A Phase 2a Randomized, Observer-blind, Dose-finding Study to Evaluate the Immunogenicity and Safety of mRNA-based Multivalent Seasonal Influenza Vaccine Candidates in Adults 18 Years of Age and Older
Phase: PHASE2
Conditions: Influenza, Human
Sponsor: GlaxoSmithKline

CONFIDENTIAL 
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Protocol Amendment 2 Final 
24 Sep 2024 
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CLINICAL STUDY PROTOCOL 
Primary study intervention(s) BIO FLU SV MRNA (GSK4382276A)  
Other study intervention(s) 
GSK’s Flu Dresden – Quadrivalent Influenza 
Vaccine 
Sanofi’s Fluzone High-Dose Quadrivalent Vaccine 
GSK’s Flu Dresden – Influenza Vaccine 
Sanofi’s Fluzone High-Dose Vaccine 
Study identifier 
222853 
Abbreviated title  
FLU SV MRNA-024 
Approval date 
24 Sep 2024 
Title 
A phase 2a randomized, observer-blind, dose-finding 
study to evaluate the immunogenicity and safety of 
mRNA-based multivalent seasonal influenza vaccine 
candidates in adults 18 years of age and older 
Brief title 
A study to find the dose and assess the immune 
response and safety of a vaccine against influenza in 
adults 18 years of age and older 
Sponsor 
GlaxoSmithKline Biologicals SA 
Rue de l'Institut 89 
1330 Rixensart 
Belgium 
Sponsor signatory 
Pascal Peeters, MD  
Senior Director, Clinical Project Lead 
Medical monitor name and contact information can be found in the local study 
contact information document. 
Based on TMF-14732712 Protocol v3.0. 
©2024 GSK group of companies or its licensor. Trademarks are property of their 
respective owners. 

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PROTOCOL AMENDMENT 2 INVESTIGATOR AGREEMENT 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of and will comply with GCP and all applicable regulatory 
requirements. 
• 
That I will comply with the terms of the clinical study site agreement. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK study intervention and other study-related duties and functions as described 
in the protocol. 
• 
To cooperate with representative(s) of GSK in the monitoring and data management 
processes of the study with respect to data entry and resolution of queries about the 
data. 

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Study identifier 
222853 
Abbreviated title  
FLU SV MRNA-024 
Approval date 
24 Sep 2024 
Title 
A phase 2a randomized, observer-blind, dose-finding study 
to evaluate the immunogenicity and safety of mRNA-based 
multivalent seasonal influenza vaccine candidates in adults 
18 years of age and older 
Investigator name  
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 

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222853 (FLU SV MRNA-024) 
 
Protocol Amendment 2 Final 
24 Sep 2024 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 2 
24 Sep 2024 
Amendment 1 
16 May 2024 
Original Protocol 
21 Mar 2024 
Amendment 2 (24 Sep 2024) 
Overall rationale for the current Amendment:  
Available clinical immunogenicity and reactogenicity data from studies FLU SV MRNA-
002 and FLU SV MRNA-024 have identified 
 
 
 
(see Section 4.3 for more details on the justification for the selected dose formulation). 
The objective of protocol amendment 2 is to consolidate the immunogenicity and 
reactogenicity data package for this formulation in both age groups 
 
  
LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RATIONALE: 
Section # and title 
Description of change 
Brief rationale 
Throughout the protocol 
 
 
Relevant protocol sections were revised 
(as listed below). 
To consolidate the immunogenicity 
and reactogenicity data package 
with the 
 
 
 
2.1. Study rationale 
4.1. Overall design 
4.2. Scientific rationale for study 
design 
4.3. Justification for dose 
Provided updated rationale and study 
design for protocol amendment 2. 
To support protocol amendment 2 
study design. 
1.2. Schema 
4.1. Overall design (Table 5) 
6.1. Study intervention(s) 
administered (Table 6) 
8.2.3. Immunological read-outs 
(Table 9) 
Addition of one new investigational study 
intervention dose formulation per age 
group and corresponding age-appropriate 
comparators. Number of participants 
updated (approximately 320 new 
participants to be enrolled; 160 younger 
adults and 160 older adults). 
Tables 5 and 6 were updated to include 
details of study interventions used in 
protocol amendment 2. 
To align with protocol amendment 
2 study design. 
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Section # and title 
Description of change 
Brief rationale 
Table 9 was updated to include additional 
participants in the study (total number of 
participants changed from 500 to 820; 
number of participants in a subset 
changed from 250 to 410). 
9.4.1. Sequence of interim 
analyses and other planned 
analyses 
9.5 Sample size determination 
(including Tables 16 and 17) 
Updated to include groups receiving the 
additional dose formulation and 
comparators in the statistical analysis. 
To align with protocol amendment 
2 study design. 
 

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TABLE OF CONTENTS  
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 4 
List of main changes in the protocol and their rationale: ........................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 12 
1. 
PROTOCOL SUMMARY ........................................................................................ 16 
1.1. 
Synopsis ..................................................................................................... 16 
1.2. 
Schema ...................................................................................................... 17 
1.3. 
Schedule of activities .................................................................................. 18 
2. 
INTRODUCTION .................................................................................................... 21 
2.1. 
Study rationale ............................................................................................ 21 
2.2. 
Background ................................................................................................ 21 
2.3. 
Benefit-risk assessment .............................................................................. 22 
2.3.1. 
Risk assessment .......................................................................... 23 
2.3.2. 
Benefit assessment ..................................................................... 26 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 26 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 26 
4. 
STUDY DESIGN .................................................................................................... 30 
4.1. 
Overall design ............................................................................................. 30 
4.2. 
Scientific rationale for study design ............................................................. 33 
4.3. 
Justification for dose ................................................................................... 34 
4.4. 
End-of-study definition ................................................................................ 35 
5. 
STUDY POPULATION ........................................................................................... 35 
5.1. 
Inclusion criteria .......................................................................................... 35 
5.2. 
Exclusion criteria ......................................................................................... 36 
5.2.1. 
Medical conditions ....................................................................... 36 
5.2.2. 
Prior/Concomitant therapy ........................................................... 37 
5.2.3. 
Prior/Concurrent clinical study experience ................................... 38 
5.2.4. 
Other exclusion criteria ................................................................ 38 
5.3. 
Lifestyle considerations ............................................................................... 38 
5.4. 
Screen failures ............................................................................................ 38 
5.5. 
Criteria for temporarily delaying administration of study intervention ........... 38 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 39 
6.1. 
Study intervention(s) administered .............................................................. 39 
6.1.1. 
Medical devices ........................................................................... 45 
6.2. 
Preparation, handling, storage, and accountability ...................................... 45 
6.3. 
Assignment to study intervention ................................................................ 45 
6.4. 
Blinding ....................................................................................................... 46 
6.4.1. 
Emergency unblinding ................................................................. 46 
6.5. 
Study intervention compliance .................................................................... 47 
6.6. 
Dose modification ....................................................................................... 47 
6.7. 
Continued access to study intervention after the end of the study ............... 47 
6.8. 
Treatment of overdose ................................................................................ 47 
6.9. 
Prior and concomitant therapy .................................................................... 47 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 48 
7.1. 
Discontinuation of study intervention ........................................................... 48 
7.2. 
Participant discontinuation/withdrawal from the clinical study ...................... 48 
7.3. 
Lost to follow-up.......................................................................................... 49 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 50 
8.1. 
Administrative and baseline procedures ..................................................... 50 
8.1.1. 
Collection of demographic data .................................................... 50 
8.1.2. 
Medical/vaccination history .......................................................... 51 
8.1.3. 
Provision of eDiary device or installing of eDiary 
application on participant’s personal device ................................. 51 
8.2. 
Immunogenicity assessments ..................................................................... 51 
8.2.1. 
Biological samples ....................................................................... 52 
8.2.2. 
Laboratory assays ....................................................................... 52 
8.2.3. 
Immunological read-outs .............................................................. 53 
8.2.4. 
Immunological correlates of protection (CoP) .............................. 53 
8.3. 
Safety assessments .................................................................................... 53 
8.3.1. 
Physical examination ................................................................... 53 
8.3.2. 
Pre-dosing body temperature ....................................................... 54 
8.3.3. 
Warnings and precautions to administration of study 
intervention .................................................................................. 54 
8.3.4. 
Myocarditis and pericarditis assessment and definitions .............. 54 
8.3.5. 
Pregnancy testing ........................................................................ 55 
8.3.6. 
Safety monitoring, committees, and pausing criteria .................... 55 
8.3.6.1. 
Study pausing criteria ................................................. 56 
8.4. 
Adverse events, serious adverse events, and other safety reporting........... 57 
8.4.1. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 57 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 59 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 59 
8.4.4. 
AESIs .......................................................................................... 59 
8.4.4.1. 
Potential immune-mediated diseases (pIMDs) ............ 59 
8.4.4.2. 
Other AESIs ............................................................... 64 
8.4.5. 
Regulatory reporting requirements for SAEs/AESIs ..................... 64 
8.4.6. 
Pregnancy ................................................................................... 65 
8.4.7. 
Contact information for reporting SAEs, AESIs, 
pregnancies and study pausing criteria ........................................ 66 
8.4.8. 
Participant card ............................................................................ 66 
8.4.9. 
Medical device deficiencies ......................................................... 66 
8.4.9.1. 
Time period for detecting medical device 
deficiencies ................................................................ 66 
8.4.9.2. 
Follow-up of medical device deficiencies .................... 67 
8.4.9.3. 
Prompt reporting of device deficiencies to the 
sponsor ...................................................................... 67 
8.4.9.4. 
Regulatory reporting requirements for device 
deficiencies ................................................................ 67 
8.5. 
Pharmacokinetics ....................................................................................... 67 
8.6. 
Pharmacodynamics .................................................................................... 67 
8.7. 
Genetics ..................................................................................................... 67 
8.8. 
Biomarkers ................................................................................................. 68 
8.9. 
Immunogenicity assessments ..................................................................... 68 

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8.10. 
Health economics ....................................................................................... 68 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 68 
9.1. 
Statistical hypotheses ................................................................................. 68 
9.2. 
Analysis sets ............................................................................................... 69 
9.3. 
Statistical analyses ..................................................................................... 69 
9.3.1. 
Definitions .................................................................................... 70 
9.3.2. 
Primary and secondary endpoints analyses ................................. 70 
9.3.2.1. 
Analysis of immunogenicity endpoints ........................ 70 
9.3.2.2. 
Analysis of reactogenicity and safety endpoints .......... 71 
9.4. 
Interim analyses .......................................................................................... 71 
9.4.1. 
Sequence of interim analyses and other planned analyses .......... 71 
9.5. 
Sample size determination .......................................................................... 72 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 74 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 74 
10.1.1. 
Regulatory and ethical considerations ......................................... 74 
10.1.2. 
Financial disclosure ..................................................................... 74 
10.1.3. 
Informed consent process ............................................................ 75 
10.1.4. 
Recruitment strategy .................................................................... 75 
10.1.5. 
Data protection ............................................................................ 76 
10.1.6. 
Committees structure ................................................................... 76 
10.1.7. 
Dissemination of clinical study data ............................................. 77 
10.1.8. 
Data quality assurance ................................................................ 77 
10.1.9. 
Source documents ....................................................................... 78 
10.1.10. Study and site start and closure ................................................... 79 
10.1.11. Publication policy ......................................................................... 80 
10.2. 
Appendix 2: Myocarditis and pericarditis ..................................................... 80 
10.2.1. 
Myocarditis and pericarditis workflow ........................................... 80 
10.2.2. 
Case definitions of probable and confirmed myocarditis, 
pericarditis, and myopericarditis ................................................... 81 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 82 
10.3.1. 
Definition of AE ............................................................................ 82 
10.3.2. 
Definition of SAE .......................................................................... 83 
10.3.3. 
Solicited events............................................................................ 84 
10.3.4. 
Unsolicited AE ............................................................................. 85 
10.3.5. 
Recording, assessment, and follow-up of AEs, SAEs, 
AESIs, and pregnancies .............................................................. 85 
10.3.5.1. AE and SAE recording ................................................ 85 
10.3.5.2. Assessment of intensity .............................................. 87 
10.3.5.3. Assessment of causality ............................................. 88 
10.3.5.4. Assessment of outcomes............................................ 89 
10.3.5.5. Follow-up of AEs, SAEs, AESIs, pregnancies 
or any other events of interest .................................... 89 
10.3.5.6. Updating of SAE, AESI and pregnancy 
information after removal of write access to the 
participant’s eCRF ...................................................... 90 
10.3.5.7. Reporting of SAEs, AESIs, and pregnancies .............. 90 
10.4. 
Appendix 4: Contraceptive and barrier guidance ......................................... 91 
10.4.1. 
Definitions .................................................................................... 91 

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10.4.1.1. WOCBP ...................................................................... 91 
10.4.1.2. Women of non-childbearing potential 
(WONCBP) ................................................................. 92 
10.4.2. 
Contraception guidance ............................................................... 92 
10.5. 
Appendix 5: Medical device AEs, ADEs, SAEs, SADEs, USADEs 
and device deficiencies: Definitions and procedures for recording, 
evaluating, follow-up, and reporting in medical device studies .................... 93 
10.5.1. 
Definition of medical device AE and ADE..................................... 93 
10.5.2. 
Definition of medical device SAE, SADE, and USADE ................. 94 
10.5.3. 
Definition of device deficiency ...................................................... 95 
10.5.4. 
Recording and follow-up of medical device AEs and/or 
SAEs and device deficiencies ...................................................... 95 
10.5.4.1. Medical device AE, SAE, and device deficiency 
recording .................................................................... 95 
10.5.4.2. Assessment of intensity .............................................. 95 
10.5.4.3. Assessment of causality ............................................. 96 
10.5.4.4. Follow-up of medical device AE/SAE and 
device deficiency ........................................................ 96 
10.5.5. 
Reporting of medical device SAEs ............................................... 96 
10.5.6. 
Reporting of SADEs ..................................................................... 97 
10.5.7. 
Reporting of medical device deficiencies for associated 
person ......................................................................................... 97 
10.6. 
Appendix 6: Protocol amendment history .................................................... 98 
11. REFERENCES ....................................................................................................... 99 
 

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LIST OF TABLES 
PAGE 
Table 1 
Schedule of activities ............................................................................. 18 
Table 2 
Intervals between study visits ................................................................. 21 
Table 3 
Objectives and endpoints ....................................................................... 26 
Table 4 
Study estimands..................................................................................... 28 
Table 5 
Study groups and interventions .............................................................. 32 
Table 6 
Study intervention(s) administered (table spreading through 
multiple pages) ....................................................................................... 40 
Table 7 
Biological samples ................................................................................. 52 
Table 8 
Laboratory assays .................................................................................. 52 
Table 9 
Immunological read-outs ........................................................................ 53 
Table 10 
Study pausing criteria ............................................................................. 57 
Table 11 
Collection and reporting of safety information ......................................... 58 
Table 12  
List of pIMDs .......................................................................................... 60 
Table 13 
Timeframes for submitting SAEs, AESIs and pregnancies to GSK ......... 65 
Table 14 
Contact information for reporting SAEs, AESIs, pregnancies and 
study pausing criteria ............................................................................. 66 
Table 15 
Analysis sets .......................................................................................... 69 
Table 16 
Half-width of 95% CI for the group difference in seroconversion 
rates by comparator and 
 (Evaluable N per group = 47) ................ 73 
Table 17 
Half-width of 95% CI for the group difference in seroconversion 
rates by comparator and 
 in part 2 of the study (protocol 
amendment 2) (Evaluable N per group = 76) ......................................... 73 
Table 18 
Solicited administration site events......................................................... 84 
Table 19  
Solicited systemic events ....................................................................... 85 
Table 20  
Intensity scales for solicited events in participants of 6 years of 
age or more ............................................................................................ 87 
Table 21 
Highly effective contraceptive methods .................................................. 92 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 17 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADE 
Adverse device effect 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CA 
Competent authority 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated standards of reporting trials 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
electronic Diary 
EoS 
End-of-study 
FDA 
Food and Drug Administration 
FSFV 
First subject first visit 
FSH 
Follicle stimulating hormone 
GBS 
Guillain-Barré Syndrome 
GCP 
Good clinical practices 
GDPR 
General data protection regulation 
HA 
Hemagglutinin 
HIPAA 
Health Insurance Portability and Accountability Act 
HLT 
High-level term 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICSR 
Individual case safety reports 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
iSRC 
Internal Safety Review Committee 
LSLV 
Last subject last visit 
MAAE 
Medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MN 
Microneutralization 
MRI 
Magnetic resonance imaging 
NH 
Northern Hemisphere 
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Abbreviation 
Definition 
PCA 
Primary completion analysis 
PI 
Personal information 
pIMD 
Potential immune-mediated diseases 
PT 
Preferred term 
QTL 
Quality tolerance limit 
RNA 
Ribonucleic acid 
RTSM 
Randomization and Trial Supply Management 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SmPC 
Summary of product characteristics 
SoA 
Schedule of activities 
SoC 
Standard of care 
SRT 
Safety review team 
SUSAR 
Suspected unexpected serious adverse reaction 
TOC 
Table of contents 
ULN 
Upper limit of normal 
USADE 
Unanticipated serious adverse device effect 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of non-childbearing potential 
 
Term 
Definition 
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 SAE. 
In an observer-blind study, the participant, the site, and sponsor personnel 
involved in the clinical evaluation of the participants are blinded while other study 
personnel may be aware of the treatment assignment. 
Caregiver 
A “caregiver” is someone who: 
• 
lives in the close surroundings of a participant and has a continuous caring 
role or 
• 
has substantial periods of contact with a participant and is engaged in their 
daily health care (e.g., a relative of the participant, a nurse who helps with 
daily activities in case of residence in a nursing home). 
In the context of a clinical study, a caregiver could include an individual appointed 
to oversee and support the participant’s compliance with protocol-specified 
procedures. 
Certified copy 
A copy (irrespective of the type of media used) of the original record that has been 
verified (e.g., 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. 
Combination product 
Combination product comprises any combination of: 
• 
drug 
• 
device 
• 
biological product. 

