Conditions: Respiratory Syncytial Virus Infections
Keywords: Respiratory syncytial virus Immunogenicity Safety Increased risk of respiratory syncytial virus lower respiratory tract disease Adults aged 50-59 years of age Older adults 60 years of age and above
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1544
Healthy volunteers: yes

Brief summary:
The aim of this study is to demonstrate the non-inferiority (NI) of the immune response and evaluate safety of RSVPreF3 older adults (OA) investigational vaccine in adults 50-59 years of age (YOA), including those who are at increased risk (AIR) of respiratory syncytial virus (RSV)-lower respiratory tract disease (LRTD), versus adults \>=60 YOA

Detailed description:

Arms:
arm 1: Healthy adults or adults with chronic stable conditions with or without treatment that do not lead to an increased risk of RSV-Lower respiratory tract disease (RSV-LRTD), aged 50-59 years old received 1 dose of RSVPreF3 OA vaccine at Day 1 and were followed until study end. arm 2: Healthy adults or adults with chronic stable conditions with or without treatment that do not lead to an increased risk of RSV-LRTD, aged 50-59 years old received 1 dose of placebo at Day 1 and were followed until study end. arm 3: Adults at increased risk of RSV-Lower respiratory tract disease (RSV-LRTD) aged 50-59 years old received 1 dose of RSVPreF3 OA vaccine at Day 1 and were followed until study end. arm 4: Adults at increased risk of RSV-LRTD aged 50-59 years old received 1 dose of placebo at Day 1 and were followed until study end. arm 5: Older adults aged 60 years old and above received 1 dose of RSVPreF3 OA vaccine at Day 1 and were followed until study end.

Interventions: intervention 1: RSVPreF3 OA investigational vaccine intervention 2: Placebo
Intervention descriptions: intervention 1: One dose administered intramuscularly at Day 1. intervention 2: One dose administered intramuscularly at Day 1.

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan Amendment 3
Study ID:  219238 
Official Title of Study:A Phase 3, observer-blind, randomized, placebo-controlled 
study to evaluate the non-inferiority of the immune response and safety of the 
RSVPreF3 OA investigational vaccine in adults 50-59 years of age, including adults at 
increased risk of respiratory syncytial virus lower respiratory tract disease, compared 
to older adults ≥60 years of age. 
NCT number: NCT05590403
Date of Document: 28 Feb 2024


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Information Type: Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: 
A Phase 3, observer-blind, randomized, placebo-controlled 
study to evaluate the non-inferiority of the immune response 
and safety of the RSVPreF3 OA investigational vaccine in 
adults 50-59 years of age, including adults at increased risk of 
respiratory syncytial virus lower respiratory tract disease, 
compared to older adults ≥60 years of age. 
Study Number: 
219238 
Compound Number: GSK3844766A 
Abbreviated Title: 
RSV OA=ADJ-018 
 
Sponsor Name: GlaxoSmithKline Biologicals SA (GSK) 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
Clintrials.gov 
Not Available 
EudraCT 
2022-001981-36 
XBU Statistical Analysis Plan (SAP) Template v2.0 17 January 2022 
Copyright 2024 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
LIST OF ABBREVIATIONS ............................................................................................. 5 
VERSION HISTORY ....................................................................................................... 7 
1. 
INTRODUCTION .................................................................................................... 10 
1.1. 
Objectives, Estimands and Endpoints ......................................................... 10 
1.2. 
Study Design .............................................................................................. 12 
2. 
STATISTICAL HYPOTHESES ............................................................................... 13 
2.1. 
Multiplicity Adjustment ................................................................................ 14 
3. 
ANALYSIS SETS ................................................................................................... 15 
3.1. 
Criteria for eliminating data from Analysis Sets ........................................... 15 
3.1.1. 
Elimination from Enrolled Set ....................................................... 15 
3.1.2. 
Elimination from ES ..................................................................... 16 
3.1.3. 
Elimination from PPS ................................................................... 16 
4. 
STATISTICAL ANALYSES ..................................................................................... 18 
4.1. 
General Considerations .............................................................................. 18 
4.1.1. 
General Methodology .................................................................. 18 
4.1.2. 
Baseline Definition ....................................................................... 19 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 19 
4.2.1. 
Definition of endpoints ................................................................. 19 
4.2.2. 
Main analytical approach ............................................................. 19 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 20 
4.3.1. 
Definition of endpoints ................................................................. 20 
4.3.2. 
Main analytical approach ............................................................. 20 
4.3.2.1. 
Safety analysis ........................................................... 20 
4.3.2.2. 
Immunogenicity analysis: humoral immune 
response .................................................................... 22 
4.3.2.2.1. 
Between groups assessment .................. 23 
4.3.2.2.2. 
Within groups assessment ...................... 23 
4.3.2.3. 
Immunogenicity analysis: CMI response ..................... 24 
4.3.3. 
Additional considerations ............................................................. 25 
4.3.3.1. 
Mixed-effects model ................................................... 25 
4.3.3.2. 
Cell-mediated immune response ................................ 25 
4.5. 
Other Safety Analyses ................................................................................ 29 
4.6. 
Other Analyses ........................................................................................... 29 
4.7. 
Interim Analyses ......................................................................................... 29 
4.7.1. 
Sequence of analyses.................................................................. 29 
4.7.2. 
Statistical considerations for interim analysis ............................... 30 
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4.8. 
Changes to Protocol Defined Analyses ....................................................... 30 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 30 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 31 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 31 
6.1.1. 
Participant Disposition ................................................................. 31 
6.1.2. 
Demographic and Baseline Characteristics .................................. 31 
6.1.3. 
Protocol Deviations ...................................................................... 31 
6.1.4. 
Participant exposure .................................................................... 32 
6.1.5. 
Concomitant Medications ............................................................. 32 
6.1.6. 
Concomitant Vaccinations ........................................................... 32 
6.1.7. 
Additional Analyses due to the COVID-19 Pandemic ................... 32 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 33 
6.2.1. 
Attributing events to vaccine doses .............................................. 33 
6.2.2. 
Handling of missing data .............................................................. 33 
6.2.2.1. 
Dates .......................................................................... 33 
6.2.2.2. 
Laboratory data .......................................................... 34 
6.2.2.3. 
Daily recording of solicited events .............................. 34 
6.2.2.4. 
Unsolicited adverse events ......................................... 35 
6.2.3. 
Data derivation ............................................................................ 35 
6.2.3.1. 
Age at vaccination in years and age category ............. 35 
6.2.3.2. 
Weight ........................................................................ 35 
6.2.3.3. 
Height ......................................................................... 35 
6.2.3.4. 
Body mass index (BMI) .............................................. 35 
6.2.3.5. 
Temperature ............................................................... 36 
6.2.3.6. 
Numerical serology results ......................................... 36 
6.2.3.7. 
Geometric mean titers (GMTs) and 
concentrations (GMCs) ............................................... 36 
6.2.3.8. 
Onset day ................................................................... 36 
6.2.3.9. 
Duration of events ...................................................... 37 
6.2.3.10. Counting rules for combining solicited and 
unsolicited adverse events ......................................... 37 
6.2.3.11. Counting rules for occurrences of solicited 
events......................................................................... 37 
6.2.4. 
Display of decimals ...................................................................... 38 
6.2.4.1. 
Percentages ............................................................... 38 
6.2.4.2. 
Demographic/baseline characteristics statistics .......... 38 
6.2.4.3. 
Serological summary statistics ................................... 38 
7. 
REFERENCES ....................................................................................................... 39 
 


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LIST OF TABLES 
PAGE 
Table 1 
Study objectives and null hypothesis ...................................................... 14 
Table 2 
List of elimination codes ......................................................................... 16 
Table 3 
 
 ................................................................... 28 
Table 4 
Power of primary NI objectives ............................................................... 31 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AF 
Atrial Fibrillation 
AIR 
At-Increased-Risk 
ANCOVA 
Analysis of Covariance 
CI 
Confidence Interval 
CMI 
Cell-Mediated Immunity 
COVID-19 
Coronavirus Disease 2019 
CSR 
Clinical Study Report 
eCRF 
electronic Case Report Form  
GMT 
Geometric Mean Titer 
GSK 
GlaxoSmithKline 
HA 
Healthy Adults 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGI 
Mean Geometric Increase 
NI 
Non-inferiority 
OA 
Older Adults 
PCA 
Primary Completion Analysis 
pIMD 
Potential Immune-Mediated Disease 
PPS 
Per-Protocol Set 
RR 
Relative Risk 
RSV 
Respiratory Syncytial Virus 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SRR 
Seroresponse rate 


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ULOQ 
Upper Limit Of Quantification 
YOA 
Years of Age 


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VERSION HISTORY 
SAP 
Version 
Approval 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
SAP 
19 October 
2022 
Final: 26 July 
2022 
Not Applicable 
Original version 
SAP 
Amendm
ent 1 
09 May 
2023 
Final: 26 July 
2022 
Section 4.3.2.1: Change 
to safety reporting for 
participant belonging to 
OA stratum who 
received placebo: SAEs 
and AESIs reported (if 
any) will be described. 
Section 4.3.2.1: 
Addition of AF as 
AESIs for tabular 
listing. 
Section 4.3.2.2.2 & 
Section 4.3.2.3: Change 
from 65-69 YOA in 60-
69 YOA in all age 
category definition 
Section 4.3.3.3: Add 
section for additional 
considerations for 
analysis of AF 
Section 4.4.1: 
 
 
. 
Section 4.4.1.2: Lower 
threshold to 3 for 
subgroup categories 
based on uCCI. 
Section 6.1.1: Summary 
of participant 
disposition will be 
additionally performed 
Section 4.3.2.1: 
Safety narrative 
will only be 
generated in 
participant 
belonging to OA 
stratum who 
received placebo, if 
SAEs and AESIs 
are reported. 
Section 4.3.2.1: 
Addition following 
project update to 
consider atrial 
fibrillation (AF) as 
Adverse Events of 
Special interest 
(AESIs) 
Section 4.3.2.2.2 & 
Section 4.3.2.3: 
Correction for age 
category 
Section 4.3.3.3: 
Supportive 
information for 
analysis of AF 
Section 4.4.1: 
Additional 
exploratory 
analysis 
Section 4.4.1.2: 
Number of 
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SAP 
Version 
Approval 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
on Screened set and 
Enrolled set. 
Section 6.1.2: 
Demography and 
baseline characteristics 
will be additionally 
performed on Screened 
set. 
Section 6.1.3: Change 
from Enrolled Set to 
Screened Set as 
analysis set for the 
summary of important 
protocol deviations 
leading to exclusions 
from any analysis set. 
Across section: Change 
from “neutralization 
antibody titer” to 
“neutralization titer”. 
participants too 
small (less than 
20%) within high-
risk subgroup with 
a threshold of 5 
Section 6.1.1: 
Addition of 
analysis for 
participant 
disposition. 
Section 6.1.2: 
Addition of 
analysis for 
demography and 
baseline 
characteristics. 
Section 6.1.3: 
Change in analysis 
set for protocol 
deviation analysis. 
Across section: 
Correction in 
wording for 
neutralization 
assay. 
SAP 
Amendm
ent 2 
15 May 
2023 
Final: 26 July 
2022 
Section 3.1.3: Addition 
of elimination code 
1060 “Randomization 
code was broken”. 
Section 3.1.3: 
Elimination code 
was added to 
eliminate 
participant whose 
randomization was 
broken from PPS 
SAP 
Amendm
ent 3 
28 Feb 
2024 
Final: 
Amendment 
1: 25 May 
2023 
Section 3.1.3: Change 
visit specification for 
elim code 1060.  
Section 3.1.3: 
Participants having 
elim code 1060 
will be eliminated 


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SAP 
Version 
Approval 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
Section 4.3.2.1: Change 
in tabulation of 
solicited event duration 
and number of days 
with Grade 3 solicited 
events. 
Addition of specific 
analysis for 
Demyelinating disorder  
Add sentences to clarify 
6 months = 183 days. 
Section 6.2.3.9: 
Addition of the 
definition of duration of 
solicited AE. 
from a specific 
visit (at which the 
condition is met) 
onwards. 
Section 4.3.2.1 & 
Section 6.2.3.9: 
Change following 
project update for 
the definition of 
duration of 
solicited 
symptoms. 
Addition of 
specific analysis 
for Demyelinating 
disorder following 
project update  
Add clarification 
for the number of 
days considered in 
6 Months safety 
follow-up. 


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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned statistical analyses for Study 
RSV OA=ADJ-018 (219238). 
1.1. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints and estimands 
Primary* 
• 
To demonstrate the NI of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-A strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-A neutralization titers expressed as group GMT 
ratio (OA-RSV/Adults-HA-RSV), 1 month after the 
RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-A neutralization titers expressed as group SRR 
difference (OA-RSV - Adults-HA-RSV), 1 month 
after the RSVPreF3 OA investigational vaccine 
administration compared to baseline. 
• 
To demonstrate the NI of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-B strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-B neutralization titers expressed as group GMT 
ratio (OA-RSV/Adults-HA-RSV), 1 month after the 
RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-B neutralization titers expressed as group SRR 
difference (OA-RSV - Adults-HA-RSV), 1 month 
after the RSVPreF3 OA investigational vaccine 
administration compared to baseline. 
• 
To demonstrate the NI of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-A strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
RSV-A neutralization titers expressed as group GMT 
ratio (OA-RSV/Adults-AIR-RSV), 1 month after the 
RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-A neutralization titers expressed as group SRR 
difference (OA-RSV - Adults-AIR-RSV), 1 month 
after the RSVPreF3 OA investigational vaccine 
administration compared to baseline. 
• 
To demonstrate the NI of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-B strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
RSV-B neutralization titers expressed as group GMT 
ratio (OA-RSV/Adults-AIR-RSV), 1 month after the 
RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-B neutralization titers expressed as group SRR 
difference (OA-RSV - Adults-AIR-RSV), 1 month 
after the RSVPreF3 OA investigational vaccine 
administration compared to baseline. 
Secondary - Safety 
• 
To evaluate the safety and reactogenicity after the 
RSVPreF3 OA investigational vaccine 
administration. 
• 
Percentage of participants reporting each solicited 
administration site event with onset within 4 days 
after study intervention administration (i.e., the day 
of study intervention administration and 
3 subsequent days). 
• 
Percentage of participants reporting each solicited 
systemic event with onset within 4 days after study 
intervention administration (i.e., the day of study 
intervention administration and 3 subsequent days). 


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Objectives 
Endpoints and estimands 
• 
Percentage of participants reporting unsolicited AEs 
within 30 days after study intervention administration 
(i.e., the day of study intervention administration and 
29 subsequent days). 
• 
Percentage of participants reporting any SAEs and 
pIMDs after study intervention administration 
(Day 1) up to Month 6. 
• 
Percentage of participants reporting SAEs and 
pIMDs related to study intervention administration 
after study intervention administration (Day 1) up to 
study end (Month 12). 
• 
Percentage of participants reporting any fatal SAEs 
after study intervention administration (Day 1) up to 
study end (Month 12). 
Secondary - Immunogenicity 
• 
To evaluate the humoral immune response to the 
RSVPreF3 OA investigational vaccine until 
12 months post-study intervention administration.  
• 
RSV-A and RSV-B neutralization titers expressed as 
GMT, at pre-study intervention administration, 1 
month, 6 months and at 12 months after study 
intervention administration.  
• 
To evaluate the CMI response after RSVPreF3 OA 
investigational vaccine administration until 
12 months post-study intervention administration.  
• 
CMI response expressed as group geometric mean 
of the frequency of RSVPreF3-specific CD4+ and/or 
CD8+ T cells expressing at least 2 activation 
markers including at least 1 cytokine among CD40L, 
4-1BB, IL-2, TNF-α, IFN-γ, IL-13, IL-17, at pre-study 
intervention administration, 1 month, 6 months and 
at 12 months after study intervention administration, 
in a subset of participants.  
Tertiary 
(Note that tertiary objectives, endpoints, and estimands are optional and might be assessed only if needed;  
therefore, not all testing might be performed and reported) 
AE=Adverse event; AIR=At increased risk; CD=Cluster of differentiation; CD40L=CD40 ligand; CMI=Cell-mediated 
immunity; GMT=Geometric mean titer; HA=Healthy adults; IFN=Interferon; IL=Interleukin; LRTD=Lower 
respiratory tract disease; NI=Non-inferiority; OA=Older adults; pIMD=Potential immune-mediated disease; 
RSV=Respiratory syncytial virus; SAE=Serious adverse event; SRR=Seroresponse rate; TNF=Tumor necrosis 
factor; YOA=Years of Age. 
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Primary estimands 
The primary scientific question of the study is to demonstrate the non-inferiority of the 
immune response of RSVPreF3 OA investigational vaccine in healthy adults 50-59 years 
of age (YOA) and adults 50-59 years at increased risk of RSV-lower respiratory tract 
disease (LRTD), versus adults ≥60 YOA, in terms of RSV-A and RSV-B neutralizing 
titer (ED60) group GMT ratios and SRR difference at 1 month after vaccination in 
eligible participants who complied with the study requirements as defined per protocol 
(refer to Section 3 for the definition of the PPS used for the primary analysis and to 
Section 4.2 for the statistical methods). 
1.2. 
Study Design 
Overview of Study Design and Key Features 
 
 
AE=Adverse event; AIR=At increased risk; GSK=GlaxoSmithKline Biologicals SA; HA=Healthy adults; n=Number; 
OA=Older adults; pIMD=Potential immune-mediated disease; RSV=Respiratory syncytial virus; SAE=Serious 
adverse event; YOA=Years of age. 
* Participants with underlying medical conditions such as chronic pulmonary and cardiovascular diseases, diabetes 
mellitus types 1 and 2, and chronic liver and renal diseases 
Note: All SAEs related to study participation, or a GSK concomitant medication/vaccine are to be recorded from the 
time the participant consents to participate in the study (prior to study vaccination) up to study end. 


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Overview of Study Design and Key Features 
Design Features 
Phase 3 study to demonstrate the non-inferiority of the immune response of RSVPreF3 OA 
investigational vaccine in adults 50-59 years of age (YOA), including those who are at 
increased risk of RSV-lower respiratory tract disease (LRTD), versus adults ≥60 YOA. 
Blinding: observer-blind for Cohort 1, and open-label for Cohort 2. The study will be 
conducted in an observer-blind manner for Cohort 1 from study start-up to Day 31 
analysis, beyond which the study will be considered single-blind (see Section 4.7.1 for 
details). 
Study intervention 
Participants will receive a single dose of study intervention (either RSVPreF3 OA 
investigational vaccine or placebo) at Visit 1 (Day 1). 
Study cohorts, 
groups 
Cohort 1 (adults 50-59 YOA), with 2 sub-cohorts (Adults-HA and Adults-AIR) and 4 parallel 
groups: 
• 
Adults-HA-RSV Group 
• 
Adults-HA-Placebo Group 
• 
Adults-AIR-RSV Group 
• 
Adults-AIR-Placebo Group 
Cohort 2 (adults ≥60 YOA) with a single group (OA-RSV Group) 
Study intervention 
Assignment 
• 
Participants in Cohort 1, Adults-HA Sub-cohort will be randomly assigned to the 
Adults-HA-RSV Group and Adults-HA-Placebo Group in a 2:1 ratio at Visit 1 (Day 1) 
to receive the RSVPreF3 OA investigational vaccine or placebo, respectively.  
• 
Participants in Cohort 1, Adults-AIR Sub-cohort will be randomly assigned to the 
Adults-AIR-RSV Group and Adults-AIR-Placebo Group in a 2:1 ratio at Visit 1 (Day 
1) to receive the RSVPreF3 OA investigational vaccine or placebo, respectively.  
• 
All participants in Cohort 2 (OA-RSV Group) will be assigned to receive the 
RSVPreF3 OA investigational vaccine. 
The randomization algorithm will use a stratification by healthy/at increased risk status and 
CMI subset (participant included in the CMI subset or not) and a minimization procedure 
accounting for the study and center within each stratum. Minimization factors will have 
equal weight in the minimization algorithm. 
Primary Completion 
Achieved (PCA) 
Analysis 
A first analysis will be performed on all immunogenicity, reactogenicity and safety data 
available and as clean as possible, when data for at least primary and secondary 
endpoints up to Visit 2 (Day 31) are available for all participants.  
Month 6 Analysis 
A second analysis will be performed on all immunogenicity and safety data available and 
as clean as possible, when data for at least secondary endpoints up to Visit 3 (Month 6) 
are available for all participants.  
End-of-study 
Analysis 
An end of study analysis will be performed when all data for at least secondary endpoints 
up to study conclusion (Visit 4, Month 12) will be available for all participants. 
2. 
STATISTICAL HYPOTHESES 
Statistical hypotheses are associated to the confirmatory primary NI objectives, which 
will be tested according to the graphical procedure detailed in Section 2.1. Global type I 
error is controlled at 2.5% (1-sided). 


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Table 1 
Study objectives and null hypothesis 
Objectives 
Null hypothesis 
Primary 
a. 
To demonstrate the NI of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-A strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
Null hypothesis 1 (H1):  
The anti-RSV-A GMT ratio (OA-RSV Group over 
Adults-HA-RSV Group) is >1.5 or the SRR 
difference (OA-RSV Group – Adults-HA-RSV Group) 
is >10% at 1 month post RSVPreF3 OA vaccine 
administration. This must be rejected in favor of the 
alternative hypothesis that the GMT ratio is ≤1.5 and 
the SRR difference is ≤10%. 
b. 
To demonstrate the NI of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-B strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
Null hypothesis 2 (H2):  
The anti-RSV-B GMT ratio (OA-RSV Group over 
Adults-HA-RSV Group) is >1.5 or the SRR 
difference (OA-RSV Group – Adults-HA-RSV Group) 
is >10% at 1 month post RSVPreF3 OA vaccine 
administration. This must be rejected in favor of the 
alternative hypothesis that the GMT ratio is ≤1.5 and 
the SRR difference is ≤10%. 
c. 
To demonstrate the NI of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-A strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
Null hypothesis 3 (H3):  
The anti-RSV-A GMT ratio (OA-RSV Group over 
Adults-AIR-RSV Group) is >1.5 or the SRR 
difference (OA-RSV Group – Adults-AIR-RSV 
Group) is >10% at 1 month post RSVPreF3 OA 
vaccine administration. This must be rejected in 
favor of the alternative hypothesis that the GMT ratio 
is ≤1.5 and the SRR difference is ≤10%. 
d. 
To demonstrate the NI of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-B strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
Null hypothesis 4 (H4):  
The anti-RSV-B GMT ratio (OA-RSV Group over 
Adults-AIR-RSV Group) is >1.5 or the SRR 
difference (OA-RSV Group – Adults-AIR-RSV 
Group) is >10% at 1 month post RSVPreF3 OA 
vaccine administration. This must be rejected in 
favor of the alternative hypothesis that the GMT ratio 
is ≤1.5 and the SRR difference is ≤10%. 
2.1. 
Multiplicity Adjustment 
The following graphical testing procedure will be applied to control the global type I 
error at 2.5% (1-sided) [Bretz, 2009]. 
 
Refer to Table 1 where H1/H2/H3/H4 labels are assigned. 


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The initial allocation of α among the null hypotheses is (0.025, 0, 0, 0), while the 
propagation rules are specified by the transition matrix: 
 
3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened Set 
All participants who were screened for eligibility. 
Study Population 
Enrolled Set 
All participants who entered the study (who were randomized or 
received study intervention or underwent a post-screening study 
procedure). 
NOTE: screening failures (who never passed screening even if 
rescreened) and participants screened but never enrolled into the 
study (met eligibility but not needed to reach the target enrolment) 
are excluded from the Enrolled Set as they did not enter the study. 
Study Population 
Exposed Set 
All participants who received the study intervention. Analysis per 
group is based on the administered intervention. 
Study Population, 
Safety 
Per-Protocol Set* 
All eligible participants who received the study intervention as per 
protocol, had immunogenicity results pre- and post-dose, complied 
with blood draw intervals, without intercurrent conditions that may 
interfere with immunogenicity and without prohibited concomitant 
medication/vaccination. Analysis per group is based on the 
administered intervention. 
Immunogenicity 
* Contribution of participants to PPS will be defined by timepoint. 
3.1. 
Criteria for eliminating data from Analysis Sets 
Elimination codes will be used to identify participants to be eliminated from analysis. 
Details are provided below for the Enrolled Set, the Exposed Set (ES) and the Per 
Protocol Set (PPS). 
3.1.1. 
Elimination from Enrolled Set 
The following codes will be used for identifying participants to be eliminated from the 
Enrolled Set: 
• 
Code 800 (Fraudulent data) 
• 
Code 900 (Invalid informed consent) 
 
0
0.5
0.5
0
0
0
1
0
0
0
0
1
0
1
0
0
  


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3.1.2. 
Elimination from ES 
The following codes will be used for identifying participants to be eliminated from the 
ES: 
• 
Code 800 (Fraudulent data) 
• 
Code 900 (Invalid informed consent)  
• 
Code 1030 (Study intervention not administered at all) 
• 
Code 1100 (OA-RSV Group administered with placebo) 
3.1.3. 
Elimination from PPS 
A participant will be excluded from the populations for analysis under the following 
conditions:  
• 
For codes 800, 900, 1030, 1050, 1070, 1080, 1090, 1100 and 2010: participants will 
be eliminated for all visits. 
• 
For codes 1040, 1060, 2040 and 2050: participants will be eliminated from a specific 
visit (at which the condition is met) onwards. 
• 
For codes 2020, 2090, 2100, 2120: participants will be eliminated at the specific visit 
at which the condition is met. 
Table 2 
List of elimination codes 
Code 
Condition under which the code is used 
Visit / 
Contact 
(timepoints) 
where the 
code is 
checked 
Applicable for 
analysis 
set/endpoint 
800 
Fraudulent data 
All 
Enrolled Set, 
ES, PPS 
900 
Invalid informed consent 
All 
Enrolled Set, 
ES, PPS 
1030 
Study intervention not administered at all 
All 
ES, PPS 
1040 
Administration of concomitant vaccine(s) forbidden in the protocol: 
• 
Use of any investigational or non-registered vaccine other 
than the study intervention during the period beginning 30 
days before the dose of study intervention, or planned use 
during the study period. 
• 
Planned or actual administration of a vaccine not foreseen 
by the study protocol in the period starting 30 days before 
and ending 30 days after the dose of study intervention 
administration, with the exception of inactivated and subunit 
influenza vaccines or COVID-19 vaccines (fully licensed or 
with EUA) which can be administered up to 14 days before 
or from 14 days after the study intervention administration. * 
• 
Previous vaccination with an RSV vaccine, including 
investigational RSV vaccines. 
All 
PPS 


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Code 
Condition under which the code is used 
Visit / 
Contact 
(timepoints) 
where the 
code is 
checked 
Applicable for 
analysis 
set/endpoint 
1050 
Randomization failure: participant not randomized in the correct 
stratum  
Visit 1 
PPS 
1060 
Randomization code was broken 
All 
PPS 
1070 
Vaccine administration not according to protocol: 
• 
Participant was vaccinated with the correct vaccine but 
containing a lower volume 
• 
Wrong replacement or study vaccine administered (not 
compatible with the vaccine regimen associated to the 
treatment number) 
• 
Route of the study vaccine is not intramuscular 
• 
Wrong reconstitution of administered vaccine 
Visit 1 
PPS 
1080 
Vaccine administration after a temperature deviation 
Vaccine administered despite a Good Manufacturing Practices 
(GMP) no-go temperature deviation 
Visit 1 
PPS 
1090 
Vaccine administration after expiration  
Visit 1 
PPS 
1100 
Other deviations related to wrong study 
treatment/administration/dose: 
OA-RSV Group = Administration of placebo 
Visit 1 
ES, PPS 
2010 
Protocol deviation linked to inclusion/exclusion criteria 
All 
PPS 
2020 
All Pre-dose results are missing 
Visit 1 
PPS 
2040 
Administration of any medication forbidden by the protocol 
• 
Use of any investigational or non-registered product (drug or 
medical device) other than the study intervention during the 
period beginning 30 days before the dose of study 
intervention, or planned use during the study period. 
• 
Chronic administration of immune-modifying drugs (defined 
as more than 14 consecutive days in total) and/or 
administration of long-acting immune modifying treatments 
or planned administration at any time up to the end of the 
study. 
− 
Up to 3 months prior to the study intervention 
administration: 
o 
For corticosteroids, this will mean prednisone 
≥20 mg/day, or equivalent. Inhaled and topical 
steroids are allowed. 
o 
Administration of immunoglobulins and/or any 
blood products or plasma derivatives. 
• 
Up to 6 months prior to study intervention administration: 
long-acting immune modifying drugs including among others 
immunotherapy (e.g., TNF-inhibitors), monoclonal 
antibodies, antitumoral medication. 
All 
PPS 
2050 
Intercurrent medical condition:  
Participants may be eliminated from the PPS for immunogenicity 
if, during the study, they incur a condition that has the capability of 
altering their immune response or are confirmed to have an 
alteration of their initial immune status. 
All 
PPS 
2090 
Participants did not comply with blood sample schedule*: 
Visit 2, Visit 
3, Visit 4 
PPS 


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Code 
Condition under which the code is used 
Visit / 
Contact 
(timepoints) 
where the 
code is 
checked 
Applicable for 
analysis 
set/endpoint 
• 
Number of days between vaccination (Visit 1) and blood 
sample (Visit 2) is outside [30-42] days. 
• 
Number of days between vaccination (Visit 1) and blood 
sample (Visit 3) is outside [180-210] days. 
• 
Number of days between vaccination (Visit 1) and blood 
sample (Visit 4) is outside [350-380] days. 
2100 
Immunological results not available post-vaccination 
Visit 2, Visit 
3, Visit 4  
PPS 
2120 
Obvious incoherence/abnormality or error in laboratory data 
• 
Unreliable released data as a result of confirmed sample 
mismatch or confirmed inappropriate sample handling at 
laboratory. 
All 
PPS 
* Note: In case an emergency mass vaccination for an unforeseen public health threat (e.g.: a pandemic) is 
recommended and/or organized by the public health authorities, outside the routine immunization program, the 
time period described above can be reduced if necessary for that vaccine provided it is used according to the local 
governmental recommendations and that the Sponsor is notified accordingly. 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
• 
For the purpose of immunogenicity analyses, any missing or non-evaluable 
immunogenicity measurement will not be replaced. The descriptive analysis 
performed for each assay at each time point will exclude participants with a missing 
or non-evaluable measurement. 
• 
The mean geometric increase (MGI) is defined as the geometric mean of the within-
participant ratios of the post-vaccination titer over pre-vaccination (Visit 1, Day 1). 
• 
Titers below the assay cut-off (LLOQ) will be replaced by half the assay cut-off 
(LLOQ/2) and titers above the upper limit of quantification (ULOQ) will be replaced 
by the ULOQ to compute GMTs, SRRs and MGIs. For the display of reverse 
cumulative curve, titers below LLOQ and above ULOQ won’t be replaced. 
• 
Confidence intervals (CIs) will use 95% confidence levels unless otherwise specified 
(e.g., primary endpoints analysis, refer to Section 4.2.2). 95% CIs for GMT and MGI 
will be based on a back transformation of CI for the mean of log10-transformed 
values. Exact 95% CIs around proportions are derived using the method of Clopper 
and Pearson [Clopper, 1934]. 95% CI for group difference in proportion will be 
based on Miettinen and Nurminen confidence interval [Miettinen, 1985]. 
• 
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation, median, minimum, and maximum. Categorical 


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data will be summarized as the number and percentage of participants in each 
category. 
• 
For the purpose of displays based on the ES, in the exceptional case of a participant 
belonging to the OA stratum and receiving placebo (e.g., due to wrong stratification), 
the participant will be excluded from ES summaries.  
4.1.2. 
Baseline Definition 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, i.e., the assessment at Visit 1 (Day 1). 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
4.2. 
Primary Endpoint(s) Analyses 
4.2.1. 
Definition of endpoints 
RSV-A and RSV-B neutralizing group GMT ratios at 1 month after the RSVPreF3 OA 
investigational vaccine administration will be computed for OA-RSV over Adults-HA-
RSV group and OA-RSV over Adults-AIR-RSV group. 
RSV-A and RSV-B neutralizing group SRR differences at 1 month after the RSVPreF3 
OA investigational vaccine administration will be computed for OA-RSV over Adults-
HA-RSV group and OA-RSV over Adults-AIR-RSV group. 
4.2.2. 
Main analytical approach 
The primary analysis set will be the PPS. If, in any group, the percentage of vaccinated 
participants with serological results excluded from the PPS is more than 5%, a second 
analysis based on the ES will be performed to complement the PPS analysis. 
Considering the sampling timepoint at 1-month post-study intervention administration: 
• 
The 2-sided 95% and 97.5% CIs for group GMT ratios (OA-RSV over Adults-HA-
RSV group and OA-RSV over Adults-AIR-RSV group) will be derived from an 
ANCOVA model on log10-transformed titers for each neutralization assay. The 
model will include the group and the baseline log10-transformed titer as covariate. 
The group GMT ratios will be based on a back transformation of group contrast in 
the ANCOVA model applied to the logarithmically transformed titers. 
• 
The SRR is defined as the proportion of participants having a fold increase in 
neutralizing titers (1-month post-study intervention administration over pre-
vaccination) ≥4. The 2-sided 95% and 97.5% CIs for group SRR difference (OA-
RSV minus Adults-AIR-RSV group and OA-RSV minus Adults-HA-RSV group) 
will be derived using the method of Miettinen and Nurminen [Miettinen, 1985]. 


