
Y 
 
 
Y 


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Code 
Description 
Maternal analysis set 
Infant analysis set 
Determined in 
mother or 
infant  
 
Enrolled 
Exposed  
Per Protocol - 
Immunogenicity 
Solicited Safety 
Exposed  
Per Protocol - 
Immunogenicity 
Modified Full 
Analysis - 
Efficacy 
Full Analysis - 
Efficacy 
Per Protocol - 
Efficacy 
Mother 
1070, 1070# 
Study treatment administered while 
contraindicated 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
1080, 1080# 
Vaccine temperature deviation 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
1090, 1090# 
Expired vaccine administered 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
1160 
No post-vaccination solicited safety 
data- Stage A participants only 
 
 
 
Y 
 
 
 
 
 
Mother 
2010, 2010# 
Protocol violation 
(inclusion/exclusion criteria) 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
2040.Vx+*, 
2040# 
Administration of any 
medication/product forbidden by the 
protocol 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
2050.Vx+*, 
2050# 
Intercurrent medical 
conditions/concomitant medications 
which are exclusionary as per 
protocol 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
2060.Vx+*, 
2060# 
Concomitant infection related to the 
vaccine which may influence the 
immune response 
 
 
Y 
 
 
Y 
 
 
Y 
Mother 
2070.Vx+*, 
2070# 
Concomitant infection not related to 
the vaccine but may influence the 
immune response 
 
 
Y 
 
 
Y 
 
 
Y 


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Code 
Description 
Maternal analysis set 
Infant analysis set 
Determined in 
mother or 
infant  
 
Enrolled 
Exposed  
Per Protocol - 
Immunogenicity 
Solicited Safety 
Exposed  
Per Protocol - 
Immunogenicity 
Modified Full 
Analysis - 
Efficacy 
Full Analysis - 
Efficacy 
Per Protocol - 
Efficacy 
Mother 
2090.Vx 
Participant did not comply with blood 
sample schedule 
 
 
Y 
 
 
 
 
 
 
Mother 
2100.Vx 
Serology result not available 
(immunogenicity sample collected 
but invalid/no result) 
 
 
Y 
 
 
 
 
 
 
Mother 
2120.Vx 
Obvious incoherence or abnormality 
or error in the data 
 
 
Y 
 
 
 
 
 
 
Mother 
2130.Vx 
Testing performed on serology 
samples not aligned with ICF 
 
 
Y 
 
 
 
 
 
 
Mother 
2110.Vx 
Immunogenicity sample collected but 
GSK decided not to test 
 
 
Y 
 
 
 
 
 
 
Infant 
800 
Fraudulent Data 
 
 
 
 
Y 
Y 
Y 
Y 
Y 
Infant 
900 
Invalid informed consent 
 
 
 
 
Y* 
Y 
Y 
Y 
Y 
Infant 
2010  
Protocol violation 
(inclusion/exclusion criteria) 
 
 
 
 
 
Y 
 
 
Y 
Infant 
2050.Vx 
Intercurrent medical conditions 
which are exclusionary as per 
protocol 
 
 
 
 
 
Y 
 
 
Y 
Infant 
2090.Vx 
Participant did not comply with blood 
sample schedule 
 
 
 
 
 
Y 
 
 
 


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Code 
Description 
Maternal analysis set 
Infant analysis set 
Determined in 
mother or 
infant  
 
Enrolled 
Exposed  
Per Protocol - 
Immunogenicity 
Solicited Safety 
Exposed  
Per Protocol - 
Immunogenicity 
Modified Full 
Analysis - 
Efficacy 
Full Analysis - 
Efficacy 
Per Protocol - 
Efficacy 
Infant 
2100.Vx 
Serology result not available 
(immunogenicity sample collected 
but invalid/no result) 
 
 
 
 
 
Y 
 
 
 
Infant 
2120.Vx 
Obvious incoherence or abnormality 
or error in the data 
 
 
 
 
 
Y 
 
 
 
Infant 
2130.Vx 
Testing performed on serology 
samples not aligned with ICF 
 
 
 
 
 
Y 
 
 
 
Infant 
2131.Vx 
Testing performed on nasal samples 
not aligned with ICF 
 
 
 
 
 
 
 
 
Y 
Infant 
2110.Vx 
Immunogenicity sample collected but 
GSK decided not to test 
 
 
 
 
 
Y 
 
 
 
Infant 
2040.Vx+, 
2040# 
Administration of any 
medication/product forbidden by the 
protocol (leading to elimination from 
PPS-E and PPS-I) 
 
 
 
 
 
Y 
 
 
Y 
Infant 
2140Vx+ 
Administration of any 
medication/product forbidden by the 
protocol (leading to elimination from 
PPS-I) 
 
 
 
 
 
Y 
 
 
 
Infant 
2240 
Administration of any 
medication/product forbidden by the 
protocol (leading to elimination from 
PPS-E) 
 
 
 
 
 
 
 
 
Y 


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Code 
Description 
Maternal analysis set 
Infant analysis set 
Determined in 
mother or 
infant  
 
Enrolled 
Exposed  
Per Protocol - 
Immunogenicity 
Solicited Safety 
Exposed  
Per Protocol - 
Immunogenicity 
Modified Full 
Analysis - 
Efficacy 
Full Analysis - 
Efficacy 
Per Protocol - 
Efficacy 
Infant 
2060.Vx, 
2060# 
Concomitant infection related to the 
vaccine which may influence 
immune response 
 
 
 
 
 
Y 
 
 
Y 
Infant 
2070.Vx, 
2070# 
Concomitant infection not related to 
the vaccine but may influence 
immune response 
 
 
 
 
 
Y 
 
 
Y 
Infant 
3100 
Birth is less than 4 weeks post-
vaccination 
 
 
 
 
 
Y 
Y 
 
Y 
* 
in case a mother withdraws consent or does not consent for the baby, we still report SAEs/AESIs for the infants if collected 
.Vx  indicates participants whose data will be eliminated from a specific endpoint/visit 
.Vx+ indicates participants whose data will be eliminated from a specific endpoint/visit onwards 
Y 
indicates exclusion  
#  
Carry forward elimination from mother to infant 
a 
Randomization code was broken (1060, 1060#) does not apply to the unblinding of all participants during the study due to the stop on study enrollment and vaccination and the 
study was fully unblinded  
 


