A Phase III, Open-label, Randomized, Controlled, Multi-country Study to Evaluate the Immune Response, Safety and Reactogenicity of an RSVPreF3 OA Investigational Vaccine When Co-administered With FLU aQIV (Inactivated Influenza Vaccine - Adjuvanted) in Adults Aged 65 Years and Above
Phase: PHASE3
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline

Protocol Amendment 1
Study ID: 218350
Official Title of Study: A Phase III, open-label, randomized, controlled, multi-country 
study to evaluate the immune response, safety and reactogenicity of an RSVPreF3 OA 
investigational vaccine when co-administered with FLU aQIV (inactivated influenza 
vaccine – adjuvanted) in adults aged 65 years and above. 
NCT number: NCT05568797
Date of Document: 16-Dec-2022

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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA (GSK) 
Rue de l’Institut, 89 
1330 Rixensart, Belgium
Primary study 
interventions and numbers 
GlaxoSmithKline Biologicals SA (GSK)’s 
investigational respiratory syncytial virus (RSV) 
vaccine BIO RSV OA=ADJ (GSK3844766A) 
Other study interventions 
Seqirus, Inc.’s inactivated quadrivalent, adjuvanted 
influenza vaccine 
eTrack study number and 
abbreviated title 
218350 (RSV OA=ADJ-017) 
EudraCT number 
2022-000623-21 
Date of protocol 
Final: 24 March 2022 
Date of protocol 
amendment 
Amendment 1 Final: 13 December 2022 
Title 
A Phase III, open-label, randomized, controlled, multi-
country study to evaluate the immune response, safety 
and reactogenicity of an RSVPreF3 OA investigational 
vaccine when co-administered with FLU aQIV 
(inactivated influenza vaccine – adjuvanted) in adults 
aged 65 years and above. 
Brief title 
A study on the immune response and safety of a 
vaccine against respiratory syncytial virus (RSV) when 
given alone or co-administered with an adjuvanted 
vaccine against influenza in adults aged 65 years and 
above. 
Based on GlaxoSmithKline Biologicals SA Protocol WS v17.2 
©2022 GSK group of companies or its licensor. 

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Protocol Amendment 1 Sponsor Signatory Approval 
eTrack study number and 
abbreviated title 
218350 (RSV OA=ADJ-017) 
EudraCT number 
2022-000623-21 
Date of protocol 
Final: 24 March 2022 
Date of protocol amendment 
Amendment 1 Final: 13 December 2022 
Title  
A Phase III, open-label, randomized, controlled, 
multi-country study to evaluate the immune 
response, safety and reactogenicity of an RSVPreF3 
OA investigational vaccine when co-administered 
with FLU aQIV (inactivated influenza vaccine – 
adjuvanted) in adults aged 65 years and above. 
Sponsor signatory 
Mathieu Peeters, MD 
Clinical Project Lead 
RSV Older Adults 
Signature 
 
 
 
Date 
 
Note: Not applicable if an alternative signature process (e.g., electronic signature or 
email approval) is used to get the sponsor approval. 

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Protocol Amendment 1 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals SA. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 
• 
That I will comply with the terms of the site agreement. 
• 
To ensure that all individuals 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 blood and serum samples) are retained 
onsite or elsewhere without the approval of GSK and the express written informed 
consent of the participant. 
• 
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 his/her 
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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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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eTrack study number and 
abbreviated title 
218350 (RSV OA=ADJ-017) 
EudraCT number 
2022-000623-21 
Date of protocol 
Final: 24 March 2022 
Date of protocol amendment 
Amendment 1 Final: 13 December 2022 
Title 
A Phase III, open-label, randomized, controlled, 
multi-country study to evaluate the immune response, 
safety and reactogenicity of an RSVPreF3 OA 
investigational vaccine when co-administered with 
FLU aQIV (inactivated influenza vaccine – 
adjuvanted) in adults aged 65 years and above. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 

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SPONSOR INFORMATION 
1. Sponsor 
GlaxoSmithKline Biologicals SA (GSK) 
89, rue de l’Institut 
1300 Rixensart, Belgium 
2. Sponsor medical expert for the study 
Refer to the local study contact information document. 
3. Sponsor study monitor 
Refer to the local study contact information document. 
4. Sponsor study contact for reporting of 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  
This section is not applicable. 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 1 
13 December 2022 
Original Protocol 
24 March 2022 
 
Type of Protocol 
Amendment 
Numbering 
Type of changes 
Global 
Amendment 1 
New changes for all 
Amendment 1 (13 December 2022) 
This amendment is considered substantial based on the criteria defined in EU 
Clinical Trial Regulation No 536/2014 of the European Parliament and the Council 
of the European Union because it significantly impacts the scientific value of the 
study. 
Overall rationale for Amendment 1:  
The purpose of this amendment was to promote from secondary objective to primary 
objective the  non-inferiority of RSV-B neutralizing antibody titers, as measured by 
GMT, when RSVPreF3 OA is co-administered with FLU aQIV, compared to RSVPreF3 
OA alone. In addition, the SAE definition of anomalies in offspring was added, 
laboratory blinding procedures were updated, and minor editorial changes were made for 
clarity but are not included in this summary table. 
List of main changes in the protocol and their rationale: 
Section # and title 
Description of change 
Brief rationale 
Section 1.3; Table 2 
(Schedule of 
Activities for the 
Control group) 
Separation of study group allocation 
from intervention number allocation, 
which were both listed together in 
Visit 1. 
To clarify that intervention number allocation takes 
place in both Visit 1 and Visit 2 and study group 
allocation takes place in Visit 1 only. 
Section 3; Table 5 
(Objectives, 
Endpoints and 
Estimands) 
Promotion of RSV-B neutralizing 
antibody assessment to a primary 
endpoint/objective.  
Updated as per recommendation by Center for 
Biologics Evaluation and Research (CBER). 
Section 6.3.5 
(Blinding and 
unblinding) 
Laboratory blinding 
To maintain study blinding during laboratory analysis 
as per recommendation by CBER. 

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Section # and title 
Description of change 
Brief rationale 
Section 9.1: 
Statistical 
hypotheses; Table 
18 
RSV-B neutralizing antibody 
assessment was added to the 
primary endpoints in Table 18. 
To align with the update of the primary objectives.  
Section 9.2: 
Analysis set; Table 
19 
The Per Protocol set (PPS) was 
updated with participant eligibility 
criteria. 
Section updated for clarity and in accordance with 
the statistical analysis plan (SAP). 
Section 9.3.1: 
Primary 
endpoints/estimands 
analysis 
To include the success Criteria of NI 
in terms of RSV-B neutralizing 
antibody. 
In accordance with the update in the primary 
objectives. 
Section 9.5: Sample 
size determination; 
Table 21 
Update of sample size 
determination to reflect the addition 
of RSV-B neutralizing antibody as a 
primary endpoint. 
In accordance with the update in the primary 
objectives. 
Section 10.3.2 
(Definition of an 
SAE) 
Addition of an SAE criterion.  
To update the definition of an SAE to include 
anomalies in the offspring of a study participant as 
per Medicines and Healthcare Products Regulatory 
Agency (MHRA) feedback. 
Section 10.3.8.1; 
Table 26 
(Assessment of 
intensity) 
To correct protocol template error in 
the Intensity scales for solicited 
events. 
Correction of “Fatigue” Grade 0 parameter From 
“Normal” to “None” in Table 26.  

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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: ........................................... 7 
1. 
PROTOCOL SUMMARY ........................................................................................ 16 
1.1. 
Synopsis ..................................................................................................... 16 
1.2. 
Schema ...................................................................................................... 16 
1.3. 
Schedule of Activities (SoA) ........................................................................ 17 
2. 
INTRODUCTION .................................................................................................... 22 
2.1. 
Study rationale ............................................................................................ 22 
2.2. 
Background ................................................................................................ 22 
2.3. 
Benefit/Risk assessment ............................................................................. 24 
2.3.1. 
Risk Assessment ......................................................................... 24 
2.3.2. 
Benefit Assessment ..................................................................... 24 
2.3.3. 
Overall Benefit/Risk Conclusion ................................................... 25 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 25 
4. 
STUDY DESIGN .................................................................................................... 27 
4.1. 
Overall design ............................................................................................. 27 
4.1.1. 
Overview of the recruitment plan.................................................. 29 
4.1.2. 
Enrollment rules ........................................................................... 29 
4.1.3. 
Caregiver support ........................................................................ 29 
4.2. 
Scientific rationale for study design ............................................................. 30 
4.3. 
Justification for dose ................................................................................... 30 
4.4. 
End of Study definition ................................................................................ 31 
5. 
STUDY POPULATION ........................................................................................... 31 
5.1. 
Inclusion criteria .......................................................................................... 32 
5.2. 
Exclusion criteria ......................................................................................... 32 
5.2.1. 
Medical conditions ....................................................................... 32 
5.2.2. 
Prior/Concomitant therapy ........................................................... 33 
5.2.3. 
Prior/Concurrent clinical study experience ................................... 34 
5.2.4. 
Other exclusions .......................................................................... 34 
5.3. 
Lifestyle considerations ............................................................................... 34 
5.4. 
Screening failures ....................................................................................... 34 
5.5. 
Criteria for temporarily delaying enrollment/study intervention 
administration ............................................................................................. 34 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY .................................. 35 
6.1. 
Study interventions administered ................................................................ 35 
6.2. 
Preparation, handling, storage, and accountability ...................................... 36 
6.3. 
Measures to minimize bias: randomization and blinding ............................. 36 
6.3.1. 
Participant identification ............................................................... 36 
6.3.2. 
Randomization to study intervention ............................................ 36 
6.3.3. 
Intervention allocation to the participant ....................................... 36 
6.3.4. 
Allocation of participants to assay subset ..................................... 37 

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6.3.5. 
Blinding and unblinding (Amended: 13 December 2022) ............. 37 
6.4. 
Study intervention compliance .................................................................... 37 
6.5. 
Dose modification ....................................................................................... 37 
6.6. 
Continued access to study intervention after the end of the study ............... 38 
6.7. 
Treatment of overdose ................................................................................ 38 
6.8. 
Concomitant therapy ................................................................................... 38 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 40 
7.1. 
Discontinuation of study intervention ........................................................... 40 
7.1.1. 
Contraindications to subsequent study intervention(s) 
administration .............................................................................. 40 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 41 
7.3. 
Lost to follow-up .......................................................................................... 41 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 42 
8.1. 
Immunogenicity assessments ..................................................................... 43 
8.1.1. 
Biological samples ....................................................................... 43 
8.1.2. 
Laboratory assays ....................................................................... 44 
8.1.3. 
Immunological read-outs .............................................................. 45 
8.1.4. 
Immunological correlates of protection ......................................... 46 
8.2. 
Safety assessments .................................................................................... 46 
8.2.1. 
Pre-intervention administration procedures .................................. 46 
8.2.1.1. 
Collection of demographic data .................................. 46 
8.2.1.2. 
Medical/vaccination history ......................................... 47 
8.2.1.3. 
History-directed physical examination/physical 
examination ................................................................ 47 
8.2.1.4. 
Warnings and precautions to administration of 
study intervention ....................................................... 47 
8.2.1.5. 
Pre-vaccination body temperature .............................. 47 
8.2.2. 
Post-vaccination procedures ........................................................ 47 
8.2.2.1. 
Safety contact at 6 months post-last 
vaccination ................................................................. 47 
8.3. 
AEs, SAEs and other safety reporting ......................................................... 48 
8.3.1. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 48 
8.3.2. 
Method of detecting AEs and SAEs and other events .................. 50 
8.3.3. 
Regulatory reporting requirements for SAEs and other 
events .......................................................................................... 50 
8.3.3.1. 
Contact information for reporting SAEs and 
pIMDs ......................................................................... 51 
8.3.4. 
Treatment of AE ........................................................................... 51 
8.3.5. 
Participant card ............................................................................ 51 
8.4. 
Pharmacokinetics ....................................................................................... 51 
8.5. 
Genetics ..................................................................................................... 52 
8.6. 
Biomarkers ................................................................................................. 52 
8.7. 
Immunogenicity assessments ..................................................................... 52 
8.8. 
Health outcomes ......................................................................................... 52 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 53 
9.1. 
Statistical hypotheses (Amended 13 December 2022) ................................ 53 
9.2. 
Analysis sets ............................................................................................... 54 

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9.2.1. 
Criteria for elimination from analysis ............................................ 54 
9.3. 
Statistical analyses ..................................................................................... 54 
9.3.1. 
Primary endpoints/estimands analysis (Amended: 13 
December 2022) .......................................................................... 54 
9.3.2. 
Secondary endpoints/estimands analyses ................................... 56 
9.4. 
Interim analyses .......................................................................................... 57 
9.4.1. 
Sequence of analyses .................................................................. 57 
9.4.2. 
Statistical considerations for interim analysis ............................... 57 
9.5. 
Sample size determination .......................................................................... 57 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 59 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 59 
10.1.1. 
Regulatory and ethical considerations ......................................... 59 
10.1.2. 
Financial disclosure ..................................................................... 60 
10.1.3. 
Informed consent process ............................................................ 60 
10.1.4. 
Data protection ............................................................................ 60 
10.1.5. 
Committees structure ................................................................... 61 
10.1.6. 
Dissemination of clinical study data ............................................. 61 
10.1.7. 
Data quality assurance ................................................................ 62 
10.1.8. 
Source documents ....................................................................... 63 
10.1.9. 
Study and site start and closure ................................................... 63 
10.1.10. Publication policy ......................................................................... 64 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 64 
10.3. 
Appendix 3: Adverse events – 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 ................................ 66 
10.3.1.2. Events NOT meeting the AE definition ........................ 67 
10.3.2. 
Definition of an SAE (Amended: 13 December 2022) .................. 67 
10.3.3. 
Solicited events ............................................................................ 68 
10.3.4. 
Unsolicited adverse events .......................................................... 68 
10.3.5. 
Adverse events of special interest (AESIs) .................................. 69 
10.3.5.1. Potential immune-mediated diseases ......................... 69 
10.3.6. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as AEs or SAEs ...................................... 73 
10.3.7. 
Recording and follow-up of AEs, SAEs, and pIMDs ..................... 74 
10.3.7.1. Time period for collecting and recording AEs, 
SAEs and pIMDs ........................................................ 74 
10.3.7.2. Follow-up of AEs, SAEs and pIMDs ........................... 75 
10.3.7.2.1. Follow-up during the study ...................... 75 
10.3.7.2.2. Follow-up after the participant is 
discharged from the study....................... 75 
10.3.7.3. Updating of SAE and pIMD information after 
removal of write access to the participant’s 
eCRF .......................................................................... 75 
10.3.8. 
Assessment of intensity and toxicity ............................................. 76 
10.3.8.1. Assessment of intensity .............................................. 76 
10.3.8.2. Assessment of causality ............................................. 77 
10.3.8.3. Medically attended visits ............................................. 78 
10.3.8.4. Assessment of outcomes ............................................ 78 