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Term 
Definition 
Each drug, device and biological product included in a combination product is a 
constituent part. 
Comparator 
Any product used as a reference (including placebo, marketed product, GSK, or 
non-GSK) for an investigational product being tested in a clinical trial. This is any 
product that is being used to assess the safety, efficacy, or other measurable 
value against the test product (IMP). 
eDiary 
Electronically recorded patient data and automated data entries on, for example, a 
handheld mobile device, tablet, or computer. 
Eligible 
Qualified for enrollment into the study based upon strict adherence to 
inclusion/exclusion criteria. 
Essential documents 
Documents that individually and collectively permit evaluation of the conduct of a 
study and the quality of the data produced. 
Intercurrent event 
Event occurring after study intervention initiation that affects either the 
interpretation or the existence of the measurements associated with the clinical 
question of interest. 
Intervention number 
A number identifying the intervention assigned to a participant, according to 
intervention allocation. 
IMP 
A pharmaceutical form of an active substance or placebo being tested or used as 
a reference in a clinical trial, including products already with a marketing 
authorization but used or assembled (formulated or packaged) in a way different 
from the authorized form, or when used for an unauthorized indication, or when 
used to gain further information about the authorized form. 
Invasive medical device 
A device which, in whole or in part, penetrates inside the body, either through a 
body orifice or throughout the surface of the body. 
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. 
LSLV 
The date on which the last participant in a clinical study was examined or received 
an intervention/treatment to collect final data for the primary outcome measures, 
secondary outcome measures, and AEs (that is, the last participant’s last visit or 
LSLV). 
Medicinal products used to 
assess endpoints 
A product given to the participant in a clinical trial as a tool to assess a relevant 
clinical trial endpoint; it is not being tested or used as a reference in the clinical 
trial. 
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)/comparator). 
Synonym: subject. 
Participant identifier 
A unique identification number assigned to each participant who consents to 
participate in the study. 
Placebo 
An inactive substance or treatment that looks the same as, and is given in the 
same way as, an active drug or intervention/treatment being studied. 
Primary completion date 
This is the date that the final participant in the study was examined or received an 
intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In other words, Primary Completion Achieved is the date of the last 
contact with the participant when data has been collected/intervention done for the 
purpose of data collection for analysis of all primary endpoints. 
In the case of clinical studies with more than 1 primary outcome measure with 
different completion dates, this term refers to the date on which data collection is 
completed for all of the primary outcomes. This date may occur prior to the study 
end or be the same date as the study end milestone. 

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Term 
Definition 
Randomization 
Process of random attribution of intervention to participants to reduce selection 
bias. 
Self-contained study 
Study with objectives not linked to the data of another study. 
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). 
Standard of care 
Medicine(s) for a specific indication, or a component of the standard care for a 
particular medical indication, based on national and/or international consensus; 
there is no regulatory significance to this term. 
Products/regimens considered standard of care may differ country to country, 
depending on consensus in individual countries. 
Study intervention 
Term used throughout the clinical study to cover all types of investigational and 
non-investigational products including medical devices and vaccines intended to 
be administered to the study participants during the study conduct. Procedures 
conducted to manage participants or to collect data are excluded from the usage 
of this term. 
Study monitor 
An individual assigned by the sponsor and responsible for assuring proper conduct 
of clinical studies at 1 or more investigational sites. 
Subset 
A group of participants for whom specific assessments are planned as compared 
to other participants or a group of participants who share a common characteristic 
(e.g., age, vaccination schedule, etc.) at the time of enrollment. 
SUSAR 
In a clinical trial, a serious adverse reaction that is considered unexpected, i.e., the 
nature or severity of which is not consistent with the reference safety information 
(e.g., IB for an unapproved IMP). All ADRs that are both serious and unexpected 
are subject to expedited reporting. 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol title: A phase 2a randomized, observer-blind, dose-finding study to evaluate the 
immunogenicity and safety of mRNA-based multivalent seasonal influenza vaccine 
candidates in adults 18 years of age and older. 
Brief title: A study to find the dose and assess the immune response and safety of a 
vaccine against influenza in adults 18 years of age and older. 
Rationale: This Phase 2a study is a dose-finding study investigating 
 
Objectives, endpoints, and estimands: The primary and key secondary objectives focus 
on the evaluation of humoral immune response induced by the investigational study 
intervention, as well as its safety and reactogenicity profile. For the full list of objectives, 
endpoints, and estimands refer to Section 3. 
Overall design: This is an observer-blind study conducted in healthy or medically stable 
participants 18-64 (younger adults, YA) and 65-85 (older adults, OA) years of age. 
Participants will be enrolled in parallel to 4 Flu mRNA groups and 1 comparator group 
per age category in the initial part of the study or 1 Flu mRNA group and 1 comparator 
group per age category in protocol amendment 2. For details refer to Section 4.1. 
Number of participants: Planned (approximate) number of participants to be enrolled: 
250 YAs (50 participants per group) and 250 OAs (50 participants per group) in the 
initial part of the study, and 160 YAs (80 participants per group) and 160 OAs (80 
participants per group) in protocol amendment 2. For details refer to Section 9.5. 
Data monitoring/other committee: A blinded Safety Review Team (SRT) will review 
available safety data on a regular basis throughout the study. If a potential safety 
concern/signal is identified that requires unblinded review, an unblinded internal Safety 
Review Committee (iSRC), independent from the project, will review available safety 
data. For details refer to Section 10.1.6. 
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1.2. 
Schema 
Figure 1 
Study design overview 
 
D: day; N: number of participants;  
*Visit 3 will be replaced by a contact if participant has received the standard of care (SoC) vaccination against 
seasonal flu after Visit 2 and prior to this visit and did not report any adverse events that would require physical 
examination on site. 
 

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1.3. 
Schedule of activities 
Table 1 
Schedule of activities 
Type of contact 
Visit 1 
Contact 1 
Visit 2 
Contact 2 
Visit 31 
Notes 
Timepoints 
Day 1 
Day 8 
Day 29 
Day 92 
Day 183 
Informed consent 
●2 
 
 
 
 
See Section 10.1.3 for more information. 
Inclusion and exclusion criteria 
●2 
 
 
 
 
See Section 5.1 and Section 5.2 for Inclusion and 
Exclusion criteria. 
Check with participant if they will appoint a caregiver and 
distribute information letter(s) to caregiver, when 
applicable 
○2 
 
 
 
 
See Section 8 for more information. 
Collect demographic data 
●2 
 
 
 
 
See Section 8.1.1 for more information. 
Collect medical history 
●2 
 
 
 
 
See Section 8.1.2 for more information. 
Collect influenza vaccination history over the past 2 years 
●2 
 
 
 
 
See Section 8.1.2 for more information. 
Physical examination 
●2 
 
○ 
 
○ 
Physical examination after Day 1 will be performed only if 
the participant indicates that there might be some 
underlying pathology(ies) or if deemed necessary by the 
investigator or delegate. See Section 8.3.1 for more 
information. 
Study intervention 
Check criteria for temporary delay of study intervention 
administration3 
●2 
 
 
 
 
See Section 5.5 for more information. 
Check contraindications, warnings, and precautions to 
vaccination 
●2 
 
 
 
 
See Section 8.3.3 for more information. 
Body temperature before study intervention 
administration 
●2 
 
 
 
 
Fever is defined as a temperature ≥38.0°C/100.4°F 
regardless the location of measurement. The preferred 
location for measuring temperature will be the oral cavity. 
Urine pregnancy test (only for female participants of 
childbearing potential) 
●2 
 
 
 
 
See Section 8.3.5 for more information. 
Randomization and intervention number allocation 
●2 
 
 
 
 
Participants will be randomized between study groups at 
an equal ratio using a stratified permuted block 
randomization with age group, country, and previous flu 
vaccination in the preceding 2 years as stratification 
factors. See Section 6.3 for more information. 

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Type of contact 
Visit 1 
Contact 1 
Visit 2 
Contact 2 
Visit 31 
Notes 
Timepoints 
Day 1 
Day 8 
Day 29 
Day 92 
Day 183 
Administration of study intervention 
● 
 
 
 
 
See Section 6.1 for more information. 
Recording of administered study intervention number 
● 
 
 
 
 
See Section 6.5 for more information. 
Distribution of “Participant card” 
○ 
 
 
 
 
See Section 8.4.8 for more information. 
Check participant’s device compatibility for eDiary data 
collection  
○ 
 
 
 
 
See Section 8.1.3 for more information. 
Training and installing4/assigning of eDiaries 
○ 
 
 
 
 
See Section 10.3.5.1 for more information. 
Review of the eDiary data by site staff 
○ 
○ 
○ 
 
 
If solicited events are ongoing on and beyond Day 29, 
they will be followed up using eDiary until resolution. 
See Section 10.3.5.1 for more information. 
Returning/uninstalling4 of eDiaries 
 
 
○ 
 
 
Participants with solicited events ongoing at Visit 2 will 
return the eDiary or uninstall the eDiary app after Visit 2, 
once the event has resolved. 
See Section 10.3.5.1 for more information. 
Laboratory assessment 
Blood sampling for humoral immunogenicity assessments 
(approximately 15 mL)  
○2,5,6 
 
○5 
 
○5,7 
See Section 8.2.1 for more information. 
Safety assessments 
Record concomitant medications/vaccinations 
● 
● 
● 
● 
● 
See Section 6.9 for more information. 
Record intercurrent medical conditions 
● 
● 
● 
● 
● 
See Table 11 for details about time period for recording 
intercurrent medical conditions. 
Recording of solicited events (Days 1–7 post-dosing) 
○8,9 
 
 
 
 
See Table 11 for details about time period for collecting 
solicited events and Section 10.3.3 for more information. 
Solicited events ongoing at the end of solicited period 
(Day 1-Day 7) are to be followed up until resolution. 
Recording of unsolicited AEs (Days 1-28 post-dosing) 
● 
● 
 
 
 
See Table 11 for details about time period for collecting 
unsolicited AEs and Section 10.3.4 for more information. 
Recording of MAAEs, AESIs, SAEs and AEs leading to 
withdrawal from study 
● 
● 
● 
● 
● 
See Table 11 for details about time period for collecting 
safety information and Section 10.3.5 for more 
information. 
Recording of pregnancies 
● 
● 
● 
● 
● 
See Section 10.3.5 for more information. 

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Type of contact 
Visit 1 
Contact 1 
Visit 2 
Contact 2 
Visit 31 
Notes 
Timepoints 
Day 1 
Day 8 
Day 29 
Day 92 
Day 183 
Recording of SAEs related to study participation, or to a 
concurrent GSK medication/vaccine 
● 
● 
● 
● 
● 
Any SAEs assessed as related to study participation 
(e.g., protocol-mandated procedures, invasive tests, or 
change in existing therapy) or related to a GSK product 
will be recorded from the time a participant consents to 
participate in the study. 
See Table 11 for details about time period for collecting 
safety information and Section 10.3.5 for more 
information. 
Study conclusion 
 
 
 
 
● 
 
AE: adverse event; AESI: adverse event of special interest; MAAE: medically attended adverse event; SAE: serious adverse event. 
Note: The double-line border following Day 29 indicates the analyses which will be performed on all data (i.e., data that are as clean as possible) for primary and secondary endpoints 
obtained up to Day 29. 
Contact may be via telephone, SMS, email, video-telephone/telemedicine or other means, depending on local best practice. 
● 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. 
1 Visit 3 (Day 183) will be replaced by a contact if participant has received the standard of care vaccination against seasonal flu after Visit 2 and prior to this visit and did not report any 
AEs that would require physical examination on site. 
2 Is used to indicate a study procedure to be performed prior to study intervention administration. 
3 If the study intervention administration is delayed for any reason, the following procedures should be performed on the day of study intervention administration: physical examination, 
body temperature measurement, urine pregnancy test, check for contraindications, warnings, and precautions to vaccination, and blood sample collection (the first blood sample 
will be destroyed if taken at an earlier time). 
4 For participants who will bring their own device. 
5 Is used to indicate a sample collection procedure that requires documentation in the validated digital collection application for samples management. 
6 Criteria for temporary delay for study intervention administration to be checked prior to taking blood sample. 
7 Blood samples should only be collected for participants who did not receive a SoC vaccination against seasonal flu after Visit 2 and prior to this visit. 
8 Is used to indicate a study procedure recorded in eDiary. 
9 Solicited events will be recorded in eCRF by sites, only when participant missed to record the event in eDiary. 
 

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Table 2 
Intervals between study visits 
Interval1 
Planned visit interval  
Allowed interval range 
Visit 12 → Contact 1 
7 days 
7-10 days 
Visit 12 → Visit 2 
28 days 
28-35 days 
Visit 12 → Contact 2 
91 days 
77-105 days 
Visit 12 → Visit 33 
182 days 
180-210 days 
1 Interval is computed as the difference between 2 dates. 
2 Visit 1 corresponds to the day of the study intervention administration. If the study intervention administration date is 
different from the ICF signature date, the study intervention administration date needs to be taken as a reference 
for calculating intervals relative to subsequent visits. 
3 Visit 3 will be replaced by a contact if participant has received the standard of care vaccination against seasonal flu 
after Visit 2 and prior to this visit and did not report any AE that would require physical examination on site. 
2. 
INTRODUCTION 
2.1. 
Study rationale 
The purpose of this Phase 2a study is to evaluate the immunogenicity and safety of the 
 seasonal influenza investigational study interventions. The study follows a Phase 
1/2 study (FLU SV MRNA-002) that investigated 
 
. In the current Phase 2a study, investigational study 
interventions 
 
 will be investigated to explore 
possible ways to 
 
Available clinical immunogenicity and reactogenicity data from this study and study FLU 
SV MRNA-002 have 
 
 
  
The objective of protocol amendment 2 is to consolidate the immunogenicity and 
reactogenicity data package for this formulation in both age groups 
 
  
See Section 4.3 for more details on the justification of the selected dose formulation. 
2.2. 
Background 
Influenza is an infectious disease caused by influenza viruses, enveloped negative-sense 
RNA viruses belonging to the Orthomyxoviridae family. Four types of influenza viruses 
have been identified, of which type A and B are primarily responsible for human disease. 
Influenza causes variable but often high rates of seasonal disease in the human 
population, with consequent significant morbidity and mortality. Uncomplicated 
influenza is characterized by the abrupt onset of general and respiratory symptoms which 
usually resolve within a week. However, in vulnerable populations such as the elderly 
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and young children, influenza can aggravate existing medical conditions and potentially 
lead to life-threatening complications. During seasonal epidemics, 5-15% of the world’s 
population is typically infected, resulting in 3-5 million cases of severe illness. Moreover, 
up to 650 000 deaths annually are associated with seasonal influenza [WHO, 2023a]. 
Annual influenza vaccination is currently the most effective strategy for controlling 
influenza and preventing its associated respiratory and non-respiratory complications and 
mortality [WHO, 2023a]. However, the effectiveness of influenza vaccines has 
historically been suboptimal, ranging from as little as 10% in years when vaccine and 
circulating strains are mismatched, to a maximum of 60% (2004 to 2023 influenza 
seasons in the United States [US]) [CDC, 2023]. 
Several parameters contribute to the limitations in terms of effectiveness and availability 
of the currently licensed influenza vaccines and use of new technologies may be needed 
to improve the immunogenicity of influenza vaccines. The mRNA technology has key 
attributes that can be leveraged to overcome the limitations of the currently licensed 
influenza vaccines including avoiding egg-adaptation mutations, rapid, and scalable 
manufacturing process, and facilitating multicomponent vaccine formulations. GSK is 
developing a seasonal influenza vaccine based on mRNAs encoding influenza HA 
, encapsulated in lipid nanoparticles. 
Please refer to the current Investigator’s Brochure (IB) for information regarding pre-
clinical and clinical studies of Flu Seasonal mRNA. 
2.3. 
Benefit-risk assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of Flu Seasonal mRNA investigational study 
intervention may be found in the IB.  
Detailed information about the known and expected benefits and risks and expected AEs 
related to the licensed influenza vaccines used as comparators can be found in the 
respective Summary of Product Characteristics (SmPC) or Prescribing Information. 
As for any vaccine, administration site (e.g., pain, swelling, erythema) and systemic (e.g., 
fever, fatigue, headache, myalgia) post-dosing events may occur within the first week of 
study intervention administration, and are anticipated to resolve within a few days of 
onset. 
 
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2.3.1. 
Risk assessment 
Potential risk of clinical significance 
Summary of data/Rationale for risk 
Mitigation strategy 
All study vaccines 
Hypersensitivity reactions, including anaphylaxis 
Hypersensitivity reactions following vaccinations are not 
uncommon but are mostly nonserious. Serious allergic 
reactions, including anaphylaxis, are usually very rare 
[McNeil, 2019]. In a Vaccine Safety Datalink (VSD) study, 
the estimated incidence of anaphylaxis was 1.3 per million 
vaccine doses administered for all vaccines and 1.6 per 
million doses for trivalent influenza vaccine 
[McNeil, 2019]. The US VSD found that most cases of 
anaphylaxis occurred shortly after vaccination 
[Law, 2021]. In general, the symptoms can be treated 
successfully if the treatment is started quickly. There is 
currently limited data on the risk of hypersensitivity 
reactions following mRNA influenza vaccines. The US 
Centers for Disease Control and Prevention (CDC) noted 
the reporting rate of anaphylaxis following mRNA Covid-
19 vaccines to be 2.5 to 4.7 cases/million doses 
administered [Shimabukuro, 2021]. 
Severe hypersensitivity events occurring within 24 hours 
of dosing will be collected as AESIs. 
Participants with a history of hypersensitivity to any 
previous vaccine or any component of the study 
intervention (including polyethylene glycol, egg protein 
and aminoglycoside antibiotics) will be excluded from 
study participation. 
All participants will be observed for 30 minutes after 
dosing. Appropriate resuscitation equipment, medication 
and trained staff will be available at the vaccination site. 
Participants will be instructed to contact the study site 
immediately for occurrence of any possible 
hypersensitivity reaction within 1 day following study 
intervention administration. 
Bell’s Palsy 
Previous studies have shown controversial results on the 
risk of Bell’s palsy after influenza vaccination 
[Ozonoff, 2021; Bardage, 2011; Huang, 2012; Wijnans, 
2017; Baxter, 2017; Mutsch, 2004]. A review of vaccine 
adverse event reporting system (VAERS) data found 
increased reporting of facial paralysis following any 
influenza vaccination seems to be higher compared with 
that following the administration of other vaccines. 
However, the authors cautioned that the findings need to 
be interpreted in light of the limitations of data generated 
from VAERS, which is exploratory rather than 
confirmatory [Kamath, 2020]. A recent review of vaccines, 
including influenza vaccines and mRNA-based Covid-19 
vaccines, and Bell’s palsy found insufficient evidence to 
confirm an excess risk of Bell’s palsy following 
Participants with a history of Bell’s palsy, will be excluded 
from the study enrollment. Moreover, pIMDs including 
Bell’s palsy will be collected as AESIs. 