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4.2. 
Criteria for eliminating data from Analysis Sets 
4.2.1. 
Elimination from Exposed Set (ES) 
4.2.2. 
Elimination from Modified Full Analysis Set for Efficacy (modified 
FAS-E) 
4.2.2.1. 
Excluded Infants from Modified Full Analysis Set for Efficacy 
An infant will be excluded from the modified FAS efficacy analysis under the following 
conditions: 
Code 
Condition under which the code 
is used 
Visit (timepoints) where the code is 
applicable 
800, 800# 
Fraudulent data 
All 
900, 900# 
Invalid informed consent 
All 
1030# 
Study vaccine not administered 
All 
3100 
Birth is less than 4 weeks post-
vaccination 
All 
#  
Carry forward elimination from mother to infant 
4.2.3. 
Elimination from Full Analysis Set for Efficacy (FAS-E) 
4.2.3.1. 
Excluded Infants from Full Analysis Set for Efficacy 
An infant will be excluded from the FAS efficacy analysis under the following 
conditions: 
Code 
Condition under which the code is 
used 
Visit (timepoints) where the code is 
applicable 
800, 800# 
Fraudulent data 
All 
900, 900# 
Invalid informed consent 
All 
1030# 
Study vaccine not administered 
All 
#  
Carry forward elimination from mother to infant 
CCI
CCI


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4.2.4. 
Elimination from Per protocol analysis set for Efficacy (PPS-E) 
4.2.4.1. 
Excluded Infants from Per protocol analysis set for Efficacy (PPS-E) 
A participant will be excluded from the PPS efficacy analysis under following conditions: 
Code 
Condition under which the code is used 
Visit (timepoints) where 
the code is applicable 
800, 800# 
Fraudulent data 
All 
900, 900# 
Invalid informed consent 
All 
1030# 
Study vaccine not administered 
All 
3100 
Birth/Delivery is less than 4 weeks post-
vaccination 
All 
1040# 
Administration of concomitant vaccine(s) 
forbidden in the protocol 
All 
1050# 
Randomisation failure 
All 
1060# 
Randomisation code was broken 
All 
1070# 
Mother got vaccinated with the correct 
vaccine but containing an incorrect volume 
All 
1070# 
Vaccination not according to protocol (site 
of injection, route of administration, wrong 
replacement of study treatment 
administered) 
All 
1070# 
Study treatment not prepared as per protocol 
(e.g. reconstitution) 
All 
1070# 
Other deviations related to wrong study 
treatment/administration/dose 
All 
1070# 
Study treatment administered while 
contraindicated 
All 
1080# 
Vaccine temperature deviation 
All 
1090# 
Expired vaccine administered 
All 
2010, 
2010# 
Protocol violation (inclusion/exclusion 
criteria) 
All 
2040* 
Administration of any medication/product 
forbidden by the protocol (leading to 
elimination from PPS-E and PPS-I) 
All 
2240* 
Administration of any medication/product 
forbidden by the protocol (leading to 
elimination from PPS-E) 
All 
2040* 
Administration of any medication/product 
forbidden by the protocol (leading to 
elimination from PPS-E and PPS-I) 
All 
2050.Vx* 
Intercurrent medical conditions/concomitant 
medications which are exclusionary as per 
protocol 
All 


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Code 
Condition under which the code is used 
Visit (timepoints) where 
the code is applicable 
2050#* 
Maternal intercurrent medical conditions 
which are exclusionary as per protocol 
All 
2060#* 
2060* 
Concomitant infection related to the vaccine 
which may influence immune response 
All 
2070#* 
2070* 
Concomitant infection not related to the 
vaccine but may influence immune response 
All 
2120.Vx 
Obvious incoherence or abnormality or 
error in data 
All 
2131.Vx 
Testing performed on nasal samples not 
aligned with ICF 
All 
.Vx  indicates participants whose efficacy data will be eliminated from a specific endpoint 
#  
Carry forward elimination from mother to infant 
* 
Attribution of these elimination codes to participant need CRDL review of individual listing 
4.2.5. 
Elimination from Per-protocol analysis Set for Immunogenicity 
(PPS-I) 
4.2.5.1. 
Excluded participants from Per-protocol analysis set for 
immunogenicity of maternal participants 
A participant will be excluded from the PPS immunogenicity analysis under the 
following conditions: 
Table 7 
Elimination code and condition for maternal participants 
Code 
Condition under which the code is 
used 
Visit (timepoints) where the code 
is applicable 
800 
Fraudulent data 
All 
900 
Invalid informed consent 
All 
1030 
Study vaccine not administered 
All 
1040.Vx+* 
Administration of concomitant 
vaccine(s) forbidden in the protocol 
All 
1050 
Randomisation failure 
All 
1060 
Randomisation code was broken 
All 
1070* 
Mother got vaccinated with the 
correct vaccine but incorrect volume 
All 
1070* 
Vaccination not according to 
protocol (site of injection, route of 
administration, wrong replacement 
of study treatment administered) 
All 
1070* 
Study treatment not prepared as per 
protocol (e.g. reconstitution) 
All 
1070* 
Other deviations related to wrong 
study treatment/administration/dose 
All 


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Code 
Condition under which the code is 
used 
Visit (timepoints) where the code 
is applicable 
1070* 
Study treatment administered while 
contraindicated  
All 
1080 
Vaccine temperature deviation 
All 
1090 
Expired vaccine administered 
All 
2010 
Protocol violation 
(inclusion/exclusion criteria) 
All 
2040.Vx+* 
Administration of any 
medication/product forbidden by the 
protocol 
Visit 2/Day 31,  
Visit 3/Delivery 
2050.Vx+* 
Intercurrent medical conditions 
which are exclusionary as per 
protocol 
Visit 2/Day 31,  
Visit 3/Delivery 
 
2060.Vx+* 
Concomitant infection related to the 
vaccine which may influence 
immune response 
Visit 2/Day 31,  
Visit 3/Delivery 
2070.Vx+* 
Concomitant infection not related to 
the vaccine but may influence 
immune response 
Visit 2/Day 31,  
Visit 3/Delivery 
2090.Vx 
Participants did not comply with 
blood sample schedule: 
• 
For PPS at Visit 2/Day 31, 
check the interval from 
vaccination to day 31  
BS = -10/+15 days; 
• 
For PPS at Visit 3/Delivery, 
check the interval from delivery 
to delivery BS = -1/+3 days 
Visit 2/Day 31,  
Visit 3/Delivery 
 
2100.Vx 
Serological results not available 
(immunogenicity sample collected but 
invalid/no result) 
Visit 1/Day 1 
Visit 2/Day 31,  
Visit 3/Delivery 
2120.Vx 
Obvious incoherence or abnormality 
or error in the data 
Visit 2/Day 31,  
Visit 3/Delivery 
2130.Vx 
Testing performed on serology 
samples not aligned with ICF 
Visit 2/Day 31,  
Visit 3/Delivery 
2110.Vx 
Immunogenicity sample collected 
but GSK decided not to test 
Visit 1/Day 1 
Visit 2/Day 31,  
Visit 3/Delivery 
* 
Attribution of these elimination codes to participant need CRDL review of individual listing 
.Vx+ indicates participants whose immunogenicity data will be eliminated from a specific visit onwards;  
.Vx indicates participants whose immunogenicity data will be eliminated from a specific visit. 