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Success criteria for NI:  
NI for each primary objective will be claimed if the upper limit of the 2-sided CI for the 
GMT ratio will be ≤1.5 and the upper limit of the 2-sided CI for the SRR difference will 
be ≤ 0.10, according to the significance level provided by the graphical testing procedure 
detailed in Section 2.1.The RSV-A and RSV-B neutralizing titer’s unit used for 
computation of the GMT ratio and SRR difference will be ED60. Refer to Section 2 for 
the definition of null and alternative hypotheses associated to each primary NI objective. 
4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Definition of endpoints 
Refer to Section 1.1 for the definition of secondary safety and immunogenicity (humoral 
and CMI response) endpoints. 
4.3.2. 
Main analytical approach 
4.3.2.1. 
Safety analysis 
The safety analysis will be performed per study group, on the ES, as follows: 
• 
The number and percentage of participants with at least one administration site event 
(solicited and unsolicited), with at least one systemic event (solicited and 
unsolicited) and with any AE (solicited and unsolicited) during the 4-day or 30-day 
follow-up period after vaccination will be tabulated with exact 95% CI. The same 
computations will be done for Grade 3 AEs, for Grade 3 non-serious AEs and for 
AEs resulting in a medically attended visit. 
Those analyses will present all solicited and unsolicited AEs, including SAEs (unless 
otherwise specified). 
• 
The number and percentage of participants with at least one administration site event 
(solicited only), with at least one systemic event (solicited only) and with any 
solicited event during the 4-day follow-up period after vaccination will be tabulated 
with exact 95% CI. The same computations will be done for Grade 3 AEs and for 
AEs resulting in a medically attended visit. 
• 
Compliance in completing solicited events information will be tabulated. 
• 
The number and percentage of participants reporting each individual solicited 
administration site or systemic event (any grade, Grade 3 and resulting in medically 
attended visit) during the 4-day follow-up period after vaccination will be tabulated 
with exact 95% CI. 
• 
For fever, the number and percentage of participants reporting fever by half degree 
(°C) cumulative increments during the 4-day follow-up period after vaccination will 
be tabulated. 


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• 
The percentage of participants with each solicited administration site event and 
solicited systemic event (any grade and Grade 3) during the 4-day follow-up period 
after vaccination will be represented graphically. 
• 
The duration in days of each individual solicited events will be tabulated using 
descriptive statistics (mean, min, Q1, median, Q3, maximum).  
• 
The number of days with Grade 3 solicited events will be tabulated for each 
individual solicited event using descriptive statistics (mean, min, Q1, median, Q3, 
maximum).  
• 
The number and percentage of participants with any unsolicited AEs during the 30-
day follow-up period with its exact 95% CI will be tabulated by group and by 
MedDRA Primary System Organ Class (SOC), High Level Term (HLT) and 
Preferred Term (PT). Similar tabulation will be done for Grade 3 unsolicited AEs, 
for any causally related unsolicited AEs, for Grade 3 causally related unsolicited AEs 
and for unsolicited AEs resulting in a medically attended visit. The analyses of 
unsolicited AEs will include SAEs, AESIs (including pIMDs and AF), unless 
otherwise specified. 
• 
The number and percentage of participants with any non-serious unsolicited AEs 
during the 30-day follow-up period with its exact 95% CI will be tabulated by group 
and by MedDRA Primary System Organ Class (SOC), High Level Term (HLT) and 
Preferred Term (PT). Similar tabulation will be done for Grade 3 non-serious 
unsolicited AEs, for any causally related non-serious unsolicited AEs, for Grade 3 
causally related non-serious unsolicited AEs and for non-serious unsolicited AEs 
resulting in a medically attended visit. 
• 
The number and percentage of participants with any unsolicited AEs reported within 
30 minutes following vaccination with its exact 95% CI will be tabulated by group 
and by MedDRA Primary System Organ Class (SOC), High Level Term (HLT) and 
Preferred Term (PT). Similar tabulation will be done for Grade 3 unsolicited AEs 
reported within 30 minutes following vaccination.  
• 
The verbatim reports of unsolicited AEs, including SAE and AESI, will be reviewed 
by a qualified person and the signs and symptoms will be coded according to the 
MedDRA Dictionary for Adverse Reaction Terminology. Every verbatim term will 
be matched with the appropriate Preferred Term. 
• 
The number and percentage of participants with at least one report of SAE classified 
by the MedDRA Primary SOC, HLT and PT from vaccination up to Month 6 will be 
tabulated with exact 95% CI.  
• 
The number and percentage of participants with at least one report of SAE classified 
by the MedDRA Primary SOC, HLT and PT, related to study intervention 
administration, from vaccination up to Month 6 and study end (Month 12) will be 
tabulated with exact 95% CI.  
• 
The number and percentage of participants with any fatal SAE, from vaccination up 
to Month 6 and study end (Month 12) will be tabulated with exact 95% CI.  


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• 
The number and percentage of participants with at least one report of pIMD 
classified by the MedDRA Primary SOC, HLT and PT from vaccination up to Month 
6 will be tabulated with exact 95% CI. 
• 
The number and percentage of participants with at least one report of pIMD 
classified by the MedDRA Primary SOC, HLT and PT, related to study intervention 
administration, from vaccination up to Month 6 and study end (Month 12) will be 
tabulated with exact 95% CI.  
• 
The number and percentage of participants with specific Demyelinating disorder 
with onset within 30 days of vaccination will be tabulated with exact 95% CI.  
• 
The number and percentage of participants with specific Serious Demyelinating 
disorder from vaccination up to Month 6 and study end (Month 12) will be tabulated 
with exact 95% CI.  
• 
All SAEs/AESIs (including pIMDs and AF) up to study end (Month 12) will also be 
described in detail in a tabular listing. 
• 
AEs/SAEs leading to study discontinuation from vaccination up to study end will be 
tabulated. 
• 
For web posting purposes, the number of occurrences and the number and percentage 
of participants with non-serious AEs (solicited and unsolicited combined) during the 
30-day follow-up period (i.e., the day of vaccination and 29 subsequent days) will be 
produced by SOC and PT. 
• 
In case of pregnancies, these will be described in detail. 
• 
In case participants belonging to the OA stratum receive placebo (i.e., participants 
eliminated from the ES following code 1100, refer to Section 3.1.2), SAEs and 
AESIs (including pIMDs and AF) reported (if any) will be described.  
• 
AF AESIs will be tabulated within the summary of AEs or SAEs according to their 
classification. 
For analysis of SAEs/AESIs (including pIMD and AF) within 6 months after vaccination, 
the reporting period will start at vaccination and will end at Day 183 after each dose, 
computed as 6 x 30.5 days = 183 days. 
Refer to Section 6.1.5 and Section 6.1.6 for the analysis of concomitant medications and 
concomitant vaccination. 
4.3.2.2. 
Immunogenicity analysis: humoral immune response 
The analysis will be based on the PPS. If, in any group, the percentage of vaccinated 
participants with serological results excluded from the PPS is more than 5%, a second 
analysis based on the ES will be performed to complement the PPS analysis. 


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4.3.2.2.1. Between groups assessment  
Considering the sampling timepoint at 1-month post-study intervention administration, 
same analysis as for primary endpoint (refer to Section 4.2.2) will be performed using 
IU/ml unit for computation of the GMT ratio and SRR difference. 
Considering the sampling timepoint at 6-month and 12-month post-study intervention 
administration, the following analysis will be performed: 
• 
The 2-sided 95% CIs for group GMT ratios (OA-RSV over Adults-HA-RSV group 
and OA-RSV over Adults-AIR-RSV group) will be derived from an ANCOVA 
model on log10-transformed titers for each neutralization assay. The model will 
include the group and the baseline log10-transformed titer as covariate. The group 
GMT ratios will be based on a back transformation of group contrast in the 
ANCOVA model applied to the logarithmically transformed titers. 
• 
The 2-sided 95% CIs for group SRR difference (OA-RSV minus Adults-AIR-RSV 
group and OA-RSV minus Adults-HA-RSV group) 
• 
Results will be reported using both ED60 and IU/ml units.  
All between groups analyses of secondary endpoints presented in this section 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 these comparisons. 
4.3.2.2.2. Within groups assessment 
For each study group, each immunological assay and at each time point that blood 
samples are collected, the following analysis will be performed: 
a. 
Percentage of participants with neutralizing titers equal to or above pre-defined assay 
cut-offs and their 2-sided 95% CIs will be tabulated. 
b. Percentage of participants having a fold increase in neutralizing titers ≥4 and their 2-
sided 95% CIs will be tabulated. 
c. 
Unadjusted GMTs and their 95% CIs will be tabulated and displayed graphically. 
d. Furthermore, to account for the multiples timepoints at which the blood samples are 
collected, a mixed effects model (see Section 4.3.3.1) will be fitted, from which the 
adjusted GMTs and their 95% CIs will be computed and tabulated. 
e. 
The kinetics of unadjusted GMTs will be plotted as a function of time for 
participants with results available at all timepoints. 
f. 
Unadjusted MGIs and their 95% CIs will be tabulated and displayed graphically. 
g. Distribution of neutralizing titers will be displayed using reverse cumulative curves. 
h. Results will be reported using both ED60 and IU/ml units.  


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The above mentioned descriptive within group immunogenicity analysis will also be 
generated by age at vaccination (50-59 YOA, 60-69 YOA, 70-79 YOA and ≥80 YOA 
years) with the exception of analysis described in point d, e and g. No graphical display 
will be produced. 
4.3.2.3. 
Immunogenicity analysis: CMI response 
The analysis will be based on the CMI subset of the PPS. If, in any group, the percentage 
of vaccinated participants with serological results excluded from the CMI subset of the 
PPS is more than 5%, a second analysis based on the CMI subset of the ES will be 
performed to complement the PPS analysis. 
At each time point blood samples are collected, the following parameters will be 
summarized by group using descriptive statistics (N, geometric mean, min, Q1, median, 
Q3, max) in the CMI subset:  
• 
Frequency of RSVPreF3-specific CD4+ and/or CD8+ T cells expressing at least 2 
activation markers including at least one cytokine among CD40L, 4-1BB, IL-2, 
TNF-α, IFN-γ, IL-13, IL-17, measured by intracellular cytokine staining (ICS) using 
Peripheral Blood Mononuclear Cells (PBMCs). 
• 
The kinetics of the frequency of RSVPreF3-specific CD4+ T cells expressing at least 
2 activation markers including at least one cytokine among CD40L, 41BB, IL-2, 
TNF-α, IFN-γ, IL-13, IL-17, measured by ICS, will be plotted as a function of time 
for participants with results available at all timepoints. 
• 
Fold increase of the frequency of RSVPreF3-specific CD4+ T cells expressing at 
least 2 activation markers including at least one cytokine among CD40L, 41BB, IL-
2, TNF-α, IFN-γ, IL-13, IL-17, measured by ICS at the post-vaccination time point 
over pre-vaccination (Visit 1, Day 1). The percentage of subjects with at least a 4-
fold increase, post-vaccination as compared to pre-vaccination will be tabulated by 
timepoint. 
• 
The frequency of RSVPreF3 specific-CD4+ T cells expressing at least 2 activation 
markers including at least one cytokine among CD40L, 41BB, IL-2, TNF-α, IFN- γ, 
IL-13, IL-17, measured by ICS, will be displayed graphically using boxplots (min, 
Q1, median, Q3, max) 
The above mentioned descriptive within group immunogenicity analysis will also be 
generated by age at vaccination (50-59 YOA, 60-69 YOA, 70-79 YOA and ≥80 YOA 
years) at the exception of the graphical displays 


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4.3.3. 
Additional considerations 
4.3.3.1. 
Mixed-effects model 
For the GMTs calculation based on the mixed effects model mentioned in Section 
4.3.2.2, repeated measures analysis of covariance (ANCOVA) model will be fitted 
including study group (OA-RSV, Adults-AIR-RSV, Adults-AIR-Placebo, Adults-HA-
RSV, Adults-HA-Placebo) and post-vaccination visit (Day 31, Months 6, 12), as fixed 
effects, pre-vaccination log10-transformed titers as a covariate and the response variable 
is the post-vaccination log10-transformed titers. The PROC MIXED procedure in SAS® 
will be used to carry out the ANCOVA. 
The following SAS codes will be used: 
            PROC MIXED DATA=SERO method=reml empirical; 
       CLASS subjid group visit ; 
 
 
MODEL post-vac=pre-vacc group visit visit*group/ noint s cl; 
 
 
REPEATED visit/type=un subject=subjid; 
 
 
LSMEANS visit*group/ E cl; 
            ODS OUTPUT LSMEANS=LS; 
            RUN; 
The above SAS codes may be adapted in case of convergence issues. 
4.3.3.2. 
Cell-mediated immune response 
The RSVPreF3-specific CD4+/ CD8+ T cell frequencies will be obtained by subtracting 
the background value to the antigen-induced value, and by setting to 1 all values less than 
or equal to zero for geometric mean calculation and graphical representation. Frequencies 
will be expressed as the number of cells per million of CD4+/ CD8+ T cells. 
More specifically, the frequencies of RSVPreF3-specific CD4+/ CD8+ T cells expressing 
at least 2 activation markers including at least one cytokine [
+
2
Freq
] will be computed as 
follows: 
4
2
2
CD
Background
background
Background
N
n
Freq
+
+
=
      and      
4
2
2
CD
Induction
Induction
Induction
N
n
Freq
+
+
=
,  
and 
+
+
+
−
=
2
2
2
Background
Induction
Specific
Freq
Freq
Freq
 
where 
+
2
Background
n
= number of CD4+ T cells expressing at least 2 activation markers including at 
least one cytokine after stimulation with medium only (background) 


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+
2
Induction
n
= number of CD4+ T cells expressing at least 2 activation markers including at 
least one cytokine after stimulation with a pool of peptides covering RSVPreF3 
(induction) 
4
/
CD
Ind
Back
N
= Total number of CD4+ T cells involved in the assay (background or induction) 
For the computation of the fold increase (post- over pre-vaccination) of the frequency of 
RSVPreF3-specific CD4+ T-cells identified as expressing at least 2 activation markers 
including at least one cytokine among CD40L, 41BB, IL-2, TNF-α, IFN-γ, IL-13, IL-17, 
the results below the lower limit of quantification (LLOQ) of the assay will be replaced 
by the value of the LLOQ. 
4.3.3.3. 
Atrial Fibrillation (AF) AESIs 
Potential AF AESIs will be identified through the MedDRA preferred term of interest 
atrial fibrillation (10003658). Sites will be prompted via query to complete any necessary 
additional information for these AESIs in the eCRF. Additional analysis might be 
performed on those additional data collected for AF AESIs. 
AF AESIs will be described in a tabular summary including the characteristics of the AE 
(seriousness, causality, maximum intensity), time to onset and outcome. 
CCI


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CCI


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CCI


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4.5. 
Other Safety Analyses 
Not Applicable. 
4.6. 
Other Analyses 
Not Applicable. 
4.7. 
Interim Analyses 
All analyses will be conducted on final data, as clean as possible. 
4.7.1. 
Sequence of analyses 
The analyses will be performed stepwise: 
• 
Day 31 (PCA): A first analysis will be performed on all immunogenicity, 
reactogenicity and safety data available and as clean as possible, when data for at 
least primary and secondary endpoints up to Visit 2 (Day 31) are available for all 
participants. This analysis will be considered as final for those endpoints*. 
• 
Month 6: A second analysis will be performed on all immunogenicity and safety 
data available and as clean as possible, when data for at least secondary endpoints up 
to Visit 3 (Month 6) are available for all participants. This analysis will be 
considered as final for those endpoints*. 
• 
An end of study analysis will be performed when all data for at least secondary 
endpoints up to study conclusion (Visit 4, Month 12) will be available for all 
participants. 
CCI


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• 
If the data for tertiary endpoints become available at a later stage, (an) additional 
analysis/analyses will be performed. 
* Each analysis can be considered as final, as it is based on data that is as clean as 
possible. However, the consecutive analysis of the same time point might slightly 
differ at the next analysis e.g., when Month 6 data are re-analyzed at the time of 
Month 12 analysis. If major changes are identified, they will be described in the 
clinical study report. 
4.7.2. 
Statistical considerations for interim analysis 
No statistical adjustment for interim analysis is required. 
4.8. 
Changes to Protocol Defined Analyses 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 26-JUL-2022). 
5. 
SAMPLE SIZE DETERMINATION 
The target sample size for the study is approximately 1520 participants: 380 participants 
each in the Adults-HA-RSV Group and Adults-AIR-RSV Group, 190 participants each in 
the Adults-HA-Placebo Group and Adults-AIR-Placebo Group and 380 participants in 
the OA-RSV Group. 
The sample size in the groups receiving the investigational vaccine is driven by the 
statistical power to prove the primary NI objectives.  
Assuming 342 evaluable participants in each group receiving the investigational vaccine, 
the power to demonstrate the primary NI objectives following the graphical testing 
procedure in Section 2.1 is presented in Table 4. Power was estimated by 10 000 
simulations, using SAS 9.4:  
• 
Individual RSV-A and RSV-B neutralizing titers at baseline and at 1-month post-
study intervention administration were modeled by a multivariate log-normal 
distribution, means and variance-covariance matrix based on historical data from 
other RSV OA vaccine clinical trials. The Adults-AIR-RSV Group was assumed to 
have the same multivariate log-normal distribution of the OA-RSV Group (i.e., same 
means and variance-covariance matrix), while the Adults-HA-RSV Group was 
assumed to have a 1.25-fold higher mean at 1-month post-study intervention 
administration for both neutralizing antibodies. 
• 
Raw p-values were obtained from shifted 1-sided t-tests (for group GMT ratios) and 
using the method of Miettinen and Nurminen (for group SRR difference). The 
p-value associated to each NI objective is the maximum between the p-values from 
the GMT ratio and from the SRR difference (co-primary endpoints). 


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• 
P-values associated to each NI objective were compared with the corresponding 
alpha, as propagated by the graphical testing procedure, to identify which NI 
objectives were successfully demonstrated at each simulation.  
Table 4 
Power of primary NI objectives 
Objective 
Power 
NI in the Adults-HA-RSV Group for the RSV-A strain 
>99% 
NI in the Adults-HA-RSV Group for the RSV-B strain 
>99% 
NI in the Adults-AIR-RSV Group for the RSV-A strain 
93.6% 
NI in the Adults-AIR-RSV Group for the RSV-B strain 
82.8% 
All 
82.7% 
All=power to demonstrate all primary NI objectives simultaneously; AIR=At increased risk; HA=Healthy adults; NI=Non-
inferiority; RSV=Respiratory syncytial virus. 
A 10% attrition rate is accounted from enrolled to evaluable participants. Participants 
who withdraw from the study will not be replaced. 
6. 
 SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
6.1.1. 
Participant Disposition 
A summary of the number and percentage of participants who completed the study as 
well as those who prematurely withdrew from the study will be provided. Reasons for 
study withdrawal will be summarized. This analysis will be based on the Screened set, 
Enrolled set, ES. 
6.1.2. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics (age at vaccination in years, sex, race, 
ethnicity, country, vital signs, Body Mass Index (BMI) and smoking status) will be 
summarized by group using descriptive statistics, as described in Section 4.1.1. This 
analysis will be based on all analysis sets. 
The following age categories will be considered in the analysis: 50-59 YOA, 60-69 YOA, 
70-79 YOA and ≥80 YOA. In addition, for web posting purposes: 18-64 YOA, 65-84 
YOA and ≥85 YOA. 
 
 
 
 
.  
6.1.3. 
Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
CCI


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• 
Data will be reviewed prior to unblinding (at the Day 31 Analysis) and freezing the 
database to ensure all important deviations (where possible without knowing the 
study intervention details) are captured and categorised in the protocol deviations 
dataset and all deviations leading to exclusions from analysis sets are captured. 
• 
This dataset will be the basis for the summaries of important protocol deviations. 
A summary of important protocol deviations leading to exclusions from any analysis set 
will be provided by group, based on the Screened Set. 
The number of participants screened for the study as well as the number of participants 
excluded from the Enrolled set, ES and the PPS analyses will be tabulated. These will be 
based on the Screened set, Enrolled Set and the ES, respectively. 
6.1.4. 
Participant exposure 
The number and percentage of participants who received the study intervention will be 
tabulated by group for the ES. 
6.1.5. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug dictionary.  
The number and percentage of participants using concomitant medication (any 
medication, any antipyretic and any antipyretic taken prophylactically) during the 4-day 
and the 30-day follow-up period after vaccination will be tabulated with exact 95% CI 
per study group. 
6.1.6. 
Concomitant Vaccinations 
The number and percentage of participants and doses with concomitant vaccination 
during the 30-day follow-up period (i.e., on the day of vaccination and 29 subsequent 
days) will be tabulated with exact 95% CI per study group. 
6.1.7. 
Additional Analyses due to the COVID-19 Pandemic 
Would COVID-19 still be classified as pandemic in one of the study countries, the 
following analyses will be performed: 
A standardized MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
The overall incidence of COVID-19 AEs (during the 30-day follow-up period), COVID-
19 SAEs and COVID-19 AEs leading to study withdrawal (from vaccination up to study 
end) will be summarized. The incidence of these events will be obtained from standard 
AE and SAE summaries (i.e., by SOC and PT). 
COVID-19 assessments (confirmed, probable and suspected diagnosis) for participants 
with COVID-19 AEs will be summarized. 


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The number and percentage of participants with previous or concomitant COVID-19 
vaccination, before and during the study (during the 30-day follow-up period after 
vaccination), will be tabulated with exact 95% CI. 
6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Attributing events to vaccine doses 
If an event starts on the same day as a study dose, the relative dose will be derived from 
the additional information provided in the eCRF using the contents of the flag indicating 
if the event occurred before or after study dose. If ‘after study dose’ is selected, the 
relative dose for the event will be the one administered on the start day of the event. If 
‘before study dose’ is selected, the event will not be attributed to the study vaccination. 
6.2.2. 
Handling of missing data 
6.2.2.1. 
Dates 
When partially completed dates (i.e., dates missing a day and/or month) are used in 
calculations, the following standard rules will be applied: 
• 
A missing day will be replaced by 15 
• 
A missing day and month will be replaced by June 30th. 
The following exceptions apply: 
• 
Adverse events start dates with missing day: 
− 
If the month is not the same as the vaccine dose, then the imputed start date will 
be the 1st of the month. 
− 
If the event starts in the same month as the vaccine dose, the flag indicating if 
the event occurred before or after vaccination (AE.AESTRTPT) will be used to 
complete the date. If ‘after vaccination’ is selected, the imputed start date will 
match the vaccine dose given during that month. If ‘before vaccination’ is 
selected, the imputed date will be one day before the vaccine dose given during 
that month. 
• 
Adverse events start dates with missing day and month: 
− If the year is not the same as the vaccine dose, then the imputed start date will be 
the 1st of January. 
− If the event starts in the same year as the vaccine dose, the flag indicating if the 
event occurred before or after vaccination (AE.AESTRTPT) will be used to 
complete the date. If ‘after vaccination’ is selected, the imputed start date will 
match the vaccine dose given during that year. If ‘before vaccination’ is selected, 
the imputed date will be one day before the vaccine dose given during that year. 
• 
Adverse event end dates with missing day: the imputed end date will be the last day 
of the month or the study conclusion date whichever comes first. 


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• 
Adverse event end dates with missing day and month: the imputed end date will be 
the last day of the year (31st of December) or the study conclusion date whichever 
comes first. 
• 
All incomplete concomitant medication/vaccination start/end dates will follow the 
rules above. 
6.2.2.2. 
Laboratory data  
Any missing or non-evaluable immunogenicity measurement will not be replaced. The 
descriptive analysis performed for each assay at each timepoint will exclude participants 
with a missing or non-evaluable measurement. This is applicable to the standard way of 
computing geometric mean titers/concentrations (GMTs/GMCs). 
Computation of GMTs/GMCs from the mixed effects model inherently accounts for the 
missingness, under the assumption that the missing data are missing at random (MAR). 
Subject having missing pre-vaccination titer will be excluded from ANCOVA and mixed 
effects models (refer Section 4.3.3.1) 
6.2.2.3. 
Daily recording of solicited events 
For studies using paper diaries which have questions in the CRF indicating the presence 
or absence of solicited events, the following rules are applicable: 
• 
Denominators for the summary of administration site (or systemic) solicited events 
will be calculated using the number of participants who respond “Yes” or “No” to 
the question concerning the occurrence of administration site (or systemic) events. 
• 
When a specific solicited event is marked as having not occurred following a specific 
study dose (i.e. SDTM CE.CEOCCUR=N for the specified post-dose period for the 
event in question), all daily measurements will be imputed as Grade 0. 
• 
When a specific solicited event is marked as having occurred following a specific 
study dose (i.e. SDTM CE.CEOCCUR=Y for the specified post-dose period for the 
event in question), any missing daily recordings will be given imputed values to 
allow them to contribute to the ‘Any’ rows but not to specific grade rows of the 
solicited event summary tables. 
The following table shows how participants contribute to each category for a specific 
solicited event over the Day X to Day Y post-dose period: 


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Solicited event category 
Participants included in the calculation of the numerator 
Any 
All participants with at least one occurrence of the adverse event at grade 1, grade 
2, or grade 3 between Day X and Day Y or with the adverse event marked as 
present and at least one missing daily recording between Day X and Day Y 
At least grade 1 
All participants with at least one occurrence of the adverse event at grade 1, grade 
2, or grade 3 between Day X and Day Y 
At least grade 2 
All participants with at least one occurrence of the adverse event at grade 2 or 
grade 3 between Day X and Day Y 
At least grade 3 
All participants with at least one occurrence of the adverse event at grade 3 
between Day X and Day Y 
6.2.2.4. 
Unsolicited adverse events 
Unsolicited adverse event summaries are including serious adverse events unless 
specified otherwise.  
As per CDISC Vaccines Therapeutic Area guide, the solicited events which continue 
beyond the observation period are stored in the Adverse Events (AE) domain, but they do 
not contribute to the summaries of unsolicited adverse events. 
Missing severity, relationship with study vaccine, and outcome of unsolicited adverse 
events will not be replaced and will appear as ‘UNKNOWN’ when displayed in a 
statistical output. 
6.2.3. 
Data derivation 
6.2.3.1. 
Age at vaccination in years and age category 
Age at vaccination in years and age categories are based on the information provided in 
the eCRF and available in DM.AGE. 
6.2.3.2. 
Weight 
Weight will be presented in kilograms. Weights reported in pounds will be converted as 
follows: 
Weight in kilograms = Weight in pounds / 2.2 
6.2.3.3. 
Height 
Height will be presented in centimeters. Heights reported in feet and inches will be 
converted as follows: 
Height in centimeters = Height in inches x 2.54 
6.2.3.4. 
Body mass index (BMI) 
BMI will be calculated as follows: 


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BMI = (Weight in kilograms) / (Height in meters)2 
6.2.3.5. 
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 
6.2.3.6. 
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 and value 
is <=ULOQ 
value 
“value” and value is >ULOQ 
ULOQ 
All other cases 
missing 
6.2.3.7. 
Geometric mean titers (GMTs) and concentrations (GMCs) 
GMT or GMC calculations are performed by taking the inverse logarithm of the mean of 
the log titre or concentration transformations. Non quantifiable neutralizing titres or 
concentrations will be converted as described in Section 6.2.3.6 for the purpose of 
GMT/GMC calculation. Cut-off values are defined by the laboratory before the analysis. 
6.2.3.8. 
Onset day 
The onset day for an event (e.g. AE, concomitant medication/vaccination) is the number 
of days between the study dose and the start date of the event. This is 1 for an event 
occurring on the same day as a study dose (and reported as starting after study dose). 


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6.2.3.9. 
Duration of events 
The duration of an event with a start and end date will be the difference between the start 
and end date plus one day, i.e., an event that starts on 03MAR2018 and ends on 
12MAR2018 has a duration of 10 days. 
For solicited administration site and systemic events: 
• 
The duration of a solicited AE with at least one day Grade > 0 is defined as End 
date(CEENDY) – Start date(CESTDY) + 1, with Start date defined as the first day 
with the symptom and End date defined as the last day with the symptom in or 
beyond the solicited period.  
• 
A missing start date will be imputed with the vaccination date. 
• 
For paper diaries, if an ongoing symptom has a missing end date, the end date will be 
considered equal to vaccination date + 29 days. Partial end dates will be imputed 
according to section 6.2.2.1. 
• 
The number of days with grade 3 solicited symptom will be defined considering each 
day with a known grading=3 (for paper CRF, if the max intensity during the ongoing 
period is 3, each day of the ongoing period will be counted as grade 3). 
6.2.3.10. 
Counting rules for combining solicited and unsolicited adverse events 
Unsolicited adverse events with missing administration site flag will be considered 
systemic. 
Solicited events will be coded by MedDRA as per the following codes: 
Solicited event 
Lower level term code 
Corresponding Lower level term decode  
Pain 
10022086 
Injection site pain 
Redness 
10022061 
Injection site erythema 
Swelling 
10053425 
Injection site swelling 
Fever 
10016558 
Fever 
Headache 
10019211 
Headache 
Fatigue 
10016256 
Fatigue 
Myalgia 
10028411 
Myalgia 
Arthralgia 
10003239 
Arthralgia 
Note that these codes might be adapted depending on the current version of MedDRA at the time of analysis. 
Multiple events with the same preferred term which start on the same day are counted as 
only one occurrence. 
6.2.3.11. 
Counting rules for occurrences of solicited events 
When the occurrences of solicited 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.  