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Potential risk of clinical significance 
Summary of data/Rationale for risk 
Mitigation strategy 
vaccination, with the exception of an intranasally 
administered influenza vaccine adjuvanted with E.coli 
heat-labile toxin. In the case of the intranasal influenza 
vaccine, the adjuvant was the suggested cause 
[Bertin, 2022]. 
Literature is sparse regarding the potential mechanism 
that may be involved. Of note, Bell’s palsy has also been 
reported to occur following influenza infection. Bell’s palsy 
is included in the product information (under Post-
Marketing Data) of some influenza vaccines (e.g., 
Fluzone Quadrivalent, Fluzone High-Dose Quadrivalent). 
Given the association between influenza infection and the 
incidence of facial palsy and due to the earlier 
associations with influenza vaccination and that the 
potential mechanism is still not completely understood, 
Bell’s palsy is proposed as an important potential risk for 
this candidate vaccine. 
Guillain-Barré Syndrome (GBS) 
An association between GBS and influenza vaccination 
was initially suggested during the 1976–1977 swine flu 
immunization campaign [Langmuir, 1984; 
Schonberger, 1979]. A meta-analysis of 39 studies 
published between 1981 to 2014 found a marginally 
statistically significant increased risk of GBS for seasonal 
flu vaccines (RR=1.22; 95% CI, 1.01-1.48) [Martin Arias, 
2015]. However, the CDC notes that the data on the 
association between GBS and seasonal flu vaccination 
are variable and inconsistent across flu seasons. If there 
is an increased risk of GBS following flu vaccination it is 
small, in the order of 1 to 2 additional GBS cases per 
million doses of flu vaccine administered [CDC, 2015]. 
The risk window of GBS is in the first 6 weeks post-
vaccination. One of the biological mechanisms for GBS 
following influenza vaccine may involve the synergistic 
effects of endotoxins and vaccine-induced autoimmunity. 
Of note, influenza infection has also been associated with 
Participants with a history of GBS, will be excluded from 
the study enrollment. Moreover, pIMDs including GBS will 
be collected as AESIs 

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Potential risk of clinical significance 
Summary of data/Rationale for risk 
Mitigation strategy 
GBS. The estimated risk of GBS after influenza has been 
reported to be 17.2 cases per 1 million patients 
hospitalized with influenza [Babazadeh, 2019]. 
A recent systematic review and meta-analysis has not 
found an association between GBS and mRNA Covid-19 
vaccines [Ogunjimi, 2023]. 
GBS has been included in the product information (under 
Warnings and Precautions and/or Post-Marketing Data) of 
some influenza vaccines (e.g., Fluarix Quadrivalent, Fluad 
Tetra, Fluzone Quadrivalent, Fluzone High-Dose 
Quadrivalent).  
Given the association between influenza infection and 
GBS and due to the earlier associations with influenza 
vaccination this potential risk needs to be evaluated for 
any possible association with the Flu Seasonal mRNA 
vaccine. 
Study procedures 
Pain and bruising 
Pain or bruising at the site where blood is drawn. 
A topical analgesic may be applied to the site where 
blood will be taken. 
Syncope and vasovagal reactions to study intervention 
administration 
Syncope (fainting) and other anxiety related reactions can 
occur as a psychogenic response to the needle injection 
following or before blood draw or dosing.  
To minimize the risk of injury associated with syncope 
before/after dosing or blood draw, all participants will be 
seated or lying down during study intervention 
administration/blood draw and will remain under 
observation for 30 minutes after the procedure. 
The decision to dose the participant will be dependent on 
the clinical judgment of the investigator. 
Bleeding following intramuscular injection 
As with other intramuscular injections, study intervention 
should be given with caution in individuals with bleeding 
disorders, such as hemophilia or on anticoagulant 
therapy, to avoid the risk of hematoma following the 
injection. 
To minimize the risk of bleeding, study intervention should 
be given with caution in individuals with thrombocytopenia 
or any coagulation disorder. 
Participants with any medical condition that in the 
judgment of the investigator would make intramuscular 
injection unsafe will be excluded from study enrollment. 
AESIs: Adverse Events of Special interest; CI: Confidence Interval; GBS: Guillain-Barré Syndrome; mRNA: messenger ribonucleic acid; pIMDs: potential Immune-mediated diseases; 
VAERS: Vaccine Adverse Event Reporting System; VSD: Vaccine Safety Datalink. 

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2.3.2. 
Benefit assessment 
The participants receiving the Flu Seasonal mRNA investigational study intervention 
may not directly benefit from this vaccination because vaccine efficacy has not been 
assessed. 
Participants may gain information and medical advice about their general health status 
through medical evaluations/assessments associated with this study (i.e., physical 
examinations). 
2.3.3. 
Overall benefit-risk conclusion 
The Flu Seasonal mRNA investigational study intervention is currently in an early stage 
of clinical development. Taking into account the measures taken to minimize risk to 
participants from this study and given the accumulation of favorable 
safety/immunogenicity data from the FLU SV MRNA-003 (217895) and the FLU SV 
MRNA-002 (217884) studies, the potential risks identified in association with the Flu 
Seasonal mRNA investigational vaccine candidates are justified by the anticipated 
benefits that may be afforded to study participants. Refer to the IB for more information. 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Table 3 
Objectives and endpoints 
 
Objectives 
Endpoints1 
Primary 
To evaluate the humoral immune response induced by 
the investigational study intervention 
• 
 titer at Day 29 
• 
Fold increase in 
titer from Day 1 to Day 29 
• 
 seroconversion from Day 1 to Day 29 
• 
 at Day 1 and Day 29 
Secondary 
To evaluate the humoral immune response induced by 
the investigational study intervention 
In a subset3 of participants: 
To evaluate the safety and reactogenicity profile of the 
investigational study intervention 
• 
Occurrence of solicited administration site and 
systemic events within 7 days (i.e., from Day 1 to 
Day 7) after study intervention administration4 
• 
Occurrence of unsolicited AEs within 28 days (i.e., 
from Day 1 to Day 28) after study intervention 
administration4 
• 
Occurrence of SAEs4 within 6 months (i.e., from 
Day 1 to Day 183) after study intervention 
administration 
• 
Occurrence of AESIs4 within 6 months (i.e., from 
Day 1 to Day 183) after study intervention 
administration 
• 
Occurrence of MAAEs4 within 6 months (i.e., from 
Day 1 to Day 183) after study intervention 
administration 
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Objectives 
Endpoints1 
Tertiary 
 
Endpoints are designed for all the participants, unless indicated otherwise in the table. 
AE: adverse event; AESI: adverse event of special interest; 
; MAAE: medically attended 
adverse event; MN: microneutralization; 
; SAE: serious adverse event. 
1 Refer to Table 4 for details of primary and secondary estimands. 
2 For all 
 used to design the investigational study interventions. 
3 Refer to Section 4.1 for the description of subset. 
4 Refer to Section 8.3 for the list of safety events and timeframe for collection. 
 
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Table 4 
Study estimands 
Ref 
# 
Population 
Objectives 
Variable (Endpoint) 
Intercurrent event (ICE)1 
Population level summary 
Description 
Handling strategy 
Primary 
1 Younger 
adults 18-
64 YOA 
and older 
adults 
 65-85 
YOA 
To evaluate the humoral 
immune response induced by 
the investigational study 
intervention  
• 
 titer at Day 29  
• 
Fold increase in 
 titer from Day 
1 to Day 29  
• 
 seroconversion from Day 1 to 
Day 29  
• 
 at Day 1 and 
Day 29  
a) 
Vaccination 
administration errors. 
b) 
Taken prohibited 
medication or 
vaccination prior to 
Day 29 blood draw. 
c) 
Day 29 blood draw 
taken out of allowed 
window3. 
d) 
Medical condition 
forbidden by protocol 
(i.e., either a 
confirmed 
immunodeficiency 
condition, new 
malignancy, or 
development of 
confirmed influenza 
disease) prior to Day 
29 blood draw 
Hypothetical strategy: 
data from participant after 
ICE will be excluded from 
the analysis. 
• 
Between-group geometric 
mean titer (GMT) ratio 
(Flu mRNA candidate over 
Comparator) with 95% 
confidence interval (CI) 
• 
Within-group geometric 
mean increase (GMI) with 
95% CI 
• 
Between-group difference 
in seroconversion rate 
(SCR4) (Flu mRNA 
candidate minus 
Comparator) with 95% CI 
• 
Between-group difference 
in 
 
 (Flu mRNA 
candidate minus 
Comparator) with 95% CI 
 
Secondary 
2 Refer to 1 To evaluate the humoral 
immune response induced by 
the investigational study 
intervention 
Refer to 1 
Refer to 1 
Refer to 1 
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Ref 
# 
Population 
Objectives 
Variable (Endpoint) 
Intercurrent event (ICE)1 
Population level summary 
Description 
Handling strategy 
3 Refer to 1 To evaluate the safety and 
reactogenicity profile of the 
investigational study intervention 
• 
Occurrence of solicited 
administration site and systemic 
events within 7 days (i.e., from Day 
1 to Day 7) after study intervention 
administration  
• 
Occurrence of unsolicited AEs 
within 28 days (i.e., from Day 1 to 
Day 28) after study intervention 
administration  
• 
Occurrence of SAEs within 6 
months (i.e., from Day 1 to Day 183) 
after study intervention 
administration  
• 
Occurrence of AESIs within 6 
months (i.e., from Day 1 to Day 183) 
after study intervention 
administration  
• 
Occurrence of MAAEs within 6 
months (i.e., from Day 1 to Day 183) 
after study intervention 
administration  
Not applicable 
Treatment policy: all data 
collected will be included 
in summaries. 
 
Proportion of participants who 
report each of the endpoint. No 
treatment comparison is 
planned. 
Endpoints are designed for all the participants, unless indicated otherwise in the table. 
AE: adverse event; AESI: adverse event of special interest; CI: confidence interval; GMI: mean geometric increase; GMT: geometric mean titer; 
ICE: 
intercurrent event; MAAE: medically attended adverse event;
 SAE: serious adverse event; SCR: seroconversion rate; 
YOA: 
years of age. 
1 Refer to Section 9.2 for more information on intercurrent events. 
2 All 
 used to design the investigational study intervention. 
3 Study discontinuation, blood sample taken out of window and missing result at pre- or post-dose are not considered intercurrent events and will be handled as missing data. More 
details will be provided in the statistical analysis plan (SAP). 
4 Refer to Section 9.3.1 for definition of SCR and 
 
5 Refer to Section 4.1 for the description of subset. 
 
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4. 
STUDY DESIGN 
4.1. 
Overall design 
Refer to Figure 1 (Section 1.2) for the overview of study design. 
• Study phase: 2a. 
• Single-country, multi-center. 
• Self-contained. 
• Study population: Healthy or medically stable participants aged 18-64 and 65-85 
years of age (Refer to Section 5 for full description of study population). 
• Study interventions: single-dose intramuscular (IM) administration of the 
investigational study intervention or the comparator. 
• 
Comparator: age-appropriate licensed influenza vaccine. 
• 
GSK's Flu Dresden-Quadrivalent Influenza Vaccine, hereafter referred to as Flu 
D-QIV (commercially available as Fluarix Quadrivalent in the US).  
• 
Sanofi's Fluzone High-Dose Quadrivalent Vaccine, hereafter referred to as 
Fluzone HD Quadrivalent (commercially available as Fluzone High-Dose 
Quadrivalent in the US). 
• 
GSK’s Flu Dresden – Influenza Vaccine, hereafter referred to as Flu D-TIV 
(commercially available as Fluarix in the US). 
• 
Sanofi’s Fluzone High-Dose Vaccine, hereafter referred to as Fluzone HD 
(commercially available as Fluzone High-Dose in the US). 
• 
Strains included in study interventions (Flu mRNA formulations and comparators) 
will be based on World Health Organization (WHO) recommendation for influenza 
virus vaccine composition for Northern Hemisphere (NH) 2023-2024 for the initial 
part of the study, and NH 2024-2025 for protocol amendment 2. It should be noted 
that following the recent recommendations from WHO and Food and Drug Agency 
(FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) 
to remove the B/Yamagata strain from influenza vaccine composition [WHO, 2023b; 
FDA, 2023], the Flu mRNA vaccine is now being developed as 
 
The comparators will be licensed quadrivalent vaccines for the initial part of the 
study and licensed trivalent vaccines for protocol amendment 2, in line with the NH 
2023-2024 and NH 2024-2025 recommendations, respectively. 
• 
For the initial part of the study: 5 groups enrolled in parallel for YAs (4 Flu mRNA 
groups and 1 comparator group) and 5 groups enrolled in parallel for OAs (4 Flu 
mRNA groups and 1 comparator group). For protocol amendment 2: 2 groups 
enrolled in parallel for YAs (1 Flu mRNA group and 1 comparator group) and 2 
groups enrolled in parallel for OAs (1 Flu mRNA group and 1 comparator group) 
(Table 5). 
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• 
Planned (approximate) number of participants to be enrolled: 250 YAs (50 
participants per group) and 250 OAs (50 participants per group) in the initial part of 
the study, and 160 YAs (80 participants per group) and 160 OAs (80 participants per 
group) in protocol amendment 2. 
• 
Method of study intervention allocation: a stratified permuted block randomization 
will be used in a 1:1 ratio allocation across groups. The stratification factors will 
include: 
• 
Country 
• 
Age group 
• 
Flu vaccination history in the preceding 2 years 
• 
A subset representing approximately 50% of the total study population, randomly 
selected and equally distributed over the groups, will be defined for this study. This 
subset will be used to further characterize the humoral immune response, i.e., virus 
microneutralization (MN) titers 
. Refer to 
Section 6.3 for more details.  
• Intended duration of the study per participant: approximately 6 months. 
• Aspects of data collection: blood samples, safety events. 
• Method of data collection: 
• 
Standardized electronic Case Report Form (eCRF). 
• 
Solicited events and the occurrence of unsolicited AEs will be collected using an 
electronic Diary (eDiary). Participants, with support from the site, will install the 
eDiary application on their own personal, handheld device (e.g., mobile phone, 
tablet) or the site will provide a device that is pre-programmed with the eDiary. 
• 
The collection of blood samples will be documented with a validated digital 
collection application for sample management. 
• 
Safety monitoring: A blinded medical monitor, designated Safety Lead (or delegate) 
and SRT will continuously monitor available safety data throughout the study. If a 
potential safety concern/signal is identified that requires unblinded review, an 
unblinded internal Safety Review Committee (iSRC), independent from the project, 
will review available safety data. Refer to Section 8.3.6 for more information on 
safety monitoring strategy applicable to this study and to Section 10.1.6 for SRT and 
iSRC composition and role. 
• 
Level of blinding: observer-blind. Refer to Section 6.4 for more information on 
blinding. 
• 
Investigational study interventions 
 
  
. Refer to Section 6.1 for more details on the 
composition of study interventions to be administered. 
 
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Table 5 
Study groups and interventions 
Study groups 
Study interventions 
Flu mRNA_1_YA 
F2G22B/DL001Z1 
Flu mRNA_2_YA 
F2H23D/DL001Z-NH1 
Flu mRNA_3_YA 
F2H23B/DL001Z-NH1 
Flu mRNA_4_YA 
F2H23H/DL001Z1 
Comparator_YA 
FDQ23A-NH (Flu D-QIV) 1,4 
Flu mRNA_9_YA* 
GSK5800544A2 
Comparator_2_YA* 
Flu D-TIV 2,4 
Flu mRNA_5_OA 
F2H23B/DL001Z-NH1 
Flu mRNA_6_OA 
F2H23A/DL001Z-NH1 
Flu mRNA_7_OA 
F2H23H/DL001Z1 
Flu mRNA_8_OA 
F2H23G/DL001Z1 
Comparator_OA 
Fluzone HD Quadrivalent1,4 
Flu mRNA_10_OA* 
GSK5800544A2 
Comparator_2_OA* 
Fluzone HD2,4  
HA: hemagglutinin; 
 
; B-Vic: B/Victoria lineage; YA: younger adult; OA: older adult. 
* Applicable to protocol amendment 2. 
1 Strains used to design study interventions for the initial part of the study are based on WHO recommendation for influenza virus vaccine composition for the 2023-2024 NH season. 
2 Strains used to design study interventions for protocol amendment 2 are based on WHO recommendation for influenza virus vaccine composition for the 2024-2025 NH season. 
3 
GSKVx000000048110; 
 GSKVx000000040033; 
 
GSKVx000000034794; 
: GSKVx000000048111; 
: GSKVx000000034797; 
 GSKVx000000034798. For protocol amendment 2:
 
GSKVx000000048110; 
: GSKVx000000063073;
: GSKVx000000034794; 
: GSKVx000000048111;
 GSKVx000000063074; 
: 
GSKVx000000034798 
4 Refer to Table 6 for the strains used in the comparator vaccines. 
 