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4.2.5.2. 
Excluded participants from Per-protocol immunogenicity (PPS-I) 
analysis set of infant participants 
An infant participant will be excluded from the PPS immunogenicity analysis under 
following conditions: 
Table 8 
Elimination code and condition for infant participants 
Code 
Condition under which the code is 
used 
Visit (timepoints) where the 
code is applicable 
800, 800# 
Fraudulent data 
All 
900, 900# 
Invalid informed consent 
All 
1030# 
Study vaccine not administered 
All 
1040.Vx#+* Administration of concomitant 
vaccine(s) forbidden in the protocol 
All 
1050# 
Randomisation failure 
All 
1060# 
Randomisation code was broken 
All 
1070#* 
Mother got vaccinated with the 
correct vaccine but incorrect volume 
All 
1070#* 
Vaccination not according to 
protocol (site of injection, route of 
administration, wrong replacement 
of study treatment administered) 
All 
1070#* 
Study treatment not prepared as per 
protocol (e.g. reconstitution) 
All 
1070#* 
Other deviations related to wrong 
study treatment/administration/dose 
All 
1070#* 
Study treatment administered while 
contraindicated  
All 
1080# 
Vaccine temperature deviation 
All 
1090# 
Expired vaccine administered 
All 
2010, 2010# Protocol violation 
(inclusion/exclusion criteria) 
All 
2040#* 
Administration of any 
medication/product forbidden by the 
protocol 
All 
2140.#* 
Administration of any 
medication/product forbidden by the 
protocol 
All 
2040Vx* 
Administration of any 
medication/product forbidden by the 
protocol 
Visit 1-NB/Birth 
Visit 2-NB/Day 43 post-birtha 
Visit 3-NB/Day 121 post-birtha 
Visit 4-NB/Day 181 post-birtha 
2140Vx* 
Administration of any 
medication/product forbidden by the 
protocol (leading to elimination 
from PPS-I) 
Visit 1-NB/Birth 
Visit 2-NB/Day 43 post-birtha 
Visit 3-NB/Day 121 post-birtha 
Visit 4-NB/Day 181 post-birtha 


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Code 
Condition under which the code is 
used 
Visit (timepoints) where the 
code is applicable 
2050.Vx#* 
Intercurrent medical conditions 
which are exclusionary as per 
protocol 
All 
2050.Vx* 
Intercurrent medical conditions 
which are exclusionary as per 
protocol 
All 
2060.Vx#+* 
2060.Vx+* 
Concomitant infection related to the 
vaccine which may influence 
immune response 
All 
2070.Vx#+* 
2070.Vx+* 
Concomitant infection not related to 
the vaccine but may influence 
immune response 
All 
2090.Vx 
Participants did not comply with 
blood sample schedule 
• 
For PPS at Visit 1/Day 1 check 
the interval of day 1 BS -0/+3 
days; 
• 
For PPS at Visit 2/Day 43 post-
birth, check the interval of day 
43 BS -12/+18 days; 
• 
For PPS at Visit 3/Day 121 
post-birth, check the interval of 
day 121 BS -10/+20 days; 
• 
For PPS at Visit 4/Day 181 
post-birth, check the interval of 
day 181 -15/+20 days 
Visit 1-NB/Birth 
Visit 2-NB/Day 43 post-birtha 
Visit 3-NB/Day 121 post-birtha 
Visit 4-NB/Day 181 post-birtha 
2100.Vx 
Serological results not available 
(immunogenicity sample collected but 
invalid/no result) 
Visit 1-NB/Birth 
Visit 2-NB/Day 43 post-birtha 
Visit 3-NB/Day 121 post-birtha 
Visit 4-NB/Day 181 post-birtha 
2120.Vx 
Obvious incoherence or abnormality 
or error in the data 
Visit 1-NB/Birth 
Visit 2-NB/Day 43 post-birtha 
Visit 3-NB/Day 121 post-birtha 
Visit 4-NB/Day 181 post-birtha 
2130.Vx 
Testing performed on serology 
samples not aligned with ICF 
Visit 1-NB/Birth 
Visit 2-NB/Day 43 post-birtha 
Visit 3-NB/Day 121 post-birtha 
Visit 4-NB/Day 181 post-birtha 
2110.Vx 
Immunogenicity sample collected 
but GSK decided not to test 
Visit 1-NB/Birth 
Visit 2-NB/Day 43 post-birtha 
Visit 3-NB/Day 121 post-birtha 
Visit 4-NB/Day 181 post-birtha 
3100 
Birth is less than 4 weeks post-
vaccination. 
All 
* 
Attribution of these elimination codes to participant need CRDL review of individual listing 


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# 
Carry forward elimination from mother to infant 
Vx+  indicates participants whose immunogenicity data will be eliminated from a specific visit onwards; 
Vx  indicates participants whose immunogenicity data will be eliminated from a specific visit. 
a 
As per Protocol Amendment 4, infant blood samples will not be collected at V2-NB, V3-NB and V4-NB. 2090.Vx, 
2100.Vx, 2120.Vx, 2130.Vx will not be applicable to infant participants whose blood samples are not collected under 
Protocol Amendment 4. 
4.2.6. 
Elimination from solicited safety set 
4.2.6.1. 
Excluded participants from Solicited safety set 
Code 1030 (Study vaccine not administered at all), code 800 (fraudulent data), code 900 
(invalid informed consent) and code 1160 (no post-vaccination solicited safety data only 
for Stage A participants) will be used for identifying participants eliminated from the 
solicited safety set.  
5. 
STATISTICAL ANALYSES 
Standard data derivation rules and stat methods are described in section 10.1 while the 
study specific data derivation rules and stat methods are described in section 9. 
5.1. 
Demography 
5.1.1. 
Analysis of demographics/baseline characteristics planned in the 
protocol 
These analyses will be performed on the Exposed set (ES) for maternal and infant 
participants and on the modified Full Analysis - Efficacy set (modified FAS-E) for infant 
participants. Analysis may also be repeated on the Per Protocol set for immunogenicity 
for maternal as well as infant participants. 
For all maternal participants, demographic characteristics (e.g., age at vaccination (18-34, 
35-39, ≥40 years of age), gestational age at vaccination (240/7 - 280/7, 281/7 - 34 0/7weeks), 
geographic ancestry) will be summarized by group and overall 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 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 variables such as gestational age 
at time of delivery (≥ 37 weeks; < 37 weeks). 
• 
Mean, median, standard deviation and range will be provided for continuous data 
such as age. 