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10.3.9. 
Reporting of SAEs and pIMDs ..................................................... 79 
10.3.9.1. Events requiring expedited reporting to GSK .............. 79 
10.3.9.2. Back-up system in case the electronic reporting 
system does not work ................................................. 79 
10.4. 
Appendix 4: Contraceptive guidance and collection of pregnancy 
information .................................................................................................. 79 
10.5. 
Appendix 5: Genetics .................................................................................. 79 
10.6. 
Appendix 6: Country-specific requirements ................................................. 80 
10.6.1. 
France ......................................................................................... 80 
10.6.1.1. Concerning the «selection of study population 
and withdrawal criteria» .............................................. 80 
10.6.1.2. Concerning the “study governance 
considerations” ........................................................... 81 
10.6.1.3. Concerning the “data management” the 
following text is added: ............................................... 82 
10.6.1.4. Concerning data privacy ............................................. 82 
10.7. 
Appendix 7: Abbreviations and glossary of terms ........................................ 83 
10.7.1. 
List of abbreviations ..................................................................... 83 
10.7.2. 
Glossary of terms ......................................................................... 88 
11. REFERENCES ....................................................................................................... 92 
 

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LIST OF TABLES 
PAGE 
Table 1 
Schedule of Activities for the Co-Ad group ............................................. 17 
Table 2 
Schedule of Activities for the Control group (Amended: 13 
December 2022) .................................................................................... 19 
Table 3 
Intervals between study visits (Co-Ad group) ......................................... 22 
Table 4 
Intervals between study visits (Control group) ........................................ 22 
Table 5 
Study objectives, endpoints and estimands (Amended: 13 
December 2022) .................................................................................... 25 
Table 6 
Study groups and interventions .............................................................. 28 
Table 7 
Study interventions administered ........................................................... 35 
Table 8 
Allocation of participants to assay subset ............................................... 37 
Table 9 
Reporting timeframe for concomitant medication for the Co-Ad 
group ...................................................................................................... 39 
Table 10 
Reporting timeframe for concomitant medication for the Control 
Group ..................................................................................................... 39 
Table 11 
Biological samples ................................................................................. 43 
Table 12 
Laboratory assays .................................................................................. 44 
Table 13 
Immunological read-outs ........................................................................ 45 
Table 14 
Timeframes for collection and reporting of safety information for 
the Co-Ad group ..................................................................................... 48 
Table 15 
Timeframes for collection and reporting of safety information for 
the Control group ................................................................................... 49 
Table 16 
Timeframes for submitting SAE and other events reports to GSK .......... 51 
Table 17 
Contact information for reporting SAEs and pIMDs ................................ 51 
Table 18 
Study objectives and null hypothesis (Amended: 13 December 
2022) ...................................................................................................... 53 
Table 19 
Analysis sets (Amended: 13 December 2022) ........................................ 54 
Table 20 
Definitions of SCR, SPR and MGI .......................................................... 56 
Table 21 
Overall power to demonstrate primary objectives: non-inferiority 
of the immunogenicity of the RSVPreF3 OA investigational 

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vaccine when co-administered with FLU aQIV compared to when 
administered alone – assuming approximately 462 participants 
are available in each group (Amended: 13 December 2022) .................. 58 
Table 22 
Evaluation of non-inferiority in terms of HI antibody SCR when 
FLU aQIV is co-administered with the RSVPreF3 OA 
investigational vaccine compared to FLU aQIV when 
administered alone assuming approximately 462 participants are 
available in each group for a range of plausible SCRs (Amended: 
13 December 2022) ............................................................................... 59 
Table 23 
Solicited administration site events ......................................................... 68 
Table 24 
Solicited systemic events ....................................................................... 68 
Table 25 
List of potential immune-mediated diseases (pIMDs) ............................. 69 
Table 26 
Intensity scales for solicited events (Amended: 13 December 
2022) ...................................................................................................... 76 
 

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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: 
GlaxoSmithKline Biologicals (GSK) is developing a new respiratory syncytial virus 
(RSV) PreFusion protein 3 (PreF3) Older Adult (OA) investigational vaccine (RSVPreF3 
OA) against RSV-associated (subtypes A and B) disease in adults ≥60 years of age 
(YOA). The vaccine development is currently in Phase III, and immunogenicity, safety, 
and reactogenicity of the candidate vaccine when co-administered with other vaccines are 
being investigated. 
The present study will assess the immunogenicity, safety and reactogenicity of the 
RSVPreF3 OA investigational vaccine when co-administered with the adjuvanted 
quadrivalent influenza vaccine, FLU aQIV, in adults aged ≥65 YOA. FLU aQIV 
(marketed as Fluad Tetra, FLUAD QUADRIVALENT and Fluad Quad) is an inactivated, 
adjuvanted influenza vaccine marketed by Seqirus, Inc., and contains 2 influenza A-like 
strains (H1N1 and H3N2) and 2 influenza B-like strains (one from the Yamagata lineage 
and one from the Victoria lineage). It is indicated for the active immunization of 
individuals ≥65 YOA against influenza disease caused by influenza virus subtypes A and 
type B contained in the vaccine. 
Previous studies with the RSVPreF3 OA candidate vaccine have assessed the immune 
response at 1 month after vaccination. 
 
 
 
Objectives and endpoints: Refer to Table 5. 
1.2. 
Schema 
Refer to Figure 1 for a schematic presentation of the study design. 
CCI

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1.3. 
Schedule of Activities (SoA) 
Study visits should preferably be done on site. If deemed necessary, study visits during the follow-up phases can be done at home or at the 
long-term care facility (LTCF), as per local regulation. 
 
 
 
Table 1 
Schedule of Activities for the Co-Ad group 
Type of contact 
Visit 1 
Visit 2* 
Contact 1 
Notes 
Timepoints 
Day 1 
Day 31 
Month 6** 
Obtain informed consent 
● 
 
 
See Section 10.1.3 for details 
Distribution of Participant card 
○ 
 
 
See Section 8.3.5 for details 
Check inclusion/exclusion criteria 
● 
 
 
See Sections 5.1 and 5.2 for Inclusion and Exclusion 
criteria 
Check with participant if he/she will appoint a caregiver and distribute 
caregiver information letter, when applicable 
○ 
○ 
 
See Sections 4.1.3 and 10.1.3 for details 
Baseline and demographic assessments 
 
Collect demographic data 
● 
 
 
See Section 8.2.1.1 for more information 
Record medical and vaccination history 
● 
 
 
See Section 8.2.1.2 for more information 
Perform history-directed physical examination 
○ 
 
 
See Section 8.2.1.3 for more information 
Laboratory assessment 
 
Blood sampling from all participants for antibody determination (~10 mL) 
●*** 
● 
 
See Section 8.1.1 for more information 
Study interventions 
 
Check contraindications, warnings and precautions to study intervention 
administration 
○ 
 
 
See Sections 7.1.1 and 8.2.1.4 for more information 
Check criteria for temporary delay for enrollment and study intervention 
administration 
○ 
 
 
See Section 5.5 for more information 
Randomization 
● 
 
 
See Section 6.3 for more information 
Study group and intervention number allocation 
○ 
 
 
See Section 6.3.2, 6.3.3 and 6.3.4 for more information 
Record body temperature before study intervention administration# 
● 
 
 
The location for measuring temperature can be oral or 
axillary 
Study intervention administration (RSVPreF3 OA investigational vaccine + 
FLU aQIV) (including 30-minute post-dosing observation) 
● 
 
 
See Section 6.1 for more information 
Recording of administered study intervention number 
● 
 
 
 
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Type of contact 
Visit 1 
Visit 2* 
Contact 1 
Notes 
Timepoints 
Day 1 
Day 31 
Month 6** 
Safety assessments 
 
Setup of eDiary  
○ 
 
 
See Section 10.3.7 for more information 
Training on use of eDiary 
○ 
 
 
See Section 10.3.7 for more information 
Recording of solicited events in eDiary (Days 1 - 7 post-dosing) 
 
 
 
See Section 10.3.3 and 10.3.7 for more information 
Recording of ongoing solicited events in eDiary if applicable (Days 8 - 30 
post-dosing) 
 
 
 
See Section 10.3.3 and 10.3.7 for more information 
Review eDiary 
 
○∫ 
 
See Section 10.3.7 for more information 
Collect eDiary or assist participant to delete application 
 
○ 
 
See Section 10.3.7 for more information 
Recording of unsolicited AEs (Days 1 - 30 post-dosing) 
● 
● 
 
See Sections 10.3.4 and 10.3.7 for more information 
Recording of concomitant medications/vaccinations 
● 
● 
● 
See Section 6.8 for more information 
Recording of intercurrent medical conditions 
● 
● 
● 
See Section 9.2.1 for more information 
Recording of SAEs and pIMDs 
● 
● 
● 
See Section 10.3.7 for more information 
Recording of AEs/SAEs leading to withdrawal from the study 
● 
● 
● 
See Section 10.3.7 for more information 
Recording of SAEs related to study participation, or to a concurrent GSK 
medication/vaccine§ 
● 
● 
● 
See Section 10.3.7 for more information 
Contact for safety follow-up 
 
 
● 
See Sections 8.2.2 and 10.3.7.2 for more information 
Study conclusion 
 
 
● 
See Section 4.4 for more information 
AE = adverse event; Co-Ad = co-administration; eCRF = electronic case report form; pIMD = potential immune-mediated disease; RSVPreF3 OA = respiratory syncytial virus 
PreFusion protein 3 older adult; SAE = serious adverse event 
Note: The double-line borders indicate the analyses that will be performed on all data obtained up to these timepoints (refer to Section 9.4). 
● 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. 
 is used to indicate a study procedure that requires documentation in the individual eDiary. 
Grey is used to indicate a study procedure that is not applicable. 
*Visit 2 should preferably be done on site. However, if deemed necessary, local regulations allow, and quality of study procedures is maintained, this study visit can be replaced by a 
home visit conducted by authorized staff. Any information from the participant required according to study procedures and not collected during the home visit can be obtained by means 
of a phone call conducted by the site staff. 
**Six months after study interventions administration. For this contact, multiple formats (e.g., email, text message, fax, or phone call) can be proposed by the study site. Refer to 
Section 8.2.2.1 for more information. 
***Sample collected at Day 1 will be used as baseline for RSV and FLU vaccination. 
Sample collected at Day 31 will be used for the post-vaccination RSV vaccine- and FLU vaccine-related testing. 
#The route for measuring temperature can be oral or axillary. Fever is defined as temperature ≥38.0°C, regardless of the location of measurement.  
∫Designated site staff should review the eDiary frequently during the active event collection period to assess participant/caregiver compliance and monitor reported events. 

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§SAEs related to study participation or to a concurrent GSK medication/vaccine should be collected from the time of consent obtained (prior to study vaccine administration) up to study 
end. 
Table 2 
Schedule of Activities for the Control group (Amended: 13 December 2022) 
Type of contact 
Visit 1 
Visit 2 
Visit 4* 
Contact 1 
Notes 
Timepoints 
Day 1 
Day 31 
Day 61 
Month 7** 
Obtain informed consent 
● 
 
 
 
See Section 10.1.3 for details 
Distribution of Participant card 
○ 
 
 
 
See Section 8.3.5 for details 
Check inclusion/exclusion criteria 
● 
 
 
 
See Sections 5.1 and 5.2 for Inclusion 
and Exclusion criteria 
Check with participant if he/she will appoint a caregiver and 
distribute caregiver information letter, when applicable 
○ 
○ 
○ 
 
See Sections 4.1.3 and 10.1.3 for details 
Baseline and demographic assessments 
 
Collect demographic data 
● 
 
 
 
See Section 8.2.1.1 for more information 
Record medical and vaccination history 
● 
 
 
 
See Section 8.2.1.2 for more information 
Perform history-directed physical examination 
○ 
 
 
 
See Section 8.2.1.3 for more information 
Laboratory assessment 
 
Blood sampling from all participants for antibody determination 
(~10 mL) 
●*** 
● 
● 
 
See Section 8.1.1 for more information 
Blood sampling for anti-RSV antibody determination, from subset 
(~10 mL) 
 
 
 
 
See Section 8.1.1 for more information 
 
 
● 
● 
 
See Section 8.1.1 for more information 
Study interventions 
 
Check contraindications, warnings and precautions to study 
intervention administration 
○ 
○ 
 
 
See Sections 7.1.1 and 8.2.1.4 for more 
information 
Check criteria for temporary delay for enrollment and/or study 
intervention administration 
○ 
○ 
 
 
See Section 5.5 for more information 
Randomization 
● 
 
 
 
See Section 6.3 for more information 
Study group allocation  
○ 
 
 
 
See Section 6.3.2, 6.3.3 and 6.3.4 for 
more information 
Intervention number allocation 
○ 
○ 
 
 
See Section 6.3.2, 6.3.3 and 6.3.4 for 
more information 
Record body temperature before study intervention administration# 
● 
● 
 
 
The location for measuring temperature 
can be oral or axillary 
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Type of contact 
Visit 1 
Visit 2 
Visit 4* 
Contact 1 
Notes 
Timepoints 
Day 1 
Day 31 
Day 61 
Month 7** 
Study intervention administration (FLU aQIV) (including 30-minute 
post-dosing observation) 
● 
 
 
 
See Section 6.1 for more information 
Study intervention administration (RSVPreF3 OA investigational 
vaccine) (including 30-minute post-dosing observation) 
 
● 
 
 
See Section 6.1 for more information 
Recording of administered study intervention number 
● 
● 
 
 
 
Safety assessments 
 
Setup of eDiary  
○ 
○† 
 
 
See Section 10.3.7 for more information 
Training on use of eDiary 
○ 
○‡ 
 
 
See Section 10.3.7 for more information 
Recording of solicited events in eDiary (Days 1 - 7 post-dosing) 
 
 
 
 
See Section 10.3.3 and 10.3.7 for more 
information 
Recording of ongoing solicited events in eDiary if applicable (Days 
8 - 30 post-dosing) 
 
 
 