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4.2. 
Scientific rationale for study design 
The purpose of this Phase 2a study is to evaluate the immunogenicity and safety of the 
seasonal influenza investigational study interventions and, specifically, 
 
 
  
Note that available clinical immunogenicity and reactogenicity data from this study and 
study FLU SV MRNA-002 have 
 
 
 The objective of protocol amendment 2 
is to consolidate the immunogenicity and reactogenicity data package for this formulation 
in both age groups 
 
The study’s primary objective and endpoints are based on the 
 
. The study is designed as an observer-blind study to ensure 
collection of unbiased safety data for the investigational study interventions to support 
the immunogenicity data findings. 
The investigational study interventions will be compared to licensed seasonal influenza 
vaccines to enable a descriptive comparison of safety and immunogenicity to SoC. The 
comparators will be licensed quadrivalent vaccines for the initial part of the study and 
licensed trivalent vaccines for protocol amendment 2, in line with the NH 2023-2024 and 
NH 2024-2025 recommendations, respectively. The investigational study interventions 
will be 
 to follow the recent recommendations from WHO and FDA VRBPAC to 
remove the B/Yamagata strain from influenza vaccine composition [WHO, 2023b; FDA, 
2023].  
The OA population is disproportionately affected by influenza complications and 
represents a high unmet need. In the study, the investigational study interventions will be 
evaluated in both YAs and OAs to confirm that any immunogenicity findings will be 
applicable for both age categories. The licensed seasonal influenza vaccines included as 
the comparator will be age-appropriate to optimize the SoC comparison. 
As a considerable safety data package in both YAs and OAs (with no safety concerns 
observed at any dose levels evaluated) has been collected in the Phase 1 FLU SV 
MRNA-003 (217895) and Phase 1/2 FLU SV MRNA-002 (217884) studies, all study 
groups in both age categories will be enrolled in this study in parallel without restrictions. 
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4.3. 
Justification for dose 
The purpose of this Phase 2a study is to explore possible ways 
 
 in a 
 HA 
. To achieve 
this, 
 
Previous studies have evaluated 
 
 
. 
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4.4. 
End-of-study definition 
A participant is considered to have completed the study if the participant has completed 
all periods of the study including the last visit or the last scheduled procedure shown in 
the SoA. 
The EoS is defined as the date of the last subject last visit (Visit 3) or date of the last 
testing/reading of human biological samples related to primary and secondary endpoints, 
whichever occurs later. If EoS is not equal to LSLV, it must be achieved no later than 8 
months after LSLV. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
• A male or female between and including 18 and 85 years of age (YAs: 18-64; OAs: 
65-85) at the time of the study intervention administration. INC#1 
• Healthy participants or medically stable patients as established by medical history and 
clinical examination. Participants with chronic medical conditions with or without 
specific treatment (e.g., chronic metabolic, cardiac, pulmonary, renal, hepatic, 
neurologic, and hematologic diseases) are allowed to participate in this study if 
considered by the investigator as medically stable. A stable medical condition is 
defined as disease not requiring significant change in therapy or hospitalization for 
worsening disease during 3 months before enrollment. INC#2 
• Body mass index (BMI) ≥18 kg/m² and ≤35kg/m2. INC#3 
• Participants who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g., completion of the diary cards, return for follow-up 
visits), independently or with the assistance of a caregiver. INC#4 
Note: In case of physical incapacity that would preclude the self-completion of the 
eDiary, either site staff can assist the OA participant (for activities performed during 
site visits) or the participant may assign a caregiver to assist him/her with this 
activity (for activities performed at home or in the long-term care facility). However, 
at no time, the site staff or caregiver will evaluate the participant’s health status 
while answering diaries and/or questionnaires or make decisions on behalf of the 
participant. 
• Written informed consent obtained from the participant prior to performance of any 
study-specific procedure. INC#5 

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• Female participants of non-childbearing potential may be enrolled in the clinical 
study. Refer to Section 10.4.1 for definitions of WOCBP, menarche and menopause. 
INC#6 
• Female participants of childbearing potential may be enrolled in the clinical study, if 
the participant: 
• Has practiced adequate contraception for 1 month prior to the study intervention 
administration, and 
• Has a negative pregnancy test within 24 hours prior to the study intervention 
administration, and 
• Has agreed to continue adequate contraception for at least 1 month after study 
intervention administration. INC#7 
Refer to Section 10.4.1 for definitions of WOCBP and adequate contraception. 
5.2. 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1. 
Medical conditions 
• 
Participant tested positive for influenza by local health authority-approved testing 
methods within 180 days prior to Day 1. EXC#1 
• 
Current or past malignancy, unless completely resolved without sequelae for 
>5 years before the study intervention administration (excluding effectively treated 
basal cell skin cancer). EXC#2 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition 
based on medical history and physical examination (no laboratory testing required). 
HIV-infected individuals may be enrolled if they have been stable on antiretroviral 
therapy for the past 6 consecutive months, i.e., their treatment has not been modified, 
their CD4 cell count is ≥200/mm³ and their viral load has been undetectable (i.e., 
HIV-RNA <50 copies/mL) (based on medical records, no laboratory testing 
required). EXC#3 
• 
Participants with a history of, or current suspicion of myocarditis, pericarditis, or 
idiopathic cardiomyopathy (including a history of myocarditis or pericarditis 
following vaccination with an mRNA COVID-19 vaccine), or presence of any 
medical condition that increases risk of myocarditis or pericarditis, including cocaine 
abuse, cardiomyopathy, endomyocardial fibrosis, hypereosinophilic syndrome, 
hypersensitivity myocarditis, eosinophilic granulomatosis with polyangiitis and 
persistent myocardial infection will be excluded from the study EXC#4 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the study intervention (including polyethylene glycol, egg proteins and 
aminoglycoside antibiotics). EXC#5 
• 
Hypersensitivity to latex. EXC#6 

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• 
Recurrent history or uncontrolled neurological disorders or seizures, including 
Guillain-Barré syndrome and Bell’s palsy, with the exception of febrile seizures 
during childhood. EXC#7 
• 
Any history of dementia or any medical condition that moderately or severely 
impairs cognition. EXC#8 
• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. EXC#9 
• 
Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the participant due to participation in the clinical study. EXC#10 
5.2.2. 
Prior/Concomitant therapy 
• 
Administration of an influenza vaccine within 180 days before enrollment or planned 
administration prior to Visit 2 (Day 29) after the study intervention administration. 
EXC#11 
• 
Previous vaccination with a mRNA influenza vaccine. EXC#12 
• 
Administration of a vaccine not foreseen by the study protocol in the period starting 
30 days (Day -30) before the study intervention administration, or planned 
administration within 28 days (Visit 2 [Day 29]) after the study intervention 
administration*. EXC#13 
*If emergency mass vaccination for an unforeseen public health threat (e.g., a 
pandemic) is recommended and/or organized by public health authorities outside the 
routine immunization program, the time period described above can be reduced, 
provided it is used according to the local governmental recommendations and 
sponsor is notified. 
• 
Use of any investigational or non-registered product (drug, vaccine or invasive 
medical device) other than the study intervention during the period beginning 
30 days before the study intervention administration, or their planned use during the 
study period. EXC#14 
• 
Administration of immunoglobulins and/or any blood products or plasma derivatives 
during the period starting 90 days before the study intervention administration or 
planned administration during the study period. EXC#15 
• 
Chronic administration of immune-modifying drugs (defined as more than 
14 consecutive days in total) and/or planned use of long-acting immune-modifying 
treatments at any time up to the end of the study. 
• Up to 3 months prior to the study intervention administration: 
For corticosteroids, this will mean prednisone equivalent 20 mg/day. Inhaled, 
intraarticular and topical steroids are allowed. 
• Up to 3 months prior to study intervention administration: long-acting immune-
modifying drugs including among others immunotherapy (e.g., TNF-inhibitors), 
monoclonal antibodies, antitumoral medication. EXC#16 

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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 intervention (drug/invasive medical device). EXC#17 
5.2.4. 
Other exclusion criteria 
• 
Pregnant or lactating female participant. EXC#18 
• 
Bedridden participants. EXC#19 
• 
Female participant planning to become pregnant or planning to discontinue 
contraceptive precautions within the 1-month post-dosing period. EXC#20 
• 
History of chronic alcohol consumption and/or drug abuse in the past 5 years as 
deemed by the investigator to render the potential participant unable/unlikely to 
provide accurate safety reports or comply with study procedures. EXC#21 
• 
Any study personnel or their immediate dependents, family, or household members. 
EXC#22 
• 
Participants with extensive tattoos covering deltoid region on both arms that would 
preclude the assessment of local reactogenicity. EXC#23 
5.3. 
Lifestyle considerations 
No lifestyle restrictions are required for this study. 
5.4. 
Screen failures 
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently assigned/randomized to study intervention/entered in the study. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the CONSORT publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes, but not 
limited to informed consent date, demography, screen failure details and eligibility 
criteria. 
5.5. 
Criteria for temporarily delaying administration of study 
intervention 
Study intervention administration may be postponed until transient conditions cited 
below are resolved: 
• 
Acute disease and/or fever at the time of randomization and/or study intervention 
administration. Fever is defined as a temperature ≥ 38.0°C/100.4°F by any route. The 
route for measuring temperature can be oral, axillary or tympanic. The preferred 
location for measuring temperature will be the oral cavity. 

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6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in the DEFINITIONS OF TERMS. 
6.1. 
Study intervention(s) administered 
Investigational study interventions listed in Table 6 
 
 
 
 
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Table 6 
Study intervention(s) administered (table spreading through multiple pages) 
Study intervention 
name 
Flu Seasonal mRNA 
F2H23D/DL001Z-NH 
F2H23B/DL001Z-NH 
F2H23A/DL001Z-NH 
Study intervention 
formulation 
Presentation 
Concentrate for dispersion for 
injection (vial) 
solution for 
dispersion for 
injection (vial 
or ampoule) 
Concentrate for dispersion for 
injection (vial) 
solution for 
dispersion for 
injection (vial 
or ampoule) 
Concentrate for dispersion for 
injection (vial) 
solution for 
dispersion for 
injection (vial 
or ampoule) 
Type 
Biologic 
Biologic 
Biologic 
Use 
Investigational 
Investigational 
Investigational 
Route of 
administration 
IM 
IM 
IM 
Administration site 
• 
Location 
Deltoid 
Deltoid 
Deltoid 
• 
Directionality 
Upper 
Upper 
Upper 
• 
Laterality1 
Non-dominant 
Non-dominant 
Non-dominant 
Number of doses to 
be administered 
1 
1 
1 
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Study intervention 
name 
Flu Seasonal mRNA 
F2G22B/DL001Z 
F2H23G/DL001Z 
F2H23H/DL001Z 
Study intervention 
formulation 
Presentation 
Concentrate for dispersion for 
injection (vial) 
solution for 
dispersion for 
injection (vial 
or ampoule) 
Concentrate for dispersion for 
injection (vial) 
solution for 
dispersion for 
injection (vial 
or ampoule) 
Concentrate for dispersion for 
injection (vial) 
solution for 
dispersion for 
injection (vial 
or ampoule) 
Type 
Biologic 
Biologic 
Biologic 
Use 
Investigational 
Investigational 
Investigational 
Volume to be 
administered by 
dose2 
0.5 mL 
0.5 mL 
0.5 mL 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and 
labeling 
Refer to the pharmacy manual for more details 
Refer to the pharmacy manual for more details 
Refer to the pharmacy manual for more details 
Manufacturer 
GSK Biologicals 
Pfizer 
GSK Biologicals 
Pfizer 
GSK Biologicals 
Pfizer 
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Study intervention 
name 
Flu Seasonal mRNA 
F2G22B/DL001Z 
F2H23G/DL001Z 
F2H23H/DL001Z 
Route of 
administration 
IM 
IM 
IM 
Administration site 
• 
Location 
Deltoid 
Deltoid 
Deltoid 
• 
Directionality 
Upper 
Upper 
Upper 
• 
Laterality1 
Non-dominant 
Non-dominant 
Non-dominant 
Number of doses to 
be administered 
1 
1 
1 
Volume 
to 
be 
administered 
by 
dose2 
0.5 mL 
0.5 mL 
0.5 mL 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging 
and 
labeling 
Refer to the pharmacy manual for more details 
Refer to the pharmacy manual for more details 
Refer to the pharmacy manual for more details 
Manufacturer 
GSK Biologicals 
Pfizer 
GSK Biologicals 
Pfizer 
GSK Biologicals 
Pfizer 
 
Study intervention name 
FDQ23A-NH (Flu D-QIV) 
Fluzone HD Quadrivalent 
Study intervention formulation 
A/Victoria/4897/2022 (H1N1), IVR-238 (15 µg HA); 
A/Darwin/06/2021 (H3N2), IVR-227 (15 µg HA); 
B/Austria/1359417/2021, BVR-26 (15 µg HA); 
B/Phuket/3073/2013 (15 µg HA); Water for injections 
A/Victoria/4897/2022 (H1N1), IVR-238 (60 µg HA); 
A/Darwin/09/2021 (H3N2), SAN-010 (60 µg HA); 
B/Michigan/01/2021 (60 µg HA); B/Phuket/3073/2013 (60 µg 
HA); Sodium phosphate-buffered isotonic sodium chloride 
solution 
Presentation 
Suspension for injection (syringe) 
Suspension for injection (syringe) 
Type  
Combination product 
Combination product 
Use 
Comparator 
Comparator 
Route of administration 
IM 
IM 
 

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Study intervention name 
FDQ23A-NH (Flu D-QIV) 
Fluzone HD Quadrivalent 
Administration site 
• 
Location 
Deltoid 
Deltoid 
• 
Directionality 
Upper 
Upper 
• 
Laterality1 
Non-dominant 
Non-dominant 
Number of doses to be administered 
1 
1 
Volume to be administered by dose2 
0.5 mL 
0.7 mL 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and labeling 
Refer to the pharmacy manual for more details 
Refer to the pharmacy manual for more details 
Manufacturer 
GSK Biologicals 
Sanofi Pasteur 
 
Study intervention 
name 
Flu Seasonal mRNA (protocol amendment 2) 
Comparators (protocol amendment 2) 
GSK5800544A 
Flu D-TIV 
Fluzone HD 
Study intervention 
formulation 
A/Victoria/4897/2022 (H1N1), IVR-
238 (15 µg HA); A/Thailand/8/2022 
(H3N2), IVR-237 (15 µg HA); 
B/Austria/1359417/2021, BVR-26 
(15 µg HA); Water for injections 
A/Victoria/4897/2022 (H1N1), IVR-
238 (60 µg HA); 
A/California/122/2022 (H3N2), 
SAN-022 (60 µg HA); 
B/Michigan/01/2021 (Victoria 
lineage) (60 µg HA); Sodium 
phosphate-buffered isotonic sodium 
chloride solution 
Presentation 
Concentrate for dispersion for injection 
(vial) 
solution for dispersion for 
injection (vial or ampoule) 
Suspension for injection (syringe) 
Suspension for injection (syringe) 
Type 
Biologic 
Combination product 
Combination product 
Use 
Investigational 
Comparator 
Comparator 
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Study intervention 
name 
Flu Seasonal mRNA (protocol amendment 2) 
Comparators (protocol amendment 2) 
GSK5800544A 
Flu D-TIV 
Fluzone HD 
Route of administration 
IM 
IM 
IM 
Administration site 
• 
Location 
Deltoid 
Deltoid 
Deltoid 
• 
Directionality 
Upper 
Upper 
Upper 
• 
Laterality1 
Non-dominant 
Non-dominant 
Non-dominant 
Number of doses to be 
administered 
1 
1 
1 
Volume 
to 
be 
administered by dose2 
0.5 mL 
0.5 mL 
0.5 mL 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and labeling 
Refer to the pharmacy manual for more details 
Refer to the pharmacy manual for 
more details 
Refer to the pharmacy manual for 
more details 
Manufacturer 
GSK Biologicals 
Pfizer 
GSK Biologicals 
Sanofi Pasteur 
HA: hemagglutinin; IM: intramuscular; NH: Northern hemisphere; WHO: World Health Organization  
1 The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the study intervention in the non-dominant arm, an injection in the dominant arm may be 
performed. 
2 Refer to the pharmacy manual for the volume after re-constitution 
 

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Study participants must be observed closely for at least 30 minutes after the 
administration of the study intervention. Appropriate medical treatment must be readily 
available during the observation period in case of anaphylaxis, syncope. 
6.1.1. 
Medical devices 
• 
Licensed vaccines used as comparator in this study are provided as a single-dose pre-
filled syringe (i.e., considered as combination product). 
• 
Other medical devices (not manufactured by or for sponsor, e.g., syringes, 
thermometers) may be provided for use in this study. 
• 
Instructions for medical device use are provided in the study Pharmacy Manual. 
• 
All device deficiencies (including malfunction, use error and inadequate labeling) 
shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.4.9 and Section 10.5) and appropriately managed by 
GSK. 
6.2. 
Preparation, handling, storage, and accountability 
• 
Instructions for the preparation of study interventions are provided in Pharmacy 
Manual. 
• 
The investigator or designee must confirm appropriate conditions (e.g., temperature) 
have been maintained during transit for all study intervention received, and any 
discrepancies are reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply, prepare, or administer study intervention.  
• 
All study intervention must be stored in a secure, environmentally controlled and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
• 
The investigator or authorized site staff is responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). 
• 
Further guidance and information for the final disposition of unused study 
interventions are provided in the Pharmacy Manual. 
6.3. 
Assignment to study intervention 
The randomization order of study intervention assignment is created by a GSK 
Randomization Generation system. A stratified and permuted block approach is 
employed to maintain equal study intervention balance within each stratum. In addition, a 
subset representing approximately 50% of the total study population, will be randomly 
selected and equally represented by study intervention within stratum 
 
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All participants will be centrally randomized to study intervention using a GSK 
Randomization and Trial Supply Management (RTSM) system. Study intervention will 
be assigned randomization number (study intervention number) and dispensed at Visit 1. 
For additional information about the study intervention number allocation or when 
RTSM system is not available, please refer to the Pharmacy Manual. 
6.4. 
Blinding 
This study will be observer-blind. Refer to DEFINITIONS OF TERMS for definition of 
observer-blind. 
The laboratory in charge of sample testing will be blinded to the study intervention 
assignment. Codes will be used to link the participant and study to each sample. There 
will be no link between the study intervention groups and the identity of the participant. 
A participant may continue in the study if that participant’s intervention assignment is 
unblinded.  
GSK’s Global Safety staff may unblind the intervention assignment for any participant 
with an SAE. If the SAE requires that an expedited safety report be sent to one or more 
regulatory agencies, a copy of the report, identifying the participant’s intervention 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy. 
6.4.1. 
Emergency unblinding 
RTSM will be programmed with blind-breaking instructions. In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding 
is warranted, the investigator may, at the investigator’s discretion, contact GSK to discuss 
the situation prior to unblinding a participant’s intervention assignment unless this could 
delay emergency treatment for the participant. If a participant’s intervention assignment 
is unblinded, GSK must be notified within 24 hours of this occurrence. The date and 
reason for the unblinding must be recorded. 
If the investigator is unable to access RTSM, they can contact the GSK helpdesk based 
on the information provided in the Pharmacy Manual. 
A physician other than the investigator (e.g., an emergency room physician) or 
participant/participant’s caregiver or family member may also request emergency access 
to the participant’s study intervention information as per participant card. 