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Demographics and baseline characteristics as well as the lifestyle characteristics may be 
reported by geographic region and by economic region (LMIC and HIC). 
5.1.2. 
Additional considerations 
Demographic characteristics will also be summarized on the Enrolled Set for public 
disclosure. 
Subgroup analysis for demographic characteristics by age category at vaccination (18 – 
34, 35-39; ≥ 40 years) for maternal participants and by gestational age at birth (≥ 37 
weeks or < 37 weeks) for infant participants will also be performed on ES or modified 
FAS-E for infant participants. 
Participants disposition will be summarized by group using descriptive statistics: 
• 
Number of maternal participants enrolled, randomised, vaccinated, eligible for 
maternal efficacy populations and withdrawn including withdrawal reasons in each 
group and overall will be tabulated. 
• 
Number of infants enrolled, eligible for infant efficacy populations and withdrawn 
including withdrawal reasons will be tabulated by group, by sub-cohort within each 
group and overall.  
Vital signs will not be summarized for this study.  
Summary of important protocol deviations leading to elimination will be tabulated by 
group and overall. An individual listing will also be provided. 
Summary of medical history will be performed on ES by Medical Dictionary for 
Regulatory Activities (MedDRA) and preferred term. 
5.2. 
Efficacy 
5.2.1. 
Analysis of primary efficacy endpoints planned in the protocol 
The primary analysis of vaccine efficacy (VE) will be based on the modified Full 
Analysis - Efficacy set for infants (modified FAS-E). A secondary analysis based on the 
Full Analysis – Efficacy set (FAS-E) and the Per Protocol - Efficacy set for infants will 
be performed to complement the modified FAS-E analysis.  


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Primary Efficacy Endpoints – Infant 
participants 
Statistical Analysis Methods 
From birth to 6 months, occurrences of 
medically assessed, RSV-associated 
severe LRTIs according to the case 
definitions.  
OR 
From birth to 6 months, occurrences of 
any medically assessed, RSV-
associated LRTIs according to the case 
definitions. 
CCI
CCI


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5.2.1.1. 
Sensitivity Analyses 
Supportive analysis of time to confirmed RSV-LRTI of any severity and time to 
confirmed severe RSV-LRTI will be conducted by using Kaplan-Meier cumulative 
incidence curves. 
Sub-group analyses by regions and by key demographic characteristics may also be 
explored. In addition, efficacy analyses stratified by VE reported for geographic regions 
(North America, Central America & Caribbean, and South America), economic regions 
(LMIC and HIC), RSV type and RSV seasonality (year-round circulation and seasonal 
circulation) may be included in the clinical study report. 
Supportive analyses on primary efficacy endpoints based on the modified FAS-E will 
also be conducted for RSV-associated LRTI cases confirmed by central laboratory tests 
and PCR confirmed local laboratory tests and by all RSV tests (central and all local 
laboratory tests). 
5.2.2. 
Analysis of secondary efficacy endpoints planned in the protocol 
The primary analysis of VE on secondary efficacy endpoints in infants will be based on 
the modified Full Analysis - Efficacy set (modified FAS-E). The analysis of vaccine 
efficacy in maternal participants will be based on the Exposed set. 
CCI