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The intensity of administration site redness/swelling and fever will be scored as follows: 
Intensity grade 
Redness/Swelling 
Fever 
0 
≤ 20 mm 
< 38.0°C (100.4°F) 
1 
> 20 - ≤ 50 mm 
≥ 38.0°C (100.4°F) - ≤ 38.5°C (101.3°F) 
2 
> 50 - ≤ 100 mm 
> 38.5°C (101.3°F) - ≤ 39.0°C (102.2°F) 
3 
> 100 mm 
> 39.0°C (102.2°F) 
6.2.4. 
Display of decimals 
6.2.4.1. 
Percentages 
Percentages and their corresponding confidence limits will be displayed with one decimal 
except for 100% in which case no decimal will be displayed.  
6.2.4.2. 
Demographic/baseline characteristics statistics 
The mean, median, and standard deviation for continuous baseline characteristics (height, 
weight, BMI, pre-dose 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/weight variables will be displayed 
without decimals. 
The maximum and minimum of transformed body temperatures will be displayed with 
one decimal. 
6.2.4.3. 
Serological summary statistics 
For each assay, GMTs and their confidence limits will be presented with one decimal, as 
well as GMT fold increase from pre-vaccination. 
GMT group ratios and their confidence limits will be displayed with 2 decimals 
regardless of the actual values. 
The mean, median, standard deviation, and quartile values for frequency of RSVPreF3 
specific-CD4+ and CD8+ T cells and for the fold increase (post over pre-vaccination) 
will be presented with one decimal. The minimum and maximum values will be 
presented with no decimal. 


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7. 
REFERENCES 
Bretz F, Willi M, Werner B, et al. A graphical approach to sequentially rejective multiple 
test procedures. Statist Med. 2009, 28:586-604. 
Charlson M.E., Pompei P., Ales K.L., MacKenzie C.R., A new method of classifying 
prognostic comorbidity in longitudinal studies: development and validation, J Chrin Dis 
1987; 40(5), 373-383.  
Clopper C.J., 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. 
Quan H., Li B., Couris C.M., Fushimi K., Graham P., Hider P., Januel J-M., Sundararajan 
V., Updating and Validating the Charlson Comorbidity Index and Score for Risk 
Adjustment in Hospital Discharge Abstracts Using Data From 6 Countries, American 
Journal of Epidemiology 2011; 173 (6). 

Prot_000.pdf: 
Protocol Amendment 1
Study ID:  219238
Official Title of Study: A Phase 3, observer-blind, randomized, placebo-controlled 
study to evaluate the non-inferiority of the immune response and safety of the 
RSVPreF3 OA investigational vaccine in adults 50-59 years of age, including adults at 
increased risk of respiratory syncytial virus lower respiratory tract disease, compared 
to older adults ≥60 years of age. 
NCT number: NCT05590403
Date of Document: 30-May-2023


CONFIDENTIAL 
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1 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA (GSK) 
Rue de l’Institut, 89 
1330 Rixensart, Belgium 
Primary study 
intervention(s) 
GSK’s investigational respiratory syncytial virus 
(RSV) vaccine BIO RSV OA=ADJ 
(GSK3844766A) 
Other study intervention(s) 
Placebo: Saline solution 
eTrack study number and 
abbreviated title 
219238 (RSV OA=ADJ-018) 
EudraCT number 
2022-001981-36 
Date of protocol 
Final: 26 July 2022 
Date of protocol amendment 
Amendment 1 Final: 25 May 2023 
Title 
A Phase 3, observer-blind, randomized, 
placebo-controlled study to evaluate the 
non-inferiority of the immune response and safety 
of the RSVPreF3 OA investigational vaccine in 
adults 50-59 years of age, including adults at 
increased risk of respiratory syncytial virus lower 
respiratory tract disease, compared to older adults 
≥60 years of age. 
Brief title 
A study on the immune response and safety of a 
vaccine against respiratory syncytial virus given to 
adults 50-59 years of age, including adults at 
increased risk of respiratory syncytial virus lower 
respiratory tract disease, compared to older adults 
60 years of age and above. 
Sponsor signatory 
Veronica Hulstrøm, MD 
Clinical Project Lead 
RSV Older Adults 
Based on GlaxoSmithKline Biologicals SA Protocol WS v17.3 
©2022 GSK group of companies or its licensor. 


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Protocol Amendment 1 Final 
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2 
Protocol Amendment 1 Investigator Agreement 
I agree: 
•
To conduct the study in compliance with this protocol, any future protocol
amendments or protocol administrative changes, with the terms of the clinical trial
agreement and with any other study conduct procedures and/or study conduct
documents provided by GSK.
•
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.
•
That I will comply with the terms of the site agreement.
•
To comply with local bio-safety legislation.
•
To ensure that all persons assisting me with the study are adequately informed about
the GSK study intervention and other study-related duties and functions as described
in the protocol.
•
To supervise any individual or party to whom I have delegated study-related duties
and functions conducted at the study site.
•
To ensure that any individual or party to whom I have delegated study-related duties
and functions conducted at the study site are qualified to perform those study-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 participant and/or the participant’s legally acceptable representative (LAR).
•
To perform no biological assays on the clinical samples other than those described in
the protocol or its amendment(s).
•
To co-operate with representative(s) of GSK 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 study.
•
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 intervention(s), and more generally about their
financial ties with the sponsor. GSK will use and disclose the information solely for
the purpose of complying with regulatory requirements.


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3 
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
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 all other documents
required by regulatory agencies for this study.


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4 
eTrack study number and 
abbreviated title 
219238 (RSV OA=ADJ-018) 
EudraCT number 
2022-001981-36 
Date of protocol 
Final: 26 July 2022 
Date of protocol amendment 
Amendment 1 Final: 25 May 2023 
Title 
A Phase 3, observer-blind, randomized, 
placebo-controlled study to evaluate the 
non-inferiority of the immune response and safety of 
the RSVPreF3 OA investigational vaccine in adults 
50-59 years of age, including adults at increased risk
of respiratory syncytial virus lower respiratory tract
disease, compared to older adults ≥60 years of age.
Investigator name 
Signature 
Date 
name, function and title 
Signature 
Date of signature 
PPD


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GSK Japan study 
representative/Joint Vaccine 
Co representative name, 
function and title 
Signature 
Date of signature 


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6 
SPONSOR INFORMATION 
1. Sponsor 
GlaxoSmithKline Biologicals SA (GSK)  
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 Serious Adverse Events (SAEs) 
GSK central back-up study contact for reporting SAEs: refer to Section 8.3.3.1.  
Study contact for reporting SAEs: refer to the local study contact information 
document. 
5. GSK Helpdesk for emergency unblinding  
Refer to Section 6.3.5.1. 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Amendment 1 (25 May 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 of significant changes in the conduct or management of the 
study. 
Overall rationale for Amendment 1: 
The purpose of this amendment is to:  
Record events of atrial fibrillation (AF) as Adverse Events of Special Interest (AESIs)
 
 
 
 
 
 
 
Other updates are described in the table below: 
 
CCI
CCI


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List of main changes in the protocol and their rationale: 
Section # and title 
Description of change 
Brief rationale 
2.3.1. Risk assessment 
The description has been updated as per the current 
GSK guidelines for the protocols. 
In parallel with the RSVpreF3 OA clinical development program, 
another RSV vaccine development program was initiated by GSK, 
with the objective to prevent RSV-associated lower respiratory tract 
illness in neonates and infants during their first 6 months of life, 
through immunization of pregnant women with a single dose of 
investigational RSV maternal vaccine candidate. This section was 
updated to include most up to date information regarding this topic, 
as per GSK’s current format. 
3. OBJECTIVES, ENDPOINTS, AND 
ESTIMANDS 
4.3. Justification for dose 
8.1.2. Laboratory assays 
8.1.3. Immunological read-outs 
9.3.1. Primary endpoints/estimands analysis 
9.5. Sample size determination 
10.2. Appendix 2: Clinical laboratory tests 
The terminology of “neutralizing antibody/ies” titer has 
been changed to “neutralization” titer.  
For alignment with the CSR and other current protocols. 
1.3. Schedule of activities (SoA) 
6.8. Concomitant therapy 
8.3.1. Time period and frequency for collecting 
AE, SAE and other safety information 
8.3.2. Method of detecting AEs and SAEs, 
pregnancies, and other events 
8.3.3. Regulatory reporting requirements for 
SAEs, pregnancies, and other events 
8.3.3.1.Contact information for reporting SAEs, 
AESIs (including pIMDs and AF) and pregnancies 
8.3.4. Treatment of AEs 
10.3.5. Adverse events of special interest (AESIs) 
10.3.5.2. Atrial fibrillation (AF) 
10.3.8. Recording and follow-up of AEs, SAEs, 
AESIs (including pIMDs and AF) and pregnancies 
pIMDs and AF adverse events meeting the AEs or 
serious adverse events (SAEs) definitions will be 
considered as adverse events of special interest (AESI) 
in this study and additional information on these events is 
to be reported in the AF follow-up questionnaire in 
electronic case report form (eCRF). 
AESIs were defined to include pIMDs and AF. 
 
 
 
 
 
CCI


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Section # and title 
Description of change 
Brief rationale 
10.3.8.1. Time period for collecting and recording 
AEs, SAEs, AESIs (including pIMDs and AF) and 
pregnancies 
10.3.8.2. Follow-up of AEs, SAEs, AESIs 
(including pIMDs and AF), pregnancies or any 
other events of interest 
10.3.8.2.1. Follow-up during the study 
10.3.8.2.2. Follow-up after the participant is 
discharged from the study 
10.3.8.3. Updating of SAE, AESIs (including 
pIMD and AF), and pregnancy information after 
removal of write access to the participant’s eCRF 
10.3.10. Reporting of SAEs, AESIs (including 
pIMDs and AF), pregnancies and other events 
10.7.1. List of abbreviations 
10.7.2. Glossary of terms 
4.3. Justification for dose 
The terminology for respiratory syncytial virus, 
RSVPreF3-binding IgG has been clarified. 
This nomenclature more precisely reflects what is indeed 
measured by the neutralization assay and the enzyme-linked 
immunosorbent assay (ELISA) respectively. 
6.3.5.1. Emergency unblinding 
The section has been updated to reflect that GSK’s 
Global Safety staff may unblind the intervention 
assignment for any participant with an SAE. If the SAE 
requires that an expedited regulatory report be sent to 
one 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. 
For alignment with current protocol template. 
 


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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 7 
List of main changes in the protocol and their rationale: ........................................... 8 
1. 
PROTOCOL SUMMARY ........................................................................................ 17 
1.1. 
Synopsis ..................................................................................................... 17 
1.2. 
Schema ...................................................................................................... 17 
1.3. 
Schedule of activities (SoA) ........................................................................ 18 
2. 
INTRODUCTION .................................................................................................... 21 
2.1. 
Study rationale ............................................................................................ 21 
2.2. 
Background ................................................................................................ 21 
2.3. 
Benefit/Risk assessment ............................................................................. 22 
2.3.1. 
Risk assessment (Amended: 25 May 2023) ................................. 22 
2.3.2. 
Benefit assessment ..................................................................... 24 
2.3.3. 
Overall Benefit/Risk conclusion .................................................... 24 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ................................................... 24 
4. 
STUDY DESIGN .................................................................................................... 26 
4.1. 
Overall design ............................................................................................. 26 
4.1.1. 
Overview of the recruitment plan.................................................. 29 
4.1.2. 
Enrollment rules ........................................................................... 29 
4.1.3. 
Caregiver support ........................................................................ 30 
4.2. 
Scientific rationale for study design ............................................................. 31 
4.2.1. 
Rationale for the use of placebo .................................................. 32 
4.2.2. 
Rationale for study blinding .......................................................... 32 
4.3. 
Justification for dose (Amended: 25 May 2023) .......................................... 32 
4.4. 
End of Study definition ................................................................................ 33 
5. 
STUDY POPULATION ........................................................................................... 33 
5.1. 
Inclusion criteria .......................................................................................... 33 
5.1.1. 
Specific inclusion criteria for all participants in Cohort 1 ............... 33 
5.1.1.1. 
Specific inclusion criteria for participants in the 
Adults-HA Sub-cohort ................................................. 34 
5.1.1.2. 
Specific inclusion criteria for participants in the 
Adults-AIR Sub-cohort ................................................ 34 
5.1.2. 
Specific inclusion criteria for Cohort 2 (OA-RSV Group) .............. 35 
5.2. 
Exclusion criteria ......................................................................................... 35 
5.2.1. 
Medical conditions ....................................................................... 35 
5.2.2. 
Prior/Concomitant therapy ........................................................... 36 
5.2.3. 
Prior/Concurrent clinical study experience ................................... 37 
5.2.4. 
Other exclusions .......................................................................... 37 
5.2.4.1. 
Other exclusions for all participants ............................ 37 
5.2.4.2. 
Other exclusions for Cohort 1 ..................................... 37 
5.3. 
Lifestyle considerations ............................................................................... 37 
5.4. 
Screening failures ....................................................................................... 37 


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5.5. 
Criteria for temporarily delaying enrollment/study intervention 
administration ............................................................................................. 38 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY .................................. 38 
6.1. 
Study intervention(s) administered .............................................................. 38 
6.2. 
Preparation, handling, storage, and accountability ...................................... 39 
6.3. 
Measures to minimize bias: randomization and blinding ............................. 40 
6.3.1. 
Participant identification ............................................................... 40 
6.3.2. 
Randomization to study intervention ............................................ 40 
6.3.3. 
Intervention allocation to the participant ....................................... 40 
6.3.4. 
Allocation of participants to CMI assay subsets ........................... 41 
6.3.5. 
Blinding and unblinding ................................................................ 41 
6.3.5.1. 
Emergency unblinding (Amended: 25 May 
2023) .......................................................................... 42 
6.3.5.2. 
Unblinding prior to regulatory reporting of SAEs ......... 43 
6.4. 
Study intervention compliance .................................................................... 43 
6.5. 
Dose modification ....................................................................................... 43 
6.6. 
Continued access to study intervention after the end of the study ............... 43 
6.7. 
Treatment of overdose ................................................................................ 43 
6.8. 
Concomitant therapy (Amended: 25 May 2023) .......................................... 44 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 45 
7.1. 
Discontinuation of study intervention ........................................................... 45 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 45 
7.3. 
Lost to follow-up .......................................................................................... 46 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 46 
8.1. 
Immunogenicity assessments ..................................................................... 47 
8.1.1. 
Biological samples ....................................................................... 47 
8.1.2. 
Laboratory assays ....................................................................... 48 
8.1.3. 
Immunological read-outs .............................................................. 49 
8.1.4. 
Immunological correlates of protection ......................................... 49 
8.2. 
Safety assessments .................................................................................... 49 
8.2.1. 
Pre-intervention administration procedures .................................. 50 
8.2.1.1. 
Collection of demographic data .................................. 50 
8.2.1.2. 
Measure/record height and weight .............................. 50 
8.2.1.3. 
Medical history (Amended: 25 May 2023) ................... 50 
8.2.1.4. 
Vaccination history ..................................................... 50 
8.2.1.5. 
Physical examination/vital signs ................................. 51 
8.2.1.6. 
Smoking status and smoking exposure history ........... 51 
8.2.1.7. 
Pregnancy test (only for women of childbearing 
potential in Cohort 1) .................................................. 51 
8.2.1.8. 
Pre-study intervention administration body 
temperature ................................................................ 51 
8.3. 
AEs, SAEs and other safety reporting ......................................................... 52 
8.3.1. 
Time period and frequency for collecting AE, SAE and 
other safety information (Amended: 25 May 2023) ....................... 52 
8.3.2. 
Method of detecting AEs and SAEs, pregnancies, and 
other events (Amended: 25 May 2023) ........................................ 53 
8.3.3. 
Regulatory reporting requirements for SAEs, pregnancies, 
and other events (Amended: 25 May 2023) ................................. 54 


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8.3.3.1. 
Contact information for reporting SAEs, AESIs 
(including pIMDs and AF) and pregnancies 
(Amended: 25 May 2023) ........................................... 55 
8.3.4. 
Treatment of AEs (Amended: 25 May 2023) ................................ 55 
8.3.5. 
Participant card ............................................................................ 55 
8.4. 
Pharmacokinetics ....................................................................................... 55 
8.5. 
Genetics ..................................................................................................... 55 
8.6. 
Biomarkers ................................................................................................. 56 
8.7. 
Immunogenicity assessments ..................................................................... 56 
8.8. 
Health outcomes ......................................................................................... 56 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 56 
9.1. 
Statistical hypotheses ................................................................................. 56 
9.2. 
Analysis sets ............................................................................................... 57 
9.2.1. 
Criteria for elimination from analysis ............................................ 57 
9.3. 
Statistical analyses ..................................................................................... 57 
9.3.1. 
Primary endpoints/estimands analysis ......................................... 58 
9.4. 
Interim analyses .......................................................................................... 58 
9.4.1. 
Sequence of analyses .................................................................. 59 
9.4.2. 
Statistical considerations for interim analysis ............................... 59 
9.5. 
Sample size determination .......................................................................... 59 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 60 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 60 
10.1.1. 
Regulatory and ethical considerations ......................................... 60 
10.1.2. 
Financial disclosure ..................................................................... 61 
10.1.3. 
Informed consent process ............................................................ 61 
10.1.4. 
Data protection ............................................................................ 62 
10.1.5. 
Committees structure ................................................................... 62 
10.1.6. 
Dissemination of clinical study data ............................................. 62 
10.1.7. 
Data quality assurance ................................................................ 63 
10.1.8. 
Source documents ....................................................................... 64 
10.1.9. 
Study and site start and closure ................................................... 64 
10.1.10. Publication policy ......................................................................... 65 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 65 
10.3. 
Appendix 3: AEs: definitions and procedures for recording, 
evaluating, follow-up, and reporting ............................................................ 66 
10.3.1. 
Definition of an AE ....................................................................... 66 
10.3.1.1. Events Meeting the AE Definition ............................... 67 
10.3.1.2. Events NOT Meeting the AE Definition ....................... 67 
10.3.2. 
Definition of an SAE ..................................................................... 68 
10.3.3. 
Solicited events ............................................................................ 69 
10.3.4. 
Unsolicited AEs ............................................................................ 69 
10.3.5. 
Adverse events of special interest (AESIs) (Amended: 25 
May 2023) .................................................................................... 70 
10.3.5.1. Potential immune-mediated diseases (pIMDs) ............ 70 
10.3.5.2. Atrial fibrillation (AF) ................................................... 75 
10.3.6. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as AEs or SAEs ...................................... 76 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs ..................... 76 
10.3.7.1. Pregnancy .................................................................. 76 


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10.3.8. 
Recording and follow-up of AEs, SAEs, AESIs (including 
pIMDs and AF) and pregnancies (Amended: 25 May 
2023) ........................................................................................... 76 
10.3.8.1. Time period for collecting and recording AEs, 
SAEs, AESIs (including pIMDs and AF) and 
pregnancies (Amended: 25 May 2023) ....................... 77 
10.3.8.2. Follow-up of AEs, SAEs, AESIs (including 
pIMDs and AF), pregnancies or any other 
events of interest (Amended: 25 May 2023) ............... 77 
10.3.8.2.1. Follow-up during the study 
(Amended: 25 May 2023) ....................... 78 
10.3.8.2.2. Follow-up after the participant is 
discharged from the study 
(Amended: 25 May 2023) ....................... 78 
10.3.8.2.3. Follow-up of pregnancies ........................ 78 
10.3.8.3. Updating of SAE, AESIs (including pIMD and 
AF), and pregnancy information after removal 
of write access to the participant’s eCRF 
(Amended: 25 May 2023) ........................................... 78 
10.3.9. 
Assessment of intensity and causality .......................................... 79 
10.3.9.1. Assessment of intensity .............................................. 79 
10.3.9.2. Assessment of causality ............................................. 80 
10.3.9.3. Medically attended visits ............................................. 81 
10.3.9.4. Assessment of outcomes ............................................ 81 
10.3.10. Reporting of SAEs, AESIs (including pIMDs and AF), 
pregnancies and other events (Amended: 25 May 2023) ............. 81 
10.3.10.1. Events requiring expedited reporting to GSK 
(Amended: 25 May 2023) ........................................... 81 
10.3.10.2. Back-up system in case the electronic reporting 
system does not work ................................................. 82 
10.4. 
Appendix 4: Contraceptive guidance and collection of pregnancy 
information .................................................................................................. 82 
10.4.1. 
Definitions .................................................................................... 82 
10.4.1.1. Woman of childbearing potential (WOCBP) ................ 82 
10.4.1.1.1. Women not considered as women 
of childbearing potential .......................... 82 
10.4.2. 
Contraception guidance ............................................................... 83 
10.4.3. 
Collection of pregnancy information ............................................. 84 
10.4.3.1. Female participants who become pregnant ................ 84 
10.5. 
Appendix 5: Grading scales for chronic diseases in scope of the AIR 
population ................................................................................................... 84 
10.5.1. 
GOLD classification ..................................................................... 84 
10.5.2. 
New York Heart Association Classification of heart failure ........... 84 
10.5.3. 
Chronic kidney disease classification ........................................... 85 
10.6. 
Appendix 6: Country-specific requirements ................................................. 86 
10.6.1. 
Germany ...................................................................................... 86 
10.6.2. 
Japan ........................................................................................... 89 
10.7. 
Appendix 7: Abbreviations and glossary of terms ........................................ 90 
10.7.1. 
List of abbreviations (Amended: 25 May 2023) ............................ 90 
10.7.2. 
Glossary of terms (Amended: 25 May 2023) ................................ 94 
10.8. 
Appendix 8: Protocol Amendment history ................................................... 98 


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11. REFERENCES ..................................................................................................... 113 


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LIST OF TABLES 
PAGE 
Table 1 
Schedule of activities (Amended: 25 May 2023) ..................................... 18 
Table 2 
Intervals between study visits ................................................................. 20 
Table 3 
Study objectives, endpoints and estimands (Amended: 25 May 
2023) ...................................................................................................... 24 
Table 4 
Study cohorts, groups, intervention and blinding .................................... 29 
Table 5 
Study interventions administered ........................................................... 39 
Table 6 
Contact information for emergency unblinding ....................................... 42 
Table 7 
Timing of collection of concomitant medication to be recorded 
(Amended: 25 May 2023) ....................................................................... 44 
Table 8 
Biological samples ................................................................................. 47 
Table 9 
Laboratory assays (Amended: 25 May 2023) ......................................... 48 
Table 10 
Immunological read-outs (Amended: 25 May 2023) ............................... 49 
Table 11 
Timeframes for collecting and reporting of safety information 
(Amended: 25 May 2023) ....................................................................... 52 
Table 12 
Timeframes for submitting SAEs, pregnancy and other events 
reports to GSK ....................................................................................... 54 
Table 13 
Contact information for reporting SAEs, AESI (including pIMDs 
and AF) and pregnancies (Amended: 25 May 2023) .............................. 55 
Table 14 
Study objectives and null hypothesis ...................................................... 56 
Table 15 
Analysis sets .......................................................................................... 57 
Table 16 
Power of primary NI objectives ............................................................... 60 
Table 17 
Solicited administration site events ......................................................... 69 
Table 18 
Solicited systemic events ....................................................................... 69 
Table 19 
List of pIMDs .......................................................................................... 70 
Table 20 
Intensity scales for solicited events in participants ≥50 YOA .................. 79 
Table 21 
Highly effective contraceptive methods .................................................. 83 


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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 27 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Rationale:  
GSK is developing an RSVPreF3 OA investigational vaccine against RSV-associated 
(subtypes A and B) disease in adults ≥60 YOA. The aim of this study is to demonstrate 
the non-inferiority (NI) of the immune response and evaluate safety of RSVPreF3 OA 
investigational vaccine in adults 50-59 YOA, including those who are at increased risk of 
RSV-lower respiratory tract disease (LRTD), versus adults ≥60 YOA, where vaccine 
efficacy against RSV-LRTD is being assessed in another clinical study. 
Objectives, endpoints and estimands: Refer to Section 3. 
1.2. 
Schema 
Refer to Figure 1 for a schematic presentation of the study design. 
 


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1.3. 
Schedule of activities (SoA) 
Table 1 
Schedule of activities (Amended: 25 May 2023) 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Notes 
Timepoint 
Day 1 
Day 31 
Month 6 
Month 12 
 
Informed consent 
● 
 
 
 
Freely given and written informed consent must be obtained 
from each study participant prior to participation in the study. 
The participant’s informed consent may be obtained prior to 
Visit 1. 
See Section 10.1.3 
Distribution of participant card 
○ 
 
 
 
See Section 8.3.5 
Check inclusion/exclusion criteria 
● 
 
 
 
See Section 5.1 and Section 5.2 
Check with participants if he/she will appoint a 
caregiver, and distribute information letter to 
caregiver, when applicable 
○ 
○ 
○ 
 
See Section 4.1.3 and Section 10.1.3 
Screening conclusion 
● 
 
 
 
See Section 5.4 
Baseline and demography assessments 
 
 
 
 
 
Collect demographic data 
● 
 
 
 
See Section 8.2.1.1  
Measure/record height and weight 
● 
 
 
 
See Section 8.2.1.2 
Record medical history  
● 
 
 
 
See Section 8.2.1.3 
Record history of vaccine administration 
● 
 
 
 
Any vaccination administered up to 1 year before 
administration of the study intervention should be recorded in 
the eCRF. Administration of Shingrix and COVID-19 vaccines 
at any timepoint (even if longer than 1 year before the study 
intervention administration) should be recorded in the eCRF. 
See Section 8.2.1.4 
Physical examination/vital signs 
● 
○a 
○a 
○a 
See Section 8.2.1.5 
Record smoking status and smoking exposure 
history (including electronic smoking devices) 
● 
 
 
 
See Section 8.2.1.6. Refer to Glossary of terms for definitions 
of current and former smoker. 
Clinical specimens for laboratory assays  
 
 
 
 
 
Blood sampling for antibody determination in all 
participants (~10 mL) 
●b 
● 
● 
● 
See Section 8.1.1  
Blood sampling for CMI response in a subset 
(~25 mL) 
●b 
● 
● 
● 
See Section 8.1.1  


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Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Notes 
Timepoint 
Day 1 
Day 31 
Month 6 
Month 12 
 
Study intervention 
 
 
 
 
 
Check criteria for temporary delay for enrollment and 
study intervention administration 
○ 
 
 
 
See Section 5.5 
Urine pregnancy test (only for women of childbearing 
potential in Cohort 1) 
●b 
 
 
 
See Section 8.2.1.7 
Study group and intervention number allocation 
○ 
 
 
 
See Section 6.3.2 and Section 6.3.3 
Record body temperature before study intervention 
administration 
● 
 
 
 
The route for measuring temperature can be oral or axillary 
(see Section 8.2.1.8). Fever is defined as temperature 
≥38.0°C/100.4°F regardless of the location of measurement. 
Study intervention administration (including 
30-minutes post-study intervention administration 
observation) 
● 
 
 
 
See Section 6.1 
Record administered study intervention number 
● 
 
 
 
 
Safety assessments 
 
 
 
 
 
Distribute diary cards 
○ 
 
 
 
A paper diary will be distributed to all study participants at 
Visit 1 (day of study intervention administration). All participants 
will record solicited events after study intervention 
administration and for 3 subsequent days (Days 1-4), 
unsolicited AEs, and concomitant medications/products after 
study intervention administration and for 29 subsequent days 
(Days 1-30). 
See Section 10.3.8 
Return of diary cards  
 
○ 
 
 
See Section 10.3.8 
Record solicited administration site and systemic 
events (Days 1–4 post-study intervention 
administration)  
● 
● 
 
 
See Section 10.3.8 and Table 11 
Record unsolicited AEs (Days 1-30 post-study 
intervention administration) in the participantsC 
● 
● 
 
 
See Section 10.3.8 and Table 11 
Record concomitant medications/vaccinations 
● 
● 
● 
● 
See Section 6.8  
Record any intercurrent medical conditions  
● 
● 
● 
● 
See Section 9.2.1 and Table 11 
Record all SAEs and pIMDsC  
● 
● 
● 
 
See Section 10.3.8 and Table 11 
Record AEs/SAEs leading to withdrawal from the 
study and pregnancies 
● 
● 
● 
● 
See Section 10.3.8 and Table 11 


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Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Notes 
Timepoint 
Day 1 
Day 31 
Month 6 
Month 12 
 
Record SAEs related to study participation, or to a 
concurrent GSK medication/vaccine 
● 
● 
● 
● 
SAEs related to study participation, or to a concurrent GSK 
medication/vaccine should be collected from the time of 
consent obtained (prior to administration of the study 
intervention) up to study end. 
See Section 10.3.8 and Table 11 
Record SAEs and pIMDs related to study 
intervention administration and fatal SAEsC 
● 
● 
● 
● 
SAEs and pIMDs related to study intervention administration 
and fatal SAEs should be collected after study intervention 
administration (Day 1) up to study end. 
See Section 10.3.8 and Table 11 
Study Conclusion 
 
 
 
● 
See Section 4.4 
Note: The double-line borders indicate the analyses which will be performed on all data (i.e., data that are as clean as possible) obtained up to this timepoints. 
AE=Adverse event; AESI= Adverse event of specific interest; CMI=Cell-mediated immunity; COVID-19=Coronavirus disease 2019; eCRF=Electronic case report form; 
pIMD=Potential immune-mediated disease; SAE=Serious adverse event. 
● 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 
a. 
If deemed necessary by the investigator. 
b. 
The blood sample and urine sample for pregnancy test should be taken on the same day, prior to study intervention administration. If the study intervention administration is 
delayed by any reason, in the event samples have been taken, the samples will need to be collected again on the day of study intervention administration and the first blood 
sample will be destroyed. 
c. 
Atrial fibrillation (AF) will be considered as AESI in this study and will be additionally reported in the AF follow-up questionnaire (electronic or paper) in eCRF. The 
collection of AF will be performed following the AE/SAE reporting periods. For AF that were reported before the implementation of this Protocol Amendment 1, 
additional available information should be encoded in the specific AF follow-up questionnaire retrospectively. 
Note: Visit 2, Visit 3 and Visit 4 should be done on site. Under special circumstances (e.g., pandemic), study visits can be done at home, or biological samples can be taken at a 
different location (see Section 8). 
Table 2 
Intervals between study visits 
Interval 
Planned visit interval  
Allowed interval range 
Visit 1→Visit 2 
30 days 
30-42 days 
Visit 1→Visit 3 
180 days 
180-210 days 
Visit 1→Visit 4 
365 days 
350-380 days 
 


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2. 
INTRODUCTION 
2.1. 
Study rationale 
GSK is developing an RSVPreF3 OA investigational vaccine against RSV-associated 
(subtypes A and B) disease in adults ≥60 YOA because of increased risk of RSV-LRTD. 
However, some younger patient groups also have an increased risk of RSV-LRTD. The 
aim of this observer-blind study is to demonstrate the NI of the immune response and to 
evaluate safety of the RSVPreF3 OA investigational vaccine in adults 50-59 YOA, 
including those who are at increased risk of RSV-LRTD, versus adults ≥60 YOA, where 
vaccine efficacy against RSV-LRTD is being assessed in another clinical study. 
2.2. 
Background 
RSV is an RNA virus of which 2 antigenically distinct subtypes exist, referred to as 
RSV-A and RSV-B [Borchers, 2013]. RSV is a highly contagious human pathogen that 
causes respiratory tract infections in people of all ages. In temperate climates throughout 
the world, RSV predictably causes fall-winter epidemics. In (sub) tropical regions, viral 
activity is more endemic, and outbreaks are less temporally focused. 
RSV is one of the important viral pathogens identified in adults with acute respiratory 
infections and is increasingly recognized as a cause of serious illness in high-risk adults, 
including those with chronic lung and heart disease. In a prospective cohort study over 
4 RSV seasons in healthy elderly patients (≥65 YOA) and high-risk adults (≥21 YOA) 
with chronic heart or lung disease, RSV infection developed annually in 3% to 7% of 
healthy elderly patients and in 4% to 10% of high-risk adults [Falsey, 2005; Shi, 2021]. 
Healthy elderly patients with RSV infection required fewer visits to the doctor’s office 
compared to those with influenza. Utilization of health care services among high-risk 
adults with either RSV infection or influenza was similar. RSV infection in the elderly 
and high-risk adults has a disease burden similar to that of a non-pandemic influenza A in 
a population with a high rate of influenza vaccination [Falsey, 2005]. 
In different populations of patients with chronic morbidities both the prevalence and 
incidence of RSV infections is increased, leading to an increase in need for medical care 
and hospitalization in high income countries. A major US study reported incidence of 
RSV-related hospitalizations among different types of high-risk patients of different age 
groups, in 2 different settings (New York City and Rochester). Adults with COPD had 
3.2–13.4 times higher hospitalization rates than those without COPD. Adults with asthma 
had 2.0-3.6 times higher estimated hospitalization rates than those without asthma. Adults 
with diabetes had 2.4–11.4 times higher hospitalization rates than those without diabetes. 
Adults with CAD had estimated RSV hospitalization rates 3.7–7.0 times higher than 
those without CAD. Estimated IRRs for CHF were the largest; adults with CHF had 
4.0-33.2 times higher hospitalization rates than those without CHF. Estimated IRRs for 
CHF were highest in the youngest age group and declined with increasing age. 
[Branche, 2022]. Different European, Asian and US studies have reported an 
exacerbation of either COPD, asthma, interstitial pulmonary fibrosis or cystic fibrosis 
ranging from 2.2% to 17% [Htar, 2020; Branche, 2022; Shi, 2021]. Patients with chronic 
renal disease as well as those with chronic liver disease have impaired immune functions 


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due to their disease pathogenesis, which is associated, in general, with increased 
susceptibility to infections [Betjes, 2013; Irvine, 2019]. 
Please refer to the current IB for information regarding pre-clinical studies, and clinical 
studies of RSVPreF3 OA investigational vaccine. 
2.3. 
Benefit/Risk assessment 
2.3.1. 
Risk assessment (Amended: 25 May 2023) 
Detailed information about the known and expected benefits and potential risks (syncope, 
hypersensitivity, pIMD) and reasonably expected AEs of RSVPreF3 OA investigational 
vaccine can be found in the IB and Development Safety Update Report. 
Potential/Identified Risk 
Mitigation Strategy 
RSVPreF3 OA investigational vaccine 
pIMDs are considered a potential risk, as for all 
vaccines containing an adjuvant system. Refer to 
Section 10.3.5.1 for details. 
 