 
See Section 10.3.3 and 10.3.7 for more 
information 
Review eDiary 
 
○∫ 
○∫ 
 
See Section 10.3.7 for more information 
Collect eDiary or assist participant to delete application 
 
 
○ 
 
See Section 10.3.7 for more information 
Recording of unsolicited AEs (Days 1 - 30 post-dosing) 
● 
● 
● 
 
See Sections 10.3.4 and 10.3.7 for more 
information 
Recording of concomitant medications/vaccinations 
● 
● 
● 
● 
See Section 6.8 for more information 
Recording of intercurrent medical conditions 
● 
● 
● 
● 
See Section 9.2.1 for more information 
Recording of SAEs and pIMDs 
● 
● 
● 
● 
See Section 10.3.7 for more information 
Recording of AEs/SAEs leading to withdrawal from the study 
● 
● 
● 
● 
See Section 10.3.7 for more information 
Recording of SAEs related to study participation, or to a concurrent 
GSK medication/vaccine§ 
● 
● 
● 
● 
See Section 10.3.7 for more information 
Contact for safety follow-up 
 
 
 
● 
See Sections 8.2.2 and 10.3.7.2 for more 
information 
Study conclusion 
 
 
 
● 
See Section 4.4 for more information 
AE = adverse event; 
; eCRF = electronic case report form; pIMD = potential immune-mediated disease; RSV = respiratory syncytial virus; SAE = serious 
adverse event 
Note: The double-line borders indicate the analyses that will be performed on all data obtained up to these timepoints (refer to Section 9.4). 
● 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. 
 is used to indicate a study procedure that requires documentation in the individual eDiary. 
Grey is used to indicate a study procedure that is not applicable. 
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*Visit 4 should preferably be done on site. However, if deemed necessary, local regulations allow, and quality of study procedures is maintained, this study visit can be replaced by a 
home visit conducted by authorized staff. Any information from the participant required according to study procedures and not collected during the home visit can be obtained by means 
of a phone call conducted by the site staff. 
**Six months after study interventions administration. For this contact, multiple formats (e.g., email, text message, fax, or phone call) can be proposed by the study site. Refer to 
Section 8.2.2.1 for more information.  
***Sample collected at Day 1 will be used as baseline for the FLU vaccination in the Control group. 
 Sample collected at Day 31 will be used for the post-vaccination FLU vaccine-related testing. This sample will also be used as baseline for the RSV vaccination in the Control group. 
Sample collected at Day 61 will be used for the post-vaccination RSV vaccine-related testing. 
#The route for measuring temperature can be oral or axillary. Fever is defined as temperature ≥38.0°C, regardless of the location of measurement. 
†Participants will be asked to bring back their eDiary at Visit 2 (Day 31) for the site to activate the second solicited symptom recording period. 
‡Training on use of eDiary at Visit 2 (Day 31) only applicable if there is a change in eDiary audience (e.g., from participant to caregiver). 
∫Designated site staff should review the eDiary frequently during the active event collection period to assess participant/caregiver compliance and monitor reported events. 
§SAEs related to study participation, or to a concurrent GSK medication/vaccine should be collected from the time of consent obtained (prior to study vaccine administration) up to 
study end. 
 

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Table 3 
Intervals between study visits (Co-Ad group) 
Co-Ad = co-administration 
Table 4 
Intervals between study visits (Control group) 
Interval 
Planned Visit Interval 
Allowed Interval Range 
Visit 1 (Day 1) → Visit 2 (Day 31) 
30 days 
30 – 37 days 
Visit 2 (Day 31) → Visit 3 (Day 45) 
14 days 
12 – 16 days 
Visit 2 (Day 31) → Visit 4 (Day 61) 
30 days 
30 – 37 days 
Visit 2 (Day 31) → Contact 1 (Month 7) 
180 days 
180 – 210 days 
2. 
INTRODUCTION 
2.1. 
Study rationale 
GSK is developing a new respiratory syncytial virus (RSV) PreFusion protein 3 (PreF3) 
Older Adult (OA) investigational vaccine (RSVPreF3 OA) against RSV-associated 
(subtypes A and B) disease in adults ≥60 years of age (YOA). The vaccine development 
is currently in Phase III, and immunogenicity, safety, and reactogenicity of the candidate 
vaccine when co-administered with other vaccines are being investigated. 
The present study will assess the immunogenicity, safety and reactogenicity of the 
RSVPreF3 OA investigational vaccine when co-administered with the adjuvanted 
quadrivalent influenza vaccine, FLU aQIV, in adults aged ≥65 YOA. FLU aQIV 
(marketed as Fluad Tetra, FLUAD QUADRIVALENT and Fluad Quad) is an inactivated, 
adjuvanted influenza vaccine marketed by Seqirus, Inc., and contains 2 influenza A-like 
strains (H1N1 and H3N2) and 2 influenza B-like strains (one from the Yamagata lineage 
and one from the Victoria lineage). It is indicated for the active immunization of 
individuals ≥65 YOA against influenza disease caused by influenza virus subtypes A and 
type B contained in the vaccine. 
Previous studies with the RSVPreF3 OA candidate vaccine have assessed the immune 
response at 1 month after vaccination. 
 
 
 
2.2. 
Background 
RSV is a ribonucleic acid (RNA) virus with 2 antigenically distinct subgroups, referred to 
as RSV A and RSV B [Borchers, 2013]. RSV is a highly contagious human pathogen that 
causes respiratory tract infections in individuals of all age groups. Symptomatic RSV 
re-infections are common and continue throughout adulthood [Simoes, 1999; Krilov, 
2011]. These re-infections generally go undiagnosed because they manifest as common 
acute upper respiratory tract infections [Graham, 2011]. However, in more vulnerable 
Interval 
Planned Visit Interval 
Allowed Interval Range 
Visit 1 (Day 1) → Visit 2 (Day 31) 
30 days 
30 – 37 days 
Visit 1 (Day 1) → Contact 1 (Month 6) 
180 days 
180 – 210 days 
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individuals (e.g., immunocompromised individuals or older adults), re-infections can also 
lead to severe disease. 
In temperate climates, RSV predictably causes fall-winter epidemics [Noyola, 2008]. In 
(sub) tropical regions, viral activity is more endemic, and outbreaks are less temporally 
focused [Borchers, 2013]. 
According to the Centers for Disease Control and Prevention (CDC) [CDC, 2018], RSV 
leads to an average of 177 000 hospitalizations and 14 000 deaths among OA in the 
United States (US) each year. As the global population ages, the morbidity and mortality 
from respiratory infections appear to be steadily increasing [Binder, 2017]. In the US, the 
burden of the disease has been shown to be significant and data indicate that RSV is 
comparable to influenza (in an influenza-vaccinated population) in terms of number of 
infections, hospitalizations, and deaths. Based on epidemiological data collected 
prospectively in 2008-2010 in 14 countries worldwide (including North America, Europe, 
and East Asia), the average percentage of documented RSV infections in OA with 
influenza-like illness is 7.4%, with values between 0% and 17.1% across countries 
[Falsey, 2014]. 
Similarly, a recent worldwide systematic review and meta-analysis assessed the global 
burden of RSV-associated acute respiratory infection (ARI) in OA. The estimated 
number of RSV-ARI cases was found to be 1.5 million with an incidence of 
6.7 cases/1000 person-years in industrialized countries. In 2015, approximately 
1.5 million episodes of RSV-ARI occurred in OA in industrialized countries, and 
approximately 14.5% of these episodes involved a hospital admission [Nam, 2019]. 
To date, no licensed vaccine or prophylactic treatment is available for RSV. Currently 
available treatment for RSV infection is limited to supportive care. Natural infection is 
known to induce only partial protective immunity [Simoes, 1999; Krilov, 2011]. 
Therefore, re-infections occur frequently throughout an individual’s lifetime, rendering 
the development of a long-lasting efficacious vaccine challenging. RSV re-infections in 
OA can result in severe RSV disease despite the presence of robust serum RSV 
neutralizing antibody (NAb) titers [Cherukuri, 2013]. 
Taking into consideration the pre-existing immunity and immunosenescence of the target 
population, the composition of GSK’s new investigational vaccine (RSVPreF3 OA) has 
been built primarily to have the potential to boost/induce durable RSV neutralizing 
antibody responses and restore/elicit RSV-specific CD4+ T cell responses to specific 
RSV epitopes. GSK intends to develop this vaccine to protect OA against 
RSV-associated (subtypes A and B) lower respiratory tract infection (LRTI) during 
several seasons. 
Please refer to the current Investigator’s Brochure (IB) for information regarding pre-
clinical and clinical studies of the RSVPreF3 OA investigational vaccine. 

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2.3. 
Benefit/Risk assessment 
2.3.1. 
Risk Assessment 
Detailed information about the known and expected benefits and risks and expected 
adverse events (AE) of the RSVPreF3 OA investigational vaccine can be found in the IB, 
and the development safety update report (DSUR). 
Potential/Identified Risk 
Mitigation Strategy 
RSV 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. 
Syncope and hypersensitivity reactions (including 
anaphylaxis). 
All participants will remain under observation at the clinical 
center for at least 30 minutes after vaccination.  
Study procedures 
IM vaccination commonly precipitates a transient and 
self-limiting local inflammatory reaction. This may 
typically include pain at injection site, 
erythema/redness, and swelling. 
As a mitigation strategy, physicians can implement the 
measures that they consider necessary. 
Pain and bruising may occur at the site where blood 
is drawn. 
As a mitigation strategy, physicians can implement the 
measures that they consider necessary. 
Syncope (fainting) can occur following or even before 
any blood draw 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, 
will remain under observation at the clinical center until 
deemed necessary by site personnel. Appropriate medical 
treatment must be readily available during this period 
 
IM = intramuscular; pIMD = potential immune-mediated diseases; RSV = respiratory syncytial virus 
For expected adverse reactions associated with FLU aQIV, please refer to the Summary 
of Product Characteristics (SmPC). 
For details of study procedures, dose, and study design justification, refer to Sections 1.3 
and 4.2. 
2.3.2. 
Benefit Assessment 
The participants may not directly benefit from vaccination with the RSVPreF3 OA 
investigational vaccine because vaccine efficacy has not been established yet. Hence it is 
not known whether the RSVPreF3 OA investigational vaccine is effective in protecting 
against RSV disease. 
An indirect benefit is that the information obtained in this study will aid the development 
of an RSV investigational vaccine, which is intended to prevent disease associated with 
RSV infection in OA. 
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). 

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All participants will receive a seasonal FLU vaccine as part of the study. Participants 
may, therefore, have the benefit of being protected against circulating strains of influenza 
during the active influenza season. 
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. 
The benefits of FLU aQIV appear to outweigh its potential risks. The established 
favorable benefit-risk profile for FLU aQIV remains unchanged for the active 
immunization of individuals as of 65 YOA against influenza disease caused by influenza 
type A and type B viruses contained in the vaccine. 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Table 5 
Study objectives, endpoints and estimands (Amended: 13 December 
2022) 
Objectives 
Endpoints and Estimands 
Primary 
• 
To demonstrate the non-inferiority of the FLU 
vaccine when co-administered with the RSVPreF3 
OA investigational vaccine compared to the FLU 
vaccine administered alone. 
• 
HI antibody titers for each of the FLU vaccine 
strains expressed as group GMT ratio, one month 
after the FLU vaccine dose. 
• 
To demonstrate the non-inferiority of the RSVPreF3 
OA investigational vaccine when co-administered 
with the FLU vaccine compared to the RSVPreF3 
OA investigational vaccine administered alone. 
• 
RSV-A neutralization antibody titers expressed as 
group GMT ratio, one month after the RSVPreF3 
OA investigational vaccine dose. 
• 
To demonstrate the non-inferiority of the 
RSVPreF3 OA investigational vaccine when co-
administered with the FLU vaccine compared to 
the RSVPreF3 OA investigational vaccine 
administered alone. 
• 
RSV-B neutralization antibody titers expressed 
as group GMT ratio, one month after the 
RSVPreF3 OA investigational vaccine dose. 
Secondary 
• 
To evaluate the non-inferiority of the FLU vaccine 
when co-administered with the RSVPreF3 OA 
investigational vaccine compared to the FLU 
vaccine administered alone. 
• 
HI seroconversion status for each of the FLU 
vaccine strains expressed as SCR, one month after 
the FLU vaccine dose. 
• 
To evaluate the humoral immune response to the 
RSVPreF3 OA investigational vaccine when 
co-administered with the FLU vaccine or 
administered alone. 
• 
RSV-A neutralization antibody titers expressed as 
MGI at one month after the RSVPreF3 OA 
investigational vaccine dose. 
• 
RSV-B neutralizing antibody titers expressed as 
MGI at one month after the RSVPreF3 OA 
investigational vaccine dose. 
• 
To evaluate the humoral immune response to the 
FLU vaccine when co-administered with the 
• 
HI antibody titers for each of the FLU vaccine 
strains expressed as GMT, at Day 1 and Day 31. 