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Secondary Efficacy 
Endpoints  
Statistical Analysis Methods 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of RSV-associated 
hospitalizations according to 
the case definitions. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause LRTIs  
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause LRTIs 
with hospitalization  
From birth (Visit 1-NB) to 12 
months, occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definitions 
From birth (Visit 1-NB) to 12 
months, occurrences of any 
medically assessed, RSV-
associated LRTIs according to 
the case definitions. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definition, for RSV 
subtype A and RSV subtype B 
separately. 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definition, for RSV subtype A 
and RSV subtype B separately. 
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Secondary Efficacy 
Endpoints  
Statistical Analysis Methods 
From birth (Visit 1-NB) to 4 
months (Visit 3-NB), 
occurrences of severe 
medically assessed, RSV-
associated LRTIs according to 
the case definition. 
From birth (Visit 1-NB) to 4 
months (Visit 3-NB), 
occurrences of any medically 
assessed, RSV-associated 
LRTIs according to the case 
definitions 
From birth (Visit 1-NB) to 6 
months (Visit 4-NB), 
occurrences of all-cause 
pneumonia 
From study intervention 
administration (Visit 1) to 6 
months post-delivery (Contact 
1), occurrence of RSV-
associated medically attended 
RTIs (RSV-MA-RTIs) 
From birth (Visit 1-NB) to 12 
months (Visit 5-NB), 
occurrences of RSV-associated 
hospitalizations according to 
the case definitions. 
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5.3. 
Immunogenicity 
5.3.1. 
Analysis of immunogenicity planned in the protocol 
All immunogenicity analyses in stage A will be based on the Per Protocol - 
Immunogenicity set.  
Note: In the immunogenicity sub-cohort, only those samples for which a pair (both 
maternal and respective infant) exist will be analyzed to evaluate secondary 
immunogenicity objectives and to assess antibody persistence in infants. 
When performing experiments to monitor the stability of the RSV NEUT A assay 
overtime, a QC panel excursion was observed for tests performed after May 2023. 
Consequently, the testing was temporarily paused and not all samples were tested. 
Secondary Immunogenicity 
Endpoints – Maternal Participants 
Statistical Analysis Methods 
• 
Neutralizing antibody titers 
against RSV-A  
Measured on blood samples collected 
at Day 1 before vaccination (Visit 1), at 
Day 31 (Visit 2), and at delivery (Visit 3). 
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Secondary Immunogenicity 
Endpoints – Cord blood / placental 
transfer 
Statistical Analysis Methods 
• 
RSVPreF3 IgG-specific 
antibody concentration 
measured on blood samples 
collected at Delivery and cord 
blood* 
• 
The ratio between cord blood* 
and maternal RSVPreF3 IgG-
specific antibody concentrations  
* or an infant blood sample collected 
within 72 hours after birth (if no cord 
blood sample can be obtained). 
Secondary Immunogenicity 
Endpoints – Infant Participants 
• 
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 72 hours after birth if no cord 
blood sample can be obtained) and at 
Day 43 (Visit 2-NB), Day 121 (Visit 3-
NB), or Day 181 (Visit 4-NB) after 
delivery in 3 sub-cohorts of infants. 
Infants born to women in the 
immunogenicity sub-cohorts will be 
randomly assigned (1:1:1) to sample 
collection at 1 of the 3 timepoints noted. 
5.3.2. 
Additional considerations 
5.3.2.1. 
Sensitivity analysis 
A sensitivity analysis will be performed based on the Per Protocol-Immunogenicity set 
excluding participants in Bangladesh. 
5.3.2.2. 
Between group analysis 
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5.4. 
Analysis of safety and reactogenicity 
5.4.1. 
Analysis of safety and reactogenicity planned in the protocol 
Safety analyses in maternal participants will include summaries by study group and age 
category (18-34, 35-39, ≥40 years of age; overall) of solicited administration site and 
systemic events (for stage A subjects), unsolicited AEs, MAEs, SAEs, MA-RTIs (RSV-
associated MA-RTIs and all-cause MA-RTIs), AEs leading to study withdrawal, 
pregnancy outcomes and pregnancy related AESIs.  
Safety analyses in infant participants will include summaries by study group, overall 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, RSV-associated hospitalizations, all-cause RTI and all-cause LRTI. 
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Safety analyses for maternal participants and infants may also be reported by economic 
region (LMIC and HIC). 
Analyses of solicited AEs will be performed on the Solicited Safety set (maternal 
participants only). Analyses of unsolicited AEs will be performed on the ES.  
Primary Safety Endpoints – Infant 
Participants 
Statistical Analysis Methods  
Occurrence of SAEs, AEs leading to study 
termination and medically attended AEs from 
birth up to 6 months after birth  
Occurrence of SAEs, AEs leading to study 
termination and medically attended AEs from 
birth up to 12 months after birth.  
Secondary Safety Endpoints – Maternal 
Participants 
Statistical Analysis Methods  
Occurrence of solicited injection site and 
systemic events in Stage A participants during 
a 7-day follow-up period after vaccination (i.e. 
the day of vaccination and 6 subsequent days). 
Occurrence of unsolicited adverse events (AEs) 
in all maternal participants during a 30-day 
follow-up period after vaccination (i.e. the day 
of vaccination and 29 subsequent days). 
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Pregnancy outcomes from Day 1 (Visit 1) up to 
6 weeks after delivery (Day 43 post-delivery, 
Visit 4). These include live birth with no 
congenital anomalies, live birth with minor 
congenital anomaly(ies) only; live birth with at 
least one major congenital anomaly, fetal 
death/still birth (antepartum or intrapartum) with 
no congenital anomalies, fetal death/still birth 
(antepartum or intrapartum) with minor 
congenital anomalies only, fetal death/still birth 
(antepartum or intrapartum) with at least 1 
major congenital anomaly; elective/therapeutic 
termination with no congenital anomalies; 
elective/therapeutic termination with minor 
congenital anomalies only, and 
elective/therapeutic termination with at least 1 
major congenital anomaly. 
Pregnancy-related adverse events (AEs) of 
special interest from Day 1 (Visit 1) up to 6 
weeks after delivery (Day 43 post-delivery, Visit 
4). These include maternal death, hypertensive 
disorders of pregnancy (gestational 
hypertension, pre-eclampsia, pre-eclampsia 
with severe features including eclampsia), fetal 
growth restriction, pathways to preterm birth 
(premature preterm rupture of membranes, 
preterm labor, provider-initiated preterm birth), 
gestational diabetes mellitus, chorioamnionitis.  
Occurrence of serious adverse events (SAEs), 
AEs leading to study termination, and medically 
attended AEs in all maternal participants from 
Visit 1 (Day 1) up to 6 months after delivery. 
Secondary Safety Endpoints – Infant 
Participants 
The occurrence of neonatal AEs of special 
interest (reported up to 6 weeks after birth). 
These include small for gestational age, low 
birth weight including very low and extremely 
low birth weight (<2500 g, <1500g, <1000g), 
congenital anomalies (major external structural 
defects, internal structural defects, functional 
defects), neonatal death (in an extremely pre-
term birth (22<GA<28 weeks), in a preterm live 
birth (28<GA<37 weeks), or in a term live birth), 
preterm birth.  
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5.4.2. 
Additional considerations 
5.4.2.1. 
Analysis of solicited events 
The analysis of solicited events will be performed on Solicited Safety Set. The intensity 
of the following solicited events will be assessed as described: 
Table 9 
Intensity scales for solicited symptoms in adults  
Adults 
Event 
Intensity grade 
Parameter 
Pain at administration 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 administration site 
Record greatest surface diameter in mm 
Swelling at administration 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 
 
 
* Preferred location for measurement will be the oral cavity. “Fever” = temperature ≥38.0°C/100.4°F regardless of the 
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The maximum intensity of local injection site (redness and swelling) will be scored at 
GSK Biologicals as follows: 
0: 
≤ 20 mm 
1: 
> 20 mm to ≤50 mm 
2: 
> 50 mm to ≤100 mm 
3: 
>100 mm 
Duration in days of solicited administration site and systemic events within 7 days after 
vaccination will be tabulated by study group and overall, and if needed by age group. The 
derivation rule of duration in days for solicited events is detailed in section 10.1.2.11. 
5.4.2.2. 
Exclusion of implausible solicited Event 
Some local and systemic events will be directly measured by the participant and cannot 
be changed even if they are biologically implausible. Therefore, these implausible 
measurements will be removed from the analysis but included in listings. Implausible 
measurements are summarized in the table below: 
Table 10 
Implausible Solicited Events 
Parameter 
Implausible measurements 
Body temperature 
≤ 33°C or ≥ 42°C 
Erythema 
Measurements < 0 mm 
For participants ≥ 6 years: ≥ 900 mm 
Swelling 
Measurements < 0 mm 
For participants ≥ 6 years: ≥ 500 mm 
5.4.2.3. 
Analysis of Unsolicited Adverse Events 
The analysis of unsolicited events will be performed on ES 
5.4.2.4. 
Combined Solicited and Unsolicited Adverse Events 
The combined analysis of solicited and unsolicited events will be performed on ES. A 
summary of participants with all combined solicited and unsolicited adverse events will 
be provided.  
Solicited adverse events will be coded by MedDRA. 
For clintrial.gov and EudraCT posting purposes, a summary of combined solicited and 
unsolicited adverse events will be produced by System Organ Class and preferred terms 
and according to occurrence of each event.  
5.4.2.5. 
Other analysis 
Other safety analysis will be performed on ES.  
Concomitant medications will be coded using the GSKDRUG dictionary. The number 
and percentage of maternal participants taking concomitant medications (any medication, 
any antipyretic and any antipyretic taken prophylactically, respectively) within 7 days 