Hypersensitivity reactions (including anaphylaxis). 
All participants will remain under observation at the clinical 
center for at least 30 minutes after study intervention 
administration.  
Participants with a history of hypersensitivity or severe 
allergic reaction to any component of the vaccine as well 
as a known latex hypersensitivity are excluded from study 
enrollment. 
Study procedures 
Intramuscular vaccination commonly precipitates a 
transient and self-limiting local inflammatory reaction. 
This may typically include pain at injection site, 
erythema/redness, and swelling. 
Physician can implement the measures that they consider 
necessary.  
Pain, redness, irritation, and bruising may occur at 
the site where blood is drawn. 
Physician can implement the measures that they consider 
necessary.  
Syncope (fainting) can occur following or even before 
any blood draw or study intervention administration 
as a psychogenic response to the needle insertion. 
Participants who mention experiencing previous episodes 
of fainting or dizziness before, during or after a blood draw 
or previous vaccination, will be asked to lie down during the 
intervention and remain under observation at the clinical 
center until deemed necessary by site personnel. 
Appropriate medical treatment must be readily available 
during this period. 
For details of study procedures, dose, and study design justification, refer to Section 1.3 
and Section 4.2. 
In parallel with the RSVPreF3 OA clinical development program, another RSV 
vaccine development program was initiated by GSK, with the objective to prevent RSV-
associated lower respiratory tract illness in neonates and infants during their first 6 
months of life, through immunization of pregnant women with a single dose of the 
investigational RSV maternal vaccine candidate. The maternal vaccine contains 
120 µg of the RSVPreF3 antigen, as does the RSVPreF3 OA vaccine, however it does 
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In 2020, GSK initiated a Phase 3, double-blind, 2:1-randomized, placebo-controlled 
study (RSV MAT-009; NCT04605159) in 24 countries to assess the safety and efficacy 
of the maternal vaccine candidate (RSVPreF3 Mat) administered to 18–49-year-old 
women in the late second or third trimester of pregnancy. 
The vaccine candidate for older adults (OA) contains the same RSV antigen as the 
RSV maternal vaccine candidate but the RSV OA vaccine is combined with GSK’s 
established AS01E adjuvant to boost the immune response in the OA population. 
The RSV OA vaccine trials in participants >60 YoA are closely monitored for safety 
with all available safety data reviewed internally. In addition, the Phase 3 RSV 
OA=ADJ-006 clinical study is monitored by an IDMC on an ongoing basis. The IDMC 
has not raised any concern for safety in the OA population. The RSV OA vaccine has 
not been studied in pregnant women to date. 
In the current study the inclusion of all participants will be restricted to those 50 YOA 
and above. This age cut-off has been chosen since on the one hand there is a high unmet 
medical need in patients with chronic comorbidities and that as of 50 YOA there is a 
strong increase in the percentage of people with chronic comorbidities while on the other 
hand for women the incidence of spontaneous pregnancies is only about 4 in 
100 000 women in this age group [Salihu, 2003]. As a precautionary measure, all women 
of childbearing potential will be required to use adequate contraception and have a 
negative pregnancy test prior to vaccination. 
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2.3.2. 
Benefit assessment 
The participants may not benefit directly from participating in this study. For those 
receiving the RSVPreF3 OA investigational vaccine, in a pre-specified efficacy interim 
analysis of an ongoing Phase 3 trial in adults aged 60 years and above, the primary 
endpoint was exceeded with no unexpected safety concerns observed (refer to IB). 
An indirect benefit is that the information obtained in this study will aid the development 
of an RSV OA vaccine, which is intended to prevent disease associated with RSV 
infection in older adults and adults at increased risk of RSV-LRTD. 
Another benefit for all study participants may include gaining information about their 
general health status through the medical evaluations/assessments associated with this 
study (i.e., physical examination). 
2.3.3. 
Overall Benefit/Risk conclusion 
The RSVPreF3 OA investigational vaccine is in clinical development. Considering the 
measures taken to minimize the risk to participants in this study, the potential risks are 
justified by the potential benefits linked to the development of this vaccine. 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Table 3 
Study objectives, endpoints and estimands (Amended: 25 May 2023) 
Objectives 
Endpoints and estimands 
Primary* 
• 
To demonstrate the NI** of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-A strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-A neutralization titers expressed as group GMT 
ratio (OA-RSV/Adults-HA-RSV), 1 month after the 
RSVPreF3 OA investigational vaccine 
administration***. 
• 
RSV-A neutralization titers expressed as group SRR 
difference (OA-RSV - Adults-HA-RSV), 1 month 
after the RSVPreF3 OA investigational vaccine 
administration compared to baseline***. 
• 
To demonstrate the NI** of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-B strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-B neutralization titers expressed as group GMT 
ratio (OA-RSV/Adults-HA-RSV), 1 month after the 
RSVPreF3 OA investigational vaccine 
administration***. 
• 
RSV-B neutralization titers expressed as group SRR 
difference (OA-RSV - Adults-HA-RSV), 1 month 
after the RSVPreF3 OA investigational vaccine 
administration compared to baseline***. 
• 
To demonstrate the NI** of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-A strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
RSV-A neutralization titers expressed as group GMT 
ratio (OA-RSV/Adults-AIR-RSV), 1 month after the 
RSVPreF3 OA investigational vaccine 
administration***. 
• 
RSV-A neutralization titers expressed as group SRR 
difference (OA-RSV - Adults-AIR-RSV), 1 month 
after the RSVPreF3 OA investigational vaccine 
administration compared to baseline***. 


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Objectives 
Endpoints and estimands 
• 
To demonstrate the NI** of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-B strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
RSV-B neutralization titers expressed as group GMT 
ratio (OA-RSV/Adults-AIR-RSV), 1 month after the 
RSVPreF3 OA investigational vaccine 
administration***. 
• 
RSV-B neutralization titers expressed as group SRR 
difference (OA-RSV - Adults-AIR-RSV), 1 month 
after the RSVPreF3 OA investigational vaccine 
administration compared to baseline***. 
Secondary - Safety 
• 
To evaluate the safety and reactogenicity after the 
RSVPreF3 OA investigational vaccine 
administration. 
• 
Percentage of participants reporting each solicited 
administration site event with onset within 4 days 
after study intervention administration (i.e., the day 
of study intervention administration and 
3 subsequent days). 
• 
Percentage of participants reporting each solicited 
systemic event with onset within 4 days after study 
intervention administration (i.e., the day of study 
intervention administration and 3 subsequent days). 
• 
Percentage of participants reporting unsolicited AEs 
within 30 days after study intervention administration 
(i.e., the day of study intervention administration and 
29 subsequent days). 
• 
Percentage of participants reporting any SAEs and 
pIMDs after study intervention administration 
(Day 1) up to Month 6. 
• 
Percentage of participants reporting SAEs and 
pIMDs related to study intervention administration 
after study intervention administration (Day 1) up to 
study end (Month 12). 
• 
Percentage of participants reporting any fatal SAEs 
after study intervention administration (Day 1) up to 
study end (Month 12). 
Secondary - Immunogenicity 
• 
To evaluate the humoral immune response to the 
RSVPreF3 OA investigational vaccine until 
12 months post-study intervention administration.  
• 
RSV-A and RSV-B neutralization titers expressed as 
GMT, at pre-study intervention administration, 1 
month, 6 months and at 12 months after study 
intervention administration.  
• 
To evaluate the CMI response after RSVPreF3 OA 
investigational vaccine administration until 
12 months post-study intervention administration.  
• 
CMI response expressed as group geometric mean 
of the frequency of RSVPreF3-specific CD4+ and/or 
CD8+ T cells expressing at least 2 activation 
markers including at least 1 cytokine among CD40L, 
4-1BB, IL-2, TNF-α, IFN-γ, IL-13, IL-17, at pre-study 
intervention administration, 1 month, 6 months and 
at 12 months after study intervention administration, 
in a subset of participants.  


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Objectives 
Endpoints and estimands 
Tertiary 
(Note that tertiary objectives, endpoints, and estimands are optional and might be assessed only if needed;  
therefore, not all testing might be performed and reported) 
AE=Adverse event; AIR=At increased risk; CD=Cluster of differentiation; CD40L=CD40 ligand; CMI=Cell-mediated 
immunity; GMT=Geometric mean titer; HA=Healthy adults; IFN=Interferon; IL=Interleukin; LRTD=Lower respiratory 
tract disease; NI=Non-inferiority; OA=Older adults; pIMD=Potential immune-mediated disease; RSV=Respiratory 
syncytial virus; SAE=Serious adverse event; SRR=Seroresponse rate; TNF=Tumor necrosis factor; YOA=Years of 
Age. 
* Refer to Section 9.3.1 for the testing sequence of primary objectives. 
** NI criteria are defined in Section 9.1. 
*** Co-primary endpoints. Refer to Section 9.1 for statistical hypotheses. 
Details related to attributes of estimand covering intercurrent events, population and 
treatment definition are provided in the Section 9. 
4. 
STUDY DESIGN 
4.1. 
Overall design 
The study design overview is presented in Figure 1. 
 
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Figure 1 
Study design overview 
 
  
AE=Adverse event; AIR=At increased risk; GSK=GlaxoSmithKline Biologicals SA; HA=Healthy adults; n=Number; OA=Older adults; pIMD=Potential immune-mediated disease; 
RSV=Respiratory syncytial virus; SAE=Serious adverse event; YOA=Years of age. 
* Participants with underlying medical conditions such as chronic pulmonary and cardiovascular diseases, diabetes mellitus types 1 and 2, and chronic liver and renal diseases 


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• 
Type of study: self-contained. 
• 
Experimental design: Phase 3, observer-blind, randomized, placebo-controlled 
study with 2 cohorts (see Figure 1): 
− 
Cohort 1 (adults 50-59 YOA), with 2 sub-cohorts (Adults-HA and Adults-AIR) 
and 4 parallel groups: 
o 
Adults-HA-RSV Group 
o 
Adults-HA-Placebo Group 
o 
Adults-AIR-RSV Group 
o 
Adults-AIR-Placebo Group 
− 
Cohort 2 (adults ≥60 YOA) with a single group (OA-RSV Group) 
• 
Duration of the study: approximately 12 months for all participants. 
• 
Primary completion date: Day 31 (1 month after the administration of study 
intervention). 
• 
Control: placebo saline solution. 
• 
Blinding: observer-blind for Cohort 1, and open-label for Cohort 2. The study will 
be conducted in an observer-blind manner for Cohort 1 from study start-up to Day 31 
analysis, beyond which the study will be considered single-blind (see Section 9.4.1 
and Section 6.3.5 for details). 
• 
Data collection: standardized eCRF. Solicited events and unsolicited AEs will be 
collected by the participant using a pDiary. New concomitant 
medications/vaccinations will be collected in the diary card as of the day of study 
intervention administration and for 29 subsequent days (Day 1 to Day 30). As of 
Day 30, the details are collected in source documents prior to entering them in the 
eCRF until study end. 
• 
Safety monitoring: the study will be conducted with oversight by the project SRT. 
Please refer to Section 10.1.5 for the SRT structure. 
• 
Vaccination schedule: Participants will receive a single dose of study intervention 
(either RSVPreF3 OA investigational vaccine or placebo) at Visit 1 (Day 1). 
• 
Study groups: Refer to Figure 1 and Table 4 for an overview of the study groups. 


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Table 4 
Study cohorts, groups, intervention and blinding 
Study 
cohort 
Groups 
Number of 
participants 
Age 
(Min-Max) 
Study intervention  
Blinding 
Cohort 1 
 
 
 
 
 
Adults-HA 
Adults-HA-RSV 
380 
50–59 YOA 
RSVPreF3 OA 
investigational vaccine 
The study will be 
conducted in an 
observer-blind 
manner for 
Cohort 1 from 
study start up to 
Day 31 analysis*  
 
Adults-HA-
Placebo 
190 
50–59 YOA 
Placebo 
Adults-AIR 
Adults-AIR-RSV 
380 
50–59 YOA 
RSVPreF3 OA 
investigational vaccine 
 
Adults-AIR-
Placebo 
190 
50–59 YOA 
Placebo 
Cohort 2 
 
 
 
 
 
 
OA-RSV 
380 
≥60 YOA 
RSVPreF3 OA 
investigational vaccine 
Open-label 
AIR=At increased risk; CSR=Clinical Study Report; HA=Healthy adults; Max=Maximum; Min=Minimum; OA=Older 
adults; RSV=Respiratory syncytial virus; YOA=Years of age. 
* Beyond Day 31 analysis the study will be considered single-blind. The GSK central study team will be unblinded to 
the data at the time of Day 31 analysis to prepare the CSR of the Day 31 analysis. The study participants will remain 
blinded until the study end. For details regarding the sequence of analysis, refer to Section 9.4.1. 
4.1.1. 
Overview of the recruitment plan 
No screening visit is planned for this study. The study is planned to be conducted at sites 
in multiple countries. The recruitment plan will be defined by each participating site. 
The recruitment plan may be adapted based on the actual number of participants enrolled 
in each country. In case a site would fall behind in participant recruitment, a 
redistribution of the enrollment target per site in the participating countries may be made. 
This would allow the other participating sites to enroll additional participants to ensure 
full and timely enrollment of the overall targeted number of participants specified in this 
protocol. 
The procedures for participants identification/recruitment must be approved by the 
IEC/IRB together with the material intended for participants identification/recruitment 
and participants use.  
4.1.2. 
Enrollment rules 
Cohort 1 
• 
Enrollment rules will be applied to ensure equal representation of participants in the 
healthy adults (Adults-HA) and at increased risk (Adults-AIR) sub-cohorts in 
Cohort 1: 
− 
Approximately 50% of healthy participants (Adults-HA-RSV Group and 
Adults-HA-Placebo Group). 
− 
Approximately 50% of participants at increased risk of RSV-LRTD 
(Adults-AIR-RSV Group and Adults-AIR-Placebo Group) 


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• 
Since the target population in the Adults-AIR Sub-cohort is heterogenous, 
enrollment will be done to ensure adequate representation of the different diseases 
(see Section 5.1.1.2). It is therefore intended to enroll: 
− 
Approximately 25% of participants with chronic pulmonary diseases 
− 
Approximately 25% of participants with chronic cardiovascular diseases 
− 
Approximately 25% of participants with diabetes mellitus types 1 and 2 
− 
The remaining 25% can be distributed freely across the above 3 disease 
categories as well as include participants with chronic renal or liver disease. 
Cohort 2 
• 
Enrollment rules will also be applied to ensure adequate representation by age 
category within Cohort 2: 
− 
Approximately 40% of participants 60-69 YOA 
− 
Approximately 30% of participants 70-79 YOA 
− 
Approximately 10% of participants ≥80 YOA 
− 
The remaining 20% can be distributed freely across the 3 age categories. 
Both cohorts 
• 
When the target number of participants is reached in a particular disease or age 
category, further enrollment of participants in that category will be stopped. If 
needed, the maximum number of participants in a particular disease or age category 
may be adapted during the study. 
For details on the enrollment rules, refer to the SPM. 
4.1.3. 
Caregiver support 
Study participants may decide to assign a caregiver to help them fulfill the study 
procedures. Please refer to the Glossary of terms for the definition of a caregiver. 
A caregiver can be appointed by the participant at any time during the study, when the 
participant feels it is necessary. Each caregiver should receive the caregiver information 
letter before providing support to the study participant. Ideally, a single caregiver should 
be appointed by the participant but, in some situations, it may happen that several 
caregivers will support a study participant throughout the conduct of the study. This 
should be recorded in the source documents. 
Caregivers may help the study participants with performing some practical study 
procedures such as receiving or making phone calls to site staff, planning study visits, 
transcribing responses to diaries, transportation to and from the study site etc. However, 
at no time, the caregiver should evaluate the participant’s health status while answering 
diaries or make decisions on behalf of the participant. At the first study visit (Visit 1) the 
site staff should inform the participant of the possibility to appoint a caregiver. Then at 


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the subsequent study visits the site staff should check again with the participant if he/she 
wishes to appoint a caregiver or if there were or will be changes of caregiver. 
4.2. 
Scientific rationale for study design 
RSV is associated with serious illness in OA and high-risk adults, including those with 
chronic lung and heart disease or other co-morbidities that may lead to increased risk of 
RSV-LRTD. The efficacy of a single dose of the RSVPreF3 OA investigational vaccine 
in the prevention of RSV-LRTD in OA ≥60 YOA has been shown in the Phase 3 clinical 
study RSV OA=ADJ-006 (refer to IB). The current study is designed as a Phase 3, 
observer-blind, placebo-controlled study to demonstrate the NI of the immune response 
and evaluate safety of RSVPreF3 OA investigational vaccine in adults 50-59 YOA, 
including those who are at increased risk of RSV-LRTD, compared to adults ≥60 YOA.  
The inclusion of a group of healthy adults (50-59 YOA) will document the 
immunogenicity in adults and in the population of OA, since immunogenicity might be 
impacted by disease and/or age in both those groups.  
There are 2 cohorts: 
• 
Cohort 1, with adults 50-59 YOA 
− 
Sub-cohort Adults-HA with the following groups 
o 
Adults-HA-RSV and 
o 
Adults-HA-Placebo 
Participants in the Adults-HA-RSV Group will receive a single dose of 
RSVPreF3 OA investigational vaccine at Visit 1 (Day 1). 
Participants in the Adults-HA-Placebo Group will receive a single injection of 
placebo at Visit 1 (Day 1). 
− 
Sub-cohort Adults-AIR with the following groups: 
o 
Adults-AIR-RSV and 
o 
Adults-AIR-Placebo 
Participants in the Adults-AIR-RSV Group will receive a single dose of 
RSVPreF3 OA investigational vaccine at Visit 1 (Day 1). 
Participants in the Adults-AIR-Placebo Group will receive a single injection of 
placebo at Visit 1 (Day 1). 
• 
Cohort 2, with adults ≥60 YOA 
− 
OA-RSV Group 
Participants in the OA-RSV Group will receive a single dose of RSVPreF3 OA 
investigational vaccine at Visit 1 (Day 1). 


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4.2.1. 
Rationale for the use of placebo 
As there is currently no licensed RSV vaccine available, placebo groups (receiving saline 
solution) will be used as control for the safety/reactogenicity assessments. 
4.2.2. 
Rationale for study blinding 
Given the difference in reconstitution and visual appearance of the RSVPreF3 OA 
investigational vaccine and the saline solution used as placebo, double blinding is not 
possible, and the study will be conducted in an observer-blind manner for Cohort 1 (until 
Day 31 analysis). As all participants in Cohort 2 will receive the same study intervention 
(RSVPreF3 OA investigational vaccine), the study will be conducted in an open-label 
manner for Cohort 2. Please refer to Glossary of terms for the definition of observer-blind 
and open-label. 
Further information on blinding and unblinding is provided in Section 6.3.5. 
4.3. 
Justification for dose (Amended: 25 May 2023) 
Based on the results up to 1 month post-Dose 2 from study RSV OA=ADJ-002, a single 
dose regimen (0.5 mL) and the formulation of 120 µg RSVPreF3/AS01E were selected 
for further evaluation in the Phase 3 clinical program. The RSV OA=ADJ-002 study was 
designed to assess the immunogenicity of a 2-dose AS01E adjuvanted or unadjuvanted 
RSVPreF3 vaccine administered according to a 0-,2-month schedule with the aim to 
maximize the immune response against RSV and vaccine efficacy over several seasons. 
Based on the data from clinical development programs for AS01-adjuvanted protein 
antigen vaccines in OA, such as Shingrix, it was expected that immunological responses 
would reach higher levels 1 month post-Dose 2 as compared with 1 month post-Dose 1. 
However, the RSV OA=ADJ-002 results demonstrated that the second dose given 
2 months after the first dose had no added value in terms of humoral and/or cellular 
immune responses. The humoral response, both in terms of RSV A neutralization 
geometric mean titers (GMTs) and RSVPreF3-binding IgG geometric mean 
concentrations, peaked 1 month after the first dose, and the second dose did not increase 
the levels observed after the first dose. 
The results from study RSV OA=ADJ-002 demonstrated statistically significant 
superiority of the 120 µg formulations in terms of RSV A neutralization titers over at 
least 1 of the 30 µg and 60 µg formulations with the same adjuvant content or 
unadjuvanted. An increase in the RSVPreF3-binding IgG GMCs and fold increase over 
baseline was also observed with increase in antigen dose from 30 µg to 120 µg. The 
data demonstrated an immunologic benefit of any AS01E or AS01B formulations over 
unadjuvanted formulations in terms of frequency of RSVPreF3specific CD4+ T cells 
expressing at least 2 markers. Importantly, the CD4+ T cells frequencies induced by the 
AS01-containing formulations in OA were close or similar to the frequencies observed in 
young adults. This was not observed following the administration of the unadjuvanted 
formulations. 
There was no safety concern detected in unadjuvanted groups to be linked to the 
RSVPreF3 antigen assessed for the first time in OA. The acceptable safety/reactogenicity 


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profile in all 120 µg groups, together with the immunological benefit demonstrated for 
the 120 µg antigen dose, supported the selection of a 120 µg based formulation. The 
results also showed that all the AS01-adjuvanted formulations evaluated are considered 
to have a clinically acceptable safety profile. The AS01-adjuvanted formulation with the 
lowest reactogenicity profile, i.e., the AS01E-based formulation, was selected. The 
immunological response observed after 1 vaccine dose of the AS01E-based formulation is 
considered adequate for a RSVPreF3 OA candidate vaccine. 
The RSVPreF3 OA investigational vaccine has not been given in its present form to 
adults 50-59 YOA.  
4.4. 
End of Study definition 
A participant is considered to have completed the study if the participant is available for 
the last scheduled procedure/contact as described in the protocol. 
EoS: LSLV (Visit 4 at Month 12) or Date of the last testing/reading released of the 
Human Biological Samples, related to primary and secondary endpoints, whichever 
occurs later. EoS must be achieved no later than 8 months after LSLV. EoS cannot be 
before LSLV.  
5. 
STUDY POPULATION 
Adherence to the inclusion and exclusion criteria specified in the protocol is essential. 
Deviations from these criteria are not allowed because they can jeopardize the scientific 
integrity, regulatory acceptability of the study or safety of the participant. 
5.1. 
Inclusion criteria 
All 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 the diary cards, attend study site 
visits, ability to access and utilize a phone or other electronic communications). 
Note: for participants in case of physical incapacity that would preclude the 
self-completion of the diary cards, either site staff can assist the participant (for 
activities performed during site visits) or the participant may assign a caregiver to 
assist him/her with this activity (for activities performed at home). However, at no 
time will the site staff or caregiver evaluate the participant’s health status while 
completing diaries or make decisions on behalf of the participant. Refer to Glossary 
of terms for the definition of caregiver. 
• 
Written or witnessed informed consent obtained from the participant prior to 
performance of any study-specific procedure. 
5.1.1. 
Specific inclusion criteria for all participants in Cohort 1 
• 
A male or female participant 50-59 YOA at the time of the study intervention 
administration. 


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• 
Female participants of non-childbearing potential may be enrolled in the study. 
Non-childbearing potential is defined as hysterectomy, bilateral oophorectomy, 
bilateral salpingectomy or post-menopause. Refer to Section 10.4.1.1.1 for 
definitions of women not considered as women of childbearing potential, and 
menopause. 
• 
Female participants of childbearing potential may be enrolled in the study, if the 
participant: 
− 
has practiced adequate contraception from 1 month prior to study intervention 
administration until study end for this study, and 
− 
has a negative pregnancy test on the day of study intervention administration. 
Refer to Section 10.4.1 for definitions of woman of childbearing potential and 
adequate contraception. 
5.1.1.1. 
Specific inclusion criteria for participants in the Adults-HA Sub-cohort 
• 
Healthy participants as established by medical history and clinical examination 
before entering into the study. 
• 
Participants with chronic stable medical conditions with or without specific 
treatment, such as hypertension, hypercholesterolemia, or hypothyroidism, and who 
are not at increased risk for RSV-LRTD (see Section 5.1.1.2), are allowed to 
participate in this study if considered by the investigator as medically stable (no 
changes in the treatment or disease severity in the past 3 months). 
5.1.1.2. 
Specific inclusion criteria for participants in the Adults-AIR Sub-cohort  
Participants should be diagnosed with at least 1 of the following medical conditions and 
have a stable condition (no changes in the treatment or disease severity in the past 3 
months): 
• 
Chronic pulmonary disease resulting in activity restricting symptoms or use of 
long-term medication: 
− 
Chronic obstructive pulmonary disease (COPD) 
o 
Global Initiative for Chronic Obstructive Lung Disease (GOLD) Grade 2-4 
(see Section 10.5.1) 
− 
Asthma  
o 
Patient on regular medication (excluding exercise asthma)  
− 
Cystic fibrosis 
− 
Other chronic respiratory diseases: lung fibrosis, restrictive lung disease, 
interstitial lung disease, emphysema or bronchiectasis 
• 
Chronic cardiovascular disease 
− 
Chronic heart failure (CHF): 


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o 
A minimum of class II symptoms according to New York Heart Association 
classification of heart failure (see Section 10.5.2)  
− 
Pre-existing coronary artery disease (CAD not otherwise specified) 
o 
Physician diagnosis of CAD based on electrocardiogram, exercise stress 
test, nuclear stress test, cardiac computed tomography scan or cardiac 
angiogram (more than the presence of hypercholesterolemia) 
− 
Cardiac arrhythmia 
o 
Patient on treatment for cardiac arrhythmia 
• 
Diabetes mellitus: types 1 and 2 
• 
Other diseases at increased risk for RSV-LRTD disease  
− 
Chronic kidney disease 
o 
G2-G3 disease (Glomerular Filtration Rate between 30 and 
90 ml/min/1.73 m2 – see section 10.5.3) 
− 
Chronic liver disease 
5.1.2. 
Specific inclusion criteria for Cohort 2 (OA-RSV Group) 
• 
A male or female participant ≥60 YOA at the time of the study intervention 
administration. 
• 
Participants with chronic stable medical conditions with or without specific 
treatment, such as diabetes, hypertension or cardiac disease are allowed to participate 
in this study if considered by the investigator as medically stable (no changes in the 
treatment or disease severity in the past 3 months). 
• 
Participants living in the general community or in an assisted-living facility that 
provides minimal assistance, such that the participant is primarily responsible for 
self-care and activities of daily living. 
5.2. 
Exclusion criteria 
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. 
Medical conditions 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition 
resulting from disease (e.g., current malignancy, human immunodeficiency virus) or 
immunosuppressive/cytotoxic therapy (e.g., medication used during cancer 
chemotherapy, organ transplantation, or to treat autoimmune disorders), based on 
medical history and physical examination (no laboratory testing required). 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the study intervention. 
• 
Hypersensitivity to latex. 