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6.5. 
Study intervention compliance 
When participants are dosed at the site, they will receive study intervention directly from 
the authorized site staff, under medical supervision. The date and time of each dose 
administered in the clinic and the treatment number will be recorded in the source 
documents. 
6.6. 
Dose modification 
Not applicable. 
6.7. 
Continued access to study intervention after the end of the 
study 
Not applicable. 
6.8. 
Treatment of overdose  
Not applicable. 
6.9. 
Prior and concomitant therapy 
At each study visit/contact, the investigator or their delegate should question the 
participant about all medications/products taken, and vaccinations received by the 
participant. 
The following prior and concomitant medication(s)/product(s)/vaccine(s) must be 
recorded in the eCRF: 
• 
All concomitant medications, including vaccines/products, administered after the 
study intervention administration (Day 1) until Visit 2 (Day 29). 
• 
Administration of any influenza vaccine 2 years prior to dosing and up to Visit 3 
(Day 183). 
• 
All concomitant medications leading to withdrawal including vaccines/products, 
administered after the study intervention administration (Day 1) until Visit 3 (Day 
183). Refer to Section 5.2.2 for more information. 
• 
All concomitant medications, which may explain/cause/be used to treat a MAAE 
including vaccines/products administered after the study intervention administration 
(Day 1) until Visit 3 (Day 183). 
• 
All concomitant medications, which may explain/cause/be used to treat an 
SAE/AESI including vaccines/products from Day 1 until Visit 3 (Day 183), as 
defined in Section 8.4.1 and Section 10.3.5. These must also be recorded in the 
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• 
Prophylactic medication (i.e., medication administered in the absence of any 
symptom and in anticipation of a reaction to the vaccination) including any 
antipyretics and/or analgesics from Day 1 to Day 7. 
• 
Vitamins and dietary supplements should not be recorded in the eCRF. 
Any medication or vaccine (including over-the-counter or prescription medicines) that 
the participant is receiving at the time of enrollment or receives during the study must be 
recorded along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
Not applicable. 
7.2. 
Participant discontinuation/withdrawal from the clinical 
study 
A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason). 
A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, or compliance reasons. 
The participant will be permanently discontinued from the study intervention and the 
study at that time. 
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 available for the study analyses. If the participant withdraws 
consent for disclosure of future information, the sponsor may retain and continue to use 
any data collected before such a withdrawal of consent.  
If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 

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The primary reason for participant discontinuation/withdrawal from the study will be 
documented in the eCRF based on the list below: 
• 
AE 
• 
Death 
• 
Lost to follow-up 
• 
Physician decision 
• 
Pregnancy 
• 
Protocol deviation 
• 
Site terminated by Sponsor 
• 
Study terminated by Sponsor 
• 
Withdrawal by participant 
• 
Other (specify). 
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 10.3.5.5). 
7.3. 
Lost to follow-up 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls, and if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• 
Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. Participants who have signed informed 
consent but are not eligible to proceed should be recorded in the eCRF with a status 
of “screen failure.” 
• 
In the event of a significant study-continuity issue (e.g., caused by a pandemic), 
alternate strategies for participant visits, assessments, study intervention distribution 
and monitoring may be implemented by the sponsor or the investigator, as per local 
health authority/ethics requirements. 
Study participants may decide to assign a caregiver to help them complete the study 
procedures. Please refer to the DEFINITIONS 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. 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 1 caregiver enters the data into eDiary to allow for timely completion. 
Caregivers may help the study participants with performing some practical study 
procedures such as receiving or making phone calls to site staff, planning study visits, 
entering participant’s responses into eDiary, transportation to and from the study site etc. 
However, at no time, the caregiver should evaluate the participant’s health status while 
answering diaries or make decisions on behalf of the participant. At the first study visit 
(Visit 1 [Day 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 
participants if they wish to appoint a caregiver or if there were or will be changes of 
caregiver. 
8.1. 
Administrative and baseline procedures 
8.1.1. 
Collection of demographic data  
Record demographic data such as year of birth, sex, race, and ethnicity in the 
participant’s eCRF. 
Collection of sex, race and ethnicity data is necessary to assess and monitor the diversity 
of the trial participants, and to determine if the trial participants are truly representative of 
the impacted population. 

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8.1.2. 
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 the study intervention administration in the eCRF. 
Flu vaccination history for the past 2 years must also be recorded in the eCRF. 
8.1.3. 
Provision of eDiary device or installing of eDiary application on 
participant’s personal device 
Participants will be encouraged to bring their own personal electronic devices (e.g., smart 
phone or tablet) to Visit 1 (Day 1). The study staff will check the compatibility of the 
participant’s device with respect to the eDiary application. 
At Visit 1 (Day 1), with support from the study staff, the participant will install the 
eDiary application on their own electronic device. Participants who do not wish to use 
their own device for study purposes or whose device is incompatible with the eDiary 
application, will be provided an electronic device by the study staff. The provisioned 
devices will have the study eDiary application already installed. 
The eDiary application will be used by the participant to self-report information related to 
their health post-dosing (e.g., solicited events). The study staff will train the participant 
and/or their caregiver (if identified by the study participant) on the use of the eDiary and 
emphasize the importance of completing the eDiary on a daily basis throughout the 
eDiary data collection period. 
Refer to Section 8.4.1 for details of collection of safety information and Section 10.3.5 
for guidelines. 
8.2. 
Immunogenicity assessments 
Planned timepoints for all immunogenicity assessments are provided in the SoA. 
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, initially not planned in this protocol, for further research and/or further 
characterizing the disease or condition studied and/or the immune response of the 
vaccine. To this end, all participants in countries where this is allowed will also be asked, 
at the time of giving consent to join this study, 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. 

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8.2.1. 
Biological samples 
An overall blood volume of approximately 45 mL* will be collected from each 
participant during the entire study period. Refer to Table 7 and SoA for information on 
volumes collected for different assessments. Refer to Laboratory Manual for details on 
collection, processing, storage and shipment of biospecimens. 
* Given that samples at Day 183 will only be collected from participants who did not 
receive a SoC vaccination against seasonal flu after Visit 2 and prior to Day 183, this 
volume represents the maximum volume that will be collected over the study period for 
participants who will have a sample collected at Day 183. 
Table 7 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Blood 
~15 
mL 
Visit 1 (Day 1) 
Blood 
~15 
mL 
Visit 2 (Day 2) 
Blood 
~15 
mL 
Visit 3 (Day 183)1 
1 Blood samples should only be collected for participants who did not receive a SoC vaccination against seasonal flu 
after Visit 2 and prior to this visit. 
8.2.2. 
Laboratory assays 
Table 8 
Laboratory assays 
Test classification 
System 
Component 
Method 
Laboratory 
Humoral Immunity 
Serum 
 
GSK or GSK 
designated lab 
1 In case of technical assay development issue, testing for this strain might not be done. 
Clinical testing with assays supporting tertiary endpoints where analyses might be 
deemed futile due to the other study results might not be performed. 
Additional testing on collected samples might be done to gain a better understanding of 
the vaccine(s), of the clinical study data and/or of the disease. These additional assays 
may not be represented in the objectives/endpoints of the study protocol. 
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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8.2.3. 
Immunological read-outs 
Table 9 
Immunological read-outs 
Blood sampling timepoint 
Group/ Subset 
name1 
No. 
participants 
(approximate) 
Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 1 (Day 1) 
Pre-dose 
All participants 
820  
Subset 
410 
Visit 2 (Day 29) 
Post-dose 
All participants 
820 
Subset 
410 
Visit 3 (Day 183) 
Post-dose 
All participants 
8202 
Subset 
4102 
No = Number. 
1Refer to Section 4.1 for the description of subset 
2 Given that samples at Visit 3 will only be collected from participants who did not receive a SoC vaccination against 
seasonal flu after Visit 2 and prior to this visit, this number represents the maximum number of participants who 
will have a sample collected for the Visit 3. 
8.2.4. 
Immunological correlates of protection (CoP) 
8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA. 
8.3.1. 
Physical examination 
• 
Prior to the study intervention administration at Visit 1 (Day 1), the investigator will 
perform physical examination of the participant including assessment of resting vital 
signs: systolic/diastolic blood pressure, heart rate and respiratory rate after at least 5 
minutes of rest, body weight and height. Vital signs are to be taken before blood 
collection for laboratory tests. 
• 
If the participant reported any pre-existing medical condition, the investigator would 
extend the physical examination according to their medical judgment to ensure that 
the participant meets all the inclusion/exclusion criteria. 
• 
If the investigator determines that the participant’s health on the day of study 
intervention administration temporarily precludes dosing, the visit will be 
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rescheduled. See 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. 
• 
Physical examination at each study visit after the study intervention administration 
visit (Visit 1 [Day 1]) will be performed only if the participant indicates during 
questioning that there might be some underlying pathology(ies) or if deemed 
necessary by the investigator or delegate. 
• 
In case of suspected myocarditis or pericarditis and an unscheduled site visit, the 
investigator will perform physical examination of the participant including 
assessment of resting vital signs: systolic/diastolic blood pressure, heart rate and 
respiratory rate after at least 5 minutes of rest, body weight and height, and blood 
oxygen saturation. 
8.3.2. 
Pre-dosing body temperature 
The body temperature of each participant needs to be measured prior to the study 
intervention administration and recorded in the eCRF. If the participant has fever on the 
day of dosing, the study intervention administration visit will be rescheduled. Refer to the 
SoA (Section 1.3) for the definition of fever for this study and preferred location for body 
temperature measurement. 
8.3.3. 
Warnings and precautions to administration of study intervention 
Warnings and precautions to administration of study intervention must be checked at 
Visit 1 (Day 1) prior to study intervention administration, as specified in SoA. For 
comparators, refer to the approved product label/package insert. 
8.3.4. 
Myocarditis and pericarditis assessment and definitions 
All participants will be educated on the symptoms that might indicate myocarditis or 
pericarditis and will receive guidance on contacting study personnel and seeking medical 
care if any of these symptoms occur. All potential cases of myocarditis or pericarditis 
should undergo diagnostic work and be clinically evaluated as recommended by 
international guidelines (e.g., guidance from the American Heart Association and 
American College of Cardiology). 
Following vaccination, participants reporting at least 1 of the following symptoms must 
contact the study site immediately and must be clinically evaluated: 
• 
acute chest pain, pressure, or discomfort 
• 
dyspnea, shortness of breath or pain with breathing 
• 
palpitations 
• 
syncope. 

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For these participants, if myocarditis or pericarditis is suspected according to the clinical 
judgment of the investigator, an unscheduled site visit should take place, except in case of 
medical emergency in which case the participant should be directed to seek immediate 
medical care as required. 
Based on symptomatology and physical examination, the investigator should arrange an 
electrocardiogram (ECG) and a blood sample for measurement of troponin (troponin I 
and/or troponin T). If no facilities are available on site, referral for ECG and/or troponin 
can be made elsewhere (for example, an emergency room). Referral should be expedited 
if necessary, according to the clinical judgment of the investigator. 
If the ECG and/or troponin testing and/or physical examination show abnormalities (see 
pre-specified abnormalities, Section 10.2), the participant should be referred to a 
cardiologist for further evaluation and management following current practice guidelines 
(e.g., American Heart Association or local standard of care). Where possible, other 
investigations should include echocardiography and/or cardiac MRI. 
For study participants presenting with cardiac symptoms and pre-specified ECG 
abnormalities, and/or abnormal troponin level and/or abnormal physical examination 
consistent with myocarditis or pericarditis, the AE myocarditis/pericarditis should be 
recorded as an AESI and reported to the sponsor within 24 hours. For these study 
participants, the eCRF should be completed with full details of cardiac signs and 
symptoms, physical examination, ECG, and troponin results, as well as results of any 
other investigations carried out (including echocardiography and cardiac MRI, if 
applicable, see Section 10.2 for details). The findings of the investigations should be 
reported to the sponsor within 24 hours of being available. 
Participants who have myocarditis or pericarditis will be followed until resolution of 
symptoms and/or cardiac evaluation has been completed, whichever comes last. 
8.3.5. 
Pregnancy testing 
• 
A urine pregnancy test must be performed for all female participants of childbearing 
potential before the administration of the study intervention. Pregnancy testing must 
be done even if the participant is menstruating at the time of the study visit. The 
study intervention may only be administered if the pregnancy test is negative. 
• 
See Section 8.4.6 for the information on study continuation for participants who 
become pregnant during the study. 
8.3.6. 
Safety monitoring, committees, and pausing criteria 
• 
Participant safety will be continuously monitored by the investigator, the medical 
monitor, the designated Safety Lead (or delegate) and the SRT throughout the study. 
Pertinent findings and conclusions are shared with the product’s SRT for review of 
the overall benefit-risk profile of the product. 
• 
The investigator, medical monitor, designated Safety Lead (or delegate) and SRT are 
blinded to participant treatment assignment. If a potential safety concern/signal is 

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identified that requires unblinded review, an unblinded internal Safety Review 
Committee (iSRC), independent from the project/product, will review available 
safety data. 
• 
The nature and duration of safety monitoring activities are specified in the SoA 
(Section 1.3) and in the endpoints (Section 3). 
Refer to Section 10.1.6 for the SRT and iSRC composition and role. 
8.3.6.1. 
Study pausing criteria 
The investigator and the SRT will monitor safety in a blinded manner, including but not 
limited to the pausing criteria outlined in Table 10. Pausing criteria mean criteria leading 
to a pause in vaccination, to enable expedited review of all information by iSRC and 
Sponsor to assess if a temporary halt of the study is warranted or not. 
To enable prompt response to a situation that could trigger a pause of vaccinations, the 
investigator must notify the Sponsor via the appropriate reporting system or the 
Sponsor’s medical monitor or designee, whichever applies, immediately and no later than 
24 hours after becoming aware of any fatalities, SAEs, Grade 3 solicited or unsolicited 
AEs (within the specified period of follow-up for unsolicited events and considered 
related to vaccination by the investigator), and update the eCRF with relevant 
information on the same day the AE information is collected. 
If a pausing criterion is potentially met based on blinded assessment by the investigator 
and/or SRT, the unblinded iSRC (chair) will confirm as soon as possible and no later than 
within 24 hours from notification whether the pausing criterion is met by assessing if the 
event(s) occurred in the (same) investigational group and impacted participants have not 
received licensed control. Only for pausing criterion 1a (see Table 10 below), the 
investigator must conservatively suspend further dosing at his/her site while this 
assessment occurs. 
Once a pausing criterion is confirmed to be met, the Sponsor will inform the 
investigator(s), triggering a pause in further dosing in all sites and at all dose levels in all 
study groups until iSRC has reviewed the relevant data. iSRC has the right to decide 
which data is unblinded for their review. 
A pause in further dosing can also be recommended by iSRC at any time during the study 
to investigate any potential (safety) concern, regardless of whether any pausing criteria 
were met. 
Once a pause is in place, the Sponsor will expeditiously further evaluate the relevant data, 
and based on iSRC recommendation, will take the decision whether the pause can be 
lifted or whether other steps such as a temporary halt, or modification or stopping of the 
study are required. 
Communications regarding any temporary halt and/or decisions regarding study 
continuation to investigators, relevant Ethics Committees, IRBs and applicable Health 
Authorities will be done as appropriate and in compliance with local regulations. 

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Table 10 
Study pausing criteria 
Pausing 
criteria 
Event 
Number of participants per dose & 
individual investigational study 
group 
(i.e., non-licensed vaccines)  
1a 
Death or any life-threatening SAE for which there is no 
alternative attributable cause as per Investigator assessment 
≥11 
1b 
Any non-life-threatening SAE that is considered related to 
vaccination as per Investigator or Sponsor assessment 
≥11 
1c 
Necrosis at the injection site  
≥11 
1d 
Confirmed myocarditis or pericarditis events not clearly 
attributable to any cause other than study vaccine 
≥11 
1e 
Anaphylaxis, unless clearly attributable to a cause other than 
study vaccine 
≥11 
2a 
Similar (Preferred Terms in same HLT based on MedDRA 
coding) Grade 3 unsolicited AEs, considered related to 
vaccination as per Investigator assessment, with an event 
onset within the specified period of follow-up for unsolicited 
events 
≥22 
AE=Adverse event; HLT = High level term; iSRC = Internal safety review committee; MedDRA = Medical dictionary for 
regulatory activities; SAE = Serious adverse event. 
1 After the first iSRC meeting triggered by the occurrence of this pausing criterion, each additional participant meeting 
this pausing criterion will thereafter trigger a pause and iSRC review. 
2 After the first iSRC meeting triggered by the occurrence of a given pausing criterion for a given event, the iSRC will 
indicate the conditions under which it requires further notification and review of the subsequent same/similar 
events. 
8.4. 
Adverse events, serious adverse events, and other safety 
reporting 
For definitions relating to safety information see Section 10.3. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and other safety 
information and remain responsible for following up all AEs (see Section 8.4.3). This 
includes events reported by the participant (or, when appropriate, by a caregiver). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3 and 
Section 10.5. 
8.4.1. 
Time period and frequency for collecting AE, SAE, and other 
safety information 
All SAEs, AESIs, MAAEs, and AEs leading to withdrawal will be collected from the day 
of study intervention administration (Day 1) until Visit 3 (Day 183) at the time points 
specified in the SoA. 