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Objectives 
Endpoints and Estimands 
RSVPreF3 OA investigational vaccine or 
administered alone. 
•
HI seroconversion status for each of the FLU
vaccine strains expressed as SCR, from Day 1 to
Day 31.
•
HI seroprotection status for each of the FLU
vaccine strains expressed as SPR, at Day 1 and
Day 31.
•
HI antibody titers for each of the FLU vaccine
strains expressed as MGI, one month after the FLU
vaccine dose.
•
To evaluate the safety and reactogenicity following
administration of the RSVPreF3 OA investigational
vaccine and the FLU vaccine, co-administered or
administered alone.
•
Percentage of participants reporting each solicited
event with onset within 7 days after vaccine
administration (i.e., the day of vaccination and
6 subsequent days).
•
Percentage of participants reporting unsolicited AEs
(pIMD, non-serious AE or serious AE) within 30
days after vaccine administration (i.e., the day of
vaccination and 29 subsequent days).
•
Percentage of participants reporting SAEs after
vaccine administration (Day 1) up to study end
(6 months after last vaccination).
•
Percentage of participants reporting pIMDs after
vaccine administration (Day 1) up to study end
(6 months after last vaccination).
FLU vaccine refers to FLU aQIV 
AE = adverse event; 
; GMT = geometric mean titer; HI = hemagglutination inhibition; MGI 
= mean geometric increase; RSVPreF3 OA = respiratory syncytial virus PreFusion protein 3 older adult; SAE = serious 
adverse event; SCR = seroconversion rate; SPR = seroprotection rate; pIMD = potential immune-mediated disease;  
SCR = percentage of vaccinees who have either a HI pre-dose titer < 1:10 and a post-dose titer ≥1:40 or a pre-dose 
titer ≥1:10 and at least a 4-fold increase in post-dose titer. 
SPR = percentage of vaccinees with a serum HI titer ≥1:40 that usually is accepted as indicating protection. 
MGI = geometric mean of the within-participant ratios of the post-dose titer over the pre-dose titer. 
Details related to attributes of estimands covering intercurrent events, population 
and treatment definition are provided in Section 9. 
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4. 
STUDY DESIGN 
4.1. 
Overall design 
Figure 1 
Study design overview 
 
AE = adverse event; N = number of participants; pIMD = potential immune-mediated disease; RSV = respiratory syncytial virus; SAE = serious adverse event  
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• 
Type of study: self-contained. 
• 
Experimental design: Phase III, randomized (ratio 1:1), open-label, multi-country 
study with 2 parallel groups (see Figure 1). 
• 
Study groups (refer to Figure 1 and Table 6 for an overview of the study 
groups): 
− 
Co-Ad (co-administration) group: Participants receiving the RSVPreF3 OA 
investigational vaccine co-administered with FLU aQIV (referred to as FLU 
vaccine). 
− 
Control group: Participants receiving the FLU aQIV (referred to as FLU 
vaccine) and the RSVPreF3 OA investigational vaccine in a sequential manner. 
• 
Duration of the study: ~6 months for participants in Co-Ad group; ~7 months for 
participants in Control group. 
• 
Primary completion date: Day 61 (1 month after the RSVPreF3 OA investigational 
vaccine dose in Control group). 
• 
Control: active comparator, i.e., sequential administration of licensed FLU vaccine 
and RSVPreF3 OA investigational vaccine. 
• 
Blinding: open-label. Refer to Section 6.3.5 for details. 
• 
Data collection: standardized electronic Case Report Form (eCRF). Solicited events 
will be collected using an electronic diary card (eDiary). Unsolicited AEs will be 
collected through questioning at study visits/contacts and reported into the eCRF. 
See Section 8.3.2 for details. 
• 
Safety monitoring: the study will be conducted with oversight by the project Safety 
Review Team (SRT). Please refer to Section 10.1.5 for the SRT structure. 
• 
Vaccination schedule: 
Co-Ad group: Participants will be receiving both the RSVPreF3 OA investigational 
vaccine and FLU vaccine at Visit 1 (Day 1). 
Control group: Participants will be receiving the FLU vaccine at Visit 1 (Day 1) and 
subsequently the RSVPreF3 OA investigational vaccine at Visit 2 (Day 31). 
Table 6 
Study groups and interventions 
Co-Ad = co-administration; RSVPreF3 OA = respiratory syncytial virus PreFusion protein 3 older adult 
Study Groups 
Number of Participants 
Age 
(Min-Max) 
Study Interventions 
Co-Ad 
~514 
≥ 65 years 
RSVPreF3 OA investigational 
vaccine 
FLU aQIV 
Control 
~514 
≥ 65 years 
RSVPreF3 OA investigational 
vaccine 
FLU aQIV 

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4.1.1. 
Overview of the recruitment plan 
No screening visit is planned for this study. The study is planned to be conducted at 
multiple 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 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) together with the 
material intended for participants’ identification/recruitment and participants use. Refer 
to the Study Procedures Manual (SPM) for additional details. 
4.1.2. 
Enrollment rules 
Overall, participants will be enrolled in 3 age categories reflecting an approximate age 
distribution in the general population with a balance between males and females. It is 
therefore intended to enroll: 
• 
Approximately 25% of participants 65-69 YOA, ~40% of participants 70-79 YOA 
and ~10% of participants ≥80 YOA. The remaining 25% can be distributed freely 
across the 3 age categories. 
• 
Approximately 40% of participants from each sex; the remaining 20% can be 
distributed freely between the 2 sexes. 
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. However, every effort should be done to 
ensure that only one caregiver enters the data into the eDiary to allow for timely 
completion. 
Caregivers may help the study participants to perform 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, 
should the caregiver evaluate the participant’s health status while completing diaries or 

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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 subsequent 
study visit(s), 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 in caregiver. 
Please refer to the SPM for additional information on the appointment of a caregiver. 
4.2. 
Scientific rationale for study design 
The influenza season coincides with the RSV season in temperate countries. Influenza 
vaccination begins at the start of the flu season, at around the same time when the 
RSVPreF3 OA investigational vaccine may potentially be recommended for 
immunization against RSV infection. To date, there is no data available on the safety and 
immunogenicity of the RSVPreF3 OA investigational vaccine when it is co-administered 
with an adjuvanted influenza vaccine. 
The current study is therefore designed to assess the immunogenicity, safety and 
reactogenicity of the RSVPreF3 OA investigational vaccine when it is co-administered 
with a FLU vaccine, compared to administration of the vaccines separately. There are 2 
parallel arms: 
• 
Co-Ad group: Participants will receive a single dose of RSV investigational vaccine 
and a single dose of FLU vaccine at Visit 1 (Day 1). 
• 
Control group: Participants will receive a single dose of FLU vaccine at Visit 1 
(Day 1), followed by a single dose of the RSV investigational vaccine at Visit 2 
(Day 31). 
The study will enroll older adults ≥ 65 YOA who are primarily responsible for self-care 
and activities of daily living. Participants may have one or more chronic medical 
conditions but should be medically stable according to the investigator. 
As the RSVPreF3 OA investigational vaccine is adjuvanted, all participants will be 
followed up for safety for 6 months post-RSV investigational vaccine administration. 
The 120 µg RSVPreF3/AS01E vaccine formulation was selected in a previous study 
(RSV OA=ADJ-002) where the vaccine was administered intramuscular (IM) according 
to a 0, 2-month vaccination schedule. Please refer to the IB for details. 
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 120 µg RSVPreF3/AS01E formulation were selected for 
further evaluation in the Phase III clinical program. The RSV OA=ADJ-002 study was 
designed to assess the immunogenicity of a 2-dose AS01-adjuvanted or unadjuvanted 
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 chronic obstructive pulmonary disease investigational 

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vaccine, it was expected that immunological responses would reach higher levels 
1 month post-Dose 2 compared to 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 response. The humoral response, both in terms of RSV-
A neutralizing antibody geometric mean titer (GMTs) and RSVPreF3 IgG geometric 
mean concentrations, peaked 1 month after the first dose, while the second dose did not 
increase the level 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 titers over at least 
one of the 30 µg and 60 µg formulations with the same adjuvant content or unadjuvanted. 
The data demonstrated an immunological benefit of any AS01E or AS01B formulations 
over unadjuvanted formulations in terms of frequency of RSVPreF3-specific CD4+ 
T cells expressing at least 2 markers among IL-2, CD40L, TNF-α, IFN-γ in vitro. 
Importantly, despite lower baseline levels of RSVPreF3-specific CD4+ T cells observed 
in OA, the AS01-containing formulations induced CD4+ T cells frequencies at a close or 
similar level than in young adults, which was not observed with 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, supports the selection of an 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. 
In the current study, the FLU vaccine will be administered as a single dose 
(recommended standard of care). 
4.4. 
End of Study definition 
A participant is considered to have completed the study if he/she returns for the last visit, 
or is available for the last scheduled contact as described in the protocol. 
End of Study (EoS): Last subject last visit (LSLV) (contact at 6 months post-last dose). 
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 and regulatory acceptability of the study or safety of the participant. 

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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 electronic diary cards 
[eDiaries], return for follow-up visits, ability to access and utilize a phone or other 
electronic communications). 
Note: In case of physical incapacity that would preclude the self-completion of the 
eDiaries, either site staff can assist the participant (for activities performed during 
site visits) or the participant may assign a caregiver (refer to Glossary of terms for 
the definition of 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. 
• 
A male or female ≥ 65 YOA at the time of the first study intervention administration. 
• 
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. 
• 
Written or witnessed informed consent obtained from the participant prior to 
performance of any study-specific procedure. 
• 
Participants who are medically stable in the opinion of the investigator at the time of 
first 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. 
5.2. 
Exclusion criteria 
The following criteria should be checked at the time of study entry. The potential 
participant MAY 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 (e.g., anaphylaxis) likely to be 
exacerbated by any component of the study interventions, in particular any history of 
severe allergic reaction to egg protein or to a previous influenza vaccine. 
• 
Hypersensitivity to latex. 

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• 
Guillain-Barré syndrome (GBS) that occurred within 6 weeks of receipt of prior 
influenza vaccine. 
• 
Serious or 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 Examination (MMSE), Mini-Cog or Montreal Cognitive 
Assessment (MoCA) 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 eDiaries, 
attend regular phone calls/study site visits). 
• 
Significant underlying illness that in the opinion of the investigator would be 
expected to prevent completion of the study (e.g., life-threatening disease likely to 
limit survival up to study end). 
• 
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 interventions during the period beginning 30 days before 
the first dose of study interventions, or planned use during the study period. 
• 
Administration of an influenza vaccine during the 6 months preceding the study FLU 
vaccine administration. 
• 
Planned or actual administration of a vaccine not foreseen by the study protocol in 
the period starting 30 days before the first study intervention administration and 
ending 30 days after the last study intervention administration. In the case of 
COVID-19 vaccines, this time window can be decreased to 14 days before and after 
each study intervention administration provided this COVID-19 vaccine use is in line 
with local governmental recommendations.  
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. 
• 
Administration of long-acting immune-modifying drugs or planned administration at 
any time during the study period (e.g., infliximab). 

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• 
Administration of immunoglobulins and/or any blood products or plasma derivatives 
during the period starting 90 days before the administration of first dose of study 
interventions or planned administration during the study period. 
• 
Chronic administration (defined as more than 14 consecutive days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 
90 days prior to the first study intervention dose or planned administration during the 
study period. For corticosteroids, this will mean prednisone ≥20 mg/day, or 
equivalent. Inhaled and topical steroids are allowed. 
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). 
Note: European Economic Community (EEC) directive 93/42/EEC defines an 
invasive medical device as ‘A device which, in whole or in part, penetrates inside the 
body, either through a body orifice or through the surface of the body’. 
5.2.4. 
Other exclusions 
• 
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 conduct that prohibits participation until study end. 
• 
Participation of any study personnel or their immediate dependents, family, or 
household members. 
5.3. 
Lifestyle considerations 
This section is not applicable. 
5.4. 
Screening failures 
This section is not applicable. 
5.5. 
Criteria for temporarily delaying enrollment/study 
intervention administration 
Enrollment/randomization/study intervention administration may be postponed within the 
permitted time interval until transient conditions cited below are resolved: 
• 
Acute disease and/or fever at the time of study intervention administration. Refer to 
Section 1.3 (SoA) for definition of fever and location for measuring temperature in 
this study. 

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• 
Participants with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be dosed at the discretion of the investigator. 
• 
Participants with symptoms suggestive of active Coronavirus Disease 2019 
(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 vaccinated at least 
14 days after the exposure, provided that the participant remains symptom-free, and 
at the discretion of the investigator. 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Refer to the Glossary of terms for the definition of study intervention. 
6.1. 
Study interventions administered 
Table 7 
Study interventions administered 
Study Intervention 
Name: 
RSVPreF3 OA Investigational 
Vaccine 
FLU aQIV (adjuvanted quadrivalent 
influenza vaccine)** 
Formulation: 
RSVPreF3 
(120 μg) 
AS01E: QS-21* (25 μg), 
MPL (25 μg), 
liposomes; Water for 
injections 
A/(H1N1) (15 μg HA)***; A/(H3N2) (15 μg 
HA)***; B/(Victoria Lineage) (15 μg HA)***; 
B/(Yamagata Lineage) (μg HA)***; adjuvanted 
with MF59C.1 (Squalene (9.75 mg), 
Polysorbate 80 (1.175 mg), Sorbitan trioleate 
(1.175 mg)); Water for injections 
Presentation: 
Vial; powder for 
suspension for 
injection 
Vial; suspension for 
suspension for 
injection 
Syringe: Suspension for injection 
Product category: 
Biologic 
Biologic 
Route of 
administration: 
Intramuscular 
Intramuscular 
Administration site: 
  Location 
Deltoid 
Deltoid 
  Directionality 
Upper 
Upper 
  Laterality 
Non-dominant 
Co-Ad group: Dominant 
Control group: Non-dominant 
No of Doses: 
1 
1 
Dose Volume: 
0.5 mL 
0.5 mL 
Packaging, labeling & 
TM: 
Refer to the SPM for more details 
Manufacturer: 
GSK 
Seqirus, Inc. 
AS01E = Adjuvant System 01; Co-Ad = co-administration; HA = Hemagglutinin; MPL = monophosphoryl lipid A; QS-21 
= Quillaja saponaria Molina, fraction 21; RSVPreF3 OA = respiratory syncytial virus PreFusion protein 3 older adult; 
SPM = Study Procedures Manual 
*Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation. 
**FLU aQIV (adjuvanted quadrivalent influenza vaccine) is marketed by Seqirus as Fluad Tetra, FLUAD 
QUADRIVALENT and Fluad Quad  
***The vaccine strains recommended by the World Health Organization for the 2022/2023 northern hemisphere 
influenza season are:  an A/Victoria/2570/2019 (H1N1)pdm09-like virus, an A/Darwin/9/2021 (H3N2)-like virus, a 
B/Austria/1359417/2021 (B/Victoria lineage)-like virus and a B/Phuket/3073/2013 (B/Yamagata lineage)-like virus. 
 Refer to the Study Procedures Manual for the volume after reconstitution. 

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Study participants must be observed closely for at least 30 minutes after the 
administration of the study interventions. Appropriate medical treatment must be readily 
available during the observation period in case of anaphylaxis or syncope. 
6.2. 
Preparation, handling, storage, and accountability 
The study interventions 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. 
Only authorized study personnel should be allowed access to the study interventions. 
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 interventions. 
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 
Approximately 1028 eligible participants will be randomly (1:1) assigned to the 2 study 
groups using a centralized randomization system on internet (Source data Base for 
Internet Randomization [SBIR]) at Visit 1 (Day 1).  
The randomization of supplies within blocks will be performed at GSK, using MATerial 
Excellence (MatEx), a program developed for use in Statistical Analysis System (SAS) 
(Cary, NC, 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 thus to 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 randomization algorithm will use a 
minimization procedure accounting for age (65-69, 70-79 or ≥80 years) and center. 
Minimization factors will have equal weight in the minimization algorithm. Refer to 
Section 4.1.2 for 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 

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first dose. The study intervention numbers to be used for subsequent dosing will be 
provided by the same automated Internet-based system (SBIR). 
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. 
6.3.4. 
Allocation of participants to assay subset 
The assay subset included in this study is described in Table 8. 
Table 8 
Allocation of participants to assay subset 
; RSV = respiratory syncytial virus   
6.3.5. 
Blinding and unblinding (Amended: 13 December 2022) 
This is an open-label study because of the difference in dosing schedules between the 
study groups. Codes will be used to link the participant and study to each sample. The 
laboratory in charge of the serum sample testing will be blinded to the intervention 
assignment. Codes will be used to link the participant and study (without any link to 
the intervention attributed to the participant) to each serum sample. 
 