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• 
Unstable chronic illness. 
• 
Any history of dementia or any medical condition that moderately or severely 
impairs cognition. 
Note: If deemed necessary for clinical evaluation, the investigator can use tools such 
as Mini-Mental State Exam, Mini-Cog or Montreal Cognitive Assessment (to 
determine cognition levels of the participant). 
• 
Recurrent or uncontrolled neurological disorders or seizures. Participants with 
medically controlled active or chronic neurological diseases can be enrolled in the 
study as per investigator assessment, provided that their condition will allow them to 
comply with the requirements of the protocol (e.g., completion of the diary cards, 
attend study site visits). Study participants may decide to assign a caregiver to help 
them complete the study procedures. For details see Section 4.1.3. 
• 
Significant underlying illness that in the opinion of the investigator would be 
expected to prevent completion of the study (e.g., life-threatening disease). 
• 
Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe. 
5.2.2. 
Prior/Concomitant therapy 
• 
Use of any investigational or non-registered product (drug, vaccine, or medical 
device) other than the study intervention during the period beginning 30 days before 
the dose of study intervention (Day -29 to Day 1), or planned use during the study 
period (up to Visit 4, Month 12). 
• 
Planned or actual administration of a vaccine not foreseen by the study protocol in 
the period starting 30 days before and ending 30 days after the dose of study 
intervention administration, with the exception of inactivated and subunit influenza 
vaccines or COVID-19 vaccines (fully licensed or with EUA) which can be 
administered up to 14 days before or from 14 days after the study intervention 
administration. 
Note: In case an emergency mass vaccination for an unforeseen public health threat 
(e.g., a pandemic) is recommended and/or organized by the public health authorities, 
outside the routine immunization program, the time period described above can be 
reduced if necessary for that vaccine provided it is used according to the local 
governmental recommendations and that the Sponsor is notified accordingly. 
• 
Previous vaccination with an RSV vaccine, including investigational RSV vaccines. 
• 
Chronic administration of immune-modifying drugs (defined as more than 
14 consecutive days in total) and/or administration of long-acting immune-modifying 
treatments or planned administration at any time up to the end of the study. 
− 
Up to 3 months prior to the study intervention administration: 
o 
For corticosteroids, this will mean prednisone ≥20 mg/day, or equivalent. 
Inhaled and topical steroids are allowed. 


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o 
Administration of immunoglobulins and/or any blood products or plasma 
derivatives. 
− 
Up to 6 months prior to study intervention administration: long-acting 
immune-modifying drugs including among others immunotherapy (e.g., TNF-
inhibitors), monoclonal antibodies, antitumoral medication. 
5.2.3. 
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 invasive medical device). 
Refer to Glossary of terms for the definition of ‘invasive medical device’. 
5.2.4. 
Other exclusions 
5.2.4.1. 
Other exclusions for all participants 
• 
History of chronic alcohol consumption and/or drug abuse as deemed by the 
investigator to render the potential participant unable/unlikely to provide accurate 
safety reports or comply with study procedures. 
• 
Bedridden participants. 
• 
Planned move during the study period that will prohibit participating in the study 
until study end. 
• 
Participation of any study personnel or their immediate dependents, family, or 
household members. 
5.2.4.2. 
Other exclusions for Cohort 1 
• 
Pregnant or lactating female. 
• 
Female planning to become pregnant or planning to discontinue contraceptive 
precautions. 
5.3. 
Lifestyle considerations 
No lifestyle restrictions are applicable for this study. 
5.4. 
Screening failures 
A screening failure is an individual who consents to participate in this study but is not 
entered in the study. 
Limited data for screening failures (including reason for screening failure and any SAEs 
related to study participation, or to a concurrent GSK medication/vaccine from the time 
of consent obtained) will be collected and reported in the eCRF. 


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5.5. 
Criteria for temporarily delaying enrollment/study 
intervention administration 
Enrollment/study intervention administration may be postponed until the transient 
conditions cited below are resolved, and prior to the end of the study enrollment period:  
• 
Acute disease and/or fever at the time of enrollment and/or study intervention 
administration. Refer to the SoA (Table 1) for definition of fever and location for 
measuring temperature in this study. 
• 
Participants with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be enrolled and/or dosed at the discretion of the 
investigator. 
• 
Participants with symptoms suggestive of active COVID-19 infection (e.g., fever, 
cough, etc.). The return of the participant to the site will follow the specific guidance 
from local public health and other competent authorities (e.g., free of symptoms, 
COVID-19 negative testing, etc.). 
• 
Participants with known COVID-19 positive contacts may be dosed at least 14 days 
after the exposure, provided that the participant remains symptom-free, and at the 
discretion of the investigator. 
• 
In case of administration of inactivated and subunit influenza vaccines or COVID-19 
vaccines (fully licensed or with EUA): postponement of study intervention 
administration within given protocol timelines and prior to the end of the study 
enrollment period, to allow respect of at least 14 days interval between flu/COVID-
19 vaccination and study intervention administration. 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Refer to the Glossary of terms for the definition of study intervention. 
6.1. 
Study intervention(s) administered  
Study interventions are mentioned in Table 5. 


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Table 5 
Study interventions administered 
Study intervention 
name: 
RSVPreF3 OA investigational vaccine 
Placebo 
Study intervention 
formulation: 
RSVPreF3 (120 µg) 
AS01E: QS-21* (25 µg), 
MPL (25 µg), liposomes; 
Water for injections q.s. 
0.5 mL 
Sodium chloride (NaCl) (0.9%); 
Water for injections 
Presentation: 
Powder for suspension 
for injection; Vial 
Suspension for 
suspension for injection; 
Vial 
Solution for injection; Syringe 
Type: 
Study 
Control 
Product category: 
Biological 
NA 
Route of 
administration:  
IM 
IM 
Administration site: 
 
 
• 
Location 
Deltoid 
Deltoid 
• 
Laterality** 
Non-dominant arm 
Non-dominant arm 
Number of doses to 
be administered: 
1 
1 
Volume to be 
administered by 
dose***: 
0.5 mL 
Approximately 0.7 mL**** 
Packaging and 
labeling: 
Refer to the SPM for more details 
Refer to the SPM for more details 
Manufacturer: 
GSK 
GSK 
GSK=GlaxoSmithKline Biologicals SA; IM=Intramuscular; MPL=Monophosphoryl lipid A; NA=Not applicable; OA=Older 
adults; SPM=Study Procedures Manual. 
* QS-21: Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of 
Agenus Inc., a Delaware, USA corporation) 
** The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the study intervention 
in the non-dominant arm, an injection in the dominant arm may be performed 
*** Refer to the SPM for the volume after reconstitution 
**** The volume of the saline pre-filled syringe may be between 0.6 mL and 0.8 mL. The full volume is to be injected. 
Study participants must be observed closely for at least 30 minutes after the 
administration of the study intervention(s). Appropriate medical treatment must be 
readily available during the observation period in case of anaphylaxis, syncope. 
6.2. 
Preparation, handling, storage, and accountability 
The study intervention(s) must be stored in a secured place within the temperature range 
specified on the study intervention’s label. The storage temperature should be 
continuously monitored and recorded with a calibrated (if not validated) temperature 
monitoring device(s).  
Only authorized study personnel should be allowed access to the study intervention(s). 
Storage conditions will be assessed by a sponsor study contact during pre-study activities. 
Refer to the SPM for more details on storage and handling of the study intervention(s). 


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6.3. 
Measures to minimize bias: randomization and blinding  
6.3.1. 
Participant identification 
Participant identification numbers will be assigned sequentially to the individuals who 
have consented to participate in the study. Each study center will be allocated a range of 
participant identification numbers. 
6.3.2. 
Randomization to study intervention 
• 
Participants in Cohort 1, Adults-HA Sub-cohort will be randomly assigned to the 
Adults-HA-RSV Group and Adults-HA-Placebo Group in a 2:1 ratio at Visit 1 
(Day 1) to receive the RSVPreF3 OA investigational vaccine or placebo, 
respectively. 
• 
Participants in Cohort 1, Adults-AIR Sub-cohort will be randomly assigned to the 
Adults-AIR-RSV Group and Adults-AIR-Placebo Group in a 2:1 ratio at Visit 1 
(Day 1) to receive the RSVPreF3 OA investigational vaccine or placebo, 
respectively. 
• 
All participants in Cohort 2 (OA-RSV Group) will be assigned to receive the 
RSVPreF3 OA investigational vaccine. 
The randomization of supplies within blocks will be performed at GSK, using MAtEx, a 
program developed for use in SAS (Cary, NC, US) by GSK. Entire blocks will be 
shipped to the study centers/warehouse(s). 
To allow GSK to take advantage of greater rates of recruitment in this multi-center study 
and to thus reduce the overall study recruitment period, an over-randomization of 
supplies will be prepared. 
6.3.3. 
Intervention allocation to the participant 
An automated internet-based system (SBIR) will be used for randomization and for 
identification of intervention material. The system’s randomization algorithm will use a 
stratification by healthy/at increased risk status and CMI subset (participant included in 
the CMI subset or not) and a minimization procedure accounting for the study and center 
within each stratum. Minimization factors will have equal weight in the minimization 
algorithm. 
Refer to Section 4.1.2 for details of the enrollment rules. 
Once a participant identification number is allocated, the randomization system will 
determine study group and will provide the study intervention number to be used for the 
dose of study intervention.  
When SBIR is not available, please refer to the SBIR user guide or SPM for specific 
instructions. 
Refer to the SPM for additional information about the study intervention number 
allocation. 


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6.3.4. 
Allocation of participants to CMI assay subsets 
The subsets are detailed below. 
Cohort 
Sub-cohort 
Group 
Number of participants 
Cohort 1 
Adults-HA 
Adults-HA-RSV 
~100 
 
Adults-HA-Placebo 
~50 
Adults-AIR 
Adults-AIR-RSV 
~100 
 
Adults-AIR-Placebo 
~50 
Cohort 2 
OA ≥60 YOA 
OA-RSV 
50 
Total 
 
 
~350 
AIR=At increased risk; HA=Healthy adults; OA=Older adults; YOA=Years of age 
Participants contributing to the CMI subset will be recruited from a selected number of 
countries and selected number of sites. In the selected sites, the investigator will allocate 
the first participants in each cohort/sub-cohort to the CMI subset until the allocated target 
is reached. 
6.3.5. 
Blinding and unblinding 
Data from Cohort 1 will be collected in an observer-blind manner. The participant, the 
site and sponsor personnel involved in the clinical evaluation of the participants are 
blinded while other study personnel may be aware of the treatment assignment. To do so, 
study intervention(s) will be prepared and administered by qualified study personnel who 
will not participate in the evaluation and review of any study endpoint (i.e., 
reactogenicity, safety). 
Refer to SPM regarding details of the tasks that can be performed by the unblinded study 
personnel. 
The laboratory in charge of sample testing will be blinded to the study intervention 
assignment. Codes will be used to link the participant and study to each sample. There 
will be no link between the study intervention groups and the identity of the participant. 
The study will be conducted in an observer-blind manner for Cohort 1 from study start-up 
to Day 31 analysis, beyond which the study will be considered single-blind. The study 
participants in Cohort 1 will remain blinded up to study end, however, the investigators 
will receive a copy of the CSR with results of the Day 31 analysis on immunogenicity, 
reactogenicity and safety data. As a consequence, the investigators could become 
unblinded to some specific participants through summary results. The individual data 
listings and participant treatment assignments will not be provided to the investigators 
until after the conclusion of the study (completion of Visit 4, Month 12 [study end]). 
Note that the GSK central study team (CRDL, Statistician, Safety Representative, etc.) 
will be unblinded to the study intervention assignment at the time of Day 31 analysis in 
order to prepare the CSR of the Day 31 analysis. 
A participant may continue in the study if that participant’s intervention assignment is 
unblinded. 


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6.3.5.1. 
Emergency unblinding (Amended: 25 May 2023) 
Unblinding a participant’s individual study intervention number should occur ONLY in 
case of a medical emergency when this information is essential for the clinical 
management or welfare of the participant. 
In case of emergency, the investigator can have unrestricted, immediate and direct access 
to the participant’s study intervention information via an automated internet-based system 
(e.g., SBIR). The investigator may contact a GSK Helpdesk (refer to Table 6) if help is 
needed to access the participant’s study intervention information (i.e., if the investigator 
is unable to access SBIR). 
A physician other than the investigator (e.g., an emergency room physician) or 
participant/participant’s caregiver or family member may also request emergency access 
to the participant’s study intervention information either via the investigator or 
investigator’s back-up (preferred option) or via the GSK Helpdesk (back-up option). The 
participant card provides contact information for the investigator(s), their back-up and 
GSK Helpdesk. 
GSK’s Global Safety staff may unblind the intervention assignment for any participant 
with an SAE. If the SAE requires that an expedited regulatory report be sent to one 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. 
Table 6 
Contact information for emergency unblinding 
GSK Helpdesk 
Available 24/24 hours and 7/7 days 
The Helpdesk is available by phone, fax and email 
Toll-free number: 
Country 
Toll-free phone number 
Germany, Spain 
00 800 4344 1111 
Canada 
1 833 541 0263 
Japan 
00 531 320 109 
Mexico 
800 123 3102 
US 
1 844 446 3133 
Phone (for countries where the toll-free number is not available): +32 2 656 68 04 
Fax: +32 2 401 25 75 
Email: rix.ugrdehelpdesk@gsk.com 


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6.3.5.2. 
Unblinding prior to regulatory reporting of SAEs 
GSK Global Safety staff may unblind the intervention assignment for any participant 
with a SUSAR. GSK Global Safety is responsible for unblinding the study intervention 
assignment within the timeframes defined for expedited reporting of SAEs (refer to 
Section 10.3.10.1). For SAEs requiring expedited reporting to 1 or more regulatory 
agencies, a copy of the report containing participant’s intervention assignment may be 
sent to investigators in accordance with local regulations and/or GSK policy. GSK policy 
requires unblinding of any unexpected SAE which is attributable/suspected to be 
attributable to the study intervention(s), prior to regulatory reporting. 
GSK policy requires unblinding of any unexpected SAE which is attributable/suspected 
to be attributable to the study interventions, prior to regulatory reporting. VCSP is 
responsible for unblinding the study intervention assignment within the timeframes 
defined for expedited reporting of SAEs (refer to Section 10.3.10.1). 
In addition, GSK VCSP staff may unblind the intervention assignment for any participant 
with a SUSAR or a SAE that is fatal or life-threatening. For SAEs requiring expedited 
reporting to 1 or more regulatory agencies, a copy of the report containing participant’s 
intervention assignment may be sent to investigators in accordance with local regulations 
and/or GSK policy. 
6.4. 
Study intervention compliance 
The study intervention will be administered at the site, and participants will receive it 
directly from the investigator or designee, under medical supervision. The date of 
administration of the study intervention dose in the clinic will be recorded in the source 
documents. 
6.5. 
Dose modification 
Section is not applicable. 
6.6. 
Continued access to study intervention after the end of the 
study 
There is no plan to provide continued access to the study intervention following the end 
of the study. 
The investigator will ask each participant if they are interested in a booster study/long-
term evaluation study. If a participant is not interested in joining the booster study/long-
term evaluation study the reason for refusal will be documented, when available, in the 
participant’s eCRF. 
6.7. 
Treatment of overdose 
Not applicable for this study. 


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6.8. 
Concomitant therapy (Amended: 25 May 2023) 
At each study visit/contact, the investigator(s) or their delegate(s) should question the 
participant about all medications/products taken, and vaccinations received by the 
participant. 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF: 
• 
All concomitant medication including vaccines/products, except vitamins and dietary 
supplements, administered during the 30-day period after the dose of study 
intervention (Day 1 to Day 30). 
• 
All concomitant medication leading to elimination from the analysis, including 
products/vaccines. Please refer to the Section 5.2.2 for further details. 
• 
All concomitant medication which may explain/cause/be used to treat an SAE/pIMD 
including vaccines/products, as defined in Section 8.3.1 and Section 10.3.8. These 
must also be recorded in the Expedited Adverse Event Report. 
• 
For all AF AESIs (including serious and non-serious), concomitant drugs which 
could be associated with development or worsening of AF must be reported in the 
AF follow-up questionnaire. 
• 
Any prophylactic medication (e.g., analgesics, antipyretics) administered on the day 
of study intervention administration (Day 1) in the absence of ANY symptom and in 
anticipation of a reaction to the study intervention administration. 
Refer to Table 7 for an overview of the timing for recording of concomitant medication 
during the study. 
The LML should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Table 7 
Timing of collection of concomitant medication to be recorded 
(Amended: 25 May 2023) 
 
Dose 1 
Study conclusion 
(Visit 4 at Month 12) 
 
Day 1 
Day 30 
All concomitant medication including vaccines/products, except 
vitamins and dietary supplements 
 
 
 
All concomitant medication including products/vaccines leading 
to elimination from the analysis 
 
 
 
All concomitant medication including vaccines/products which 
may explain/cause/be used to treat an SAE/ pIMD/AF*) 
 
 
 
Any prophylactic medication 
 
 
 
AF: Atrial Fibrillation; pIMD=Potential immune-mediated disease; SAE=Serious adverse event. 
Note: The collection period for the concomitant medications to be recorded in eCRF is indicated in gray. 
AESI= Adverse event of specific interest 
* For all AF AESIs (including serious and non-serious), concomitant drugs which could be associated with 
development or worsening of AF must be reported in the AF follow-up questionnaire. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
Not applicable. 
7.2. 
Participant discontinuation/withdrawal from the study 
A participant is considered to have withdrawn from the study if no new study procedure 
has been performed or no new information has been collected for them since the date of 
withdrawal/last contact. 
From an analysis perspective, a study ‘withdrawal’ refers to any participant who was not 
available for the concluding contact planned in the protocol.  
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. 
The primary reason for study withdrawal will be documented in the eCRF, based on the 
list below: 
• 
AEs requiring expedited reporting to GSK (refer to Section 10.3.10.1 for the details) 
• 
Unsolicited non-serious AEs 
• 
Solicited AE 
• 
Withdrawal by participant, not due to an AE* 
• 
Migrated/Moved from the study area 
• 
Lost to follow-up 
• 
Sponsor study termination 
• 
Other (specify). 
* If a participant is withdrawn from the study because the participant has withdrawn 
consent and the reason for withdrawal was provided, the investigator must document this 
reason in the eCRF. 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE/AESI until the 
event is resolved (see Section 10.3.8.2). 


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7.3. 
Lost to follow-up 
Participants will be considered ‘lost to follow-up’ if they fail to return for scheduled visits 
and cannot be contacted by the study site. 
Please refer to the SPM for a description of actions to be taken before considering the 
participant lost to follow-up. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are only permitted when necessary for the management 
of immediate safety concerns for the participant. 
Immediate safety concerns should be discussed with the sponsor as soon as they occur or 
when the study team becomes aware of them. The purpose of this communication is to 
determine if new participant(s) should receive the study intervention. 
In case of doubts of immediate safety concerns regarding the inclusion of a possible 
participant, inclusion should be postponed until a decision can be made. 
Study procedures and their timing are summarized in the SoA (Section 1.3). 
All screening evaluations must be completed, and the results reviewed before confirming 
that potential participants meet all eligibility criteria.  
The investigator will maintain a 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. 
The SPM provides the investigator and site personnel with detailed administrative and 
technical information that does not impact participant safety. 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, the 
following measures may be implemented for enrolled participants: 
• 
Follow-up visits (Visit 2, 3 and/or 4) may be conducted at the participant’s home (by 
the site staff or by a home care service system), if appropriate. If home visits are not 
possible, telephone calls or other means of virtual contacts may be used. 
• 
Diary cards may be transmitted from and to the site by electronic means if allowed 
by local regulations and or conventional mail or collected at home. 
• 
Biological samples may be collected at a different location* other than the study site 
or at participant’s home. Biological samples should not be collected if they cannot be 
processed in a timely manner or appropriately stored until the intended use. 


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* 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 European Medicines Agency Guidance on 
the Management of Clinical Trials during the COVID-19 pandemic (version 2, 
27 March 2020) for more details. 
Impact on the PPS for immunogenicity will be determined on a case-by-case basis. 
8.1. 
Immunogenicity assessments 
Biological samples (Table 8) will be used for research planned in the protocol and for 
purposes related to the improvement, development and quality assurance of the 
laboratory tests described in this protocol.  
Findings in this or future studies may make it desirable to use samples acquired in this 
study for research not planned in this protocol. In this case, all participants in countries 
where this is allowed will be asked to give consent to allow GSK or a contracted partner, 
to use the samples for further research. The further research will be subject to prior 
IEC/IRB approval, if required by local legislation. 
Information on further research and its rationale can be obtained from GSK.  
Sample testing will be done in accordance with the recorded consent of the individual 
participant.  
By default, collected samples will be stored for a maximum of 20 years. This storage 
period begins when the last participant performs the last study visit. This timeline can be 
adapted based on local laws, regulations or guidelines requiring different timeframes or 
procedures. In all cases, the storage period should be aligned with participant’s consent. 
These additional requirements must be formally communicated to, discussed and agreed 
with GSK. 
8.1.1. 
Biological samples 
Table 8 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Subset name* 
Blood for humoral 
response 
~10 
mL 
Visit 1 (Day 1) 
Visit 2 (Day 31) 
Visit 3 (Month 6) 
Visit 4 (Month 12) 
All participants 
Blood for CMI 
~25 
mL 
Visit 1 (Day 1) 
Visit 2 (Day 31) 
Visit 3 (Month 6) 
Visit 4 (Month 12) 
CMI subset 
Urine for pregnancy test 
— 
— 
Visit 1 (Day 1) 
Women of Childbearing 
Potential in Cohort 1  
CMI=Cell-mediated immunity. 
* Refer to Section 6.3.4 for subset description. 


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An overall volume of 40 mL will be collected from all study participants during the entire 
study period. Additionally, 100 mL will be collected from the participants enrolled in the 
CMI subset during the entire study period. Refer to Table 10 and SoA (Table 1) for 
information on volumes collected for different assessments. 
8.1.2. 
Laboratory assays 
All laboratory testing (Table 9) will be performed at GSK laboratory or in a laboratory 
designated by GSK. 
Table 9 
Laboratory assays (Amended: 25 May 2023) 
Assay type 
System 
Component 
Challenge 
Method 
Laboratory 
Humoral 
Immunity 
(Antibody 
determination) 
Serum 
RSV-A neutralization 
titer  
 
Neutralization 
GSK* 
Serum 
RSV-B neutralization 
titer  
Neutralization 
GSK* 
CMI  
PBMC 
CD40L, 4-1BB, IL-2, 
TNF-α, IFN-γ, IL-13, 
IL-17 secreting CD4+ 
and CD8+ T cells 
Peptide pool 
covering 
RSVPreF3 
ICS 
GSK* 
CD=Cluster of differentiation; CD40L=CD40 ligand; CLS=Clinical laboratory sciences; CMI=Cell-mediated immunity; 
CRO=Contract research organization; GSK=GlaxoSmithKline Biologicals SA; ICS=Intracellular cytokine staining; 
IFN=Interferon; IL=Interleukin; PBMC=Peripheral blood mononuclear cell; RSV=Respiratory syncytial virus; 
TNF=Tumor necrosis factor. 
* GSK laboratory refers to the CLS in Rixensart, Belgium; Wavre, Belgium. CLS may delegate testing to a contracted 
CRO. 
Additional testing on serum and frozen PBMC samples to characterize the immune 
response to RSV/to the investigational RSV OA vaccine/vaccine components may be 
performed if deemed necessary for accurate interpretation of the data and/or should such 
test(s) become available in the GSK’ laboratory or a laboratory designated by GSK. 
Please refer to Section 10.2 for a brief description of the assays performed in the study. 
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 
Immunological read-outs are described in Table 10. 
Table 10 
Immunological read-outs (Amended: 25 May 2023) 
Blood sampling time point 
Subset name 
No. of 
participants 
Component 
Type of contact and 
time point 
Sampling time 
point 
Humoral immunity (on serum samples) 
Visit 1 (Day 1) 
Pre-Adm 
All 
participants 
~1520 
RSV-A neutralization titer 
RSV-B neutralization titer 
Visit 2 (Day 31) 
Day 31 
All 
participants 
~1520 
RSV-A neutralization titer 
RSV-B neutralization titer 
Visit 3 (Month 6) 
Month 6 
All 
participants 
~1520 
RSV-A neutralization titer 
RSV-B neutralization titer 
Visit 4 (Month 12) 
Month 12 
All 
participants 
~1520 
RSV-A neutralization titer 
RSV-B neutralization titer 
CMI (on PBMC samples) 
Visit 1 (Day 1) 
Pre-Adm 
CMI subset 
~350 
IL-2, CD40L, TNF-α, IFN-γ, IL-13, IL-17 or 4-
1BB secreting CD4+ and CD8+ T cells 
Visit 2 (Day 31) 
Day 31 
CMI subset 
~350 
IL-2, CD40L, TNF-α, IFN-γ, IL-13, IL-17 or 4-
1BB secreting CD4+ and CD8+ T cells 
Visit 3 (Month 6) 
Month 6 
CMI subset 
~350 
IL-2, CD40L, TNF-α, IFN-γ, IL-13, IL-17 or 4-
1BB secreting CD4+ and CD8+ T cells 
Visit 4 (Month 12) 
Month 12 
CMI subset 
~350 
IL-2, CD40L, TNF-α, IFN-γ, IL-13, IL-17 or 4-
1BB secreting CD4+ and CD8+ T cells 
CD=Cluster of differentiation; CD40L=CD40 ligand; CMI=Cell-mediated immunity; IL=Interleukin; IFN=Interferon; 
Pre-Adm=Pre-study intervention administration; RSV=Respiratory syncytial virus; TNF=Tumor necrosis factor; 
PBMC=Peripheral blood mononuclear cell. 
8.1.4. 
Immunological correlates of protection 
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigen used in the RSVPreF3 OA investigational vaccine. 
8.2. 
Safety assessments 
The investigator(s) and their designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE. The investigator and designees 
are responsible for following up AEs that are serious, considered related to the study 
intervention or the study, or that caused the participant’s withdrawal from the study. 


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8.2.1. 
Pre-intervention administration procedures 
8.2.1.1. 
Collection of demographic data 
Record demographic data such as year of birth, age at the time of study intervention 
administration, sex, race* and ethnicity* in the participant’s eCRF. 
* Differences in the safety and efficacy of certain medical products, including vaccines 
[Haralambieva, 2013; Pérez-Losada, 2009; Kollmann, 2013] have been observed in 
racially and ethnically distinct subgroups. These differences may be attributable to 
intrinsic factors (e.g., genetics, metabolism, elimination), extrinsic factors (e.g., diet, 
environmental exposure, sociocultural issues), or interactions between these factors. 
Therefore, both geographic ancestry (race) and ethnicity will be collected for all study 
participants. 
8.2.1.2. 
Measure/record height and weight 
Measure the participant’s height and weight and record the values in the eCRF. 
8.2.1.3. 
Medical history (Amended: 25 May 2023) 
Obtain the participant’s medical history by interviewing the participant and/or review of 
the participant’s medical records. Record any pre-existing conditions, signs and/or 
symptoms present prior to the study intervention administration in the eCRF. 
A pre-defined list of current co-morbidities [Quan, 2011] to be recorded will be available 
in the eCRF (In addition to the chronic diseases listed in Section 5.1, additional 
information on rheumatologic diseases, hemiplegia and paraplegia will be collected). 
8.2.1.4. 
Vaccination history 
Obtain the participant’s vaccination history by interviewing the participant and/or review 
of the participant’s vaccination records. 
Any vaccine administered up to 1 year before study vaccine administration should be 
recorded in the eCRF with date of vaccination. For history of influenza vaccination, 
information about the vaccine formulation (e.g., adjuvanted or non-adjuvanted or 
high-dose) should be recorded. 
Administration of Shingrix and any COVID-19 vaccine at any timepoint (even if longer 
than 1 year before the study vaccine administration) should be recorded in the eCRF. The 
date of vaccinations should be collected and recorded in the eCRF. 


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8.2.1.5. 
Physical examination/vital signs 
• 
At minimum, temperature, vital signs (e.g., heart rate, respiratory rate and blood 
pressure) must be collected. 
• 
Vital signs are to be taken after at least 10 minutes of rest and before blood 
collection for laboratory tests and will consist of systolic/diastolic blood pressure, 
heart rate and respiratory rate by counting the number of breaths for 1 minute. 
• 
Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• 
Collected information needs to be recorded in the eCRF. 
• 
If the investigator determines that the participant’s health on the day of study 
intervention administration temporarily precludes dosing, the visit will be 
rescheduled. Refer to the Section 5.5 for the list of criteria for temporary delay of 
study intervention administration. 
• 
Physical examination at the study visits after the study intervention administration 
visit (Visit 2, Visit 3 and/or Visit 4), will be performed only if the participant 
indicates during questioning that there might be some underlying pathology(ies) or if 
deemed necessary by the investigator or delegate. 
8.2.1.6. 
Smoking status and smoking exposure history 
The smoking status will be collected in the eCRF, differentiating tobacco use (cigarettes, 
cigars, cigarillos, pipes, etc.) and use of electronic smoking devices (e-cigarettes). Refer 
to Glossary of terms for the definitions of current and former smoker. 
Smoking exposure history should be recorded as number of years for both current and 
former smokers. When applicable, the number of years of exposure should be collected 
separately for tobacco and electronic smoking devices. 
All data will be recorded in the participant’s eCRF. 
8.2.1.7. 
Pregnancy test (only for women of childbearing potential in Cohort 1) 
Female participants of childbearing potential in Cohort 1 must perform a urine pregnancy 
test before the administration of the dose of study intervention. Pregnancy testing must be 
performed even if the participant is menstruating at the time of the study visit. The study 
intervention may only be administered if the pregnancy test is negative. 
Refer to Section 10.4.3.1 for the information on study continuation for participants who 
become pregnant during the study. 
8.2.1.8. 
Pre-study intervention administration body temperature 
The body temperature of each participant needs to be measured prior to study 
intervention administration and recorded in the eCRF. The route for measuring 
temperature can be oral or axillary. If the participant has fever (defined as temperature 
≥38.0°C/100.4°F regardless of the location of measurement) on the day of study 
intervention administration, the visit will be rescheduled (refer to Section 5.5 for details). 


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8.3. 
AEs, SAEs and other safety reporting 
8.3.1. 
Time period and frequency for collecting AE, SAE and other 
safety information (Amended: 25 May 2023) 
An overview of the protocol-required reporting periods for AEs, SAEs, and AESIs 
(including pIMDs and AF) is given in Table 11. 
Table 11 
Timeframes for collecting and reporting of safety information 
(Amended: 25 May 2023) 
 
Pre-Adm* 
 Adm 
 
 
Study conclusion 
 
D1 
D1 
D4# 
D30 
6 months post-dose 
 
12 months post-dose 
Solicited 
administration site 
and systemic 
events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All SAEs† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study 
participation** or 
concurrent GSK 
medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading 
to withdrawal from 
the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs and pIMDs 
related to study 
intervention 
administration and 
fatal SAEs† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intercurrent 
medical 
conditions*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adm=Study intervention administration; AE=Adverse event; D=Day; GSK=GlaxoSmithKline Biologicals SA; 
pIMD=Potential immune-mediated disease; Pre-Adm=Pre-study intervention administration; SAE=Serious adverse 
event. 
* Corresponds to the day when informed consent is obtained (Day 1, prior to study intervention administration). 
# Day 4 is not a visit/contact at site. 