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SAEs assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) will be collected from 
the time a participant consents to participate in the study. 
All AEs will be collected from the start of study intervention until Day 7 (for solicited 
events) or Day 28 (for unsolicited AEs) at the timepoints specified in the SoA. 
Medical occurrences not linked to the study participation that begin before the start of 
study intervention but after obtaining informed consent will be recorded as medical 
history/current medical conditions, not as AEs. 
Complete list of safety events to be collected in this study and the timeframes for their 
collection and reporting are provided in Table 11. 
Table 11 
Collection and reporting of safety information 
Event 
Pre- 
Dose1 
Dose 
D1 
D7
D28 
D183 
Administration site solicited events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Systemic solicited events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study participation, 
study intervention, or to a 
concurrent GSK medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AESIs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs leading to withdrawal from 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intercurrent medical conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE: adverse event; AESI: adverse event of special interest; MAAE: medically attended adverse event; SAE: serious 
adverse event. 
1 i.e., consent obtained. 
The details on the follow-up of AE and SAE can be accessed in Section 8.4.3. The shaded regions in the table indicate 
time period of data collection. 

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All SAEs will be recorded and reported to the sponsor immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 8.4.5, Section 10.3 and 
Section 10.5. The investigator will submit any updated SAE data to the sponsor within 24 
hours of it being available. 
For the timeframes for reporting AESIs see Section 8.4.5, Table 13. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 11. 
Investigators are not obligated to actively seek information on AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, after a participant has been discharged from the study, the investigator 
must record it in the medical records per the local country requirements. If the 
investigator considers the event to be reasonably related to the study intervention or study 
participation, the investigator must promptly notify the sponsor. 
See Section 8.4.7 for contact information. 
8.4.2. 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AESIs (as defined in  
Section 8.4.4) will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Section 10.3.5.5 and Section 10.5.4.4. 
The investigator should follow-up on influenza-like illness (ILI) cases occurring during 
the study and aim to confirm the diagnosis by local health authority-approved testing 
methods for flu detection. These cases will be considered as intercurrent medical 
conditions and will be managed as described in Section 8.4.1 and Section 9.2. 
8.4.4. 
AESIs 
8.4.4.1. 
Potential immune-mediated diseases (pIMDs) 
pIMDs are a subset of AESIs that include autoimmune diseases and other inflammatory 
and/or neurologic disorders of interest which may or may not have an autoimmune 
etiology. AEs that need to be recorded and reported as pIMDs include those listed in the 
Table 12. 

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In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire, and a list of preferred terms (PTs) and PT codes corresponding to the 
below diagnoses will be available to investigators at study start. 
The investigator(s) must exercise their medical/scientific judgment to determine whether 
other diseases have an autoimmune origin (i.e., pathophysiology involving systemic or 
organ-specific pathogenic autoantibodies) and should also be recorded as a pIMD. In 
addition, the investigator should categorize each pIMD either as a new onset condition (if 
it started following vaccination) or as an exacerbation of a pre-existing chronic condition 
(if it exacerbated following vaccination) in the eCRF. 
Table 12  
List of pIMDs 
Blood disorders and 
coagulopathies 
Cardio-pulmonary inflammatory 
disorders 
Endocrine disorders 
• 
Antiphospholipid syndrome 
• 
Autoimmune aplastic anemia 
• 
Autoimmune hemolytic anemia, 
including: 
• Warm antibody hemolytic 
anemia 
• 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” 
• 
Idiopathic pulmonary fibrosis, 
including: 
• Idiopathic interstitial 
pneumonia (Interstitial lung 
disease, Pulmonary 
fibrosis, Immune-mediated 
pneumonitis) 
• Pleuroparenchymal 
fibroelastosis (PPFE) 
• 
Pulmonary alveolar proteinosis 
(PAP) 
• Frequently used related 
terms include: “pulmonary 
alveolar lipoproteinosis”, 
“phospholipidosis” 
• 
Addison’s disease 
• 
Autoimmune / Immune-
mediated thyroiditis, including: 
• Hashimoto thyroiditis 
(autoimmune 
hypothyroidism, 
lymphocytic thyroiditis) 
• Atrophic thyroiditis  
• Silent thyroiditis  
• Thyrotoxicosis 
• 
Autoimmune diseases of the 
testis and ovary, including: 
• Autoimmune oophoritis 
• Autoimmune ovarian 
failure 
• Autoimmune orchitis 
• 
Autoimmune hyperlipidemia 
• 
Autoimmune hypophysitis 
• 
Diabetes mellitus type I 
• 
Graves’ or Basedow’s 
disease, including: 
• Marine Lenhart syndrome 
• Graves' ophthalmopathy, 
also known as thyroid eye 
disease (TED) or 
endocrine ophthalmopathy 
• 
Insulin autoimmune syndrome 
• 
Polyglandular autoimmune 
syndrome, including: 
• Polyglandular 
autoimmune syndrome 
type I, II and III 
Eye disorders 
Gastrointestinal disorders 
Hepatobiliary disorders 
• 
Ocular Autoimmune / 
Immune-mediated disorders, 
including: 
• Acute macular 
neuroretinopathy (also known 
• 
Autoimmune / Immune-
mediated pancreatitis 
• 
Celiac disease 
• 
Inflammatory Bowel disease, 
including: 
• Crohn’s disease  
• 
Autoimmune cholangitis 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 

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as acute macular outer 
retinopathy) 
• Autoimmune/Immune-mediat
ed retinopathy  
• Autoimmune/Immune-mediat
ed uveitis, including idiopathic 
uveitis and sympathetic 
ophthalmia  
• Cogan's syndrome: an 
oculo-audiovestibular disease 
• Ocular pemphigoid 
• Ulcerative keratitis 
• Vogt-Koyanagi-Harada 
disease 
• Microscopic colitis  
• Terminal ileitis 
• Ulcerative colitis  
• Ulcerative proctitis 
Musculoskeletal and connective 
tissue disorders 
Neuroinflammatory/neuromuscul
ar disorders 
Renal disorders 
• 
Gout, including: 
• Gouty arthritis 
• 
Idiopathic inflammatory 
myopathies, including: 
• Dermatomyositis 
• Inclusion body myositis 
• Immune-mediated necrotizing 
myopathy 
• Polymyositis 
• 
Mixed connective tissue disorder 
• 
Polymyalgia rheumatica (PMR) 
• 
Psoriatic arthritis (PsA) 
• 
Relapsing polychondritis 
• 
Rheumatoid arthritis, including: 
• Rheumatoid arthritis 
associated conditions 
• Juvenile idiopathic arthritis 
• Palindromic rheumatism 
• Still's disease 
• Felty’s syndrome 
• 
Sjogren’s syndrome 
• 
Spondyloarthritis, including: 
• Ankylosing spondylitis 
• Juvenile spondyloarthritis 
• Keratoderma blenorrhagica 
• Psoriatic spondylitis  
• Reactive Arthritis 
• Undifferentiated 
spondyloarthritis 
• 
Systemic Lupus Erythematosus, 
including: 
• Lupus associated conditions 
(e.g., Cutaneous lupus 
erythematosus, Lupus 
nephritis, etc.) 
• Complications such as 
shrinking lung syndrome 
(SLS) 
• 
Acute disseminated 
encephalomyelitis (ADEM) and 
other 
inflammatory-demyelinating 
variants, including:  
• Acute necrotising 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)*, including: 
• Variants such as Miller 
Fisher syndrome and the 
acute motor and sensory 
axonal neuropathy 
(AMSAN) 
• 
Idiopathic cranial nerve 
palsies/paresis and 
inflammations (neuritis), 
including: 
• Cranial nerve neuritis (e.g., 
Optic neuritis) 
• 
Autoimmune/Immune-mediate
d glomerulonephritis, 
including: 
• IgA nephropathy 
• IgM nephropathy 
• C1q nephropathy 
• Fibrillary 
glomerulonephritis 
• Glomerulonephritis rapidly 
progressive 
• Membranoproliferative 
glomerulonephritis 
• Membranous 
glomerulonephritis 
• Mesangioproliferative 
glomerulonephritis 
• Tubulointerstitial nephritis 
and uveitis syndrome 

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• 
Systemic Scleroderma (Systemic 
Sclerosis), including: 
• Raynaud’s syndrome 
• Systemic sclerosis with 
diffuse scleroderma 
• Systemic sclerosis with 
limited scleroderma (also 
known as CREST syndrome) 
• Idiopathic nerve 
palsies/paresis (e.g., Bell’s 
palsy) 
• Melkersson-Rosenthal 
syndrome 
• Multiple cranial nerve 
palsies/paresis 
• 
Multiple Sclerosis (MS), 
including: 
• Clinically isolated syndrome 
(CIS)  
• Malignant MS (the Marburg 
type of MS)  
• Primary-progressive MS 
(PPMS) 
• Radiologically isolated 
syndrome (RIS) 
• Relapsing-remitting MS 
(RRMS) 
• Secondary-progressive MS 
(SPMS) 
• Uhthoff's phenomenon 
• 
Myasthenia gravis, including: 
• Ocular myasthenia 
• Lambert-Eaton myasthenic 
syndrome 
• 
Narcolepsy (with or without 
presence of unambiguous 
cataplexy) 
• 
Peripheral inflammatory 
demyelinating neuropathies 
and plexopathies, including 
• 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), 
including: 
• Acute partial transverse 
myelitis (APTM) 

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• Acute complete transverse 
myelitis (ACTM) 
Skin and subcutaneous tissue 
disorders 
Vasculitis 
Other (including multisystemic) 
• 
Alopecia areata 
• 
Autoimmune / Immune-mediated 
blistering dermatoses, including: 
• Bullous Dermatitis 
• Bullous Pemphigoid  
• Dermatitis herpetiformis  
• Epidermolysis bullosa 
acquisita (EBA)  
• Linear IgA-mediated bullous 
dermatosis (LABD), also 
known as Linear IgA disease 
• Pemphigus 
• 
Erythema multiforme 
• 
Erythema nodosum 
• 
Lichen planus, including: 
• Liquen planopilaris 
• 
Localised Scleroderma 
(Morphoea) 
• Eosinophilic fasciitis (also 
called Shulman syndrome) 
• 
Psoriasis 
• 
Pyoderma gangrenosum 
• 
Reactive granulomatous 
dermatitis, including: 
• Interstitial granulomatous 
dermatitis 
• Palisaded neutrophilic 
granulomatous dermatitis 
• 
Stevens-Johnson Syndrome 
(SJS), including: 
• Toxic Epidermal Necrolysis 
(TEN)  
• SJS-TEN overlap 
• 
Sweet’s syndrome, including: 
• Acute febrile neutrophilic 
dermatosis 
• 
Vitiligo 
• 
Large vessels vasculitis*, 
including: 
• 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: 
• 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) 
• Granulomatosis with 
polyangiitis  
• 
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, 
including: 
• 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 
• 
Immunoglobulin G4 related 
disease 
• 
Langerhans' cell histiocytosis 
• 
Multisystem inflammatory 
syndromes, including: 
• Kawasaki’s disease 
• Multisystem inflammatory 
syndrome in adults 
(MIS-A) 
• Multisystem inflammatory 
syndrome in children 
(MIS-C) 
• 
Overlap syndrome 
• 
Raynaud’s phenomenon 
• 
Sarcoidosis, including: 
• Loefgren syndrome 
• Susac's syndrome 
Note: Table 12 contains diseases/conditions which do not necessarily match MedDRA PTs, given the frequent 
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8.4.4.2. 
Other AESIs 
The following events are also considered as AESIs in this study. 
• 
Severe hypersensitivity reactions within 24 hours after study intervention 
administration 
• 
Myocarditis/pericarditis. Refer to Section 8.3.4 for myocarditis/pericarditis 
assessment and definitions. 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as AESI. Symptoms, signs, or conditions which might (or might not) lead to one 
of the above diagnoses, should be recorded and reported as AEs but not as AESI until the 
final or definitive diagnosis has been made, and alternative diagnoses eliminated or 
shown to be less likely. 
8.4.5. 
Regulatory reporting requirements for SAEs/AESIs 
• 
Prompt notification by the investigator to the sponsor of an SAE/AESI is essential so 
that legal obligations and ethical responsibilities toward the safety of participants and 
the safety of a study intervention under clinical investigation are met. See 
Section 8.4.1 for reporting timeframes. 
• 
For SAEs/AESIs, the investigator must always provide an assessment of causality at 
the time of the initial report, as defined in the Section 10.3.5.3. 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements. 
• 
Investigators have to report to the sponsor pregnancies, medication errors, abuse and 
misuse even in an absence of an AE/SAE as these may be subjected to local 
regulatory reporting requirements for the sponsor. 
• 
Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 

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Table 13 
Timeframes for submitting SAEs, AESIs and pregnancies to GSK 
Type of event 
Initial reports 
Follow-up of relevant information on a 
previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours1,2 
paper/electronic AEs report 
24 hours2 
paper/electronic AEs report 
Pregnancies  
24 hours2 
paper pregnancy notification 
report/electronic pregnancy 
report 
24 hours2 
paper pregnancy follow-up 
report/electronic pregnancy 
report 
AESIs  
24 hours1,3 
paper/electronic AEs report 
24 hours2 
paper/electronic AEs report 
AE = adverse event; AESIs = adverse event of special interest; SAE = serious adverse event. 
1 Paper AEs Report will be dated and signed by the investigator (or designee). For each SAE/AESI, the 
investigator(s) must document in the medical notes that they have reviewed the SAE/AESI and have provided 
an assessment of causality. 
2 Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
3 Timeframe allowed once the investigator determines that the event meets the protocol definition of an AESI.  
8.4.6. 
Pregnancy 
• 
Details of all pregnancies in female participants will be collected after the start of 
study intervention (Visit 1 [Day 1]) and until Visit 3 (Day 183). 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
female participant pregnancy. 
• 
Any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• 
The female participant will be followed to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the female participant and the 
neonate and the information will be forwarded to the sponsor. See Table 13 for 
reporting timeframes. 
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• 
Any female participant who becomes pregnant while participating in the study will 
be allowed to continue the study until the end unless she withdraws consent or the 
investigator decides that it is in the participant’s best interest to be discontinued from 
the study. 

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8.4.7. 
Contact information for reporting SAEs, AESIs, pregnancies and 
study pausing criteria  
Table 14 
Contact information for reporting SAEs, AESIs, pregnancies and 
study pausing criteria 
Study contact for questions regarding SAEs, AESIs, 
pregnancies and SAEs linked to device deficiencies 
Study contact for reporting of study pausing criteria 
Contact GSK’s local and/or medical contacts 
If a pausing criterion is met, the investigator must 
immediately inform the GSK’s local and/or medical 
contacts 
Contacts for reporting SAEs, AESIs, pregnancies 
and SAEs linked to device deficiencies 
Available 24/24 hours and 7/7 days 
ogm28723@gsk.com 
Fax: +32 2 656 8009 
Backup study contact for escalation of study 
pausing criteria 
Refer to the local study contact information document.  
AESI = adverse event of special interest; GSK = GlaxoSmithKline Biologicals SA; SAE = serious adverse event 
8.4.8. 
Participant card 
The investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
always keep the participant card in their possession for the duration of the study. In an 
emergency, this card serves to inform the responsible attending physician 
/caregiver/family member that the participant is in a clinical study and that relevant 
information may be obtained by contacting the investigator(s) or their back up. 
8.4.9. 
Medical device deficiencies 
Medical devices are being provided for use in this study as the study intervention. To 
fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of device deficiency that 
occur during the study with such devices. 
If the site(s) uses non-sponsor medical devices, i.e., medical devices not provided by 
GSK, then the investigators are obligated to report any device deficiencies to the legal 
manufacturer of the devices directly. 
The definition of a medical device deficiency can be found in Section 10.5. 
Note: Deficiencies fulfilling the definition of an AE/SAE will follow the processes 
outlined in Section 10.5 of the protocol. 
8.4.9.1. 
Time period for detecting medical device deficiencies 
• 
Medical device deficiencies that result in an incident will be detected, documented, 
and reported during all periods of the study in which the medical device is used. 
• 
If the investigator learns of any device deficiency at any time after a participant has 
been discharged from the study, and such a deficiency is considered reasonably 

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related to a medical device provided for the study, the investigator will promptly 
notify the sponsor. 
The method of documenting medical device deficiencies is provided in Section 10.5. 
8.4.9.2. 
Follow-up of medical device deficiencies 
• 
Follow-up applies to all participants, including those who discontinue study 
intervention. 
• 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
• 
New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator. 
8.4.9.3. 
Prompt reporting of device deficiencies to the sponsor 
• 
Device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical 
device deficiency. 
• 
The medical device deficiency report form will be sent to the sponsor by email. If 
email is unavailable, then fax should be utilized. 
• 
The sponsor will be the contact for the receipt of device deficiency reports. 
8.4.9.4. 
Regulatory reporting requirements for device deficiencies 
• 
The investigator will promptly report all device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfill the 
legal responsibility to notify appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices being used in clinical 
studies. 
• 
The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC. 
8.5. 
Pharmacokinetics 
Pharmacokinetics is not evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamics is not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 

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8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity assessments 
Immunogenicity is described in Section 8.2. 
8.10. 
Health economics  
Health economics are not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
The SAP will be finalized prior to first participant first visit and it will include a more 
technical and detailed description of the statistical analyses including demography, 
tertiary endpoint analyses and supporting analyses, if applicable. This Section is a 
summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.1. 
Statistical hypotheses 
There is no formal hypothesis testing in this study; where statistical methods are applied, 
the emphasis will be on estimation with 95% confidence intervals (CIs). 