 
  
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 each study intervention dose will be recorded in the source documents. 
6.5. 
Dose modification 
This section is not applicable. 
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6.6. 
Continued access to study intervention after the end of the 
study 
During the study conclusion contact, the investigator will ask each participant if they are 
interested in participating to join a booster study/long-term study. If a participant is not 
interested in joining the booster study/long-term study, the reason for refusal will be 
documented, when available, in the participant’s eCRF. 
There is no plan to provide continued access to the study intervention following the end 
of the study. 
6.7. 
Treatment of overdose 
This section is not applicable. 
6.8. 
Concomitant therapy 
At each study visit/contact, the investigator or his/her delegate 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 medications and vaccinations, except vitamins and dietary 
supplements, administered during the 30-day period following each dose of study 
intervention. 
• 
All concomitant medication leading to discontinuation of the study intervention or 
elimination from the analysis, including products/vaccines. Please refer to the 
Sections 5.2.2 and 9.2.1 for further details. 
• 
All concomitant medication which may explain/cause/be used to treat a serious 
adverse event (SAE)/pIMD including vaccines/products, as defined in Sections 8.3.1 
and 10.3.7. These must also be recorded in the Expedited Adverse Event report. 
• 
Any prophylactic medication (e.g., analgesics, antipyretics) administered on the day 
of study vaccination (Day 1 in the Co-Ad group, Day 1 and Day 31 in the Control 
group) in the absence of ANY symptom and in anticipation of a reaction to the 
vaccination. 
Refer to Table 9 (Co-Ad group) and Table 10 (Control group) for an overview of the 
reporting timeframe for concomitant medication during the study. 
The Local Medical Lead (LML) should be contacted if there are any questions regarding 
concomitant or prior therapy. 

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Table 9 
Reporting timeframe for concomitant medication for the Co-Ad 
group  
 
Visit 1 
 
Visit 2 
Contact 1 
Day 1 
Day 30 
Day 31 
Month 6 
All concomitant medications and 
vaccinations, except vitamins and 
dietary supplements 
 
 
 
 
 
 
 
 
 
 
 
 
All concomitant medication leading to 
discontinuation of the study 
intervention or elimination from the 
analysis, including products/vaccines 
 
 
 
 
 
 
 
 
 
 
 
 
All concomitant medication which may 
explain/cause/be used to treat a 
serious adverse event (SAE)/pIMD 
including vaccines/products 
 
 
 
 
 
 
 
 
 
 
 
 
Any prophylactic medication  
 
 
 
 
 
 
 
 
 
 
 
 
Grey shading indicates applicable timeframe for reporting of concomitant medication 
Co-Ad = co-administration 
Table 10 
Reporting timeframe for concomitant medication for the Control 
Group 
Event 
Visit 1 
 
Visit 2 
 
Visit 4  
Contact 1 
Day 1 
Day 30 
Day 31 
Day 60 
Day 61 
Month 7 
All concomitant medications and 
vaccinations, except vitamins and 
dietary supplements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All concomitant medication leading to 
discontinuation of the study 
intervention or elimination from the 
analysis, including products/vaccines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All concomitant medication which may 
explain/cause/be used to treat a 
serious adverse event (SAE)/pIMD 
including vaccines/products 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any prophylactic medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grey shading indicates applicable timeframe for reporting of concomitant medication 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
‘Discontinuation’ of study intervention refers to any participant who has not received all 
planned doses of study intervention. A participant who discontinued study intervention 
may continue other study procedures (e.g., safety or immunogenicity), planned in the 
study protocol at the discretion of the investigator. 
The primary reason for premature discontinuation of the study intervention will be 
documented on the eCRF as follows: 
• 
AE requiring expedited reporting to GSK. 
• 
Unsolicited non-serious AE. 
• 
Solicited AE. 
• 
Not willing to be vaccinated. 
• 
Other (specify). 
7.1.1. 
Contraindications to subsequent study intervention(s) 
administration 
The eligibility of participants in the Control group for subsequent study intervention 
administration must be confirmed before administering the RSV investigational vaccine 
at Visit 2. 
Participants who meet any of the criteria listed below or criteria listed in Sections 5.2.1 
and 5.2.2 should not receive additional doses of study intervention. Such participants 
should be encouraged to continue other study procedures, at the investigator’s discretion 
(Section 10.3.7.2). All relevant criteria for discontinuation of study intervention 
administration must be recorded in the eCRF. 
• 
Participants who experience any SAE judged to be possibly or probably related to 
study intervention (FLU vaccine administered at Visit 1) and that, in the opinion of 
the investigator, may pose additional risk to the participant if he/she receives the 
second study intervention (RSV investigational vaccine). 
• 
Participants who develop any new condition that, in the opinion of the investigator, 
may pose additional risk to the participant if he/she continues to participate in the 
study. 
• 
Anaphylaxis following the administration of study intervention(s) from Visit 1 
onwards. 
• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 

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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 him/her 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: 
• 
AE requiring expedited reporting to GSK. Please refer to the section 10.3.9.1 for the 
details. 
• 
Unsolicited non-serious AE. 
• 
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 he/she 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 until the event 
is resolved (see Section 10.3.7.2). 
7.3. 
Lost to follow-up 
A participant will be considered ‘lost to follow-up’ if he/she fails 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. 

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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 the participant(s) should discontinue the study intervention. 
Study procedures and their timing are summarized in the SoA (Section 1.3). 
The SPM provides the investigator and site personnel with detailed administrative and 
technical information that does not impact participant safety. 
If local regulations allow and quality of study procedures is maintained, participants can 
be offered remote visits (e.g., telemedicine, home visits) for the collection of biological 
samples and/or safety data/safety assessment(s). These remote visits must be performed 
by qualified study staff/healthcare professionals (HCPs). Refer to the SoA (Section 1.3) 
for the timing of these visits. Details of how these visits will be conducted are outlined in 
the SPM. 
Following procedures can be performed remotely/virtually (refer to the Glossary of terms 
for the definitions of telemedicine, remote and virtual visits): 
• 
Safety follow-up may be performed by telemedicine which will use secure video 
conferences, phone calls, and a web portal and/or mobile application (or eDiary) as a 
way of communicating with the participant and monitoring the participant’s 
progress. In addition, qualified study staff/HCPs may also identify AEs and report 
them to the investigator for evaluation.  
• 
Biological samples may be collected remotely by qualified study staff/HCPs. 
Biological samples should be collected only if they can be processed in a timely 
manner and appropriately stored until the intended use. 
 
 
 
• 
In exceptional situations (e.g., pandemic), the following approach may be 
considered: 
− 
If despite best efforts it is not possible to administer the dose of study 
intervention as defined in the protocol (see Table 3 and Table 4), additional 30 
days may be added to the Visit 2 interval (only for RSV investigational vaccine 
administration in the Control group). 
Impact on the per protocol set for immunogenicity will be determined on a case-by-case 
basis. 
For information on the role of a caregiver in study assessments and procedures, please 
refer to Section 4.1.3. 
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8.1. 
Immunogenicity assessments 
Biological samples 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 the participant’s 
consent. These additional requirements must be formally communicated to, discussed, 
and agreed with GSK. 
8.1.1. 
Biological samples 
Table 11 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Group* 
Blood for humoral response 
~10 
mL 
Visit 1 (Day 1) 
Visit 2 (Day 31) 
All participants in the  
Co-Ad group  
Blood for humoral response 
~10 
mL 
Visit 1 (Day 1) 
Visit 2 (Day 31) 
Visit 4 (Day 61) 
All participants in the 
Control group 
; Co-Ad = co-administration; HI = hemagglutination inhibition; RSV = respiratory syncytial  
virus 
*Refer to Section 6.3.4 for subset description. 
The approximate volume of blood that will be collected per participant during the entire 
study period is as follows: 
• 
Co-Ad group: 2 x ~10 mL = ~20 mL. 
• 
Control group: 3 x ~10 mL = ~30 mL. 
• 
 
 
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8.1.2. 
Laboratory assays 
All laboratory testing will be performed at a GSK laboratory or in a laboratory designated 
by GSK. 
Table 12 
Laboratory assays 
Assay type 
System 
Component 
Challenge 
Method 
Laboratory 
Humoral 
immunity 
(antibody 
determination) 
Serum 
RSV-A antibody 
 
Neutralization 
GSK* 
RSV-B antibody 
Neutralization 
H1N1 strain equivalent to vaccine 
strain (hemagglutinin antibody) 
HI 
H3N2 strain equivalent to vaccine 
strain (hemagglutinin antibody) 
B/Yamagata strain equivalent to 
vaccine strain (hemagglutinin 
antibody) 
B/Victoria strain equivalent to 
vaccine strain (Hemagglutinin 
antibody) 
HI = hemagglutination inhibition; ICS = intracellular cytokine staining; 
; 
RSV = respiratory syncytial virus 
*GSK laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. CLS may 
delegate testing to a contracted third party. 
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 
Table 13 
Immunological read-outs 
Blood sampling timepoint 
Subset tested 
N of 
participants 
Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Humoral immunity (on serum samples) 
Co-Ad group 
 
 
 
 
Visit 1 (Day 1) 
Pre-dose 1 
All participants  
~514 
RSV-A neutralizing antibody 
All participants 
~514 
RSV-B neutralizing antibody  
 
 
All participants  
~514 
H1N1 strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
 
 
All participants  
~514 
H3N2 strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
 
 
All participants  
~514 
B/Yamagata strain equivalent to vaccine 
strain (Hemagglutinin antibody) 
 
 
All participants  
~514 
B/Victoria strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
Visit 2 (Day 31) 
Post-dose 1  
All participants  
~514 
RSV-A neutralizing antibody 
 
 
All participants 
~514 
RSV-B neutralizing antibody  
 
 
All participants  
~514 
H1N1 strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
 
 
All participants  
~514 
H3N2 strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
 
 
All participants  
~514 
B/Yamagata strain equivalent to vaccine 
strain (Hemagglutinin antibody) 
 
 
All participants  
~514 
B/Victoria strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
Control group 
 
 
 
 
Visit 1 (Day 1) 
Pre-FLU dose 
All participants  
~514 
H1N1 strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
 
 
All participants  
~514 
H3N2 strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
 
 
All participants  
~514 
B/Yamagata strain equivalent to vaccine 
strain (Hemagglutinin antibody) 
 
 
All participants  
~514 
B/Victoria strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
Visit 2 (Day 31) 
Post-FLU dose 
All participants  
~514 
H1N1 strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
 
 
All participants  
~514 
H3N2 strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
 
 
All participants  
~514 
B/Yamagata strain equivalent to vaccine 
strain (Hemagglutinin antibody) 
 
 
All participants  
~514 
B/Victoria strain equivalent to vaccine strain 
(Hemagglutinin antibody) 
 
Pre-RSV dose 
All participants  
~514 
RSV-A neutralizing antibody 
 
 
All participants 
~514 
RSV-B neutralizing antibody  
Visit 4 (Day 61) 
Post-RSV dose 
All participants  
~514 
RSV-A neutralizing antibody 
 
 
All participants 
~514 
RSV-B neutralizing antibody  
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Blood sampling timepoint 
Subset tested 
N of 
participants 
Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Co-Ad = co-administration; N = number; 
; RSV = respiratory syncytial 
virus; Immunological correlates of protection 
8.1.4. 
Immunological correlates of protection 
No generally accepted immunological correlate of protection has been demonstrated for 
the antigens used in the RSVPreF3 OA investigational vaccine or the FLU vaccine. 
Although there is no accepted correlate of protection against influenza, either seasonal or 
pandemic, the protective role of antibodies against hemagglutinin is well established 
[Rimmelzwaan, 2008; Cox, 2013]. The serum hemagglutination inhibition (HI) assay is 
commonly used to measure the humoral response to hemagglutinin. HI titers have been 
shown to correlate with protection from infection in human studies and titers of 1:40 or 
greater have been accepted as a surrogate marker of potential vaccine efficacy by 
regulators [Hannoun, 2004; EMEA, 1997; FDA, 2007]. 
8.2. 
Safety assessments 
The investigator and his/her 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 
interventions. 
8.2.1. 
Pre-intervention administration procedures 
8.2.1.1. 
Collection of demographic data 
Record demographic data such as year of birth, sex, race* and ethnicity* in the 
participant’s eCRF. 
*Differences in the safety and efficacy of certain medical products, including vaccines 
[Borchers, 2013; Pérez-Losada , 2009; Kollmann, 2013], have been observed in racially 
and ethnically distinct subgroups. These differences may be attributable to intrinsic 
factors (e.g., genetics, metabolism, elimination), extrinsic factors (e.g., diet, 
environmental exposure, sociocultural issues), or interactions between these factors. 
Therefore, both geographic ancestry (race) and ethnicity will be collected for all study 
participants. 
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8.2.1.2. 
Medical/vaccination history 
Obtain the participant’s medical/vaccination 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 study 
intervention in the eCRF. 
Any vaccine administered up to 1 year before study vaccine administration should be 
recorded in the eCRF with date of vaccination. Any flu vaccine administered up to 3 
years before study intervention should be recorded with the date of vaccination and 
information about the vaccine formulation (e.g., adjuvanted or non-adjuvanted or high 
dose). 
8.2.1.3. 
History-directed physical examination/physical examination 
• 
History-directed physical examination will be performed for each participant. 
• 
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 Section 5.5 for the list of criteria for temporary delay of study 
intervention administration. 
• 
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health-care provider. 
8.2.1.4. 
Warnings and precautions to administration of study intervention 
Warnings and precautions to administration of study intervention must be checked at 
each visit with planned administration of study intervention. 
8.2.1.5. 
Pre-vaccination body temperature 
The body temperature of each participant needs to be measured prior to any study 
intervention administration and recorded in the eCRF. The route for measuring 
temperature can be oral or axillary. If the participant has fever (fever is defined as 
temperature ≥38.0°C regardless the location of measurement) on the day of vaccination, 
the vaccination visit will be rescheduled within the allowed interval for this visit (refer to 
Table 3 and Table 4). 
8.2.2. 
Post-vaccination procedures 
8.2.2.1. 
Safety contact at 6 months post-last vaccination 
Six months after the last dose of study intervention (i.e., Month 6 for participants in the 
Co-Ad group and Month 7 for participants of the Control group), each participant should 
be contacted to check if he/she has experienced any SAEs or pIMDs since the last study 

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intervention administration, and to collect information on concomitant 
medications/vaccinations. 
Multiple formats can be proposed by the site staff to organize these contacts. This contact 
may be done via email, text message, fax, or phone call, for example. The most 
appropriate format should be agreed between site staff and the study participant. 
Text messages, email and fax may be used as a screening to check if the participant has 
anything to report. If the participant answers "Yes" for at least one of the items of 
interest, a phone call must be done to get the details on the event(s). 
Data collected via phone calls and text messages will have to be recorded in source 
documents. E-mails and faxes can be archived in source documents. Receipt of the 
message must be confirmed by the participant or caregiver, as applicable. 
8.3. 
AEs, SAEs and other safety reporting 
8.3.1. 
Time period and frequency for collecting AE, SAE, and other 
safety information 
An overview of the protocol required reporting periods for AE, SAEs and pIMDs is given 
in Table 14 (Co-Ad group) and Table 15 (Control group). 
Table 14 
Timeframes for collection and reporting of safety information for the 
Co-Ad group 
Event 
Visit 1 
Visit 1 
 
 
Visit 2 
Contact 1 
Day 1 
Day 1 
Day 7 
Day 30 
Day 31 
Month 6** 
Pre- 
Dose* 
RSV + FLU 
vacc. 
 