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** Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests such as 
blood sampling) or related to a GSK product will be recorded from the time a participant consents to participate in the 
study 
*** Intercurrent medical conditions: A condition that has the capability of altering the immune response to the study 
vaccine or is confirmed to have an alteration of the participant’s initial immune status. 
† AF will be considered as AESI in this study and will be additionally reported in the AF follow-up 
questionnaire in eCRF. 
AF reporting will follow the same reporting periods as for unsolicited AEs and SAEs. 
Non-serious AF with an onset during the 30-day period following study vaccine 
administration will be collected. The reporting of AF meeting SAE definition (serious 
AF) will be performed according to the SAE reporting period. Fatal AF and Serious 
AF judged as related to study vaccination will be reported according to the fatal SAE 
and related SAE reporting period, respectively. For AF that were reported before the 
implementation of this Protocol Amendment 1, additional available information should 
be encoded in the specific AF follow-up questionnaire retrospectively. 
The investigator or designee will record and immediately report all SAEs in enrolled 
participants to the sponsor or designee via the Expedited AE Reporting Form. Reporting 
should, under no circumstances, occur later than 24 hours after the investigator becomes 
aware of an SAE, as indicated in Section 10.3.10. The investigator will submit any 
updated SAE data to the sponsor within 24 hours of it being available.  
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting periods defined in Table 11. Investigators are not obligated to actively seek AEs 
or 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 
if the investigator considers the event to be reasonably related to the study intervention, 
the investigator will promptly notify the study contact for reporting SAEs mentioned in 
the Table 13. 
8.3.2. 
Method of detecting AEs and SAEs, pregnancies, and other 
events (Amended: 25 May 2023) 
Detection and recording of AEs/SAEs/AESI (including pIMDs and AF)/pregnancies are 
detailed in Section 10.3.8.  
Assessment of AE/SAE intensity, causality and outcome are described in Section 10.3.9.  
Open-ended and non-leading verbal questioning of participants is the preferred method of 
acquiring information related to an AE/SAE/AESI (including pIMDs and 
AF)/pregnancy. 


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8.3.3. 
Regulatory reporting requirements for SAEs, pregnancies, and 
other events (Amended: 25 May 2023) 
Once an investigator (or designee) becomes aware that a study participant has 
experienced an SAE/ AESI (including pIMDs and AF)/pregnancy, it must be reported to 
GSK using the required documentation and within the timeframes mentioned in Table 12. 
This is essential for GSK to meet legal obligations and ethical responsibilities for 
participant safety and the safety of a study intervention under clinical investigation. 
For SAEs/ AESI (including pIMDs and AF), the investigator must 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 preparation of an investigator 
safety report of SUSAR must be followed. These reports will be forwarded to 
investigators as necessary. 
The sponsor has the legal responsibility to notify local authorities/regulatory agencies 
about the safety of an investigational study intervention. 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/ AESI 
(including pIMDs and AF)/pregnancies. 
Table 12 
Timeframes for submitting SAEs, 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 
24 hours*, ‡‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
Pregnancies 
24 hours* 
electronic pregnancy report 
24 hours* 
electronic pregnancy report 
pIMDs  
24 hours**, ‡‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
Serious AF† 
24 hours* 
Electronic expedited AEs 
Report + AF follow-up 
questionnaire 
24 hours* 
Electronic expedited AEs 
Report + AF follow-up 
questionnaire 
GSK=GlaxoSmithKline Biologicals SA; pIMD=Potential immune-mediated disease; SAE=Serious adverse event. 
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
** Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD. 
‡‡ For each SAE/pIMD, the investigator(s) must document in the medical notes that they have reviewed the SAE/pIMD 
and have provided an assessment of causality. 
† Only AF meeting SAE definition will be reported in electronic Expedited AE Report and in the specific AF 
follow-up questionnaire. Non-serious AF will be reported in the non-serious adverse event eCRF screen and in 
the AF follow-up questionnaire. For AF that were reported before the implementation of this Protocol 
Amendment 1, additional available information should be encoded in the specific AF follow-up questionnaire 
retrospectively. 


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8.3.3.1. 
Contact information for reporting SAEs, AESIs (including pIMDs and 
AF) and pregnancies (Amended: 25 May 2023) 
Table 13 
Contact information for reporting SAEs, AESI (including pIMDs and 
AF) and pregnancies (Amended: 25 May 2023) 
Study contact for questions regarding SAEs, AESIs (including pIMDs and AF), 
pregnancies 
Refer to the local study contact information document 
Back-up study contact for reporting SAEs, AESIs (including pIMDs and AF), 
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. 
Treatment of AEs (Amended: 25 May 2023) 
Any medication, vaccine or products administered for the treatment of an SAE/pIMD 
should be recorded in the Expedited Adverse Event Report of the participant’s eCRF 
screen (refer to Section 10.3.10.1). For the AF, this information will be captured in the 
Expedited Adverse Events Report and in the AF follow-up questionnaire in eCRF. 
8.3.5. 
Participant card 
The investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
always keep the participant card in their possession for the duration of the study. In an 
emergency, this card serves to inform the responsible attending 
physician/caregiver/family member that the participant is in a clinical study and that 
relevant information may be obtained by contacting the investigator(s) or their back-up. 
8.4. 
Pharmacokinetics 
Pharmacokinetics are not evaluated in this study. 
8.5. 
Genetics 
Genetics are not evaluated in this study. 


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8.6. 
Biomarkers 
Not applicable for this study. 
8.7. 
Immunogenicity assessments 
Immunogenicity is described in Section 8.1. 
8.8. 
Health outcomes 
Not applicable for this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical hypotheses 
Statistical hypotheses are associated to the confirmatory primary NI objectives, which 
will be tested according to the graphical procedure detailed in Section 9.3.1. Global type I 
error is controlled at 2.5% (1-sided). 
Table 14 
Study objectives and null hypothesis 
Objectives 
Null hypothesis 
Primary 
• 
To demonstrate the NI of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-A strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
Null hypothesis 1 (H1):  
The anti-RSV-A GMT ratio (OA-RSV Group over 
Adults-HA-RSV Group) is >1.5 or the SRR 
difference (OA-RSV Group – Adults-HA-RSV Group) 
is >10% at 1 month post RSVPreF3 OA vaccine 
administration. This must be rejected in favor of the 
alternative hypothesis that the GMT ratio is ≤1.5 and 
the SRR difference is ≤10%. 
• 
To demonstrate the NI of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-B strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
Null hypothesis 2 (H2):  
The anti-RSV-B GMT ratio (OA-RSV Group over 
Adults-HA-RSV Group) is >1.5 or the SRR 
difference (OA-RSV Group – Adults-HA-RSV Group) 
is >10% at 1 month post RSVPreF3 OA vaccine 
administration. This must be rejected in favor of the 
alternative hypothesis that the GMT ratio is ≤1.5 and 
the SRR difference is ≤10%. 
• 
To demonstrate the NI of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-A strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
Null hypothesis 3 (H3):  
The anti-RSV-A GMT ratio (OA-RSV Group over 
Adults-AIR-RSV Group) is >1.5 or the SRR 
difference (OA-RSV Group – Adults-AIR-RSV 
Group) is >10% at 1 month post RSVPreF3 OA 
vaccine administration. This must be rejected in 
favor of the alternative hypothesis that the GMT ratio 
is ≤1.5 and the SRR difference is ≤10%. 


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Objectives 
Null hypothesis 
• 
To demonstrate the NI of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-B strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
Null hypothesis 4 (H4):  
The anti-RSV-B GMT ratio (OA-RSV Group over 
Adults-AIR-RSV Group) is >1.5 or the SRR 
difference (OA-RSV Group – Adults-AIR-RSV 
Group) is >10% at 1 month post RSVPreF3 OA 
vaccine administration. This must be rejected in 
favor of the alternative hypothesis that the GMT ratio 
is ≤1.5 and the SRR difference is ≤10%. 
AIR=At increased risk; GMT=Geometric mean titer; H1=Null hypothesis 1; H2=Null hypothesis 2; H3=Null 
hypothesis 3; H4= Null hypothesis 4; HA=Healthy adults; LRTD=Lower respiratory tract disease; NI=Non-inferiority; 
OA=Older adults; RSV=Respiratory syncytial virus; SRR=Seroresponse rate; YOA=Years of age. 
9.2. 
Analysis sets 
Analysis sets are presented in Table 15. 
Table 15 
Analysis sets 
Analysis set 
Description 
Screened Set 
All participants who were screened for eligibility. 
Enrolled Set 
All participants who entered the study (who were randomized or received study 
intervention or underwent a post-screening study procedure). 
NOTE: screening failures (who never passed screening even if rescreened) and 
participants screened but never enrolled into the study (met eligibility but not 
needed to reach the target enrollment) are excluded from the Enrolled Set as they 
did not enter the study. 
Exposed Set 
All participants who received the study intervention. Analysis per group is based 
on the administered intervention. 
Per-Protocol Set* 
All eligible participants who received the study intervention as per protocol, had 
immunogenicity results pre- and post-dose, complied with blood draw intervals, 
without intercurrent conditions that may interfere with immunogenicity and without 
prohibited concomitant medication/vaccination. Analysis per group is based on the 
administered intervention. 
* Contribution of participants to PPS will be defined by timepoint. 
9.2.1. 
Criteria for elimination from analysis 
If a participant meets 1 of the criteria mentioned in the Section 5.2.1 (medical conditions) 
or Section 5.2.2 (concomitant therapy), they may be eliminated from per-protocol 
analysis. 
Participants may be eliminated from the PPS for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response 
(intercurrent medical condition) or are confirmed to have an alteration of their initial 
immune status. Refer to Glossary of terms for the definition of intercurrent medical 
conditions. 
9.3. 
Statistical analyses 
The SAP will be developed and finalized before FSFV. This section is a summary of the 
planned statistical analyses of the confirmatory primary endpoints. Descriptive analyses 
of demography, immunogenicity, and safety will be detailed in the SAP. 


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9.3.1. 
Primary endpoints/estimands analysis 
Considering the sampling timepoint at 1 month post-study intervention administration, 
the 2-sided 95% and 97.5% Cis for group GMT ratios (OA-RSV Group over 
Adults-HA-RSV Group and OA-RSV Group over Adults-AIR-RSV Group) will be 
derived from an ANCOVA model on log10-transformed titers for each neutralization 
assay. The model will include the group (OA-RSV Group, Adults-HA-RSV Group and 
Adults-AIR-RSV Group) and the baseline log10-transformed titer as covariate.  
The SRR is defined as the proportion of participants having a fold increase in 
neutralization titers (1 month post-study intervention administration over pre-study 
intervention administration) ≥4. The 2-sided 95% and 97.5% Cis for group SRR 
difference (OA-RSV Group minus Adults-HA-RSV Group and OA-RSV Group minus 
Adults-AIR-RSV Group) will be derived using the method of Miettinen and Nurminen 
Miettinen, 1985] (Amended: 25 May 2023). 
Missing data will not be replaced. 
NI for each primary objective will be claimed to be successful if the upper limit of the 
2-sided CI for the GMT ratio will be ≤1.5 and the upper limit of the 2-sided CI for the 
SRR difference will be ≤0.10, according to the significance level provided by the 
graphical testing procedure. 
The following graphical testing procedure will be applied to control the global type I 
error at 2.5% (1-sided) [Bretz, 2009]. 
 
Refer to Table 14 where H1/H2/H3/H4 labels are assigned. 
The initial allocation of α among the null hypotheses is (0.025, 0, 0, 0), while the 
propagation rules are specified by the transition matrix: 
 
The primary analysis set will be the PPS. 
9.4. 
Interim analyses 
All analyses will be conducted on final data, as clean as possible. 


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9.4.1. 
Sequence of analyses 
The analyses will be performed stepwise: 
• 
Day 31 (PCA): A first analysis will be performed on all immunogenicity, 
reactogenicity and safety data available and as clean as possible, when data for at 
least primary and secondary endpoints up to Visit 2 (Day 31) are available for all 
participants. This analysis will be considered as final for those endpoints 
The GSK central study team (CRDL, Statistician, Safety Representative, etc.) will be 
unblinded to the details of the treatment assignments at the time of the Day 31 
analysis in order to prepare the CSR of the Day 31 analysis. Refer to Section 6.3.5 
for details of blinding and unblinding procedures. 
• 
Month 6: A second analysis will be performed on all immunogenicity and safety 
data available and as clean as possible, when data for at least secondary endpoints up 
to Visit 3 (Month 6) are available for all participants. This analysis will be 
considered as final for those endpoints. 
• 
An end of study analysis will be performed when all data for at least secondary 
endpoints up to study conclusion (Visit 4, Month 12) will be available for all 
participants. 
• 
If the data for tertiary endpoints become available at a later stage, (an) additional 
analysis/analyses will be performed. 
9.4.2. 
Statistical considerations for interim analysis 
No statistical adjustment for interim analysis is required. 
9.5. 
Sample size determination 
The target sample size for the study is approximately 1520 participants: 380 participants 
each in the Adults-HA-RSV Group and Adults-AIR-RSV Group, 190 participants each in 
the Adults-HA-Placebo Group and Adults-AIR-Placebo Group and 380 participants in 
the OA-RSV Group. 
The sample size in the groups receiving the investigational vaccine is driven by the 
statistical power to prove the primary NI objectives.  
Assuming 342 evaluable participants in each group receiving the investigational vaccine, 
the power to demonstrate the primary NI objectives following the graphical testing 
procedure in Section 9.3.1 is presented in Table 16. Power was estimated by 10 000 
simulations, using SAS 9.4:  
• 
Individual RSV-A and RSV-B neutralization titers at baseline and at 1 month post-
study intervention administration were modeled by a multivariate log-normal 
distribution, means and variance-covariance matrix based on historical data from 
other RSV OA vaccine clinical trials. The Adults-AIR-RSV Group was assumed to 
have the same multivariate log-normal distribution of the OA-RSV Group (i.e., same 


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means and variance-covariance matrix), while the Adults-HA-RSV Group was 
assumed to have a 1.25-fold higher mean at 1 month post-study intervention 
administration for both neutralization titers (Amended: 25 May 2023). 
• 
Raw p-values were obtained from shifted 1-sided t-tests (for group GMT ratios) and 
using the method of Miettinen and Nurminen (for group SRR difference). The 
p-value associated to each NI objective is the maximum between the p-values from 
the GMT ratio and from the SRR difference (co-primary endpoints). 
• 
P-values associated to each NI objective were compared with the corresponding 
alpha, as propagated by the graphical testing procedure, to identify which NI 
objectives were successfully demonstrated at each simulation.  
Table 16 
Power of primary NI objectives 
Objective 
Power 
NI in the Adults-HA-RSV Group for the RSV-A strain 
>99% 
NI in the Adults-HA-RSV Group for the RSV-B strain 
>99% 
NI in the Adults-AIR-RSV Group for the RSV-A strain 
93.6% 
NI in the Adults-AIR-RSV Group for the RSV-B strain 
82.8% 
All 
82.7% 
All=power to demonstrate all primary NI objectives simultaneously; AIR=At increased risk; HA=Healthy adults; NI=Non-
inferiority; RSV=Respiratory syncytial virus. 
A 10% attrition rate is accounted from enrolled to evaluable participants. 
Participants who withdraw from the study will not be replaced. 
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 CIOMS International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB, 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.  


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• 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• 
The investigator will be responsible for the following: 
− 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. 
− 
Notifying the IRB/IEC of SAE(s) or other significant safety findings as required 
by IRB/IEC procedures. 
− 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
10.1.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study. 
10.1.3. 
Informed consent process 
The investigator(s) or their representative(s) must fully explain the nature of the study to 
the participant and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary.  
Freely given and written/witnessed informed consent must be obtained from each 
participant, as appropriate, prior to participation in the study.  
The content of the ICF must meet the requirements of 21 CFR 50, local regulations, ICH 
guidelines, HIPAA requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written or witnessed informed consent 
was obtained before the participant was enrolled in the study and the date the consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.  
Participants must be re-consented if a new version of the ICF(s) or an ICF addendum is 
released during their participation in the study.   
A copy of the ICF(s) must be provided to the participants.  


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10.1.4. 
Data protection 
Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets transferred to the sponsor will contain only the identifier. Name and 
any other information which would identify the participant will not be transferred.  
GSK will ensure protection of the personal data of the investigator and site staff which is 
collected within the framework of and for the purpose of the study, in accordance with 
the Data Privacy Notice that will be sent to the site staff. 
The participants must be informed that: 
• 
Their personal study-related data will be used by the sponsor in accordance with 
local data protection law.  
• 
Their medical records may be examined by Clinical Quality Assurance auditors or 
other authorized personnel appointed by the sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 
The participants must be notified about their rights regarding the use of their personal 
data in accordance with the data privacy section of the ICF. 
10.1.5. 
Committees structure 
GSK will obtain favorable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiation of the study in that country. This includes IRBs/IECs for review and approval 
of the protocol and subsequent amendments, ICF and any other documentation. 
Safety oversight will be provided by a blinded SRT composed of GSK RSV OA project 
team members. 
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 
applicable regulations/GSK policy. GSK will aim to register protocols summaries prior to 
study start and target results summaries submission within 12 months of primary/ study 
completion date. Where external regulations require earlier disclosure, GSK will follow 
those timelines.  
Where required by regulation, summaries will also be posted on applicable national or 
regional clinical study 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. 


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GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
GSK intends to make anonymized patient-level data from this study 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 study 
participants are used to maximum effect in the creation of knowledge and understanding. 
10.1.7. 
Data quality assurance 
The investigator should maintain a record of the location(s) of their respective essential 
documents, including source documents (see Glossary of terms for the exact definition of 
essential and source documents). The document storage system used during the study and 
for archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval.  
Essential study documents may be added or removed where justified (in advance of study 
initiation) based on their importance and relevance to the study. When a copy is used to 
replace an original document (e.g., source documents, CRF), the copy should fulfill the 
requirements for certified copies (see Glossary of terms for the exact definition of 
certified copies).  
All participant data related to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
The investigator must maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the site’s study participants (see 
Glossary of terms for the exact definition of source documents) that supports information 
entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies for such review and inspection.  
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data (see Glossary of terms for the exact definition of 
source data).  
Study monitors will perform ongoing source data verification to confirm that data entered 
in the eCRF by authorized site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data must be traceable, not obscure 
the original entry, and be fully explained if necessary (e.g., via an audit trail). The safety 
and rights of participants must be protected, and the study conducted in accordance with 
the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
QTLs will be pre-defined in the Quality Plan to identify systematic issues that can impact 
participant safety and/or the reliability of study results. These pre-defined parameters will 


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be monitored during the study. Important deviations from the QTLs and remedial actions 
taken will be summarized in the CSR. 
Study records and source documents pertaining to the conduct of this study, including 
signed ICFs, must be retained by the investigator for 25 years from issuance of the final 
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 to establish the existence of the participant and 
substantiate the integrity of collected data. The investigator should maintain a record of 
the location(s) of their source documents.  
Data transcribed into the eCRF from source documents must be consistent with those 
source documents; any 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. 
Definitions of what constitutes source data and documents can be found in the Glossary 
of terms. 
10.1.9. 
Study and site start and closure 
Start of study is defined as FSFV. 
First act of recruitment 
The first act of recruitment is the first site initiated. 
Study/Site termination  
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at its sole discretion, provided there is sufficient notice given to 
account for all participants safe exit from study.  
Regular closure of study sites 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 enough notice 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 


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• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication policy 
GSK aims to submit the results of the study for publication in searchable, peer reviewed 
scientific literature within 18 months from the LSLV for interventional studies and 
follows the guidance from the ICMJE. 
10.2. 
Appendix 2: Clinical laboratory tests 
RSV-A and RSV-B neutralization assays (Amended: 25 May 2023) 
The serum neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralize RSV entry and replication in a host cell line. 
Virus neutralization is performed by incubating a fixed amount of RSV-A strain (Long, 
ATCC No. VR-26) or RSV-B strain (18537, ATCC No. VR-1580) with serial dilutions of 
the test serum. The serum-virus mixture is then transferred onto a layer of Vero cells 
(African Green Monkey, kidney, Cercopitheus aethiops, ATCC CCL 81) and incubated 
for 2 days to allow infection of the Vero cells by non-neutralized virus and the formation 
of plaques in the cell layer. Following a fixation step, RSV-infected cells are detected 
using a primary antibody directed against RSV (Polyclonal anti-RSV-A/B IgG) and a 
secondary antibody conjugated to horse-radish peroxidase, allowing the visualization of 
plaques after coloration with TrueBlue peroxidase substrate. Viral plaques are counted 
using an automated microscope coupled to an image analyzer (Scanlab system with a 
Reading software or equivalent). For each serum dilution, a ratio, expressed as a 
percentage, is calculated between the number of plaques at each serum dilution and the 
number of plaques in the virus control wells (no serum added). The serum neutralization 
titer is expressed in Estimated Dilution 60 and corresponds to the inverse of the 
interpolated serum dilution that yields a 60% reduction in the number of plaques 
compared to the virus control wells, as described by others [Barbas, 1992; Bates, 2014]. 
The ED60 neutralization titers will also be converted in concentration in International 
Units per milliliter (IU/mL). Secondary standards calibrated against the international 
reference (NIBSC 16/284) [McDonald, 2018; McDonald, 2020] are included in every run 
to allow conversion into international units per millimeters. 


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Intracellular cytokine staining  
The ICS is used to assess RSVPreF3-specific CD4+ and/or CD8+ T cells expressing at 
least 2 activation markers including at least 1 cytokine among CD40L, 4-1BB, IL-2, 
TNF-α, IFN-γ, IL-13, IL-17 (secondary endpoint). 
As previously described [Moris, 2011], thawed PBMCs are stimulated in vitro in the 
presence of anti-CD28 and anti-CD49d antibodies either with pools of 15-mer peptides 
overlapping by 11 amino acids and spanning the sequence of the RSVPreF3 protein, or 
with medium. After 2 hours of incubation at 37oC, Brefeldin A is added to inhibit 
cytokine secretion during an additional overnight incubation at 37oC. Cells are 
subsequently harvested, stained for surface markers (CD4+ and CD8+) and then fixed. 
Fixed cells are then permeabilized and stained with labeled antibodies specific for the 
following immune markers: 
• 
CD3+: phenotyping T cells; 
• 
CD40L (CD154), expressed on activated CD4+ T cells, [Chattopadhyay, 2005; 
Frentsch, 2005; Samten, 2000; Stubbe, 2006]; 
• 
IL-2: key for the development, survival and function of T cells [Boyman, 2012]; 
• 
TNF-α: anti-viral/intracellular factor, pro-inflammatory cytokine, cytotoxicity 
[Sedger, 2014]; 
• 
IFN-γ: anti-viral factor, associated with the Th1-like profile [Schoenborn, 2007]; 
• 
4-1BB (CD137), expressed on activated CD4+ and CD8+ T cells [Wölfl, 2008]; 
• 
IL-13: associated with the Th2-like profile [Bao, 2015]; 
• 
IL-17: associated with the Th17-like profile [Korn, 2009]. 
After staining with the markers above, the cellular samples are analyzed by 
flow-cytometry allowing to determine the frequency of CD4+ and/or CD8+ T cells 
expressing the marker(s) of interest per million of CD4+ and/or CD8+ T cells. 
10.3. 
Appendix 3: AEs: definitions and procedures for recording, 
evaluating, follow-up, and reporting  
10.3.1. 
Definition of an AE  
An AE is any untoward medical occurrence (an unfavorable/unintended sign – including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) in a clinical 
study participant that is temporally associated with the study intervention. The AE may or 
may not be considered related to the study intervention. 


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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 administration of the study 
intervention even though they may have been present before study start. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug, disease or other 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either the 
study intervention or a concurrent medication. 
• 
Signs or symptoms temporally associated with administration of the study 
intervention. 
• 
Signs, symptoms that require medical attention (e.g., hospital stays, physician 
visits and emergency room visits). 
• 
Pre- or post-intervention events that occur as a result of protocol-mandated 
procedures (i.e., invasive procedures, modification of participant’s previous 
therapeutic regimen). 
• 
Clinically significant abnormal laboratory findings or other abnormal assessments 
that are present at baseline and significantly worsen following the start of the study 
will also be reported as AEs or SAEs. 
• 
AEs to be recorded as solicited AEs are described in the Section 10.3.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
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 before 
the study intervention. These events will be recorded in the medical history section 
of the eCRF.  
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 


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10.3.2. 
Definition of an 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 hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” 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, diarrhea, influenza like illness, and accidental trauma 
(e.g., sprained ankle) which may interfere or prevent everyday life functions but do 
not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant. 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) 
g. Other situations 
Medical or scientific judgment must be exercised in deciding whether reporting is 
appropriate in other situations. Important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition should 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; and 
convulsions that do not result in hospitalization. 


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10.3.3. 
Solicited events 
h. Solicited administration site events 
The following administration site events will be solicited (Table 17): 
Table 17 
Solicited administration site events 
Pain at administration site 
Redness at administration site 
Swelling at administration site  
i. 
Solicited systemic events 
The following systemic events will be solicited (Table 18): 
Table 18 
Solicited systemic events 
Fever 
Headache 
Myalgia (muscle pain) 
Arthralgia (joint pain) 
Fatigue (tiredness) 
Note: Participants will be instructed to measure and record the temperature in the 
evening. If additional temperature measurements are taken at other times of the day, 
participants will be instructed to record the highest temperature in the diary card. 
10.3.4. 
Unsolicited AEs 
An unsolicited AE is an AE that was either not included in the list of solicited events or 
could be included in the list of solicited events but with an onset outside the specified 
period of follow-up for solicited events. Unsolicited AEs must have been communicated 
by a participant who has signed the informed consent. Unsolicited AEs include both 
serious and non-serious AEs. 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, or an emergency room visit, or visit to/by a health care 
provider). The participants 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 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 or perceived as a concern by the 
participant will be collected during an interview with the participants and by review of 
available medical records at the next visit. 


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10.3.5. 
Adverse events of special interest (AESIs) (Amended: 25 May 
2023) 
Adverse events of special interest (AESIs) collected during this study include potential 
immune-mediated diseases (pIMDs) and Atrial Fibrillation (AF). 
10.3.5.1. 
Potential immune-mediated diseases (pIMDs) 
 pIMDs are a subset of AESIs that include autoimmune diseases and other inflammatory 
and/or neurologic disorders of interest which may or may not have an autoimmune 
etiology. AEs that need to be recorded and reported as pIMDs include those listed in the 
Table 19. Please refer to the Section 10.3.8.1 for reporting details. 
The investigator(s) must exercise their medical/scientific judgment to determine whether 
other diseases have an autoimmune origin (i.e., pathophysiology involving systemic or 
organ-specific pathogenic autoantibodies) and should also be recorded as a pIMD. 
Table 19 
List of pIMDs 
Medical Concept 
Additional Notes 
Blood disorders and coagulopathies 
Antiphospholipid syndrome 
 
Autoimmune aplastic anemia 
 
Autoimmune hemolytic anemia 
• 
Includes warm antibody hemolytic anemia and cold antibody hemolytic 
anemia 
Autoimmune lymphoproliferative 
syndrome (ALPS) 
 
Autoimmune neutropenia  
 
Autoimmune pancytopenia 
 
Autoimmune thrombocytopenia 
• 
Frequently used related terms include: “autoimmune thrombocytopenic 
purpura”, “idiopathic thrombocytopenic purpura (ITP)”, “idiopathic 
immune thrombocytopenia”, “primary immune thrombocytopenia”. 
Evans syndrome 
 
Pernicious anemia 
 
Thrombosis with 
thrombocytopenia syndrome 
(TTS) 
 
Thrombotic thrombocytopenic 
purpura 
• 
Also known as “Moschcowitz-syndrome” or “microangiopathic 
hemolytic anemia” 
Cardio-pulmonary inflammatory disorders 
Idiopathic 
Myocarditis/Pericarditis 
Including but not limited to: 
• 
Autoimmune/Immune-mediated myocarditis 
• 
Autoimmune/Immune-mediated pericarditis 
• 
Giant cell myocarditis 
Idiopathic pulmonary fibrosis 
Including but not limited to: 


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Medical Concept 
Additional Notes 
• 
Idiopathic interstitial pneumonia (frequently used related terms include 
“Interstitial lung disease”, “Pulmonary fibrosis”, “Immune-mediated 
pneumonitis”) 
• 
Pleuroparenchymal fibroelastosis (PPFE) 
Pulmonary alveolar proteinosis 
(PAP) 
• 
Frequently used related terms include: “pulmonary alveolar 
lipoproteinosis”, “phospholipidosis” 
Endocrine disorders 
Addison’s disease 
 
Autoimmune / Immune-mediated 
thyroiditis  
Including but not limited to: 
• 
Hashimoto thyroiditis (autoimmune hypothyroidism, lymphocytic 
thyroiditis) 
• 
Atrophic thyroiditis  
• 
Silent thyroiditis  
• 
Thyrotoxicosis 
Autoimmune diseases of the 
testis and ovary 
• 
Includes autoimmune oophoritis, autoimmune ovarian failure and 
autoimmune orchitis 
Autoimmune hyperlipidemia 
 
Autoimmune hypophysitis 
 
Diabetes mellitus type I 
 
Grave's or Basedow’s disease 
• 
Includes Marine Lenhart syndrome, and Graves' ophthalmopathy, also 
known as thyroid eye disease (TED) or endocrine ophthalmopathy 
Insulin autoimmune syndrome 
 
Polyglandular autoimmune 
syndrome 
• 
Includes Polyglandular autoimmune syndrome type I, II and III 
Eye disorders 
Ocular Autoimmune / Immune-
mediated disorders 
Including but not limited to: 
• 
Acute macular neuroretinopathy (also known as acute macular outer 
retinopathy) 
• 
Autoimmune/Immune-mediated retinopathy  
• 
Autoimmune/Immune-mediated uveitis, including idiopathic uveitis and 
sympathetic ophthalmia  
• 
Cogan's syndrome: an oculo-audiovestibular disease 
• 
Ocular pemphigoid 
• 
Ulcerative keratitis 
• 
Vogt-Koyanagi-Harada disease 
Gastrointestinal disorders 
Autoimmune / Immune-mediated 
pancreatitis 
 
Celiac disease 
 
Inflammatory Bowel disease  
Including but not limited to:  
• 
Crohn’s disease  
• 
Microscopic colitis  
• 
Terminal ileitis 


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Medical Concept 
Additional Notes 
• 
Ulcerative colitis  
• 
Ulcerative proctitis 
Hepatobiliary disorders 
Autoimmune cholangitis 
 
Autoimmune hepatitis 
 
Primary biliary cirrhosis 
 
Primary sclerosing cholangitis 
 
Musculoskeletal and connective tissue disorders  
Gout 
• 
Includes gouty arthritis 
Idiopathic inflammatory 
myopathies 
Including but not limited to: 
• 
Dermatomyositis 
• 
Inclusion body myositis 
• 
Immune-mediated necrotizing myopathy 
• 
Polymyositis 
Mixed connective tissue disorder 
 
Polymyalgia rheumatica (PMR) 
 
Psoriatic arthritis (PsA) 
 
Relapsing polychondritis 
 
Rheumatoid arthritis  
Including but not limited to: 
• 
Rheumatoid arthritis associated conditions 
• 
Juvenile idiopathic arthritis 
• 
Palindromic rheumatism 
• 
Still's disease 
• 
Felty’s syndrome 
Sjögren’s syndrome 
 