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following vaccination, 30 days following vaccination, up to 6 weeks post-delivery and up 
to 6 months post-delivery will be summarized by group. A listing will also be provided. 
The number and percentage of infants taking previous and concomitant 
medications/vaccinations from birth up to 6 weeks after birth, 6 months after birth and 1 
year after birth will be summarized by group. A listing will also be provided. 
6. 
ANALYSIS INTERPRETATION 
All comparative analyses will be descriptive with the aim to characterize the difference in 
immunogenicity between groups. These descriptive analyses should be interpreted with 
caution considering that there is no adjustment for multiplicity for most of these 
comparisons. 
7. 
CONDUCT OF ANALYSES 
7.1. 
Sequence of analyses 
An interim analysis of safety endpoints for both maternal and infant participants has been 
performed, with the focus on demonstrating the safety profile at Day 43 post-delivery. 
The interim analysis was deemed necessary following the identification of the safety 
signals documented in protocol amendment 4, which assisted in the better 
characterization of the safety information including the signals. The interim analysis was 
performed after all infants completed the 43 days post-delivery timepoint. The safety 
endpoints are identical to those listed in section 2, and the statistical analysis methods are 
similar to section 5.4.1. with minor modifications. In addition, summaries of 
demographics, participant disposition, concomitant medication/vaccinations and medical 
history was included. This analysis was performed by an external Independent Data 
Analysis Center (IDAC). In addition, monthly safety analyses are conducted, where most 
of the analyses have been generated by IDAC and monitored by the SRT on a monthly 
basis and by an Independent Data Monitoring Committee (IDMC) on a bi-monthly basis. 
Additional non-standardized ad-hoc analyses (safety signal deep dive) are performed by 
internal GSK.  
6 Month Post-delivery interim analysis occurred as described below: 
• 
When all maternal and infant participants enrolled completed 6 months follow-up 
post-delivery/birth (to evaluate primary and secondary efficacy endpoints, 
reactogenicity and safety) 
Final analysis will occur as described below: 
• 
When all infant participants have completed Visit 5-NB (month 12, LSLV), a final 
safety analysis (for all maternal and infant participants in both Stage A and Stage B), 
a final secondary efficacy analysis up to 12 months follow up post birth, and a final 
immunogenicity analysis will be performed. Analyses of any evaluated tertiary 
endpoints may also be performed. 
6 Month Post-delivery interim analysis was performed by internal GSK, so will be the 
final analysis.  


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If the data for tertiary endpoints becomes available at a later stage, (an) additional 
analysis/analyses will be performed. 
Description 
 
Disclosure Purpose 
 
Day 43 post-delivery interim analysis 
Internal 
6 Month post-delivery interim analysis 
Public Disclosure. 
Final Analysis at Month 12 post birth 
Public Disclosure, Study Report 
7.2. 
Statistical considerations for interim analyses 
Not applicable. 
8. 
CHANGES FROM PLANNED ANALYSES 
• 
By-participant listings of SAEs, AEs leading to study withdrawal, MAEs, adverse 
pregnancy outcomes and pregnancy related AESIs will be prepared and released. 
Such listings have already been released in earlier analyses. Due to study 
enrolment/vaccination stop, the study has been unblinded already before the final 
analysis. 
• 
A sensitivity analysis for immunogenicity results excluding participants from 
Bangladesh, for which HIV testing was not performed before their enrollment into 
the study, has been added. 
• 
Between group evaluations for immunogenicity analysis was clarified to be 
performed among RSV MAT and Control instead of vaccination groups, the wording 
has been corrected. 
• 
In February 2022, enrollment and vaccination were stopped because of an imbalance 
in preterm births and associated neonatal deaths observed between the RSVPreF3-
Mat and placebo groups. Subsequently the study was unblinded, and therefore the 
presented VE endpoints are descriptive. 
• 
Subgroup analyses by economic region (LMIC and HIC) will be performed for 
demography, efficacy, and safety evaluations. 
• 
Subgroup analyses by gestational age at birth will be performed for demography and 
safety evaluations. 
• 
Sensitivity analysis for primary efficacy endpoints by using a negative binominal 
regression model have been removed.  
9. 
NON-STANDARD DATA DERIVATION RULES AND 
STATISTICAL METHODS 
The following sections describe additional derivation rules and statistical methods which 
are not presented in section 10.1. 