 
 
Study Conclusion 
Administration site and 
systemic solicited events 
(eDiary) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study 
participation or concurrent 
GSK medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to 
withdrawal from the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intercurrent medical 
conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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AE = adverse event; Co-Ad = co-administration; pIMD = potential immune-mediated disease; SAE = serious adverse 
event; Vacc. = vaccination 
 
shading indicates applicable timeframe for reporting of safety information. 
 
 
shading indicates reporting timeframe applicable if solicited symptoms persist after 7 days. 
*Collection of SAEs related to study participation or GSK medication/vaccines starts as of informed consent (prior to  
study intervention administration). 
**Six months after study interventions co-administration. 
Table 15 
Timeframes for collection and reporting of safety information for the 
Control group 
Event 
Visit 1 Visit 1 
 
 
Visit 2 
 
 
Visit 4  
Contact 1 
Day 1 Day 1 Day 7 
Day 
30 
Day 
31 
Day 
37 
Day 
60 
Day 61 Month 7*** 
Pre- 
Dose* 
FLU 
vacc. 
 
 
RSV 
vacc. 
 
 
 
Study 
Conclusion 
Administration site and 
systemic solicited events 
(eDiary) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study 
participation or concurrent 
GSK medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to 
withdrawal from the 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intercurrent medical 
conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vacc. = vaccination; AE = adverse event; SAE = serious adverse event; pIMD = potential immune-mediated disease 
 
shading indicates applicable timeframe for reporting of safety information. 
 
 
shading indicates reporting timeframe applicable if solicited symptoms persist after 7 days. 
*Collection of SAEs related to study participation or GSK medication/vaccines starts as of informed consent (prior to  
study intervention administration). 
***Six months after study interventions co-administration. 
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 10.3.9. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available. 
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A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting periods defined in Table 14. 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 
he/she 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 17. 
8.3.2. 
Method of detecting AEs and SAEs and other events 
Detection and recording of AE/SAE/pIMD are detailed in Section 10.3.7. 
Assessment of AE/SAE intensity, causality and outcome are described in Section 10.3.8. 
Open-ended and non-leading verbal questioning of participants is the preferred method of 
acquiring information related to an AE/SAE/pIMD. 
8.3.3. 
Regulatory reporting requirements for SAEs and other events 
Once an investigator (or designee) becomes aware that a study participant has 
experienced an SAE/pIMD, it must be reported to GSK using the required 
documentation, and within the timeframes mentioned in Table 16. This is essential for 
meeting GSK legal obligations and ethical responsibilities for participant safety and the 
safety of a study intervention under clinical investigation. 
For SAEs/pIMDs, the investigator must always provide an assessment of causality at the 
time of the initial report, as defined in the Section 10.3.8.2. 
Local regulatory requirements and sponsor policy for preparation of an investigator 
safety report of Suspected Unexpected Serious Adverse Reactions (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, IEC/IRB and investigators. 
Please refer to Section 10.3.9 for further details regarding the reporting of SAEs/pIMDs. 

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Table 16 
Timeframes for submitting SAE 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 AE 
Report 
24 hours* 
electronic Expedited AE Report 
pIMDs 
24 hours**, ‡‡  
electronic Expedited AE 
Report 
24 hours* 
electronic Expedited AE Report 
SAE = serious adverse event; pIMD = potential immune-mediated disease; AE = 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. 
‡‡ The investigator will be required to confirm review of the SAE/pIMD causality within 72 hours of submission of the 
SAE/pIMD. 
8.3.3.1. 
Contact information for reporting SAEs and pIMDs 
Table 17 
Contact information for reporting SAEs and pIMDs 
Study contact for questions regarding SAEs and pIMDs 
Refer to the local study contact information document 
Back up study contact for reporting SAEs and pIMDs 
Available 24/24 hours and 7/7 days: 
 
GSK Clinical Safety & Pharmacovigilance 
Outside US sites: 
US sites only: 
8.3.4. 
Treatment of AE 
Any medication administered for the treatment of an SAE/pIMD should be recorded in 
the Expedited AE Report of the participant’s eCRF screen (refer to Section 10.3.9.1). 
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 his/her possession for the duration of the study. In an 
emergency, this card serves to inform the responsible attending physician/care 
giver/family member that the participant is in a clinical study and that relevant 
information may be obtained by contacting the investigator or his/her back up. 
8.4. 
Pharmacokinetics 
Pharmacokinetics are not evaluated in this study. 
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8.5. 
Genetics 
Genetics are not evaluated in the current study. 
8.6. 
Biomarkers 
Biomarkers are not evaluated in the current study. 
8.7. 
Immunogenicity assessments 
Immunogenicity is described in Section 8.1. 
8.8. 
Health outcomes 
This section is not applicable. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical hypotheses (Amended 13 December 2022) 
Statistical hypotheses are associated with the confirmatory primary NI objectives, 
which will be tested sequentially to control overall Type I error.  
Global type I error is controlled at 2.5% (1-sided). 
The non-inferiority margins associated to each objective are provided in Table 18. 
Table 18 
Study objectives and null hypothesis (Amended: 13 December 2022) 
Objectives 
Null hypothesis 
Primary 
• 
To demonstrate the non-inferiority of the FLU vaccine 
when co-administered with the RSVPreF3 OA 
investigational vaccine compared to the FLU vaccine 
administered alone. 
• 
True Group GMT ratio between the FLU vaccine 
(Control group) divided by the RSVPreF3 OA 
investigational vaccine when co-administered with 
the FLU vaccine (Co-Ad group) in HI antibody 
titers for each of the FLU vaccine strains one 
month after the FLU vaccine dose is above 1.5. 
• 
To demonstrate the non-inferiority of the RSVPreF3 
OA investigational vaccine when co-administered 
with the FLU vaccine compared to the RSVPreF3 OA 
investigational vaccine administered alone. 
• 
True Group GMT ratio between the RSVPreF3 
OA investigational vaccine (Control group) divided 
by the RSVPreF3 OA investigational vaccine 
when co-administered with the FLU vaccine (Co-
Ad group) in RSV-A neutralization antibody titers 
one month after the RSVPreF3 OA investigational 
vaccine dose is above 1.5. 
• 
To demonstrate the non-inferiority of the 
RSVPreF3 OA investigational vaccine when co-
administered with the FLU vaccine compared to 
the RSVPreF3 OA investigational vaccine 
administered alone. 
• 
True Group GMT ratio between the RSVPreF3 
OA investigational vaccine (Control group) 
divided by the RSVPreF3 OA investigational 
vaccine when co-administered with the FLU 
vaccine (Co-Ad group) in RSV-B neutralization 
antibody titers one month after the RSVPreF3 
OA investigational vaccine dose is above 1.5. 
Co-Ad = co-administration; FLU vaccine refers to FLU aQIV; GMT = geometric mean titer; HI = hemagglutination 
inhibition; RSVPreF3 OA = respiratory syncytial virus PreFusion protein 3 older adult 
Statistical testing of each endpoint will be organized sequentially to control overall 
Type I error.  

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9.2. 
Analysis sets 
Table 19 
Analysis sets (Amended: 13 December 2022) 
Analysis set 
Description 
Enrolled 
Participants who were randomized or received study intervention or have 
undergone an invasive procedure. 
Exposed  
All participants who received a study intervention. Analysis per group is based on 
the study intervention administered. 
Per Protocol  
All eligible participants: 
• 
who received at least one study intervention as per protocol in control 
group and all study interventions in the Co-Ad group, 
• 
had immunogenicity results pre- and post-dose, 
• 
complied with blood draw intervals (refer to Table 3 and Table 4) (contribution 
of participants to Per Protocol set at specific timepoint will be defined by 
timepoint), 
• 
without intercurrent medical conditions that may interfere with immunogenicity 
and, 
• 
without prohibited concomitant medication/vaccination. 
9.2.1. 
Criteria for elimination from analysis 
If the participant meets one of the criteria mentioned below or ones listed in the Section 
7.1.1, (contraindication to subsequent vaccination) or 5.2.1 (medical conditions) or 5.2.2 
(concomitant therapy), he/she may be eliminated from per protocol analysis. 
In case of unplanned administration of any medication mentioned in Section 5.2.2 during 
the study, this will be considered as a protocol deviation and the participant may be 
eliminated from the Per Protocol set (PPS). 
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 Statistical Analysis Plan (SAP) will be developed and finalized before First Subject 
First Visit (FSFV). This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. Supportive analyses, safety and demography 
summaries will be described in the SAP. 
9.3.1. 
Primary endpoints/estimands analysis (Amended: 13 December 
2022) 
The primary endpoints/estimands are described in Section 3. The confirmatory analyses 
of non-inferiority will be based on the PPS. 

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• 
Method for non-inferiority of the FLU vaccine in terms of HI GMT ratio for each of 
the FLU vaccine strains at one month after the FLU vaccine dose (i.e., at Day 31 for 
both groups): 
The 2-sided 95% confidence interval (CI) for Group GMT ratio between the FLU 
vaccine administered alone (Control group) over the RSVPreF3 OA investigational 
vaccine when co-administered with the FLU vaccine (Co-Ad group) will be derived 
from an ANCOVA model* on log10 transformed titer. 
• 
Method for non-inferiority of RSV investigational vaccine in terms of RSV-A 
neutralization antibody GMT ratio at one month after the RSVPreF3 OA 
investigational vaccine dose (i.e., at Day 31 for the Co-Ad group and at Day 61 for 
the Control group): 
The 2-sided 95% CI for Group GMT ratio between the RSVPreF3 OA 
investigational vaccine administered alone (Control group) over the RSVPreF3 OA 
investigational vaccine when co-administered with the FLU vaccine (Co-Ad group) 
will be derived from an ANCOVA model* on log10 transformed titer. 
• 
Method for non-inferiority of RSV investigational vaccine in terms of RSV-B 
neutralization antibody GMT ratio at 1 month after the RSVPreF3 OA 
investigational vaccine dose (i.e., at Day 31 for the Co-Ad group and at Day 61 for 
the Control group). 
The 2-sided 95% CI for Group GMT ratio between the RSVPreF3 OA 
investigational vaccine administered alone (Control group) over the RSVPreF3 
OA investigational vaccine when co-administered with the FLU vaccine (Co-Ad 
group) will be derived from an ANCOVA model* on log10 transformed titer. 
*The model will include the treatment group and age category (age at vaccination: 65-
69, 70-79 or ≥80 years) as fixed effects, and the pre-dose log10-transformed titer as 
covariate. Missing data will not be replaced. Titers below the assay cut-off will be 
replaced by half the assay cut-off; titers above the upper limit of quantification (ULOQ) 
will be replaced by the ULOQ. 
Success criteria for non-inferiority and testing sequence: 
The following testing sequence will be used: 
• 
Sequence 1: 
− 
The upper limit (UL) of the 2-sided 95% CI on the Group GMT ratio (Control 
group divided by Co-Ad group) for each of the FLU vaccine strains are ≤ 1.5. 
 AND 
− 
The UL of the 2-sided 95% CI on the Group GMT ratio (Control group divided 
by Co-Ad group) for RSV-A neutralizing antibody is ≤ 1.5. 
• 
Sequence 2: 
− 
The UL of the 2-sided 95% CI on the Group GMT ratio (Control group 
divided by Co-Ad group) for RSV-B neutralizing antibody is ≤ 1.5 

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Testing will progress in sequence 2 only if the sequence 1 is a success, so that no 
further adjustment of alpha is required. 
9.3.2. 
Secondary endpoints/estimands analyses 
• 
Method for evaluation of non-inferiority of the FLU vaccine in terms of HI 
seroconversion rate (SCR) for each of the FLU vaccine strains at one month after the 
FLU vaccine dose (i.e., at Day 31 for both groups): 
− 
The 2-sided 95% CI on group difference in SCR (Control group minus Co-Ad 
group) will be computed based on the method of Miettinen and Nurminen 
[Miettinen, 1985]. 
− 
Reference criteria for evaluation of non-inferiority: 
The UL of the 2-sided 95% CI on the group difference (Control group minus 
Co-Ad group) in SCR is ≤10% for anti-HI antibodies. 
• 
The other secondary endpoints are described in Section 3. Descriptive analyses of 
demography, immunogenicity, and safety will be detailed in the SAP. 
Table 20 
Definitions of SCR, SPR and MGI 
Abbreviation/Term 
Definition 
HI SCR 
The percentage of vaccinees who have either a HI pre-dose titer < 1:10 and a post-dose 
titer ≥1:40 or a pre-dose titer ≥1:10 and at least a 4-fold increase in post-dose titer. 
HI SPR 
The percentage of vaccinees with a serum HI titer ≥1:40 that usually is accepted as 
indicating protection. 
MGI 
The geometric mean of the within-participant ratios of the post-dose titer over the pre-
dose titer. 
HI = hemagglutination inhibition; SCR = seroconversion rate; SPR = seroprotection rate; MGI = mean geometric 
increase 
• 
Additionally, the Center for Biologics Evaluation and Research (CBER) and 
Committee for Medicinal Products for Human Use (CHMP) criteria for HI SPR and 
SCR will be assessed as follows: 
CBER’s criteria: 
− 
The lower limit (LL) of the 95% CI for SCR should be ≥30% in participants 
≥65 YOA. 
− 
The LL of the 95% CI for SPR should be ≥60% in participants ≥65 YOA. 
CHMP’s criteria: 
At least one of the 3 following criteria should be met: 
− 
The point estimates of SPR > 60%, SCR > 30%, and MGI > 2.0 for elderly 
≥60 YOA for each of the antigen strains. 