Spondyloarthritis 
Including but not limited to:  
• 
Ankylosing spondylitis 
• 
Juvenile spondyloarthritis 
• 
Keratoderma blenorrhagica 
• 
Psoriatic spondylitis  
• 
Reactive Arthritis (Reiter's Syndrome) 
• 
Undifferentiated spondyloarthritis 
Systemic Lupus Erythematosus  
• 
Includes Lupus associated conditions (e.g., Cutaneous lupus 
erythematosus, Lupus nephritis, etc.) or complications such as 
shrinking lung syndrome (SLS) 
Systemic Scleroderma (Systemic 
Sclerosis) 
• 
Includes Reynolds syndrome (RS), systemic sclerosis with diffuse 
scleroderma and systemic sclerosis with limited scleroderma (also 
known as CREST syndrome) 
Neuroinflammatory/neuromuscular disorders 
Acute disseminated 
encephalomyelitis (ADEM) and 
Includes the following: 
• 
Acute necrotizing myelitis 


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Medical Concept 
Additional Notes 
other inflammatory 
demyelinating variants  
• 
Bickerstaff's brainstem encephalitis  
• 
Disseminated necrotizing leukoencephalopathy (also known as 
Weston-Hurst syndrome, acute hemorrhagic leuko-encephalitis, or 
acute necrotizing hemorrhagic encephalomyelitis)  
• 
Myelin oligodendrocyte glycoprotein antibody-associated disease 
• 
Neuromyelitis optica (also known as Devic’s disease) 
• 
Noninfective encephalitis / encephalomyelitis / myelitis 
• 
Postimmunization encephalomyelitis  
Guillain-Barré syndrome (GBS) 
• 
Includes variants such as Miller Fisher syndrome and the acute motor 
and sensory axonal neuropathy (AMSAN) 
Idiopathic cranial nerve 
palsies/paresis and 
inflammations (neuritis) 
Including but not limited to: 
• 
Cranial nerve neuritis (e.g., Optic neuritis) 
• 
Idiopathic nerve palsies/paresis (e.g., Bell’s palsy) 
• 
Melkersson-Rosenthal syndrome 
• 
Multiple cranial nerve palsies/paresis  
Multiple Sclerosis (MS) 
Includes the following: 
• 
Clinically isolated syndrome (CIS)  
• 
Malignant MS (the Marburg type of MS)  
• 
Primary-progressive MS (PPMS) 
• 
Radiologically isolated syndrome (RIS) 
• 
Relapsing-remitting MS (RRMS) 
• 
Secondary-progressive MS (SPMS) 
• 
Uhthoff's phenomenon  
Myasthenia gravis 
• 
Includes ocular myasthenia and Lambert-Eaton myasthenic syndrome 
Narcolepsy 
• 
Includes narcolepsy with or without presence of unambiguous 
cataplexy 
Peripheral inflammatory 
demyelinating neuropathies and 
plexopathies 
Including but not limited to: 
• 
Acute Brachial Radiculitis (also known as Parsonage-Turner 
Syndrome or neuralgic amyotrophy) 
• 
Antibody-mediated demyelinating neuropathy 
• 
Chronic idiopathic axonal polyneuropathy (CIAP) 
• 
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), 
including atypical CIDP variants (e.g., multifocal acquired 
demyelinating sensory and motor neuropathy also known as Lewis-
Sumner syndrome) 
• 
Multifocal motor neuropathy (MMN)  
Transverse myelitis (TM) 
• 
Includes acute partial transverse myelitis (APTM) and acute complete 
transverse myelitis (ACTM) 
Renal disorders 
Autoimmune / Immune-mediated 
glomerulonephritis  
Including but not limited to: 
• 
IgA nephropathy 
• 
IgM nephropathy 
• 
C1q nephropathy 
• 
Fibrillary glomerulonephritis 


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Medical Concept 
Additional Notes 
• 
Glomerulonephritis rapidly progressive 
• 
Membranoproliferative glomerulonephritis 
• 
Membranous glomerulonephritis 
• 
Mesangioproliferative glomerulonephritis 
• 
Tubulointerstitial nephritis and uveitis syndrome 
Skin and subcutaneous tissue disorders 
Alopecia areata 
 
Autoimmune / Immune-mediated 
blistering dermatoses  
Including but not limited to:  
• 
Bullous Dermatitis 
• 
Bullous Pemphigoid  
• 
Dermatitis herpetiformis  
• 
Epidermolysis bullosa acquisita (EBA)  
• 
Linear IgA-mediated bullous dermatosis (LABD), also known as Linear 
IgA disease 
• 
Pemphigus  
Erythema multiforme 
 
Erythema nodosum 
 
Lichen planus 
• 
Includes liquen planopilaris 
Localized Scleroderma 
(Morphoea) 
• 
Includes Eosinophilic fasciitis (also called Shulman syndrome) 
Psoriasis 
 
Pyoderma gangrenosum 
 
Reactive granulomatous 
dermatitis  
Including but not limited to 
• 
Interstitial granulomatous dermatitis 
• 
Palisaded neutrophilic granulomatous dermatitis 
Stevens-Johnson Syndrome 
(SJS) 
Including but not limited to:  
• 
Toxic Epidermal Necrolysis (TEN)  
• 
SJS-TEN overlap 
Sweet’s syndrome 
• 
Includes Acute febrile neutrophilic dermatosis 
Vitiligo 
 
Vasculitis 
Large vessels vasculitis  
Including but not limited to: 
• 
Arteritic anterior ischemic optic neuropathy (AAION or arteritic AION) 
• 
Giant cell arteritis (also called temporal arteritis)  
• 
Takayasu's arteritis  
Medium sized and/or small 
vessels vasculitis  
Including but not limited to: 
• 
Anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis (type 
unspecified)  
• 
Behcet's syndrome  
• 
Buerger’s disease (thromboangiitis obliterans) 
• 
Churg–Strauss syndrome (allergic granulomatous angiitis)  


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Medical Concept 
Additional Notes 
• 
Erythema induratum (also known as nodular vasculitis) 
• 
Henoch-Schonlein purpura (also known as IgA vasculitis) 
• 
Microscopic polyangiitis 
• 
Necrotizing vasculitis 
• 
Polyarteritis nodosa 
• 
Single organ cutaneous vasculitis, including leukocytoclastic vasculitis, 
hypersensitivity vasculitis and acute hemorrhagic edema of infancy 
(AHEI) 
• 
Wegener's granulomatosis  
Other (including multisystemic) 
Anti-synthetase syndrome 
 
Capillary leak syndrome 
• 
Frequently used related terms include: “systemic capillary leak 
syndrome (SCLS)” or “Clarkson's Syndrome” 
Goodpasture syndrome 
• 
Frequently used related terms include: “pulmonary renal syndrome” 
and “anti-Glomerular Basement Membrane disease (anti-GBM 
disease)” 
Immune-mediated enhancement 
of disease 
• 
Includes vaccine associated enhanced disease (VAED and VAERD). 
Frequently used related terms include “vaccine-mediated enhanced 
disease (VMED)”, “enhanced respiratory disease (ERD)”, “vaccine-
induced enhancement of infection”, “disease enhancement”, “immune 
enhancement”, and “antibody-dependent enhancement (ADE) 
Immunoglobulin G4 related 
disease 
 
Langerhans' cell histiocytosis 
 
Multisystem inflammatory 
syndromes 
Including but not limited to: 
• 
Kawasaki’s disease 
• 
Multisystem inflammatory syndrome in adults (MIS-A) 
• 
Multisystem inflammatory syndrome in children (MIS-C)  
Overlap syndrome 
 
Raynaud’s phenomenon 
 
Sarcoidosis 
• 
Includes Loefgren syndrome 
Susac's syndrome 
 
10.3.5.2. 
Atrial fibrillation (AF) 
AEs of AF are considered as AESI in this study. 
When there is enough evidence to make the above diagnosis, the AE must be reported 
as AESI. Symptoms, signs or conditions which might (or might not) represent AF, 
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. 
For each case of AF reported in the AE or SAE section in the eCRF, additional 
information will be collected in a specific ‘AF follow-up questionnaire’ eCRF screen. 


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10.3.6. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as AEs or SAEs  
In the absence of a diagnosis, abnormal laboratory findings assessments or other 
abnormal results 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 Section 10.3.1 and 
Section 10.3.2).  
The investigator(s) must exercise their medical and scientific judgment in deciding 
whether an abnormal laboratory finding, or other abnormal assessment is clinically 
significant. 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs 
10.3.7.1. 
Pregnancy 
Female participants who become pregnant after administration of the study intervention 
may continue the study at the discretion of the investigator. 
While pregnancy itself is not considered an AE or SAE, any abnormal pregnancy 
outcome or complication or elective termination of a pregnancy for medical reasons will 
be recorded and reported as an SAE. Please refer to Section 10.3.2 for definition of SAE. 
10.3.8. 
Recording and follow-up of AEs, SAEs, AESIs (including pIMDs 
and AF) and pregnancies (Amended: 25 May 2023) 
The participants will be instructed to contact the investigator immediately should they 
experience any signs or symptoms they perceive as serious.  
When an AE/SAE/AESIs (including pIMDs and AF) occurs, it is the investigator’s 
responsibility to review all documentation (e.g., hospital progress notes, laboratory and 
diagnostics reports) related to the event. The investigator will then record all relevant 
information regarding an AE/SAE/AESIs (including pIMDs and AF) on the eCRF. The 
investigator may not send photocopies of the participant’s medical records to GSK 
instead of appropriately completing the eCRF.  
There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all participant identifiers will be blinded on 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/AESIs (including pIMDs and AF) instead of individual 
signs/symptoms. 
A pDiary will be used in this study to capture solicited administration site or systemic 
events. The pDiary will be distributed to all participants at Visit 1. The participant should 
be trained on how and when to complete the pDiary. If a participant is unable or not 
willing to complete the pDiary him/herself, he/she may be helped by a caregiver (refer to 
Glossary of terms for the definition of caregiver). 


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Anyone who measures administration site or systemic events and who will record the 
event in the pDiary, e.g., the study caregiver, should have received a caregiver 
information letter explaining the role of the caregiver prior to completing the pDiary. 
This training must be documented in the participant’s source record. 
If any individual other than the participant is making entries in the pDiary, their identity 
must be documented in the participant’s source record. 
Collect and verify completed pDiary during discussions with the participant on Visit 2. 
Any unreturned pDiary will be sought from the participant through telephone call(s) or 
any other convenient procedure. 
The investigator or delegate will transcribe the required information into the eCRF in 
English.  
10.3.8.1. 
Time period for collecting and recording AEs, SAEs, AESIs (including 
pIMDs and AF) and pregnancies (Amended: 25 May 2023) 
Refer to Table 11 for an overview of the protocol required reporting periods for AEs, 
SAEs, pIMDs and pregnancies. 
All solicited administration site and systemic events with onset during the 4 days 
following administration of the study intervention, and all unsolicited AEs that occur 
during the 30 days following administration of the study intervention must be recorded 
into the appropriate section of the eCRF, irrespective of their intensity. 
Non-serious AF with an onset during the 30-day period following study vaccine 
administration will be collected. 
The time period for collecting and recording all SAEs and pIMDs will begin at the first 
receipt of study intervention and will end 6 months after study intervention 
administration. AF reporting will follow the same reporting periods as for AEs and 
SAEs (Table 11). 
All AEs/SAEs/AESIs (including pIMDs and AF) leading to withdrawal from the study 
and pregnancies will be collected and recorded from the time of the first receipt of study 
intervention until the participant is discharged from the study. SAEs related to study 
participation or to a concurrent GSK medication/vaccine will be collected from the time 
consent is obtained until the participant is discharged from the study. All pIMDs related 
to study participation will be collected until study end. 
10.3.8.2. 
Follow-up of AEs, SAEs, AESIs (including pIMDs and AF), pregnancies 
or any other events of interest (Amended: 25 May 2023) 
After the initial AE/SAE/AESI (including pIMDs and AF)/pregnancy or any other event 
of interest, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs, AESIs (including pIMDs and AF) (as defined in 
Section 10.3.5.1) will be followed until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up. 


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10.3.8.2.1. Follow-up during the study (Amended: 25 May 2023) 
AEs/AESIs (including pIMDs and AF) documented at a previous visit/contact and 
defined as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the end of the study or the participant is lost to follow-up. 
If a participant dies during their participation in the study or during a recognized follow-
up period, GSK will be provided with any available post-mortem findings, including 
histopathology. 
10.3.8.2.2. Follow-up after the participant is discharged from the study (Amended: 
25 May 2023) 
The investigator will provide any new or updated relevant information to GSK on a 
previously reported SAE/pIMD using a paper/electronic Expedited Adverse Events 
Report and/or pregnancy report as applicable. For AF cases, the investigator will provide 
any new or updated relevant information on previously reported AF to GSK using a 
paper/electronic Expedited Adverse Events Report and the AF follow-up questionnaire 
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 SAE/pIMD as fully as possible. 
10.3.8.2.3. Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the electronic pregnancy report and the 
Expedited Adverse Events Report if applicable. Generally, the follow-up period does not 
need to be longer than 6 to 8 weeks after the date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it should always be reported as such. 
Furthermore, the investigator must report any SAE occurring as a result of a post-study 
pregnancy that is considered by the investigator to be reasonably related to the study 
intervention, to GSK as described in the Section 10.3.10. 
10.3.8.3. 
Updating of SAE, AESIs (including pIMD and AF), and pregnancy 
information after removal of write access to the participant’s eCRF 
(Amended: 25 May 2023) 
When additional SAE, AESI (including pIMD and AF), or pregnancy information is 
received after write access to the participant’s eCRF is removed, 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 Section 8.3.3.1 or to GSK Global Safety department within the 
defined reporting timeframes specified in the Table 12). 


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10.3.9. 
Assessment of intensity and causality 
10.3.9.1. 
Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described in Table 20: 
Table 20 
Intensity scales for solicited events in participants ≥50 YOA 
Event 
Intensity grade 
Parameter 
Pain at administration site 
0 
None 
 
1 
Mild: Any pain neither interfering with nor preventing 
normal everyday activities. 
 
2 
Moderate: Painful when limb is moved and interferes with 
everyday activities. 
 
3 
Severe: Significant pain at rest. Prevents normal 
everyday activities. 
Redness at administration site 
Greatest surface diameter in mm 
Swelling at administration site 
Greatest surface diameter in mm  
Temperature* 
Temperature in °C/°F 
Headache 
0 
None/Normal 
 
1 
Mild: Headache that is easily tolerated 
 
2 
Moderate: Headache that interferes with normal activity 
 
3 
Severe: Headache that prevents normal activity 
Fatigue (tiredness) 
0 
None/Normal 
 
1 
Mild: Fatigue that is easily tolerated 
 
2 
Moderate: Fatigue that interferes with normal activity 
 
3 
Severe: Fatigue that prevents normal activity 
Myalgia (muscle pain) 
0 
None/Normal 
 
1 
Mild: Myalgia present but does not interfere with activity 
 
2 
Moderate: Myalgia that interferes with normal activity 
 
3 
Severe: Myalgia that prevents normal activity 
Arthralgia (joint pain) 
0 
None/Normal 
 
1 
Mild: Arthralgia present but does not interfere with 
activity 
 
2 
Moderate: Arthralgia that interferes with normal activity 
 
3 
Severe: Arthralgia that prevents normal activity 
* Refer to the SoA (Section 1.3) for the definition of fever and the location for temperature measurement. 
The maximum intensity of administration site redness/swelling, and fever will be scored 
at GSK as follows: 
Intensity grade 
Redness/Swelling 
Fever 
0 
≤20 mm 
<38.0°C (100.4°F) 
1 
>20 - ≤50 mm 
≥38.0°C (100.4°F) - ≤38.5°C (101.3°F) 
2 
>50 - ≤100 mm 
>38.5°C (101.3°F) - ≤39.0°C (102.2°F) 
3 
>100 mm 
>39.0°C (102.2°F) 
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 judgment. 


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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 adults, such an AE would, for example, prevent attendance at 
work/school and would necessitate the administration of 
corrective therapy). 
An AE that is assessed as Grade 3 (severe) should not be confused with 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 
The investigator must assess the relationship between study intervention and the 
occurrence of each unsolicited AE/SAE using clinical judgment. 
Alternative possible causes, such as the natural history of underlying disease, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study intervention will be considered and investigated. The investigator will also consult 
the IB while making their 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 intervention? 
YES 
: 
There is a reasonable possibility that the study intervention 
contributed to the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to 
the administration of the study intervention. There are other, more 
likely causes and administration of the study intervention is not 
suspected to have contributed to the AE. 
If an event meets the criteria to be determined ‘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. 


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• 
Lack of efficacy of the study intervention, if applicable. 
• 
An error in study intervention 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(s) may change their 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 AE the participant experiences, the participant will be 
asked if they received medical attention (defined as hospitalization, or an otherwise 
unscheduled visit to or from medical personnel for any reason, including emergency 
room visits). This information will be recorded in the eCRF. 
10.3.9.4. 
Assessment of outcomes 
The investigator will assess the outcome of all serious and non-serious unsolicited AEs 
recorded during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
10.3.10. 
Reporting of SAEs, AESIs (including pIMDs and AF), pregnancies 
and other events (Amended: 25 May 2023) 
10.3.10.1. Events requiring expedited reporting to GSK (Amended: 25 May 2023) 
Once an investigator becomes aware that an SAE has occurred in enrolled participant, the 
investigator (or designee) must complete information in the electronic Expedited Adverse 
Events Report WITHIN 24 HOURS, even if the investigator does not have complete 
information on the SAE. It must be completed as thoroughly as possible, with all 
available details of the event.  
The SAE report must be updated WITHIN 24 HOURS of the receipt of updated 
information on the SAE. The investigator will always provide an assessment of causality 
at the time of the initial report. 


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Refer to the Table 12 for the details on timeframes for reporting of SAEs/AESIs 
(including pIMDs and AF)/pregnancies. 
The investigator will be required to confirm the review of SAE causality within 72 hours 
of submission of the SAE. 
Refer to Section 10.3.10.2 for information on back-up systems in case the electronic 
reporting system does not work. 
10.3.10.2. Back-up system in case the electronic reporting system does not work 
If the electronic reporting system does not work, the investigator (or designee) must fax 
or email a completed, dated and signed paper Expedited Adverse Events Report to the 
study contact for reporting SAEs (refer to Sponsor Information) or to GSK VCSP 
department within 24 hours of becoming aware of the SAE.  
Investigator (or designee) must complete the electronic Expedited Adverse Events Report 
within 24 hours after the electronic reporting system is working again. 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 
pregnancy information 
10.4.1. 
Definitions 
10.4.1.1. 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
10.4.1.1.1. Women not considered as women of childbearing potential 
• 
Premenopausal female with 1 of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral oophorectomy 
− 
Documented bilateral salpingectomy 
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview. 
• 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 


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• 
Females on HRT and whose menopausal status is in doubt will be required to use a 
non-hormonal, highly effective contraception method if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrolment. 
10.4.2. 
Contraception guidance 
• 
Female participants of childbearing potential are eligible to participate if they agree 
to use a highly effective contraceptive method consistently and correctly according 
to the methods listed in GSK’s list of highly effective contraceptive methods (Table 
21). 
Table 21 
Highly effective contraceptive methods 
Highly Effective Contraceptive Methods That Are User Dependent* 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Intravaginal 
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Injectable 
• 
Oral (only if allowed by local regulations or if part of standard medical practice in the country) 
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion or ligation 
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used.)  
Male partner sterilization prior to the female participant’s entry into the study, and this male is the sole partner for that 
participant, 
(The information on the male sterility can come from the site personnel’s review of the participant’s medical 
records; medical examination and/or semen analysis, or medical history interview provided by her or her 
partner). 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.)  
* Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects in clinical studies. 


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10.6. 
Appendix 6: Country-specific requirements 
10.6.1. 
Germany 
Explanatory statement concerning Gender Distribution (Article 7, paragraph 2 (12) 
of the German GCP ORDER). 
For this study, there is no intention to conduct specific analyses investigating the 
relationship between gender and the safety, immunogenicity and efficacy of the 
investigational RSV OA vaccine. Recruitment will include both males and females. To 
not expose pregnant women and their fetuses/children to an investigational vaccine, 
females enrolled in this study will either be of non-childbearing potential (i.e., 
hysterectomy, bilateral oophorectomy, bilateral salpingectomy or post-menopause), or if 
she is of childbearing potential, she must have a negative pregnancy test and use 
appropriate methods of contraception for the study duration (refer to the study protocol, 
Section 5.1 “Inclusion criteria” and Section 5.2 “Exclusion criteria”). Women who are 
pregnant, planning to become pregnant or breastfeeding are excluded from this study. 
Remote Source Data Verification during exceptional situations in Germany 
Frequent instream monitoring of safety data by the central study team at GSK is required 
for this study. Instream review of study data items and processes should be considered 
during exceptional situations/circumstances, such as with pandemics like COVID-19, 
focusing on key data points, patient assessments and processes that are critical to ensure 
the rights, safety and well-being of study participants and the integrity of the study and 
data. Prior to any rSDV activity a written agreement by the Investigator will be obtained. 
The agreement includes the extent and the method of rSDV activities. Monitoring Plan 
and Study-Specific Risk Register will be updated to include rSDV activities and CRAs 
will be guided for the conduct of rSDV. 
Option 1 Transfer of redacted Source Documentation 
Process for transfer and review of redacted source documentation provided by the site: 
• 
The CRA instructs study site on the source data needed for the remote SDV 
activities. 
• 
The CRA instructs site staff they must pseudonymize the requested documentation, 
do a quality check that anonymized (redacted) areas cannot be read, and then 
delivers the documentation to the CRA in an encrypted form of communication (the 
site should have a documented process). 
• 
The minimum requirements regarding quality of the copies will be agreed with the 
site upfront: 
− 
For the scanning of paper documents resolution will be a minimum of 300 dpi. 
− 
For the scanning of photographs and images resolution will be 600 dpi 
minimum. 
− 
Color scanners must be able to produce copies that match the original. 


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− 
A4 format as final size without loss of information. 
− 
Documents will be saved as PDF. 
− 
In order to maintain quality standards, a captured image will not be subjected to 
non- uniform scaling (i.e., sizing) or re-sampling to a lower resolution. 
• 
Redacted source document scans will be sent to the CRA via email using 1 of the 
following secure options: 
a. 
TLS connection: 
TLS connections are intended to support significant mail flow between GSK and 
external partners in a secure manner. 
b. GSK Secure 
In cases where only a handful of users are communicating or the volume of emails is 
low, the use of GSK secure, the GSK ad-hoc message encryption solution is 
recommended. 
c. 
Password protected PDF attachment 
A password protected scan (PDF) will be attached to an email. The password to open 
the attachment will be send in a separate email. 
• 
The CRA may use the secure email website to assess whether the sites email address 
is secure (i.e., encrypted). 
 
• 
Prior to starting remote SDV the CRA ensures that the provided documents are 
complete and does not contain any personal information. 
− 
In case the CRA detects any personal information that has not been redacted, the 
CRA informs the study site and deletes the files (incl. the Recycle bin). 
− 
A Data Breach must be reported Data Breach Web Report Form. 
• 
Use of an external PC screen is recommended. The CRA will not generate any 
copies from the source data received. 
• 
Source data verification/review will be conducted according to the process outlined 
in the GSK Monitoring SOP. 
• 
After completion of SDV activities, the CRA deletes all copies/images of participant 
data received from the site. This includes the deletion of the recycle bin and any 
temporary files. 
• 
A statement confirming that all documents were destroyed will be provided by the 
CRA via email to the site. 


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• 
Details of what was monitored remotely will be documented in the appropriate 
section of the Monitoring Visit Report. 
Option 2 – Review of Subject Source Documentation remotely 
Process for use of Webcams, WebEx, MS Teams for viewing participant source 
remotely: 
• 
The CRA ensures that the site personnel sharing information with GSK have 
authority to do so. 
• 
Remote SDV activities will be performed exclusively by the assigned site monitor. 
• 
Prior to conducting any remote SDV activities the CRA ensures that a written 
informed consent, covering the proposed SDV activities, has been signed by the 
study patient. 
• 
For CRAs using GSK laptops, only use GSK approved video conferencing tools 
(e.g., MS Teams or GSK WebEx). Live image transmission is fully encrypted and 
protected for authorized user. By using these systems, it will be assured that data will 
be viewed only but not transmitted/stored. 
• 
FSP/Local CRO CRAs not using GSK laptops, only MS Teams via Remote Access 
Application may be used for meetings between the CRA and the site. WebEx is not 
permitted from non-GSK laptops. Other tools like FaceTime, WhatsApp or Zoom are 
not permitted since they do not have sufficient encryption features. GSK does not 
have enterprise contract/privacy agreement with these providers. 
• 
Prior to the remote monitoring visit, the CRA instructs study site on the specific data 
needed for the remote SDV. 
• 
Source data verification will be conducted according to the process outlined in the 
Monitoring SOP. 
• 
The use of a headset is required, do not use computer audio. 
• 
The CRA does not capture screens or take pictures of screens to ensure we are not 
transferring content outside of clinical sites. 
• 
WebEx or Teams do not store or have access to any data, GSK staff is not allowed to 
make or store any screenshots or save any data which has been shared. 
• 
Details of what was monitored remotely will be documented in the appropriate 
section of the Monitoring Visit Report. 
• 
In case of technical malfunctions or if the security of the transmission is no longer 
ensured, we will pause rSDV activities. GSK Issue Management Procedures will be 
initiated. 


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10.6.2. 
Japan 
Regulatory and Ethical Considerations 
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (MHW Notification 
No.28 dated 27 March 1997)” and Pharmaceuticals and Medical Devices Act. 
The statement “To assume responsibility for the proper conduct of the study at this site.” 
on the Protocol Investigator Agreement Page means the investigator’s responsibility 
defined by Japanese GCP. 
GSK will submit the clinical trial notification to the regulatory authorities in accordance 
with Pharmaceuticals and Medical Devices Act before conclusion of any contract for the 
conduct of the study with study sites. 
Study Period 
Study Period is included in Exhibit 1. 
Study Administrative Structure 
Sponsor information is included in Exhibit 1. List of Medical Institutions and 
Investigators is included in Exhibit 2. 
Unapproved Medical Device 
If unapproved medical devices are used in the study, further details will be added in 
Exhibit 3. In case no unapproved medical devices are used, Exhibit 3 will not be attached. 


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10.7. 
Appendix 7: Abbreviations and glossary of terms 
10.7.1. 
List of abbreviations (Amended: 25 May 2023) 
AE: 
Adverse event 
AESI: 
Adverse events of special interest 
AF 
Atrial Fibrillation 
AIR: 
At increased risk 
ANCOVA: 
Analysis of covariance 
AS01B: 
Adjuvant system containing MPL, QS-21 and liposome 
(50 μg MPL and 50 μg QS-21) 
AS01E: 
Adjuvant system containing MPL, QS-21 and liposome 
(25 μg MPL and 25 μg QS-21) 
CAD: 
Coronary artery disease 
CD: 
Cluster of differentiation  
CHF: 
Chronic heart failure 
CI: 
Confidence interval 
CIOMS: 
Council for International Organizations of Medical 
Sciences 
CKD: 
Chronic kidney disease 
CKD-EPI: 
Chronic Kidney Disease Epidemiology Collaboration 
CLS: 
Clinical laboratory sciences 
CMI: 
Cell-mediated immunity 
COPD: 
Chronic obstructive pulmonary disease 
COVID-19: 
Coronavirus disease 2019 
CRA: 
Clinical research associate 
CRDL: 
Clinical research and development lead 
CRO: 
Contract research organization 


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CSR: 
Clinical study report 
DPI: 
Dots per inch 
eCRF: 
Electronic case report form  
EoS: 
End of study 
ES: 
Exposed Set 
EUA: 
Emergency use authorization 
FEV: 
Forced expiratory volume 
FSFV: 
First subject first visit 
FSH: 
Follicle stimulating hormone 
GCP: 
Good Clinical Practice 
GFR: 
Glomerular filtration rate 
GMT: 
Geometric mean titer 
GOLD: 
Global Initiative for Chronic Obstructive Lung Disease 
GSK: 
GlaxoSmithKline Biologicals SA 
HA: 
Healthy adults 
HIPAA: 
Health Insurance Portability and Accountability Act 
HRT: 
Hormonal replacement therapy 
IB: 
Investigator’s brochure 
ICF: 
Informed consent form 
ICH: 
International Council on Harmonization 
ICMJE:  
International Committee of Medical Journal Editors 
ICS: 
Intracellular cytokine staining 
IDMC: 
Independent data monitoring committee  
IEC: 
Independent Ethics Committee 
IFN: 
Interferon 


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IL: 
Interleukin 
IM: 
Intramuscular 
IRB: 
Institutional Review Board 
IRR: 
Incidence rate ratio 
LAR: 
Legally acceptable representative 
LML:  
Local medical lead 
LRTD:  
Lower respiratory tract disease 
LSLV: 
Last subject last visit 
MAtEx: 
MATerial EXcellence 
MDRD: 
Modification of Diet in Renal Disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MET: 
Metabolic equivalent of task 
NI: 
Non-inferiority 
OA: 
Older adults 
PBMC:  
Peripheral blood mononuclear cells 
PCA: 
Primary Completion Achieved 
PDF: 
Portable document format 
pDiary: 
Paper diary  
pIMD: 
Potential immune-mediated disease 
PPS: 
Per-Protocol Set 
QS-21: 
Quillaja saponaria Molina, fraction 21 (Licensed by 
GSK from Antigenics LLC, a wholly owned subsidiary 
of Agenus Inc., a Delaware, USA corporation) 
QTL: 
Quality tolerance limit 
RNA: 
Ribonucleic acid 
rSDV: 
Remote source data verification 


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RSV: 
Respiratory syncytial virus 
SAE: 
Serious adverse event 
SAP: 
Statistical analysis plan 
SAS: 
Statistical analysis system 
SBIR: 
Source data Base for Internet Randomization 
SDV: 
Source document verification 
SoA: 
Schedule of activities 
SOP: 
Standard operating procedure 
SPM: 
Study Procedures Manual 
SRR: 
Seroresponse rate 
SRT: 
Safety review team 
SUSAR: 
Suspected unexpected serious adverse reaction 
TLS: 
Transport layer security 
TNF: 
Tumor necrosis factor 
US: 
United States 
VCSP: 
Vaccines Clinical Safety and Pharmacovigilance 
WOCBP: 
Woman of childbearing potential 
YOA: 
Years of age 


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10.7.2. 
Glossary of terms (Amended: 25 May 2023) 
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 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. 
Adverse event of special 
interest 
An adverse event of special interest (serious or non-
serious) is one of scientific and medical concern 
specific to the sponsor’s product or program, for which 
ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. Such an 
event might warrant further investigation in order to 
characterize and understand it. Depending on the 
nature of the event, rapid communication by the trial 
sponsor to other parties (e.g., regulators) might also be 
warranted. 
Blinding: 
A procedure in which 1 or more parties to the study 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 
study, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a serious adverse 
event. 
In an observer-blind study, the participant, the site and 
sponsor personnel involved in the clinical evaluation of 
the participants are blinded while other study personnel 
may be aware of the treatment assignment. The study 
will be conducted in an observer-blind manner for 
Cohort 1 from study start-up to Day 31 analysis at Day 
31, beyond which the study will be considered single-
blind. This means that the investigator and/or his staff 
will be aware of the intervention assignment, but the 
participant will not. 
In an open-label study, no blind is used. Both the 
investigator and the participant know the identity of the 


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intervention assigned. The study will be conducted in an 
open-label manner for Cohort 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 their 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 (such as transcribing responses to diaries, 
receiving phone calls, planning study visits, etc.). 
However, at no time, the caregiver should evaluate the 
participant’s health status while answering diaries or 
make decisions on behalf of the participant. 
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. 
Current smoker: 
A person who is currently smoking or who has stopped 
smoking within 6 months before study start. 
Eligible: 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Enrolled participant: 
All participants who entered the study (who were 
randomized or received study intervention or underwent 
a post-screening procedure) 
NOTE:  screening failures (who never passed screening 
even if rescreened) and participants screened but never 
enrolled into the study (met eligibility but not needed) 
are excluded from the Enrolled Analysis Set as they did 
not enter the study. 
Refer to the Section 9.2 for the definition of ‘Enrolled 
Set’ applicable to the study. 