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9.1. 
Gestational age at vaccination 
Gestational age at vaccination in weeks for maternal participants will be entered by the 
investigator and used for our analyses. It will not be derived from the estimated date of 
delivery. 
9.2. 
Immunogenicity 
For a given participant and given immunogenicity measurement, missing or non-
evaluable measurements will not be replaced. Therefore, an analysis will exclude 
participants with missing or non-evaluable measurements. 
• 
For the within-group assessment, the descriptive analysis performed for each assay at 
each timepoint will exclude participants with a missing or non-evaluable 
measurement. 
• 
For the between group assessments, statistical model will be fitted based on the 
participants having a result at both the baseline and the considered timepoint. 
The GMT/GMC and its 95% CI will be obtained by exponentiating the mean and its 
95% CI of the log-transformed titres/concentrations. All CI computed will be two-sided 
95% CI. 
Placental transfer is defined as the ratio of RSVPreF3 IgG-specific antibody 
concentrations between cord blood (or blood sample from infants collected within 3 days 
after birth if cord blood is not available) and maternal blood sample at delivery (or within 
3 days after delivery if blood sample is not collected during delivery).  
9.2.1. 
Assay cut-offs  
9.2.1.1. 
Assay cut-offs for serology results 
A seronegative participant is a participant whose antibody titre is below the cut-off value 
of the assay. A seropositive participant is a participant whose antibody titre is greater 
than or equal to the cut-off value of the assay. The cut-off tests for immunogenicity 
evaluation will be as per following: 
System 
Component 
Method 
Unit 
Cut-off 
(LLOQ) 
ULOQ 
Serum 
RSV-A Neutralising Antibody  
Serum 
RSVPreF3 IgG antibody 
concentrations 
Serum 
RSV-B Neutralising Antibody*  
Note: the assay cut-off (LLOQ), ULOQ and units may be further adjusted at time of analysis. 
*: RSV-B neutralizing antibody titers will no longer be assessed as part of the secondary immunogenicity endpoints. 
9.2.1.1.1. Assay cut-offs for central nasal swabs 
System 
Component 
Method 
Unit 
Cut-off  
Nasal Swab 
RSV-A positive 
Nasal Swab 
RSV-B positive 
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9.2.2. 
RTI and LRTI 
Cases will be classified (during data analyses) according to the definitions that follow. 
Table 11 
MA-RTI case definitions for data analysis in maternal participants 
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 of the Protocol 
2 RSV (nasal swab) sampling and testing as specified in Table 14 of the Protocol. 
3 Hospitalization is defined as admission for observation or treatment based on the judgement of a health care 
provider. 
MA-RTI = Maternal, medically attended respiratory tract illness 
Table 12 
RTI/LRTI case definitions for data analysis in infants 
RSV-RTI 
Runny nose, OR Blocked nose, OR Cough 
AND 
Confirmed RSV infection 4,5 
RSV-LRTI 
History of cough OR difficulty in breathing 1 
AND  
SpO2 < 95%2, OR RR increase 3 
AND  
Confirmed RSV infection 4,5 
RSV-severe LRTI 
Meeting the case definition of RSV-LRTI 
AND 
SpO2 < 93%2, OR lower chest wall in-drawing OR inability to feed OR failure to 
respond/unconscious 
RSV hospitalization 
Confirmed RSV infection 4,5 
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  
All-cause LRTI hospitalization 
Hospitalized due to all cause LRTI as defined above 
Definitions based on [Modjarrad, 2016]; except that definitions for severe and very severe  RSV LRTI have been 
merged. 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.  
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 
5 RSV (nasal swab) sampling and testing 
6 Hospitalization is defined as admission for observation or treatment based on the judgement of a health care 
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For RSV infection the sponsor will analyse 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. 
In the event the collection of a nasal swab for testing by the sponsor is impossible, results 
from locally collected samples, tested with locally approved tests, may also be considered 
for the determination of a case of RSV infection. 
For the analysis of RTI episode, a new RTI episode will be defined as any occurrence of 
cough and/or difficulty in breathing with an interval of at least 7 consecutive days 
without cough and/or difficulty in breathing since the last/previous episode of RTI.  
9.2.2.1. 
Alternative LRTI / Severe LRTI case definitions for data analysis in 
infants 
To meet an alternative case definition, a participant must have at least one item from each 
column. 
Note: As per protocol amendment 5, the alternative case definitions will no longer be 
considered for data analysis in infants. 
Table 13 
Alternative LRTI / Severe LRTI case definitions in infants 
RSV confirmed 
Documented PE findings 
indicating lower respiratory 
tract involvement 
Objective measures of clinical severity 
LRTI 
Confirmed RSV 
infection 
Rhonchi 
Increased respiratory rate (bpm) 
Crackles (Rales) 
• 
≥ 60 for < 2 mo 
Wheeze 
• 
≥ 50 for 2-6 mo 
 
Hypoxemia 
 
• 
SpO2 <95% at ≤1800 meters 
 
• 
SpO2 <92% at > 1800 meters 
 
New onset apnea 
 
Nasal flaring 
 
Retractions 
 
Grunting 
 
 
Severe LRTI 
Confirmed RSV 
infection 
Rhonchi 
Hypoxemia 
Crackles (Rales) 
• 
Sp02 <93% at ≤1800 meters 
Wheeze 
• 
Sp02 <90% at > 1800 meters 
 
Acute hypoxic or ventilatory failure 
 
Dehydration due to respiratory distress 
requiring IV hydration 
 
Failure to respond or unconscious 
9.2.3. 
Hematology and Biochemistry parameters 
In order to assess the impact of fluid shifts on the antibody concentration/titer, hematocrit 
will be evaluated at all three blood sampling timepoints (Day 1, Day 31, and delivery) for 
a subset of maternal (Stage A) participants in the immunogenicity sub-cohort, if deemed 
necessary.  


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Note that hematocrit sample collection will end once Protocol Amendment 2 becomes 
effective in the different countries/sites. 
9.3. 
Statistical Method 
Study Specific statistical methods for immunogenicity analysis are described in section 
5.3. 
10. 
ANNEXES  
10.1. 
Business rules for standard data derivations and statistical 
methods 
This section contains GSK Vaccines’ standard rules for data display and derivation for 
clinical and epidemiological studies. These rules will be applied along with those detailed 
in section 9 (additional study-specific rules). 
10.1.1. 
Handling of missing data 
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10.1.2. 
Data derivation 
10.1.2.1. 
Age at vaccination in days 
When age at vaccination is to be displayed in days, it will be calculated as: 
Age = date of vaccination minus date of birth 
10.1.2.2. 
Age at vaccination in months 
When age at vaccination is to be displayed in months, it will be calculated as the number 
of complete calendar months between the date of birth (DOB) and the date of 
vaccination. For example: 
DOB = 10JUN2017, Date of vaccination = 09JUL2018 -> Age = 12 months 
DOB = 10JUN2017, Date of vaccination = 10JUL2018 -> Age = 13 months 
10.1.2.3. 
Age at vaccination in years 
When age at vaccination is to be displayed in years, it will be calculated as the number of 
complete calendar years between the date of birth and the date of vaccination. For 
example: 
DOB = 10SEP1983, Date of vaccination = 09SEP2018 -> Age = 34 years 
DOB = 10SEP1983, Date of vaccination = 10SEP2018 -> Age = 35 years 
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10.1.2.4. 
Weight 
Weight will be presented in kilograms or grams. Weights reported in pounds will be 
converted as follows: 
Weight in kilograms = Weight in pounds / 2.2 
Weight in grams = (Weight in pound / 2.2) ·1000 
10.1.2.5. 
Height/Length 
Height/Length will be presented in centimeters. Heights/Lengths reported in feet and 
inches will be converted as follows: 
Height/Length in centimeters = Height/Length in inches x 2.54 
10.1.2.6. 
Body mass index (BMI) 
BMI will be calculated as follows: 
BMI = (Weight in kilograms) / (Height in meters)2 
10.1.2.7. 
Temperature 
Temperatures will be presented in degrees Celsius (°C). Temperatures reported in degrees 
Fahrenheit (°F) will be converted as follows: 
Temperature (Celsius) = ((Temperature (Fahrenheit) - 32) x 5)/9 
10.1.2.8. 
Numerical serology results 
Numerical serology results will be derived from the content of IS.ISORRES in the SDTM 
dataset. For assays with a specific cut-off, the following derivation rules apply: 
IS.ISORRES 
Derived value 
“NEG”, “-“, or “(-)” 
cut-off/2 
“POS”, “+”, or “(+)” 
cut-off 
“< value” and value is <= assay cut-off 
cut-off/2 
“< value” and value is > assay cut-off 
Value 
“> value” and value is < assay cut-off 
cut-off/2 
“> value” and value is >= assay cut-off 
Value 
“value” and value is < cut-off 
cut-off/2 
“value” and value is >= cut-off 
Value 
All other cases 
Missing 
10.1.2.9. 
Geometric mean titres (GMTs) and concentrations (GMCs) 
Geometric Mean Titre (GMT) or Concentration (GMC) calculations are performed by 
taking the inverse logarithm of the mean of the log titre or concentration transformations. 
Non quantifiable antibody titres or concentrations will be converted as described in 