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9.4. 
Interim analyses 
9.4.1. 
Sequence of analyses 
The analyses will be performed stepwise: 
A final analysis will be conducted once all immunogenicity data (as clean as possible) are 
available for the primary and secondary endpoints. This final analysis will include 
immunogenicity and safety data up to Visit 2/Day 31 (Co-Ad group) or Visit 4/Day 61 
(Control group). Participants who undergo Visit 2, Visit 3, or Visit 4 assessments out of 
the allowed visit interval (see Table 3 and Table 4) may be excluded from the final 
analysis.  
• 
An EoS analysis with all data (including data obtained until 6 months post-last dose) 
will be performed. 
9.4.2. 
Statistical considerations for interim analysis 
This section is not applicable. 
9.5. 
Sample size determination 
The target enrollment will be 1028 participants (514 in the group receiving the 
RSVPreF3 OA investigational vaccine co-administered with FLU aQIV [Co-Ad group] 
and 514 in the Control group where RSVPreF3 OA investigational vaccine and FLU 
aQIV are administered in a sequential manner). This allows to obtain at least 924 
evaluable participants (462 in the Co-Ad group and 462 in the Control group) for the 
evaluation of the primary objectives, assuming that 10% of the enrolled participants will 
not be evaluable. 
Participants who withdraw from the study will not be replaced. 
Each objective will be evaluated with a nominal type I error of 2.5%. 

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Table 21 
Overall power to demonstrate primary objectives: non-inferiority of 
the immunogenicity of the RSVPreF3 OA investigational vaccine 
when co-administered with FLU aQIV compared to when 
administered alone – assuming approximately 462 participants are 
available in each group (Amended: 13 December 2022) 
Endpoint  
Standard 
deviation of 
log10 
concentration 
Reference 
ratio 
Non 
inferiority 
margin 
Type II 
error 
Power 
FLU non-inferiority* (1-sided test with alpha=2.5%)  
GMTs HI H1N1 strain 
0.6 
1.05 
1.5 
2.5% 
97.5% 
GMTs HI H3N2 strain 
0.6 
1.05 
1.5 
2.5% 
97.5% 
GMTs HI B/Yamagata 
0.6 
1.05 
1.5 
2.5% 
97.5% 
GMTs HI B/Victoria strain 
0.6 
1.05 
1.5 
2.5% 
97.5% 
RSV-A non-inferiority* (1-sided test with alpha = 2.5%) 
GMTs RSV-A 
neutralization antibody 
0.45 
1.05 
1.5 
0.1% 
99.9% 
RSV-B Non-inferiority* (1-sided test with alpha = 2.5%) 
GMTs RSV-B 
neutralization antibody 
0.45 
1.05 
1.5 
0.1% 
99.9% 
Global Type II error to show non-inferiority 
~10.0% 
 
Global power 
~90.0% 
GMT = geometric mean titer; HI = hemagglutination inhibition; RSV = respiratory syncytial virus 
*Pass 2019 alpha = 2.5%, Two-Sample T-Tests for Non-Inferiority Assuming Equal Variance and Equal mean 
For RSV: non-inferiority limit = 0.176 (=log10[1.5]). 
For each Flu vaccine strain: non-inferiority limit = 0.176 (=log10[1.5]). 
Reference Ratio= 0.0212 (=log10[1.05]) 
Considering a potential slight interference of 1.05 in true GMTs in both groups with a 
common population standard error of 0.45 for the RSV-A and RSV-B neutralization 
antibodies and 0.6 for each of the FLU strains in log10 transformed concentration, the 
study has at least 90.0% power to meet the primary objectives. 
Nominal powers to evaluate the secondary objective 
The nominal power to evaluate the non-inferiority on SCR for each of the FLU strains is 
above 86%, depending on the plausible rates. 

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Table 22 
Evaluation of non-inferiority in terms of HI antibody SCR when FLU 
aQIV is co-administered with the RSVPreF3 OA investigational 
vaccine compared to FLU aQIV when administered alone assuming 
approximately 462 participants are available in each group for a 
range of plausible SCRs (Amended: 13 December 2022) 
N evaluable 
participants per 
group 
Threshold 
Plausible 
rates in 
Control 
group** 
Type II error 
Nominal Power 
 
FLU vaccine: Non-inferiority* in terms of SCR 
462 
10% 
70% 
8.7% 
91.3% 
462 
10% 
50% 
13.9% 
86.1% 
462 
10% 
35% 
11.0% 
89.0% 
462 
10% 
25% 
6.1% 
93.9% 
SCR = Seroconversion Rate. 
*Pass 2019 alpha = 2.5%, for SCR – Non-inferiority: Proportions – Two independent Proportions – Non-Inferiority Tests 
for the Difference Between Two Proportions.  
** SCR observed in the Control group in Zoster-004 study range from 35.3% to 60.9%. 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
− 
Applicable International Council on Harmonization (ICH) Good Clinical 
Practice (GCP) Guidelines. 
− 
Applicable laws and regulations. 
• 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IEC/IRB by the investigator for review and 
approval. These documents will be signed and dated by the investigator before the 
study is initiated. 
• 
Any protocol amendments will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• 
The investigator will be responsible for the following: 

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− 
Providing written summaries of the status of the study to the IEC/IRB annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IEC/IRB. 
− 
Notifying the IEC/IRB of SAE(s) or other significant safety findings as required 
by IEC/IRB procedures. 
− 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IEC/IRB, 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 or his/her representative 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 and participant informed assent, as appropriate, prior to participation in the 
study. 
The content of the informed consent form (ICF) must meet the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable, and the IEC/IRB 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. 
10.1.4. 
Data protection 
Participants will be assigned a unique identifier by the sponsor. 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. 

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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: 
• 
His/her personal study-related data will be used by the sponsor in accordance with 
local data protection law. 
• 
His/her medical records may be examined by Clinical Quality Assurance auditors or 
other authorized personnel appointed by the sponsor, by appropriate IEC/IRB 
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 
initiating the study in that country. This includes IECs/IRBs for review and approval of 
the protocol and subsequent amendments, ICF and any other documentation. 
Safety oversight will be provided by an 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. 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 

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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 document). 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, IEC/IRB 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. 
Quality tolerance limits (QTLs) will be pre-defined in the state location(s) to identify 
systematic issues that can impact participant safety and/or the reliability of study results. 
These pre-defined parameters will be monitored during the study. Important deviations 

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from the QTLs and remedial actions taken will be summarized in the Clinical Study 
Report (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 
First act of recruitment 
The start of study is defined as FSFV at a country-level. 
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: 

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• 
Failure of the investigator to comply with the protocol, the requirements of the 
IEC/IRB or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
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 International Committee of Medical Journal Editors 
(ICMJE). 
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. 
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 Vero cells culture 
(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 (HRP), 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 titer is expressed in Estimated Dilution 60 (ED60) 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]. For the testing of Phase III studies, secondary standards 
calibrated against the international reference [NIBSC 16/284; McDonald, 2018; 

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McDonald, 2020] will be included in every run to allow conversion into international 
units. 
Hemagglutination inhibition assay 
HI antibody titers are determined using the method derived from the WHO Manual on 
Animal Influenza Diagnosis and Surveillance, WHO/CDS/CSR/NCS/2002.5. 
Measurements are conducted on thawed frozen serum samples with a standardized and 
comprehensively validated micro method using 4 hemagglutinating units (4 HAU) of the 
appropriate antigens and a 0.45% fowl erythrocyte suspension. Non-specific serum 
inhibitors are removed by heat treatment and receptor-destroying enzymes. 
Starting with an initial dilution of 1:10, a dilution series (by a factor of 2) is prepared up 
to an end dilution of 1:10 240. The titration endpoint is taken as the highest dilution step 
that shows complete inhibition of hemagglutination. All assays are performed in 
triplicate, and the final titer corresponds to the GMT of the 3 values. The usual cut-off 
value is = 10 1/DIL. 
 
 
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10.3. 
Appendix 3: Adverse events – 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. 
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. 
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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. 
10.3.2. 
Definition of an SAE (Amended: 13 December 2022) 
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. 

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f. 
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 
one 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. 
10.3.3. 
Solicited events 
a. Solicited administration site events 
The following administration site events will be solicited: 
Table 23 
Solicited administration site events 
Pain  
Erythema/Redness  
Swelling  
b. Solicited systemic events 
The following systemic events will be solicited: 
Table 24 
Solicited systemic events 
Fever  
Headache 
Fatigue 
Myalgia 
Arthralgia 
Note: participants will be instructed to measure and record the oral or axillary 
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 
electronic diary. 
10.3.4. 
Unsolicited adverse events 
An unsolicited adverse event is an adverse event that was not included in a list of 
solicited events using a Participant Diary. Unsolicited events must have been 
spontaneously 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 

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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. 
10.3.5. 
Adverse events of special interest (AESIs) 
pIMDs are the only AESIs collected during this study. 
10.3.5.1. 
Potential immune-mediated diseases 
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 
Table 25. Please refer to the Section 10.3.7.1 for reporting details. 
The investigator must exercise his/her 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 25 
List of potential immune-mediated diseases (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 

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Medical concept 
Additional notes 
Idiopathic pulmonary fibrosis 
Including but not limited to: 
• 
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 
• 
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 

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Medical concept 
Additional notes 
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 
other inflammatory 
demyelinating variants  
Includes the following: 
• 
Acute necrotizing myelitis 
• 
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) 

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Additional notes 
• 
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 
• 
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 
 
Reactive granulomatous 
dermatitis  
Including but not limited to 
• 
Interstitial granulomatous dermatitis 
• 
Palisaded neutrophilic granulomatous dermatitis 
Lichen planus 
• 
Includes liquen planopilaris 
Localized Scleroderma 
(Morphoea) 
• 
Includes Eosinophilic fasciitis (also called Shulman syndrome) 
Psoriasis 
 
Pyoderma gangrenosum 
 
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 

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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) 
• 
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 
 
10.3.6. 
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 Sections 10.3.1 and 
10.3.2). 
The investigator must exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding, or other abnormal assessment is clinically 
significant. 

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10.3.7. 
Recording and follow-up of AEs, SAEs, and pIMDs 
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 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 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 instead of individual signs/symptoms. 
An eDiary will be used in this study to capture solicited administration site or systemic 
events:  
The participant should be trained on how and when to complete the eDiary. Anyone who 
measures administration site or systemic events and who will record the event in the 
eDiary should be trained on using the eDiary. This training must be documented in the 
participant’s source record. If any individual other than the participant is making entries 
into the eDiary, their identity should be documented in the participant’s source records. 
Data on solicited events reported in the eDiary will be electronically transferred to the 
eDiary vendor, where it can be monitored by appropriately qualified site staff and 
sponsor staff through a web-based portal. Appropriately qualified site staff should 
monitor eDiary data online at frequent intervals for subject compliance and reported 
events that were of concern to the subject. 
Completion of the eDiary should be verified during discussions with the participant at 
Visit 2 (all participants) and Visit 4 (only participants in the Control group). 
Refer to the SPM for more information regarding the use of eDiary. 
10.3.7.1. 
Time period for collecting and recording AEs, SAEs and pIMDs 
All solicited events that occur during the 7 days following administration of each dose of 
study intervention (Day of study intervention administration and the 6 following days) 
must be recorded in the eDiary, irrespective of intensity. For solicited events that are still 
ongoing between Day 8 and Day 30, participants will also be instructed to record these in 
the eDiary, irrespective of intensity. 

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All unsolicited AEs that occur during the 30 days following administration of the study 
interventions (Day of study intervention administration and 29 following days) must be 
recorded into the appropriate section of the eCRF, irrespective of their intensity. 
The time period for collecting and recording SAEs and pIMDs will begin at the first 
receipt of study interventions and will end 6 months after the last administration of the 
study interventions. 
All AEs/SAEs leading to withdrawal from the study 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. 
10.3.7.2. 
Follow-up of AEs, SAEs and pIMDs 
After the initial AE/SAE and pIMDs or any other event of interest, the investigator is 
required to proactively follow each participant at subsequent visits/contacts. All SAEs 
and pIMDs will be followed until the event is resolved, stabilized, otherwise explained, 
or the participant is lost to follow-up. 
10.3.7.2.1. Follow-up during the study 
AEs (serious or non-serious) or pIMDs 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. 
10.3.7.2.2. 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 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. 
10.3.7.3. 
Updating of SAE and pIMD information after removal of write access to 
the participant’s eCRF 
When additional SAE or pIMD 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 VCSP department within the defined reporting timeframes specified in 
the Table 16). 

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10.3.8. 
Assessment of intensity and toxicity 
10.3.8.1. 
Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 
Table 26 
Intensity scales for solicited events (Amended: 13 December 2022) 
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 
Headache 
0 
None 
 
1 
Mild: Headache that is easily tolerated 
 
2 
Moderate: Headache that interferes with normal activity 
 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
None 
 
1 
Mild: Fatigue that is easily tolerated 
 
2 
Moderate: Fatigue that interferes with normal activity 
 
3 
Severe: Fatigue that prevents normal activity 
Myalgia 
0 
None 
 
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 
0 
None 
 
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 Section 1.3 (SoA) for the definition of fever and the preferred location for temperature measurement. 
The maximum intensity of local injection site erythema/swelling and fever will be scored 
at GSK as follows: 
 
Erythema/swelling 
Fever 
0: 
≤ 20 mm 
< 38.0°C 
1: 
> 20 - ≤ 50 mm 
≥ 38.0°C - ≤ 38.5°C 
2: 
> 50 - ≤ 100 mm 
> 38.5°C - ≤ 39.0°C 
3: 
> 100 mm 
> 39.0°C 
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 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. 
10.3.8.2. 
Assessment of causality 
The investigator must assess the relationship between study intervention and the 
occurrence of each unsolicited AE/SAE using clinical judgment. Where several different 
interventions were administered, the investigator should specify, when possible, if the 
unsolicited AE/SAE could be causally related to a specific intervention. When a causal 
relationship to a specific study intervention cannot be determined, the investigator should 
indicate the unsolicited AE/SAE to be related to all interventions. 
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 and/or SmPC and/or Prescribing Information for marketed products to assist in 
making his/her assessment. 
Causality should be assessed by the investigator using the following question: 
Is there a reasonable possibility that the unsolicited AE may have been caused by the 
study 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. 