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Essential documents: 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of 
the data produced. 
eTrack: 
GSK’s tracking tool for clinical studies. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per protocol analysis. 
Former smoker: 
A person who stopped smoking for at least 6 months at 
the time of study start.  
Immunological correlate 
of protection: 
A correlate of risk that has been validated to predict a 
certain level of protection from the targeted endpoint. 
Intercurrent medical 
condition: 
A condition that has the capability of altering the 
immune response to the study vaccine or is confirmed to 
have an alteration of the participant’s initial immune 
status. 
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. 
Invasive medical device: 
An invasive medical device is a device which, in whole 
or in part, penetrates inside the body, either through a 
body orifice or through the surface of the body. 
Investigational vaccine: 
A pharmaceutical form of an active ingredient being 
tested in a clinical study, 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 
study at a study site. If a study is conducted by a team of 
individuals at a study site, the investigator is the 
responsible leader of the team and may be called the 
principal investigator.  
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified 


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individual or party to perform those study-related duties 
and functions. 
Participant: 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the 
study intervention (vaccine(s)/product(s)/control). 
Synonym: subject 
Participant number: 
A unique identification number assigned to each 
participant who consents to participate in the study. 
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 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 ICH defines a protocol amendment as: ‘A written 
description of a change(s) to or formal clarification of a 
protocol.’ GSK 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 intervention to 
participants to reduce selection bias. 
Screened participant 
All participants who were screened for eligibility. 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
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 follow-up period following study 
intervention administration. 
Source data: 
All information in original records and certified copies 
of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. 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 


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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, laboratories and at medico-
technical departments involved in the clinical study). 
Study intervention: 
Any investigational or marketed product(s) or placebo 
intended to be administered to a participant during the 
study. 
Study monitor: 
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
Unsolicited adverse event: 
Any AE reported in addition to those solicited during the 
clinical study. Also, any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event. 
10.8. 
Appendix 8: 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 
Original Protocol 
26 July 2022 
Amendment 1 
25 May 2023 
Detailed description of the current Protocol amendment 
Sponsor signatory 
Mathieu Peeters, MD 
Clinical & Epidemiology Project Lead 
Vx Clinical Sciences 
Veronica Hulstrøm, MD 
Clinical Project Lead 
RSV Older Adults 
Section 1.3. Schedule of Activities 
Table 1: Schedule of activities (Safety Assessments) 


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Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Notes 
Timepoint 
Day 1 
Day 31 Month 6 Month 
12 
 
Safety assessments 
 
 
 
 
 
Distribute diary cards 
○ 
 
 
 
A paper diary will be distributed to all 
study participants at Visit 1 (day of study 
intervention administration). All 
participants will record solicited events 
after study intervention administration 
and for 3 subsequent days (Days 1-4), 
unsolicited AEs, and concomitant 
medications/products after study 
intervention administration and for 29 
subsequent days (Days 1-30). 
See Section 10.3.8 
Return of diary cards  
 
○ 
 
 
See Section 10.3.8 
Record solicited administration 
site and systemic events (Days 
1–4 post-study intervention 
administration)  
● 
● 
 
 
See Section 10.3.8 and Table 11 
Record unsolicited AEs (Days 1-
30 post-study intervention 
administration) in the 
participantsC 
● 
● 
 
 
See Section 10.3.8 and Table 11 
Record concomitant 
medications/vaccinations 
● 
● 
● 
● 
See Section 6.8  
Record any intercurrent medical 
conditions  
● 
● 
● 
● 
See Section 9.2.1 and Table 11 
Record all SAEs and pIMDsC  
● 
● 
● 
 
See Section 10.3.8 and Table 11 
Record AEs/SAEs leading to 
withdrawal from the study and 
pregnancies 
● 
● 
● 
● 
See Section 10.3.8 and Table 11 
Record SAEs related to study 
participation, or to a concurrent 
GSK medication/vaccine 
● 
● 
● 
● 
SAEs related to study participation, or to 
a concurrent GSK medication/vaccine 
should be collected from the time of 
consent obtained (prior to administration 
of the study intervention) up to study 
end. 
See Section 10.3.8 and Table 11 
Record SAEs and pIMDs related 
to study intervention 
administration and fatal SAEsC 
● 
● 
● 
● 
SAEs and pIMDs related to study 
intervention administration and fatal 
SAEs should be collected after study 
intervention administration (Day 1) up to 
study end. 
See Section 10.3.8 and Table 11 
Study Conclusion 
 
 
 
● 
See Section 4.4 
Note: The double-line borders indicate the analyses which will be performed on all data (i.e., data that are as clean as 
possible) obtained up to this timepoints. 
AE=Adverse event; AESI= Adverse event of specific interest; CMI=Cell-mediated immunity; COVID-19=Coronavirus 
disease 2019; eCRF=Electronic case report form; pIMD=Potential immune-mediated disease; SAE=Serious 
adverse event. 
● 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 
If deemed necessary by the investigator. 
The blood sample and urine sample for pregnancy test should be taken on the same day, prior to study intervention 
administration. If the study intervention administration is delayed by any reason, in the event samples have been 


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taken, the samples will need to be collected again on the day of study intervention administration and the first 
blood sample will be destroyed. 
Atrial fibrillation (AF) will be considered as AESI in this study and will be additionally reported in the AF follow-
up questionnaire (electronic or paper) in eCRF. The collection of AF will be performed following the 
AE/SAE reporting periods. For AF that were reported before the implementation of this Protocol 
Amendment 1, additional available information should be encoded in the specific AF follow-up 
questionnaire retrospectively. 
Note: Visit 2, Visit 3 and Visit 4 should be done on site. Under special circumstances (e.g., pandemic), study visits can 
be done at home, or biological samples can be taken at a different location (see Section 8). 
Section 2.3.1. Risk assessment 
The vaccine candidate for OA contains the same RSV antigen as the RSV maternal 
candidate vaccine but it is combined with GSK’s established AS01 adjuvant to boost the 
immune response in the older adult population.  
The RSV OA vaccine trials in participants 60 YOA and older are closely monitored for 
safety with all available safety data reviewed internally. In addition, the Phase 3 RSV 
OA=ADJ-006 clinical study is monitored by an IDMC on an ongoing basis. The IDMC 
met most recently on 08 June 2022 and did not raise any concerns in the OA population. 
But the RSV OA vaccine has not been studied in pregnant women. 
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The vaccine candidate for older adults (OA) contains the same RSV antigen as the 
RSV maternal vaccine candidate but the RSV OA vaccine is combined with GSK’s 
established AS01E adjuvant to boost the immune response in the OA population. 
The RSV OA vaccine trials in participants >60 YoA are closely monitored for safety 
with all available safety data reviewed internally. In addition, the Phase 3 RSV 
OA=ADJ-006 clinical study is monitored by an IDMC on an ongoing basis. The IDMC 
has not raised any concern for safety in the OA population. The RSV OA vaccine has 
not been studied in pregnant women to date. 
In the current study the inclusion of all participants will be restricted to those 50 YOA 
and above. This age cut-off has been chosen since on the one hand there is a high unmet 
medical need in patients with chronic comorbidities and that as of 50 YOA there is a 
strong increase in the percentage of people with chronic comorbidities while on the other 
hand for women the incidence of spontaneous pregnancies is only about 4 in 
100 000 women in this age group [Salihu, 2003]. As a precautionary measure, all women 
of childbearing potential will be required to use adequate contraception and have a 
negative pregnancy test prior to vaccination. 
Section 3. Objectives, endpoints, and estimands 
Table 3. Study objectives, endpoints and estimands 
Within the table, every instance of “neutralization antibody titers” has been changed to 
“neutralization titers”. 
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Objectives 
Endpoints and estimands 
Primary* 
• 
To demonstrate the NI** of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-A strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-A neutralization antibody titers expressed as 
group GMT ratio (OA-RSV/Adults-HA-RSV), 
1 month after the RSVPreF3 OA investigational 
vaccine administration***. 
• 
RSV-A neutralization antibody titers expressed as 
group SRR difference (OA-RSV - Adults-HA-RSV), 1 
month after the RSVPreF3 OA investigational 
vaccine administration compared to baseline***. 
• 
To demonstrate the NI** of the humoral immune 
response in healthy participants 50-59 YOA 
compared to OA (≥60 YOA) for the RSV-B strain 
after RSVPreF3 OA investigational vaccine 
administration. 
• 
RSV-B neutralization antibody titers expressed as 
group GMT ratio (OA-RSV/Adults-HA-RSV), 
1 month after the RSVPreF3 OA investigational 
vaccine administration***. 
• 
RSV-B neutralization antibody titers expressed as 
group SRR difference (OA-RSV - Adults-HA-RSV), 1 
month after the RSVPreF3 OA investigational 
vaccine administration compared to baseline***. 
• 
To demonstrate the NI** of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-A strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
RSV-A neutralization antibody titers expressed as 
group GMT ratio (OA-RSV/Adults-AIR-RSV), 
1 month after the RSVPreF3 OA investigational 
vaccine administration***. 
• 
RSV-A neutralization antibody titers expressed as 
group SRR difference (OA-RSV - Adults-AIR-RSV), 
1 month after the RSVPreF3 OA investigational 
vaccine administration compared to baseline***. 
• 
To demonstrate the NI** of the humoral immune 
response in participants 50-59 YOA at increased 
risk of RSV-LRTD compared to OA (≥60 YOA) for 
the RSV-B strain after RSVPreF3 OA investigational 
vaccine administration. 
• 
RSV-B neutralization antibody titers expressed as 
group GMT ratio (OA-RSV/Adults-AIR-RSV), 
1 month after the RSVPreF3 OA investigational 
vaccine administration***. 
• 
RSV-B neutralization antibody titers expressed as 
group SRR difference (OA-RSV - Adults-AIR-RSV), 
1 month after the RSVPreF3 OA investigational 
vaccine administration compared to baseline***. 
Secondary - Safety 
• 
To evaluate the safety and reactogenicity after the 
RSVPreF3 OA investigational vaccine 
administration. 
• 
Percentage of participants reporting each solicited 
administration site event with onset within 4 days 
after study intervention administration (i.e., the day 
of study intervention administration and 
3 subsequent days). 
• 
Percentage of participants reporting each solicited 
systemic event with onset within 4 days after study 
intervention administration (i.e., the day of study 
intervention administration and 3 subsequent days). 
• 
Percentage of participants reporting unsolicited AEs 
within 30 days after study intervention administration 
(i.e., the day of study intervention administration and 
29 subsequent days). 
• 
Percentage of participants reporting any SAEs and 
pIMDs after study intervention administration 
(Day 1) up to Month 6. 
• 
Percentage of participants reporting SAEs and 
pIMDs related to study intervention administration 
after study intervention administration (Day 1) up to 
study end (Month 12). 


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Objectives 
Endpoints and estimands 
• 
Percentage of participants reporting any fatal SAEs 
after study intervention administration (Day 1) up to 
study end (Month 12). 
Secondary - Immunogenicity 
• 
To evaluate the humoral immune response to the 
RSVPreF3 OA investigational vaccine until 
12 months post-study intervention administration.  
• 
RSV-A and RSV-B neutralization antibody titers 
expressed as GMT, at pre-study intervention 
administration, 1 month, 6 months and at 12 months 
after study intervention administration.  
• 
To evaluate the CMI response after RSVPreF3 OA 
investigational vaccine administration until 
12 months post-study intervention administration.  
• 
CMI response expressed as group geometric mean 
of the frequency of RSVPreF3-specific CD4+ and/or 
CD8+ T cells expressing at least 2 activation 
markers including at least 1 cytokine among CD40L, 
4-1BB, IL-2, TNF-, IFN-, IL-13, IL-17, at pre-study 
intervention administration, 1 month, 6 months and 
at 12 months after study intervention administration, 
in a subset of participants.  
Tertiary 
(Note that tertiary objectives, endpoints, and estimands are optional and might be assessed only if needed; 
therefore, not all testing might be performed and reported) 
Section 4.3. Justification for dose 
Based on the results up to 1 month post-Dose 2 from study RSV OA=ADJ-002, a single 
dose regimen (0.5 mL) and the formulation of 120 µg RSVPreF3/AS01E were selected 
for further evaluation in the Phase 3 clinical program. The RSV OA=ADJ-002 study was 
designed to assess the immunogenicity of a 2-dose AS01E adjuvanted or unadjuvanted 
RSVPreF3 vaccine administered according to a 0-,2-month schedule with the aim to 
maximize the immune response against RSV and vaccine efficacy over several seasons. 
Based on the data from clinical development programs for AS01-adjuvanted protein 
antigen vaccines in OA, such as Shingrix and the COPD investigational vaccine, it was 
expected that immunological responses would reach higher levels 1 month post-Dose 2 as 
compared with 1 month post-Dose 1. However, the RSV OA=ADJ-002 results 
demonstrated that the second dose given 2 months after the first dose had no added value 
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in terms of humoral and/or cellular immune responses. The humoral response, both in 
terms of RSV A neutralizing antibody neutralization geometric mean titers (GMTs) and 
RSVPreF3-binding IgG geometric mean concentrations, peaked 1 month after the first 
dose, and the second dose did not increase the levels observed after the first dose. 
The results from study RSV OA=ADJ-002 demonstrated statistically significant 
superiority of the 120 µg formulations in terms of RSV A neutralizing neutralization 
titers over at least 1 of the 30 µg and 60 µg formulations with the same adjuvant content 
or unadjuvanted. An increase in the RSVPreF3-binding IgG GMCs and fold increase 
over baseline was also observed with increase in antigen dose from 30 µg to 120 µg. 
The data demonstrated an immunologic benefit of any AS01E or AS01B formulations 
over unadjuvanted formulations in terms of frequency of RSVPreF3specific CD4+ T 
cells expressing at least 2 markers. Importantly, the CD4+ T cells frequencies induced by 
the AS01-containing formulations in OA were close or similar to the frequencies 
observed in young adults. This was not observed following the administration of the 
unadjuvanted formulations. 
There was no safety concern detected in unadjuvanted groups to be linked to the 
RSVPreF3 antigen assessed for the first time in OA. The acceptable safety/reactogenicity 
profile in all 120 µg groups, together with the immunological benefit demonstrated for 
the 120 µg antigen dose, supported the selection of a 120 µg based formulation. The 
results also showed that all the AS01-adjuvanted formulations evaluated are considered 
to have a clinically acceptable safety profile. The AS01-adjuvanted formulation with the 
lowest reactogenicity profile, i.e., the AS01E-based formulation, was selected. The 
immunological response observed after 1 vaccine dose of the AS01E-based formulation is 
considered adequate for a RSVPreF3 OA candidate vaccine. 
The RSVPreF3 OA investigational vaccine has not been given in its present form to 
adults 50-59 YOA.  
Section 6.3.5.1. Emergency unblinding 
GSK’s Global Safety staff may unblind the intervention assignment for any participant 
with an SAE. If the SAE requires that an expedited regulatory report be sent to one 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. 
Section 6.8 Concomitant therapy 
• 
For all AF AESIs (including serious and non-serious), concomitant drugs which 
could be associated with development or worsening of AF must be reported in the 
AF follow-up questionnaire. 


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Table 7. Timing of collection of concomitant medication to be recorded 
 
Dose 1 
Study conclusion 
(Visit 4 at Month 12) 
 
Day 1 
Day 30 
All concomitant medication including vaccines/products, except 
vitamins and dietary supplements 
 
 
 
All concomitant medication including products/vaccines leading 
to elimination from the analysis 
 
 
 
All concomitant medication including vaccines/products which 
may explain/cause/be used to treat an SAE/ pIMD/AF*) 
 
 
 
Any prophylactic medication 
 
 
 
AF: Atrial Fibrillation; pIMD=Potential immune-mediated disease; SAE=Serious adverse event. 
Note: The collection period for the concomitant medications to be recorded in eCRF is indicated in gray. 
AESI= Adverse event of specific interest 
* For all AF AESIs (including serious and non-serious), concomitant drugs which could be associated with 
development or worsening of AF must be reported in the AF follow-up questionnaire. 
Section 8.1.2. Laboratory assays 
Table 9. Laboratory assays 
Assay type 
System 
Component 
Challenge 
Method 
Laboratory 
Humoral 
Immunity 
(Antibody 
determination) 
Serum 
RSV-A antibody 
neutralization 
 
Neutralization 
GSK* 
Serum 
RSV-B antibody 
neutralization 
Neutralization 
GSK* 
CMI  
PBMC 
CD40L, 4-1BB, IL-2, 
TNF-, IFN-, IL-13, 
IL-17 secreting CD4+ 
and CD8+ T cells 
Peptide pool 
covering 
RSVPreF3 
ICS 
GSK* 
Section 8.1.3. Immunological read-outs 
Table 10. Immunological read-outs 
Blood sampling time point 
Subset name 
No. of 
participants 
Component 
Type of contact and 
time point 
Sampling time 
point 
Humoral immunity (on serum samples) 
Visit 1 (Day 1) 
Pre-Adm 
All 
participants 
~1520 
RSV-A neutralizing antibody neutralization 
titer 
RSV-B neutralizing antibody neutralization 
titer 
Visit 2 (Day 31) 
Day 31 
All 
participants 
~1520 
RSV-A neutralizing antibody neutralization 
titer 
RSV-B neutralizing antibody neutralization 
titer 
Visit 3 (Month 6) 
Month 6 
All 
participants 
~1520 
RSV-A neutralizing antibody neutralization 
titer 
RSV-B neutralizing antibody neutralization 
titer 
Visit 4 (Month 12) 
Month 12 
All 
participants 
~1520 
RSV-A neutralizing antibody neutralization 
titer 


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Blood sampling time point 
Subset name 
No. of 
participants 
Component 
Type of contact and 
time point 
Sampling time 
point 
RSV-B neutralizing antibody neutralization 
titer 
CMI (on PBMC samples) 
Visit 1 (Day 1) 
Pre-Adm 
CMI subset 
~350 
IL-2, CD40L, TNF-, IFN-, IL-13, IL-17 or 
4-1BB secreting CD4+ and CD8+ T cells 
Visit 2 (Day 31) 
Day 31 
CMI subset 
~350 
IL-2, CD40L, TNF-, IFN-, IL-13, IL-17 or 
4-1BB secreting CD4+ and CD8+ T cells 
Visit 3 (Month 6) 
Month 6 
CMI subset 
~350 
IL-2, CD40L, TNF-, IFN-, IL-13, IL-17 or 
4-1BB secreting CD4+ and CD8+ T cells 
Visit 4 (Month 12) 
Month 12 
CMI subset 
~350 
IL-2, CD40L, TNF-, IFN-, IL-13, IL-17 or 
4-1BB secreting CD4+ and CD8+ T cells 
Section 8.2.1.3. Medical history 
A pre-defined list of current co-morbidities [Quan, 2011] to be recorded will be available 
in the eCRF (In addition to the chronic diseases listed in Section 5.1, additional 
information on rheumatologic diseases, hemiplegia and paraplegia will be collected). 
Section 8.3.1. Time period and frequency for collecting AE, SAE and other safety 
information 
An overview of the protocol-required reporting periods for AEs, SAEs, and AESIs 
(including pIMDs and AF) is given in Table 11. 
Table 11. Timeframes for collecting and reporting of safety information 
 
Pre-Adm* 
 
Adm 
 
 
Study conclusion 
 
D1 
 
D1 
D4# 
D30 
6 months post-dose 
 
12 months post-
dose 
SAEs and pIMDs 
related to study 
intervention 
administration and 
fatal SAEs† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
† AF will be considered as AESI in this study and will be additionally reported in the AF follow-up 
questionnaire in eCRF. 
AF reporting will follow the same reporting periods as for unsolicited AEs and SAEs. 
Non-serious AF with an onset during the 30-day period following study vaccine 
administration will be collected. The reporting of AF meeting SAE definition (serious 
AF) will be performed according to the SAE reporting period. Fatal AF and Serious 
AF judged as related to study vaccination will be reported according to the fatal SAE 
and related SAE reporting period, respectively. For AF that were reported before the 
implementation of this Protocol Amendment 1, additional available information should 
be encoded in the specific AF follow-up questionnaire retrospectively. 


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Section 8.3.2. Method of detecting AEs and SAEs, pregnancies, and other events 
Detection and recording of AEs/SAEs/AESI (including pIMDs and AF)/pregnancies are 
detailed in Section 10.3.8.  
Assessment of AE/SAE intensity, causality and outcome are described in Section 10.3.9.  
Open-ended and non-leading verbal questioning of participants is the preferred method of 
acquiring information related to an AE/SAE/AESI (including pIMDs and 
AF)/pregnancy. 
Section 8.3.3. Regulatory reporting requirements for SAEs, pregnancies, and other events 
Once an investigator (or designee) becomes aware that a study participant has 
experienced an SAE/AESI (including pIMDs and AF)/pregnancy, it must be reported to 
GSK using the required documentation and within the timeframes mentioned in Table 12. 
This is essential for GSK to meet legal obligations and ethical responsibilities for 
participant safety and the safety of a study intervention under clinical investigation. 
For SAEs/AESI (including pIMDs and AF), the investigator must always provide an 
assessment of causality at the time of the initial report, as defined in the Section 10.3.9.2. 
Please refer to Section 10.3.10 for further details regarding the reporting of SAEs/AESI 
(including pIMDs and AF)/pregnancies. 
Table 12. Timeframes for submitting SAEs, 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 
24 hours*, ‡‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
Pregnancies 
24 hours* 
electronic pregnancy report 
24 hours* 
electronic pregnancy report 
pIMDs  
24 hours**, ‡‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
Serious AF† 
24 hours* 
Electronic expedited AEs 
Report + AF follow-up 
questionnaire 
24 hours* 
Electronic expedited AEs 
Report + AF follow-up 
questionnaire 
GSK=GlaxoSmithKline Biologicals SA; pIMD=Potential immune-mediated disease; SAE=Serious adverse event. 
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
** Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD. 
‡‡ For each SAE/pIMD, the investigator(s) must document in the medical notes that they have reviewed the SAE/pIMD 
and have provided an assessment of causality. 
† Only AF meeting SAE definition will be reported in electronic Expedited AE Report and in the specific AF 
follow-up questionnaire. Non-serious AF will be reported in the non-serious adverse event eCRF screen 
and in the AF follow-up questionnaire. For AF that were reported before the implementation of this 
Protocol Amendment 1, additional available information should be encoded in the specific AF follow-up 
questionnaire retrospectively. 
Section 8.3.3.1. Contact information for reporting SAEs, AESIs (including pIMDs and 
AF) and pregnancies 


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Table 13. Contact information for reporting SAEs, AESIs (including pIMDs and AF) 
and pregnancies 
Study contact for questions regarding SAEs, AESIs (including pIMDs and AF), 
pregnancies 
Refer to the local study contact information document 
Back-up study contact for reporting SAEs, AESI (including pIMDs and AF), 
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 (primary) and PV.ICSRManagement@gsk.com 
(in CC) 
Fax: 1 610 787 7053 
US sites only: 
Fax: 1 610 787 7053 
Canadian sites only: 
Fax: 1 866 903 4718 
Section 8.3.4. Treatment of AEs  
Any medication, vaccine or products administered for the treatment of an SAE/pIMD 
should be recorded in the Expedited Adverse Event Report of the participant’s eCRF 
screen (refer to Section 10.3.10.1). For the AF, this information will be captured in the 
Expedited Adverse Events Report and in the AF follow-up questionnaire in eCRF. 
Section 9.5. Sample size determination 
• 
Individual RSV-A and RSV-B neutralizing antibody neutralization titers at baseline 
and at 1 month post-study intervention administration were modeled by a 
multivariate log-normal distribution, means and variance-covariance matrix based on 
historical data from other RSV OA vaccine clinical trials. The Adults-AIR-RSV 
Group was assumed to have the same multivariate log-normal distribution of the OA-
RSV Group (i.e., same means and variance-covariance matrix), while the 
Adults-HA-RSV Group was assumed to have a 1.25-fold higher mean at 1 month 
post-study intervention administration for both neutralizing antibodies neutralization 
titers. 
Section 10.2. Appendix 2: Clinical laboratory tests 
RSV-A and RSV-B neutralization assays 
The serum neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralize RSV entry and replication in a host cell line. 


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Virus neutralization is performed by incubating a fixed amount of RSV-A strain (Long, 
ATCC No. VR-26) or RSV-B strain (18537, ATCC No. VR-1580) with serial dilutions of 
the test serum. The serum-virus mixture is then transferred onto a monolayer of Vero 
cells (African Green Monkey, kidney, Cercopitheus aethiops, ATCC CCL 81) and 
incubated for 2 days to allow infection of the Vero cells by non-neutralized virus and the 
formation of plaques in the cell monolayer. Following a fixation step, RSV-infected cells 
are detected using a primary antibody directed against RSV (Polyclonal anti-RSV-A/B 
IgG) and a secondary antibody conjugated to horse-radish peroxidase, allowing the 
visualization of plaques after coloration with TrueBlue peroxidase substrate. Viral 
plaques are counted using an automated microscope coupled to an image analyzer 
(Scanlab system with a Reading software or equivalent). For each serum dilution, a ratio, 
expressed as a percentage, is calculated between the number of plaques at each serum 
dilution and the number of plaques in the virus control wells (no serum added). The 
serum neutralizing antibody neutralization titer is expressed in Estimated Dilution 60 
and corresponds to the inverse of the interpolated serum dilution that yields a 60% 
reduction in the number of plaques compared to the virus control wells, as described by 
others [Barbas, 1992; Bates, 2014]. The ED60 neutralization titers will also be 
converted in concentration in International Units per milliliter (IU/mL). Secondary 
standards calibrated against the international reference (NIBSC 16/284) [McDonald, 
2018; McDonald, 2020] are included in every run to allow conversion into international 
units per millimeters. 
Section 10.3.5. Adverse events of special interest (AESIs) 
pIMDs are the only AESIs collected for this study. 
Adverse events of special interest (AESIs) collected during this study include potential 
immune-mediated diseases (pIMDs) and Atrial Fibrillation (AF). 
Section 10.3.5.1. Potential immune-mediated diseases (pIMDs) 
Section 10.3.5.2. Atrial fibrillation (AF) 
AEs of AF are considered as AESI in this study. 
When there is enough evidence to make the above diagnosis, the AE must be reported 
as AESI. Symptoms, signs or conditions which might (or might not) represent AF, 
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. 
For each case of AF reported in the AE or SAE section in the eCRF, additional 
information will be collected in a specific ‘AF follow-up questionnaire’ eCRF screen. 
Section 10.3.8. Recording and follow-up of AEs, SAEs, AESIs (including pIMDs and 
AF) and pregnancies  


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When an AE/SAE/AESIs (including pIMDs and AF) occurs, it is the investigator’s 
responsibility to review all documentation (e.g., hospital progress notes, laboratory and 
diagnostics reports) related to the event. The investigator will then record all relevant 
information regarding an AE/SAE/AESIs (including pIMDs and AF) on the eCRF. The 
investigator may not send photocopies of the participant’s medical records to GSK 
instead of appropriately completing the eCRF.  
There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all participant identifiers will be blinded on 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/AESIs (including pIMDs and AF) instead of individual 
signs/symptoms. 
Section 10.3.8.1. Time period for collecting and recording AEs, SAEs, AESIs (including 
pIMDs and AF) and pregnancies 
All solicited administration site and systemic events with onset during the 4 days 
following administration of the study intervention, and all unsolicited AEs that occur 
during the 30 days following administration of the study intervention must be recorded 
into the appropriate section of the eCRF, irrespective of their intensity. 
Non-serious AF with an onset during the 30-day period following study vaccine 
administration will be collected. 
The time period for collecting and recording all SAEs and pIMDs will begin at the first 
receipt of study intervention and will end 6 months after study intervention 
administration. AF reporting will follow the same reporting periods as for AEs and 
SAEs (Table 11). 
All AEs/SAEs/AESIs (including pIMDs and AF) leading to withdrawal from the study 
and pregnancies will be collected and recorded from the time of the first receipt of study 
intervention until the participant is discharged from the study. SAEs related to study 
participation or to a concurrent GSK medication/vaccine will be collected from the time 
consent is obtained until the participant is discharged from the study. All pIMDs related 
to study participation will be collected until study end. 
Section 10.3.8.2. Follow-up of AEs, SAEs, AESIs (including pIMDs and AF), 
pregnancies or any other events of interest 
After the initial AE/SAE/AESI (including pIMDs and AF)/pregnancy or any other event 
of interest, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs, AESIs (including pIMDs and AF) (as defined in 
Section 10.3.5.1) will be followed until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up. 


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Section 10.3.8.2.1. Follow-up during the study 
AEs/AESIs (including pIMDs and AF) documented at a previous visit/contact and 
defined as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the end of the study or the participant is lost to follow-up. 
Section 10.3.8.2.2. Follow-up after the participant is discharged from the study 
The investigator will provide any new or updated relevant information to GSK on a 
previously reported SAE/pIMD using a paper/electronic Expedited Adverse Events 
Report and/or pregnancy report as applicable. For AF cases, the investigator will provide 
any new or updated relevant information on previously reported AF to GSK using a 
paper/electronic Expedited Adverse Events Report and the AF follow-up questionnaire 
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 SAE/pIMD as fully as possible. 
Section 10.3.8.3. Updating of SAE, AESIs (including pIMD and AF), and pregnancy 
information after removal of write access to the participant’s eCRF 
When additional SAE, AESI (including pIMD and AF), or pregnancy information is 
received after write access to the participant’s eCRF is removed, 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 Section 8.3.3.1 or to GSK Global Safety department within the 
defined reporting timeframes specified in the Table 12). 
Section 10.3.10. Reporting of SAEs, AESIs (including pIMDs and AF), pregnancies and 
other events 
Section 10.3.10.1. Events requiring expedited reporting to GSK 
Refer to the Table 12 for the details on timeframes for reporting of SAEs/AESIs 
(including pIMDs and AF)/pregnancies. 
Section 10.7.1. List of abbreviations 
AF 
Atrial Fibrillation 
Section 10.7.2. Glossary of terms 


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Adverse event of special 
interest 
An adverse event of special interest (serious or non-
serious) is one of scientific and medical concern 
specific to the sponsor’s product or program, for which 
ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. Such an 
event might warrant further investigation in order to 
characterize and understand it. Depending on the 
nature of the event, rapid communication by the trial 
sponsor to other parties (e.g., regulators) might also be 
warranted. 


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11. 
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Signature Page for  219238 TMF-16090080 v2.0
Signature Page for TMF-16090080 v2.0
Reason for signing: Approved
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Date of signature: 30-May-2023 14:04:57 GMT+0000
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