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9.2. 
Analysis sets 
Table 15 
Analysis sets 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened   
All participants who were screened for eligibility.  
Study Population  
Enrolled  
Participants who received the study intervention, had an 
immunogenicity blood draw at pre-dose or were randomized. 
Note that as per good clinical practice (GCP) enrolled 
participants should have completed the informed consent 
process and participants should be eligible before initiating 
any study procedure. 
Note: screening failures (who never passed screening, even 
if rescreened) and participants screened but never enrolled 
into the study (met eligibility but not needed) are excluded 
from the Enrolled analysis set as they did not enter the study. 
Study Population  
Exposed  
All participants who received the study intervention. Analysis 
per group is based on the study intervention administered. 
Safety  
Per Protocol Set (PPS)  All eligible participants who received a study intervention 
dose as per protocol, had immunogenicity results at both Day 
1 and Day 29 for at least 1 vaccine
 antigen, complied with 
Day 1 and Day 29 blood draw intervals (refer to Table 2 ), 
without intercurrent conditions* that may interfere with 
immunogenicity and without prohibited concomitant 
medication/vaccination before Visit 2 (Day 29). 
Immunogenicity data at Day 183 will be censored in case of 
non-compliance with the blood sample visit, in case 
intercurrent conditions* that may interfere with 
immunogenicity have occurred, or if prohibited concomitant 
medication/vaccination were taken before Day 183. The 
analysis will be done according to the study intervention that 
participants received. 
Demography, Immunogenicity  
* Note: Intercurrent medical conditions that may lead to elimination of immunogenicity results from the PPS are the 
occurrence of either a confirmed immunodeficiency condition, new malignancy, or development of confirmed 
influenza disease. 
9.3. 
Statistical analyses 
The primary and secondary endpoints are described in Section 3. The primary analyses of 
immunogenicity endpoints will be based on the PPS. The analysis of reactogenicity and 
safety endpoints will be based on the Exposed Set (ES). All analyses at interim will be 
based on ES. 
All analyses will be done separately for OAs and YAs, unless specified otherwise. 
Missing data will not be imputed unless otherwise indicated. 
CCI

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9.3.1. 
Definitions 
Abbreviation/term 
Definition 
 SCR  
The percentage of dosed participants who have either a 
pre-dose titer <1:10 and 
a post-dosing 
titer 
or a pre-dose 
 titer 
and at least a 
 
increase in post-dosing 
 titer. 
 SCR  
  
The percentage of dosed participants with a 
 ≥1:40. 
SCR: seroconversion 
rate; 
. 
9.3.2. 
Primary and secondary endpoints analyses  
9.3.2.1. 
Analysis of immunogenicity endpoints  
The group differences between each investigational study intervention candidate and the 
comparator group will be assessed separately as follows for each 
 antigen: 
• 
At each post-dosing timepoint and for each age group separately, the 2-sided CI for 
between-group GMT ratio between investigational study intervention and (over) the 
comparator group will be derived from an ANCOVA model on log10 transformed 
concentration. The ANCOVA model will include group (i.e., each of the 
investigational study intervention and the comparator group), actual age of 
participants, country, flu vaccination history in the preceding 2 years, and log10-
transformed titer at pre-dosing as fixed effects. The adjusted GMT and GMI in each 
group will be obtained from the same model with 95% CI. Missing data will not be 
replaced.  
• 
For a given age group, the 2-sided 95% CI for the group difference in SCR between 
an investigational study intervention and (minus) the comparator group will be 
computed at Day 29 based on the method of Miettinen and Nurminen [Miettinen, 
1985]. 
• 
For 
 only: the percentage of participants achieving 
, defined as 
having post-dosing titer 
 will be summarized by age group with associated 
exact 95% CI. 
Titer values below the assay 
 will be replaced by 
. 
All analyses will be performed separately for each age group and study part (where part 1 
consists of the study groups in the initial part of the study and part 2 consists of the study 
groups in the protocol amendment 2), unless otherwise indicated. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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9.3.2.2. 
Analysis of reactogenicity and safety endpoints  
The percentage of participants reporting each individual solicited administration site 
event (any grade, Grade ≥2, Grade 3 and MAAEs) and solicited systemic event (any 
grade, Grade ≥2, Grade ≥3 and MAAEs) within the 7-day follow-up period (i.e., Day 1-
Day 7 post-dosing) will be tabulated for each group according to the maximum grade in 
Day 1-Day 7 period. 
The same summaries will be generated for any administration site solicited events, any 
systemic solicited events, and any solicited events. 
When available, information related to solicited events (e.g., occurrence, grading) 
collected by study staff when daily eDiary is missing/incorrect will be used in these 
summaries. 
The verbatim reports of unsolicited AEs will be reviewed by a qualified person and the 
signs and symptoms will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) Dictionary for Adverse Reaction Terminology. Every verbatim 
term will be matched with the appropriate PT. The percentage of participants with any 
unsolicited AEs within the 28-day follow-up period (i.e., Day 1 to Day 28 post-dosing) 
with its exact 95% CI will be tabulated by group and by MedDRA PT and System Organ 
Class (SOC). Similar tabulation will be done for Grade 3 unsolicited AEs, for any 
causally related unsolicited AEs, for Grade 3 causally related unsolicited AEs and for 
unsolicited AEs resulting in a medically attended visit. 
The percentage of participants with at least 1 report of SAE, with at least 1 report of 
MAAE and with at least 1 report of AESI, respectively, classified by the MedDRA SOC 
and PT and reported from Day 1 up to study end will be tabulated with exact 95% CI. 
The percentage of participants using concomitant medication (any medication, any 
antipyretic and any antipyretic taken prophylactically, respectively) during the 28-day 
follow-up period (i.e., Day 1 to Day 28 post-dosing) will be summarized by group. 
9.4. 
Interim analyses 
9.4.1. 
Sequence of interim analyses and other planned analyses 
In addition to the analyses detailed below, additional analyses (e.g., safety analyses) may 
be conducted to support the SRT and iSRC decisions, as described in Section 8.3.6. Refer 
to the Section 10.1.6 for the SRT and iSRC roles. 
A primary completion analysis (PCA) is foreseen and will be conducted upon availability 
of all primary and secondary endpoints up to Day 29 for participants enrolled in parallel 
in the 4 Flu mRNA groups and 1 comparator group per age category of the initial part of 
the study 
  
An interim analysis will be conducted upon availability of all primary and secondary 
endpoints up to Day 29 for participants enrolled in parallel in 1 Flu mRNA group and 1 
CCI

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comparator group per age category of protocol amendment 2 to enable consolidation of 
the immunogenicity and reactogenicity data package for the selected dose formulation 
 An additional interim analysis will be 
performed based on availability of safety endpoints up to last visit (Day 183) for 
participants enrolled in the initial part of the study.  
A restricted study team will be unblinded to individual participant data and all efforts will 
be made to ensure the participants, investigators and monitoring staff blinding is 
maintained up to study end. The rest of the study team will have access to aggregated 
unblinded summaries but will remain blinded to individual participant data and treatment 
assignment until the end of the study. It is possible, however, due to the limited sample 
size, that unblinding occurs for a few participants having a specific AE or SAE (e.g., an 
AE/SAE occurring only in a single participant). Therefore, anyone having access to the 
results could become unblinded regarding those few specific cases. 
Note that the Day 29 interim analysis will be triggered once the planned number of 
subjects have had up to Day 29 safety follow-up and immunogenicity blood draw 
collected. Considering potential over-enrolments, all other participants not included in 
this analysis, will be included in the final analysis. 
A final analysis with all primary and secondary endpoints obtained until the last visit 
(Day 183) will be performed and made available to the investigators and submitted to 
regulatory authorities, as appropriate. 
Analysis of tertiary endpoints may be performed at a later stage. 
9.5. 
Sample size determination 
The primary objective is to explore how the different candidates of Flu mRNA vaccine 
compare to licensed comparator group(s). 
In the initial part of the study, the sample size of 47 evaluable participants in each dose 
level cohort and age group, is expected to provide a 95% CI for group difference in SCR 
with a lower half-width ≤ 20% for difference in SCR for the different strains (Table 16) 
and a 95% CI with an expected half-width of 1.6 fold for the group GMT ratio 
considering a population standard deviation of 0.5 in log10 transformed GMT post-dosing 
and 5% of unevaluable participants per group. 
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Table 16 
Half-width of 95% CI for the group difference in seroconversion 
rates by comparator and 
 (Evaluable N per group = 47) 
Comparator 
Proportion (%)1 
95% CI of Proportion (%)1 
Lower Half-width of  
95 CI (%) 
Flu D-QIV 
59.3 
57.5; 61.1 
20 
Flu D-QIV  
76.2 
72.3; 79.6 
18 
Flu D-QIV  
68.3 
63.6; 72.8 
19 
Fluzone HD 
Quadrivalent 
43.3 
39.4; 47.3 
19 
Fluzone HD 
Quadrivalent 
51.0 
48.3; 52.9 
20 
Fluzone HD 
Quadrivalent 
62.0 
50.1; 71.8 
20 
 
 
Flu D-QIV: GSK's Flu Dresden-Quadrivalent Influenza Vaccine; Fluzone HD Quadrivalent: Sanofi’s Fluzone High-Dose 
Quadrivalent Vaccine.  
In part 2 of the study (protocol amendment 2), a sample size of 76 evaluable participants 
in each study group and age group, is expected to provide a 95% CI for group difference 
in SCR with a lower half-width ≤ 16% for difference in SCR for the different strains 
(Table 17) and a 95% CI with an expected half-width of 1.45 fold for the group GMT 
ratio considering a population standard deviation of 0.5 in log10 transformed GMT post-
dosing and 5% of unevaluable participants per group. The increased sample size is aimed 
at increasing the level of precision for the estimated CIs. 
Table 17 
Half-width of 95% CI for the group difference in seroconversion 
rates by comparator and 
 in part 2 of the study (protocol 
amendment 2) (Evaluable N per group = 76) 
Comparator 
Proportion (%)1 
95% CI of Proportion (%)1 
Lower Half-width of  
95 CI (%) 
Flu D-TIV 
59.3 
57.5; 61.1 
16 
Flu D-TIV  
76.2 
72.3; 79.6 
14 
Flu D-TIV  
68.3 
63.6; 72.8 
15 
Fluzone HD 
43.3 
39.4; 47.3 
15 
Fluzone HD 
51.0 
48.3; 52.9 
16 
Fluzone HD 
62.0 
50.1; 71.8 
16 
 
 
Flu D-TIV: GSK's Flu Dresden Influenza Vaccine; Fluzone HD: Sanofi’s Fluzone High-Dose Vaccine.  
 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines. 
• Applicable ICH GCP guidelines. 
• Applicable laws and regulations. 
• 
The protocol, protocol amendments, ICF, IB and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• 
Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
The investigator will be responsible for the following, as applicable: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures. 
• 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, 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 
course of the study and for 1 year after completion of the study. 

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10.1.3. 
Informed consent process 
• 
The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participants and answer all questions 
regarding the study. 
• 
Potential participants must be informed that their participation is voluntary. They 
will be required to physically sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection (e.g., HIPAA and GDPR requirements), where applicable, and the 
IRB/IEC or study center. 
• 
Sample testing will be done in accordance with the recorded consent of the 
individual participant. 
• 
By default, collected samples for the study will be stored for a maximum of 20 years. 
This storage period begins when the last participant completes the last study visit. 
This timeline can be adapted based on local laws, regulations or guidelines requiring 
different timeframes or procedures. In all cases, the storage period should be aligned 
with participant’s consent. These additional requirements must be formally 
communicated to, discussed and agreed with GSK.  
• 
The medical record must include a statement that physical informed consent was 
obtained before the participant was enrolled in the study and the date the physical 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• 
Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
• 
A physical copy of the ICF(s) must be provided to the participant. 
The ICF will contain a separate section that addresses the use of remaining samples for 
optional further research related and not related to this study. The investigator or 
authorized designee will explain to each participant the objectives of the further research. 
Participants will be told that they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the storage period. 
In case of unexpected pregnancy, participant must be informed that personal information 
(PI) such as date of birth, sex of the baby will be collected as part of safety follow-up. 
Consent for collection of information about the baby may be obtained from the 
participant and/or their partner as per local regulations. 
10.1.4. 
Recruitment strategy 
Printed and digitalized advertising and recruitment materials may be used to support 
recruitment. 
All advertisement and participant’s facing materials will be approved as per local 
regulations before their use. 

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10.1.5. 
Data protection 
• 
Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• 
Validated digital collection application will be used by sites to track collection of 
laboratory samples. Participant’s identification number and individual QR code will 
be used to identify blood samples at the time of sample collection/processing. 
However, no personal information or lab data will be captured in this application. 
• 
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. 
• 
The participant must be informed that their personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant, that their data will be used as described in 
the informed consent. 
• 
The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• 
The contract between sponsor and study sites specifies responsibilities of the parties 
related to data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure 
or access.  
• 
GSK has a global, internal policy that requires all GSK staff and complementary 
workers to report data incidents or breaches immediately, using dedicated tools. 
Clear procedures are defined for assessing and investigating data breaches to identify 
and to take appropriate remediation steps, to contain and to mitigate any risks for 
individuals resulting from a breach, in compliance with applicable laws. 
10.1.6. 
Committees structure 
• 
A SRT is in place for each GSK product. It comprises a global cross-functional team 
responsible for the ongoing assessment of benefit-risk for a product. The SRT 
contribute to the continual assessment of incoming new efficacy and safety 
information. The SRT includes safety, clinical, and statistics experts from GSK . The 
role of the SRT is to oversee the safety of participants and study conduct (in blinded 
fashion). 

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• 
The iSRC is a cross-functional committee including safety, clinical, and statistics 
experts from GSK. The iSRC members are independent of the project. The role of 
the iSRC is to oversee the safety of participants and study conduct if unblinded 
review is required. 
For more details, refer to the SRT framework and the iSRC charter. 
10.1.7. 
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 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 (adult population). 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, including a summary of trial results 
understandable to laypersons. The investigator is encouraged to share the layperson 
summary of results with the study participants, as appropriate. The full study report 
will be made available upon request, after decision on marketing authorization by 
regulatory authorities. 
• 
Where required by regulation, the names of the sponsor signatory and investigator 
signatory will be made public. 
• 
GSK will provide the investigator with the randomization codes and participant-level 
line listings for their site only after completion of the full statistical analysis. 
• 
GSK intends to make anonymized participant-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. Data will be shared with researchers in a non-
identifying way, and appropriate measures will be taken to protect PI; these measures 
will comply with data protection and privacy laws that apply. 
10.1.8. 
Data quality assurance 
• 
All participant data relating to the study will be recorded on printed or eCRFs 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. 
• 
Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 

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• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• 
Quality Tolerance Limits (QTLs) will be predefined in the QTL Report to identify 
systematic issues that can impact participant right, safety and/or reliability of study 
results. These predefined parameters will be monitored during the study, and 
important deviations from the QTLs and remedial actions taken will be summarized 
in the Clinical Study Report (CSR). 
• 
Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring, 
involvement of central reading mechanism) methods, responsibilities, and 
requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on site monitoring) are provided in the monitoring 
plan. 
• 
The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for a minimum period of 15 years from the issue 
of the final CSR/equivalent summary, or in accordance with applicable law, 
whichever is longer. 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. In the event of a 
conflict between this protocol and the fully executed clinical study agreement, the 
protocol shall prevail with respect to records retention. 
10.1.9. 
Source documents 
• 
For this study there will be no source data recorded directly into the eCRF (i.e., no 
prior written or electronic record of data is available).  
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the eCRF/eDiaries or entered in the eCRF/eDiaries that are 
transcribed from source documents must be consistent with the source documents or 
the discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
• 
For this study there will be source data recorded directly into the validated digital 
collection application for samples management (i.e., sample identifier). Data 
reported in the digital collection application or entered in it that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
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• 
Definition of what constitutes source data and its origin can be found in 
DEFINITIONS OF TERMS. 
• 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• 
The sponsor or designee will perform monitoring to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and 
that the study is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
10.1.10. 
Study and site start and closure 
Start of study and first act of recruitment 
The start of study and the first act of recruitment are defined as FSFV (first ICF signature 
date) at a country-level. 
Study/Site termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• 
Discontinuation of further study intervention development. 
For site termination: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines. 
• 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator. 
• 
Total number of participants included earlier than expected. 
If the study is prematurely terminated or temporarily 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 
temporary suspension, as specified by the applicable regulatory requirements. The 

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investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up. 
10.1.11. 
Publication policy 
GSK seeks to publish medically or scientifically significant results in searchable peer-
reviewed scientific literature within 18 months from LSLV. We follow International 
Committee of Medical Journal Editors standards for authorship and use Good 
Publications practices to guide our publications. 
10.2. 
Appendix 2: Myocarditis and pericarditis  
10.2.1. 
Myocarditis and pericarditis workflow 
 
*Abnormalities triggering cardiology referral 
** AESIs will be referred for independent evaluation and diagnosis of myocarditis and pericarditis 
Abnormalities triggering cardiology referral include: 
1. Electrocardiogram abnormalities: 
• 
ST-segment or T-wave abnormalities; 
• 
Paroxysmal or sustained atrial, supraventricular, or ventricular arrhythmias; or 

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• 
AV nodal conduction delays or intraventricular conduction defects. 
• 
PR-depression 
2. Troponin level above upper limit of normal (any type of troponin) 
3. Pericardial rub on physical examination 
10.2.2. 
Case definitions of probable and confirmed myocarditis, 
pericarditis, and myopericarditis 
Condition 
Definition 
Acute myocarditis 
Probable case 
Confirmed case 
Presence of ≥1 new or worsening of the 
following clinical symptoms:1 
• 
Chest pain, pressure, or discomfort  
• 
Dyspnea, shortness of breath, or pain 
with breathing  
• 
Palpitations 
• 
Syncope 
Presence of ≥1 new or worsening of the 
following clinical symptoms:1 
• 
Chest pain, pressure, or discomfort  
• 
Dyspnea, shortness of breath, or pain 
with breathing  
• 
Palpitations 
• 
Syncope 
AND 
AND 
≥1 new finding of:  
• 
Troponin level above upper limit of 
normal (any type of troponin) 
• 
Abnormal ECG or rhythm monitoring 
findings consistent with myocarditis3 
• 
Abnormal cardiac function or wall motion 
abnormalities on echocardiogram  
• 
Cardiac MRI findings consistent with 
myocarditis4 
≥1 new finding of:  
• 
Histopathologic confirmation of 
myocarditis2 
• 
Cardiac MRI findings consistent with 
myocarditis4 in the presence of troponin 
level above upper limit of normal (any 
type of troponin) 
AND 
AND 
No other identifiable cause of the symptoms 
and findings 
No other identifiable cause of the symptoms 
and findings 
Acute pericarditis5 
Presence of ≥2 new or worsening of the following clinical features:  
• 
Acute chest pain6 
• 
Pericardial rub on exam  
• 
New ST-elevation or PR-depression on ECG  
• 
New or worsening pericardial effusion on echocardiogram or MRI  
Myopericarditis 
This term may be used for patients who meet criteria for both myocarditis and pericarditis.  
MRI: magnetic resonance imaging; ECG: electrocardiogram 
1 Persons who lack the listed symptoms but who meet other criteria may be classified as subclinical myocarditis 
(probable or confirmed). 
2 Using the Dallas criteria [Aretz, 1987]. Autopsy cases may be classified as confirmed clinical myocarditis on the basis 
of meeting histopathologic criteria if no other identifiable cause. 
3 To meet the ECG or rhythm monitoring criterion, a probable case must include at least one of 1) ST-segment or T-
wave abnormalities; 2) Paroxysmal or sustained atrial, supraventricular, or ventricular arrhythmias; or 3) AV nodal 
conduction delays or intraventricular conduction defects. 
4 Using either the original or the revised Lake Louise criteria [Ferreira, 2018]. 
5 Refer to Adler et al. [Adler, 2015]. 