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Possible contributing factors include: 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the 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 one of the criteria used when determining regulatory 
reporting requirements. The investigator may change his/her opinion of causality after 
receiving additional information and update the SAE information accordingly. 
10.3.8.3. 
Medically attended visits 
For each solicited and unsolicited AE the participant experiences, the participant will be 
asked if he/she/the participant 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 eDiary/eCRF, as 
applicable. 
10.3.8.4. 
Assessment of outcomes 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as: 
• 
Recovered/resolved. 
• 
Recovering/resolving. 
• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal (SAEs only). 

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10.3.9. 
Reporting of SAEs and pIMDs 
10.3.9.1. 
Events requiring expedited reporting to GSK 
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. 
Refer to the Table 16 for the details on timeframes for reporting of SAEs/pIMDs. 
The investigator will be required to confirm the review of SAE causality in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE. 
Refer to Section 10.3.9.2 for information on back-up systems in case the electronic 
reporting system does not work. 
10.3.9.2. 
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 
This section is not applicable. 
10.5. 
Appendix 5: Genetics 
This section is not applicable. 

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10.6. 
Appendix 6: Country-specific requirements 
Following information will only be applicable in case France will be selected as 
participating country. 
10.6.1. 
France 
This appendix includes all applicable requirements of French Public Health Code/specific 
local GSK requirements and identifies, item per item, the mandatory modifications or 
additional information to the study protocol. 
10.6.1.1. 
Concerning the «selection of study population and withdrawal criteria» 
The following vulnerable subject populations will be excluded: minors, protected 
subjects, adult subjects not in condition to express their consent, subjects deprived of 
liberty, subjects receiving psychiatric cares, subjects hospitalized in a Health and Social 
Establishment for other purpose than the participation to the study. 
A subject will be eligible for inclusion in this study if he /she is either affiliated to or 
beneficiary of a social security category (French Public Health Code law L.1121-8-1) 
(except for a participant to a non-interventional study or to a participant to an 
interventional study if authorized by the Ethics Committee). 
It is the investigator’s responsibility to ensure and to document (in the source document - 
subject notes) that the subject: 
• 
is either affiliated to or beneficiary of a social security category;  
• 
has got an authorization by the Ethics Committee. 
• 
Subjects will be compensated for the inconvenience of participating in the study. The 
amount of compensation is stated in the ICF. Subjects not completing the study for 
whatever reason could be compensated generally on a pro rata basis. 
• 
According to French Public Health Code law (L.1121-16 and R.1121-16), the 
following people must be registered in National File (“Fichier National”): 
− 
Healthy volunteer. 
− 
Subjects if the aim of the study is not linked to their disease. 
− 
Subjects on request of the Ethics Committee regarding study risks and 
constraints. 
The following details will be described: 
− 
Reference of the study 
− 
Surname and first name 
− 
Date and place of birth 
− 
Gender 

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− 
Dates of beginning and termination of the study 
− 
Exclusion period during which the subject cannot participate to another study 
(French Public Health Code law L.1121-12) 
− 
The total amount of compensation, if any. 
The subjects’ registration in National File (“Fichier National”) should be documented in 
the source document - subject notes and monitored by the CRA. 
10.6.1.2. 
Concerning the “study governance considerations” 
• 
In section “Regulatory and Ethical Considerations, including the Informed 
Consent Process” of study protocol 
− 
Concerning the process for informing the subject and/or his/her legally 
authorized representative, the following text is added:  
− 
French Patient ICF is a document which summarizes the main features of the 
study and allows collection of the subject and/or his/her legally authorized 
representative written consent. It also contains a reference to the authorization of 
ANSM and the approval from the French Ethics Committee. 
− 
Concerning the process for obtaining subject informed consent: 
− 
Concerning the management of the Patient Informed Consent Forms, the 
following text is added: 
French Patient ICF is in duplicate (triplicate for minor subject). 
The first page of the Patient ICF is given to the investigator. The copy is kept by the 
patient or legally authorized representative. 
• 
NOTIFICATION TO THE HOSPITAL DIRECTOR 
In accordance with Article L1123-13 of the French Public Health Code, the Hospital 
Director is informed of the commitment to the trial in her/his establishment. The Hospital 
Director is supplied with the protocol and any information needed for the financial 
disposition, the name of the investigator(s), the number of sites involved in his 
establishment and the estimated time schedule of the trial (R.1123-69). 
• 
INFORMATION TO THE HOSPITAL PHARMACIST 
In accordance with Article R.1123-70 of the French Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in her/his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows her/him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning the 
product(s) of the trial (e.g., included in the IB), the name of the investigator(s), the 
number of sites involved in her/his establishment and the estimated time schedule of the 
trial. 

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• 
Ethnic origin 
In accordance with the data privacy regulation, the ethnic origin, as any personal data, 
can only be collected if the collection of this data is strictly necessary and relevant for the 
purpose of the study. 
• 
TESTING OF BIOLOGICAL SAMPLES 
In accordance with the French Public Health Code law – article L1211-2, a biological 
sample without identified purpose at the time of the sample and subject’s preliminary 
information is not authorized. 
10.6.1.3. 
Concerning the “data management” the following text is added: 
Within the framework of this clinical trial, data regarding the identity of the investigators 
and/or co-investigators and/or the pharmacists if applicable, involved in this clinical trial, 
and data regarding the subjects recruited in this clinical trial (subject number, treatment 
number, subjects status with respect to the clinical trial, dates of visit, medical data) will 
be collected and computerized in GSK data bases by GSK or on its behalf, for reasons of 
follow up, clinical trial management and using the results of said clinical trial. According 
to the data privacy regulation, each of these people aforesaid has a right of access, 
correction, and opposition on their own data through GSK (Clinical Operations 
Department). 
10.6.1.4. 
Concerning data privacy 
In accordance with the applicable data privacy regulation, personal data are processed in 
a manner that ensures appropriate security, including protection against unauthorized or 
unlawful processing and against accidental loss, destruction, or damage, using 
appropriate technical or organizational measures. The processing is whether deemed to be 
compliant with one of the methodology of reference (MR-001) or has been the subject of 
a request for authorization to the CNIL. The Investigator has, regarding the processing 
data related to her/him, a right of access, of rectification, erasure and of opposition with 
GSK in accordance with the legal provisions. 

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10.7. 
Appendix 7: Abbreviations and glossary of terms 
10.7.1. 
List of abbreviations 
AAION 
Arteritic Anterior Ischemic Optic Neuropathy 
ACTM 
Acute Complete Transverse Myelitis 
ADE: 
Adverse Device Effect 
ADE 
Antibody-Dependent Enhancement 
ADEM 
Acute Disseminated Encephalomyelitis  
AE: 
Adverse Event 
AESIs 
Adverse events of special interest 
AHEI 
Acute Hemorrhagic Edema of Infancy 
ALPS 
Autoimmune lymphoproliferative syndrome  
AMSAN 
Acute Motor and Sensory Axonal Neuropathy 
ANCA 
Anti-Neutrophil Cytoplasmic Antibody 
APTM 
Acute Partial Transverse Myelitis 
ARI 
Acute Respiratory Infection 
CBER 
Center for Biologics Evaluation and Research 
CDC 
Centers for Disease Control and Prevention  
CHMP 
Committee for Medicinal Products for Human Use 
CI:  
Confidence Interval 
CIAP 
Chronic Idiopathic Axonal Polyneuropathy 
CIDP 
Chronic Inflammatory Demyelinating Polyradiculoneuropathy 
CIS 
Clinically Isolated Syndrome 
CIOMS 
Council for International Organizations of Medical Sciences  
CLS: 
Clinical Laboratory Sciences 
CCI

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CoP: 
Correlate of Protection 
COVID-19: 
Coronavirus Disease 2019 
CREST 
Calcinosis, Raynaud's Phenomenon, Esophageal Dysmotility, 
Sclerodactyly, and Telangiectasia 
CSR: 
Clinical Study Report 
DRE: 
Disease-related event 
EBA 
Epidermolysis Bullosa Acquisita 
eCRF: 
electronic Case Report Form 
ED60 
Estimated Dilution 60 
eDiary 
Electronic Diary 
EEC 
European Economic Community 
EMA: 
European Medicines Agency 
EoS: 
End of Study 
ERD 
Enhanced Respiratory Disease 
ES:  
Exposed Set 
FDA: 
Food and Drug Administration, United States of America 
FSFV 
First Subject First Visit 
GBS: 
Guillain-Barré Syndrome 
GCP: 
Good Clinical Practice 
GMT: 
Geometric Mean Titer 
GSK: 
GlaxoSmithKline 
HAU 
Hemagglutinating Units 
HCPs 
Healthcare Professionals 
HI: 
Hemagglutination inhibition 
HIPAA 
Health Insurance Portability and Accountability Act 
HRP 
horse-radish peroxidase 

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IAF: 
Informed Assent Form 
IB: 
Investigator’s Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Council on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC: 
Independent Ethics Committee 
IM: 
Intramuscular/Intramuscularly 
IND: 
Investigational New Drug 
IRB: 
Institutional Review Board 
iSRC: 
Internal Safety Review Committee 
ITP 
Idiopathic Thrombocytopenic Purpura 
IWRS: 
Interactive Web Response System 
LABD 
Linear IgA-Mediated Bullous Dermatosis 
LL 
Lower Limit 
LML: 
Local Medical lead 
LRTI 
Lower Respiratory Tract Infection 
LSLV: 
Last Subject Last Visit 
LTCF 
Long-Term Care Facility 
MatEx 
MATerial Excellence 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MGI: 
Mean Geometric Increase 
MIS-A 
Multisystem Inflammatory Syndrome in Adults 
MIS-C 
Multisystem Inflammatory Syndrome in Children 
MMN 
Multifocal Motor Neuropathy 
MMSE 
Mini-Mental State Examination 

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MoCA 
Mini-Cog or Montreal Cognitive Assessment 
MS 
Multiple Sclerosis 
NAb 
Neutralizing Antibody 
OA: 
Older Adult 
PAP 
Pulmonary alveolar proteinosis 
pIMD: 
Potential Immune-Mediated Disease 
PMR 
Polymyalgia Rheumatica 
PPFE 
Pleuroparenchymal fibroelastosis 
PPS: 
Per Protocol Set 
PRE: 
Population-Related event 
PreF3 
PreFusion Protein 3 
PsA 
Psoriatic Arthritis 
PRO: 
Patient-Related Outcomes 
QTL: 
Quality Tolerance Limit 
RIS 
Radiologically Isolated Syndrome 
RNA 
Ribonucleic Acid 
RS 
Reynolds Syndrome 
RSV: 
Respiratory Syncytial Virus 
RSVPreF3 OA: 
Respiratory Syncytial Virus PreFusion Protein 3 Older Adult 
investigational vaccine 
SADE: 
Serious Adverse Device Effect 
SAE: 
Serious Adverse Event 
SAP:  
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SBIR: 
Source data Base for Internet Randomization  
SCLS 
Systemic Capillary Leak Syndrome 

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SCR: 
Seroconversion Rate 
SDV: 
Source Document Verification 
SJS 
Stevens-Johnson Syndrome 
SLS 
Shrinking Lung Syndrome 
SmPC: 
Summary of Product Characteristics 
SoA: 
Schedule of Activities 
SPM: 
Study Procedures Manual 
SPR: 
Seroprotection Rate 
SRT: 
Safety Review Team 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TED 
Thyroid Eye Disease 
TEN 
Toxic Epidermal Necrolysis 
TTS 
Thrombosis With Thrombocytopenia Syndrome 
UL 
Upper Limit 
ULOQ 
Upper Limit of Quantification 
US 
United States 
USADE: 
Unanticipated Serious Adverse Device Effect 
VAED 
Vaccine Associated Enhanced Disease 
VMED 
Vaccine-Mediated Enhanced Disease 
YOA: 
Year Of Age 

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10.7.2. 
Glossary of terms 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation participant, temporally associated with the use of 
a medicinal product, whether or not considered related to the 
medicinal product. 
An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or 
disease (new or exacerbated) temporally associated with the 
use of a medicinal product. For marketed medicinal products, 
this also includes failure to produce expected benefits (i.e., 
lack of efficacy), abuse or misuse. 
Blinding: 
A procedure in which 1 or more parties to the 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 open-label study, no blind is used. Both the investigator 
and the participant know the identity of the intervention 
assigned. 
Caregiver: 
A ‘caregiver’ is someone who: 
• 
Lives in the close surroundings of a participant and has a 
continuous caring role or 
• 
Has substantial periods of contact with a participant and 
is engaged in his/her daily health care (e.g., a relative of 
the participant, a nurse who helps with daily activities in 
case of residence in a nursing home). 
In the context of this study, a caregiver can be appointed by 
the participant to oversee and support the participant’s 
compliance with protocol-specific procedures (such as 
transcribing responses to eDiaries, receiving phone calls, 
planning study visits, etc.). However, at no time, the caregiver 
should evaluate the participant’s health status while 
completing eDiaries or make decisions on behalf of the 
participant. 

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Certified copy: 
A copy (irrespective of the type of media used) of the original 
record that has been verified (i.e., by a dated signature or by 
generation through a validated process) to have the same 
information, including data that describe the context, content, 
and structure, as the original. 
Eligible: 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Enrollment: 
The process of registering a participant into a clinical study by 
assigning participant identification number after signing the 
ICF. 
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. 
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. 
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 

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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 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 amendment: 
The International Council on Harmonization (ICH) defines a 
protocol amendment as: ‘A written description of a change(s) 
to or formal clarification of a protocol.’ GSK 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. 
Protocol 
administrative change: 
A protocol administrative change addresses changes to only 
logistical or administrative aspects of the study.  
Randomization: 
Process of random attribution of intervention to participants to 
reduce selection bias. 
Remote visit: 
This term refers to the visit conducted in the place other than 
the study site. 
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. 

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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 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. 
Unsolicited adverse 
event: 
Any AE reported in addition to those solicited during the 
clinical study. Also, any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse event. 
 

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11. 
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Signature Page for  218350 TMF-15163714 v1.0
Signature Page for TMF-15163714 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 16-Dec-2022 13:30:02 GMT+0000
PPD