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section 10.1.2.8 for the purpose of GMT/GMC calculation. Cut-off values are defined by 
the laboratory before the analysis. 
10.1.2.10. Onset day 
The onset day for an event (e.g. AE, medication, vaccination) is the number of days 
between study vaccination and the start date of the event. This is 1 for an event occurring 
on the same day as vaccination (and reported as starting after vaccination). 
The onset day for an event (e.g. neonatal AEs, SAEs, AEs of special interest) for infants 
is the number of days between birth and the start date of the event (or date of diagnosis). 
This is 1 for an event occurring on the same day as birth. 
10.1.2.11. Duration of events 
The duration of an event with a start and end date will be the number of days between the 
start and end dates plus one day, i.e. an event that starts on 03MAR2018 and ends on 
12MAR2018 has a duration of 10 days. 
The duration of solicited events will be calculated as the sum of the individual days with 
the adverse event reported at grade 1 or higher during the solicited adverse event period. 
10.1.2.12. Counting rules for combining solicited and unsolicited adverse events 
For output combining solicited and unsolicited adverse events, all serious adverse events 
will be considered systemic events since the administration site flag is not included in the 
expedited adverse event CRF pages. Unsolicited adverse events with missing 
administration site flag will also be considered systemic. 
Multiple events with the same preferred term which start on the same day are counted as 
only one occurrence. 
10.1.2.13. Counting rules for occurrences of solicited adverse events 
When the occurrences of solicited adverse events are summarized, each event recorded as 
having occurred during a specific period will be counted as only one occurrence 
regardless of the number of days on which it occurs. Also, in the case of co-administered 
study vaccines, an injection site reaction recorded for a participant following multiple 
vaccines will be counted as only one occurrence. 
10.1.3. 
Display of decimals 
10.1.3.1. 
Percentages 
Percentages and their corresponding confidence limits will be displayed with one decimal 
except for 100% in which case no decimal will be displayed. 


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10.1.3.2. 
Differences in percentages 
Differences in percentages and their corresponding confidence limits will be displayed 
with two decimals. 
10.1.3.3. 
Demographic/baseline characteristics statistics 
The mean, median, and standard deviation for continuous baseline characteristics (height, 
weight, body mass index (BMI), pre-vaccination body temperature) will be presented 
with one decimal. 
The minimum and maximum values and quartile values (if required) will be presented 
with the same number of decimals as the observed values.  
The maxima and minima of transformed height/length/weight variables will be displayed 
without decimals, with the exception of infant studies where three decimals will be 
displayed for transformed birth weight. 
The maximum and minimum of transformed body temperatures will be displayed with 
one decimal. 
10.1.3.4. 
Serological summary statistics 
The number of decimals used when displaying geometric mean titers (GMT) or 
concentrations (GMC) and their confidence limits is assay specific based on the 
magnitude of the assay result post-dose and the clinically relevant assay threshold. The 
same number of decimals will be used for a given assay regardless of the timepoint 
presented. 
Lowest clinically 
relevant threshold 
Example 
Number of decimals to 
display 
<0.3 
Diphtheria, tetanus, anti-PRP 
3 
>=0.3 and <4 
Streptococcus pneumoniae, 
Meningococal bactericide 
2 
>=4 and <1000 
Measles, rubella, varicella, 
polio 
1 
>=1000 
CMI 
0 
GMT/GMC fold increase from pre-dose follows the same principle. Namely when the 
lowest clinically relevant threshold is 2 fold, 2 decimals are displayed while when the 
lowest clinically relevant threshold is 4 fold, 1 decimal is displayed. 
GMT or GMC group ratios and their confidence limits will be displayed with 2 decimals 
regardless of the actual values. 


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10.1.4. 
Statistical methodology 
10.1.4.1. 
Exact confidence intervals around proportions 
The exact confidence intervals around within-group proportions are derived using the 
method of Clopper and Pearson [Clopper, 1934]. 
10.1.4.2. 
Standardized asymptotic confidence intervals around differences in 
proportions 
The standardized asymptotic confidence intervals around differences in proportions are 
derived using the method of Miettinen and Nurminen [Miettinen, 1985] 
10.1.4.3. 
Adjusted GMT or GMC ratios 
The CI for GMC ratio and adjusted CMT will be obtained using an ANOVA model on 
the logarithm transformed titers. The ANOVA model will include the vaccine group as 
the fixed effect (3 groups) and the country effect. The GMC ratio and their 95% CI will 
be derived by exponential transformation of the corresponding group contrast in the 
model. 
When between-group GMT or GMC ratios are computed and adjusted for two-level 
categorical co-variables, these co-variables should be included as dummy continuous 
variables in the SAS procedure. It should also be clear whether the model is limited to the 
data from some groups. 
10.2. 
TFL TOC 
The Table Figure Listing (TFL) TOC which itemizes the planned list of TFL and their 
associated lay-out is developed as a separate document. There will be one TOC document 
for the interim analysis of Day43PD and another for the 6-month PD interim analysis and 
the final analysis. 


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11. 
REFERENCES 
Clopper CJ, Pearson E. The Use of Confidence or Fiducial Limits Illustrated in the case 
of the Binomial. Biometrika. 1934; 26:404-13. 
Miettinen, O.S. and Nurminen, M. Comparative analysis of two rates. Statistics in 
Medicine, 1985; 4: 213-226. 
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.