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6 Typically described as pain made worse by lying down, deep inspiration, or cough, and relieved by sitting up or 
leaning forward, although other types of chest pain might occur. 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting 
10.3.1. 
Definition of AE 
AE definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events meeting the AE definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
Significant failure of an expected pharmacologic or biological action. 
• 
Events that occur as a result of protocol-mandated procedures (i.e., invasive 
procedures, modification of participant’s previous therapeutic regimen). 

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Events NOT meeting the AE definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (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 
diseases 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. 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. 
Results in death. 
b. Is life-threatening. 
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, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
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 AE. 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. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity. 
• 
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, 

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influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant. 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy). 
g. Is a suspected transmission of any infectious agent via an authorized medicinal 
product. 
h. Other situations: 
• 
Possible Hy’s Law case: ALT ≥3x ULN AND total bilirubin ≥2x ULN (for 
participants with known Gilbert’s syndrome these criteria only apply if total 
bilirubin ≥2xULN, and direct bilirubin ≥2xULN and at least doubled from baseline 
value) or INR >1.5 must be reported as SAE. 
• 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
10.3.3. 
Solicited events  
• 
Definition of solicited event 
• 
Solicited events are predefined administration site events and systemic events for 
which the participant is specifically questioned, and which are noted by the 
participant in their eDiary. 
a. Solicited administration site events 
The following administration site events will be solicited: 
Table 18 
Solicited administration site events 
All age groups 
Pain at administration site 
Redness at administration site 
Swelling at administration site 
Lymphadenopathy1 
1 Defined as localized axillary, cervical or supraclavicular swelling or tenderness ipsilateral to the injection arm. 
b. Solicited systemic events 
The following systemic events will be solicited: 

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Table 19  
Solicited systemic events 
Fever 
Headache 
Myalgia (muscle pain) 
Arthralgia (joint pain) 
Fatigue (tiredness) 
Chills 
Note: Participants will be instructed to measure and record the temperature in the 
evening. If additional temperature measurements are taken at other times of the day, 
participants will be instructed to record the highest temperature in the eDiary. The 
preferred location for measuring temperature will be the oral cavity. 
10.3.4. 
Unsolicited AE  
• 
Definition of unsolicited AE 
• 
An unsolicited AE is an AE that was either not included in the list of solicited 
events or could be included in the list of solicited events but with an onset outside 
the specified period of follow-up for solicited events. Unsolicited AEs must have 
been communicated by participant who has signed the informed consent. 
Unsolicited AEs include both serious and nonserious AEs. 
• 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare 
provider). The participant will be instructed to contact the site as soon as possible 
to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant concern. Detailed information about reported 
unsolicited AEs will be collected by qualified site personnel and documented in 
the participant’s records. 
• 
Unsolicited AEs that are not medically attended nor 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. 
Recording, assessment, and follow-up of AEs, SAEs, AESIs, and 
pregnancies  
10.3.5.1. 
AE and SAE recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the paper Expedited Adverse Events 
Report/eCRF. 

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• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant identifier, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
An eDiary will be used in this study to capture solicited administration site or systemic 
events and the occurrence of unsolicited AEs. 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. 
For each solicited and unsolicited AE the participant experiences, the participant will be 
asked if they received medical attention (defined as unscheduled visit to or from medical 
personnel for any reason, including emergency room visits). This information will be 
recorded in the participant’s eDiary and in the participant’s eCRF as part of normal AE 
reporting (for unsolicited AEs). If the collection of solicited events was not possible for 
any reasons via the eDiary and solicited events were reported to the investigator by the 
participant, then it would be possible for it to be reported directly to the site staff and 
submitted (e.g., via the eCRF). Medical attention received for SAEs/AESIs will have to 
be reported using the normal AE reporting process in the eCRF. 
If any individual other than the participant is making entries in the eDiary, their identity 
must be documented in the participant’s source record. 
All solicited events that occur during 7 days following administration of the dose of study 
intervention (Day 1 to Day 7) must be recorded into the eDiary, irrespective of intensity. 
An automatic reminder to complete the eDiary will be sent to the participants during this 
time frame. The solicited events ongoing at Day 7 will be followed up until resolution 
using eDiary. 
The occurrence of all unsolicited AE during 28 days following the administration of the 
dose study intervention (Day 1 to Day 28) must be recorded into the eDiary. An 
automatic reminder to complete the eDiary will be sent to the participants during this 
time frame. 
eDiary device should be returned to the site after the end of the relevant data collection 
period on Day 29 (Visit 2)*. If eDiary application was installed on participant’s own 
device, it must be uninstalled after Day 29*. 
*The return of the eDiary might be postponed if the solicited event is ongoing beyond 
Day 28. 
Daily eDiary compliance will be checked by the investigator or delegate on the eDiary 
portal. In case of non-compliance, the investigator should contact the participant to 

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remind the importance of daily entries. All other AEs occurring within this time frame 
should be recorded into the appropriate section of the eCRF, irrespective of their intensity 
or whether or not they are considered related to the study intervention. 
After review and verbal discussion of the eDiary entries with the participant, if there are 
eDiary errors, the investigator will complete his/her own assessment in the relevant 
sections of the eCRF. 
Any unreturned eDiary will be sought from the participant through telephone call(s) or 
any other convenient procedure. 
10.3.5.2. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE, AESI, SAE, and 
device deficiency reported during the study and assign it to one of the following 
categories: 
• 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
• 
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
• 
Severe: 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
The intensity of the following solicited events will be assessed as described: 
Table 20  
Intensity scales for solicited events in participants of 6 years of age 
or more 
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 site1 
0 
<25 mm 
1 
≥25 - ≤50 mm 
2 
≥51 - ≤100 mm 
3 
>100 mm 
Swelling at administration site1 
0 
<25 mm 
1 
≥25 - ≤50 mm 

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Event 
Intensity grade 
Parameter 
2 
≥51 - ≤100 mm 
3 
>100 mm 
Lymphadenopathy2 
0 
None 
1 
Mild: lymphadenopathy present but does not interfere with 
activity  
2 
Moderate: lymphadenopathy that interferes with normal 
activity 
3 
Severe: lymphadenopathy that prevents normal activity 
Fever3 
0 
<38.0°C (100.4°F) 
1 
≥38.0°C (100.4°F) - ≤38.4°C (101.1°F) 
2 
≥38.5°C (101.2°F) - ≤38.9°C (102.0°F) 
3 
≥39°C (102.1°F) 
Headache 
0 
None 
1 
Mild: Symptom is present but does not interfere with 
activity. 
2 
Moderate: Interferes with normal activity. 
3 
Severe: Prevents normal activity. 
Myalgia (muscle pain) 
0 
None 
1 
Mild: Symptom is present but does not interfere with 
activity. 
2 
Moderate: Interferes with normal activity. 
3 
Severe: Prevents normal activity. 
Arthralgia (joint pain) 
0 
None. 
1 
Mild: Symptom is present but does not interfere with 
activity. 
2 
Moderate: Interferes with normal activity. 
3 
Severe: prevents normal activity. 
Fatigue 
0 
None 
1 
Mild: Symptom is present but does not interfere with 
activity. 
2 
Moderate: Interferes with normal activity. 
3 
Severe: Prevents normal activity. 
Chills 
0 
None 
1 
Mild: chills present but do not interfere with activity 
2 
Moderate: chills that interfere with normal activity 
3 
Severe: chills that prevent normal activity 
1 Greatest surface diameter in mm. 
2 Defined as localized axillary, cervical or supraclavicular swelling or tenderness ipsilateral to the administration arm. 
3 Refer to the SoA for the definition of fever and the preferred location for temperature measurement. 
10.3.5.3. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each unsolicited AE/SAE/AESI/device deficiency. The 
investigator will use clinical judgment to determine the relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 

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• 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• 
The investigator must review and provide an assessment of causality for each 
unsolicited AE/SAE and document this in the medical notes. There may be situations 
in which an SAE has occurred and the investigator has minimal information to 
include in the initial report to GSK. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to GSK. 
• 
The investigator may change their opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.3.5.4. 
Assessment of outcomes 
The investigator will assess the outcome of all serious and nonserious unsolicited AEs 
recorded during the study as: 
• 
Recovered/resolved. 
• 
Recovering/resolving. 
• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal (SAEs only). 
10.3.5.5. 
Follow-up of AEs, SAEs, AESIs, pregnancies or any other events of 
interest 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any postmortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
After the initial AE/SAE/AESI/pregnancy or any other event of interest, the investigator 
is required to proactively follow each participant at subsequent visits/contacts. 

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All SAEs, and AESI (as defined in the Section 8.4.4), will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up. 
Other nonserious AEs must be followed until Day 183 or until the participant is lost to 
follow-up. 
Follow-up during the study 
AEs/AESIs/SAE 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-study (Day 183) 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 postmortem findings, including 
histopathology. 
Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the paper pregnancy follow-up 
report/electronic pregnancy report and the AE Report if applicable. Generally, the follow-
up period does not need to be longer than 6 to 8 weeks after the estimated date of 
delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it should always be reported as such. 
Furthermore, the investigator must report any SAE occurring as a result of a post-study 
pregnancy that is considered by the investigator to be reasonably related to the study 
intervention, to GSK as described in the Section 10.3.5.7. 
10.3.5.6. 
Updating of SAE, AESI and pregnancy information after removal of 
write access to the participant’s eCRF 
When additional SAE, AESI or pregnancy information is received after write access to 
the participant’s eCRF is removed, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be sent to the study contact for reporting SAEs (see Section 8.4.3). 
10.3.5.7. 
Reporting of SAEs, AESIs, and pregnancies 
SAE reporting to GSK via an electronic data collection tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 

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• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, pregnancy exposure, related to any GSK product that is not part of 
the study design, they will report these events to GSK or to the concerned CA via the 
national spontaneous reporting system. These will be classified as spontaneous 
individual case safety reports (ICSRs). 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
SAE reporting to GSK via paper data collection tool 
• 
Email/facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of email/facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
10.4. 
Appendix 4: Contraceptive and barrier guidance 
10.4.1. 
Definitions 
10.4.1.1. 
WOCBP 
Women in the following categories are considered WOCBP (fertile): 
• 
Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective 
of the occurrence of menarche or following menarche. 
• 
From the time of menarche until becoming postmenopausal unless permanently 
sterile (see below). 
Note: Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty including breast development and 
pubic hair growth. 

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10.4.1.2. 
Women of non-childbearing potential (WONCBP) 
Women in the following categories are considered WONCBP: 
• 
Premenarchal: Tanner stage 1 (prepubertal). 
• 
Permanently sterile due to one of the following procedures: 
a. Documented hysterectomy. 
b. Documented bilateral salpingectomy. 
c. Documented bilateral oophorectomy. 
For permanently sterile individuals due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. If reproductive status is 
questionable, additional evaluation should be considered. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
• 
Postmenopausal female. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• 
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more than 
one FSH measurement is required. 
• 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception guidance 
• 
Female participants of childbearing potential are eligible to participate if they agree 
to use a highly effective contraceptive method consistently and correctly according 
to the methods listed in GSK’s list of highly effective contraceptive methods (Table 
21). 
Table 21 
Highly effective contraceptive methods 
Highly effective contraceptive methods that are user dependent1 
Failure rate of <1% per year when used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation. 
• 
Oral. 
• 
Intravaginal. 
• 
Transdermal. 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation. 
• 
Injectable. 

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• 
Oral. 
Highly effective methods that are user independent 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation. 
• 
IUD. 
• 
IUS. 
• 
Bilateral tubal occlusion/ligation. 
• 
Vasectomized partner. 
• 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP, and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. 
• 
Male partner sterilization prior to the female participant’s entry into the clinical study, and this male is the sole 
partner for that participant. 
• 
The information on the male sterility can come from the site personnel’s review of the participant’s medical 
records; medical examination and/or semen analysis, or medical history interview provided by her or her 
partner. 
• 
Sexual abstinence. 
• 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of 
the participant. 
IUD = Intrauterine device; IUS = Intrauterine hormone-releasing system; WOCBP = Woman of childbearing potential. 
1 Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies. 
10.5. 
Appendix 5: Medical device AEs, ADEs, SAEs, SADEs, 
USADEs and device deficiencies: Definitions and 
procedures for recording, evaluating, follow-up, and 
reporting in medical device studies 
• 
Both the investigator and the sponsor will comply with all local reporting 
requirements for medical devices. 
• 
The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list 
of sponsor medical devices. 
10.5.1. 
Definition of medical device AE and ADE 
Medical device AE and ADE definition  
• 
A medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether or not considered related to the investigational medical 
device. 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 an investigational medical device. This 
definition includes events related to the investigational medical device or 
comparator and events related to the procedures involved except for events in 
users or other persons, which only include events related to investigational 
devices. 

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• 
An ADE is defined as an AE related to the use of an investigational medical 
device. This definition includes any AE resulting from insufficient or inadequate 
instructions for use or any malfunction of the investigational medical device as 
well as any event resulting from use error or from intentional misuse of the 
investigational medical device. 
10.5.2. 
Definition of medical device SAE, SADE, and USADE 
A medical device SAE is any serious AEs that: 
a. Led to death. 
b. Led to serious deterioration in the health of the participant, that either resulted in: 
• 
A life-threatening illness or injury. 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, if it were more severe. 
• 
A permanent impairment of a body structure or a body function. 
• 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE. 
• 
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
• 
Chronic disease (MDR 2017/745). 
c. Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
d. Is a suspected transmission of any infectious agent via a medicinal product. 
SADE definition 
• 
A SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of an SAE. 
• 
Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less 
fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is 
defined as a serious ADE that by its nature, incidence, severity or outcome has not 
been identified in the current version of the IB (see Section 2.3). 

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10.5.3. 
Definition of device deficiency 
Device deficiency definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequacy of the information supplied by 
the manufacturer. 
10.5.4. 
Recording and follow-up of medical device AEs and/or SAEs and 
device deficiencies 
10.5.4.1. 
Medical device AE, SAE, and device deficiency recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice and on the appropriate form. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the AE/SAE/device deficiency 
form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant identifier, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
• 
For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency. 
• 
A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent 
recurrence. 
• 
If the site during the course of the study becomes aware of any serious, nonserious 
incident (including device deficiencies and malfunctions) related to any GSK 
product that is not part of the study design, they will report these events to GSK or to 
the concerned competent authorities (CA) via the national spontaneous reporting 
system. These will be classified as spontaneous ICSRs. 
10.5.4.2. 
Assessment of intensity 
See Section 10.3.5.2. 

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10.5.4.3. 
Assessment of causality 
See Section 10.3.5.3. 
10.5.4.4. 
Follow-up of medical device AE/SAE and device deficiency 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
• 
New or updated information will be recorded in the originally completed form. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
10.5.5. 
Reporting of medical device SAEs 
Medical Device SAE Reporting to GSK via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next table) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
table) or to the medical monitor by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, pregnancy exposure, related to any GSK device they will report 
these events to GSK or to the concerned CA via the national spontaneous reporting 
system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 

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Medical device SAE reporting to GSK via paper data collection tool 
• 
Email/Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of email/facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE paper data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE paper data collection tool within the designated reporting 
time frames. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
10.5.6. 
Reporting of SADEs 
SADE Reporting to GSK 
Note: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs that must fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. 
• 
Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency. 
• 
The sponsor will review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national 
regulations. 
• 
Contacts for SAE reporting can be found in Section 8.4.7. 
10.5.7. 
Reporting of medical device deficiencies for associated person 
Reporting to GSK 
If an Associated Person (e.g., spouse, caregiver, site staff) experiences a device 
deficiency, the medical device deficiency information, and any associated AE/SAE 
information will be reported to GSK. The associated person will be provided with the 
authorization to contact physician letter. 
If follow-up information is required, authorization to contact physician (or other 
licensed medical practitioner) must be signed to obtain consent. 
• 
Medical device deficiencies that are not related to an AE or SAE should be 
reported via email to gsk-rd.complaints@gsk.com, using the medical device 
deficiency report form. 

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• 
If the medical device deficiency is related to a nonserious AE and not linked to an 
SAE, please send the medical device deficiency report form with details of the 
associated AE via email to gsk-rd.complaints@gsk.com only. 
• 
If the device incident is linked to an SAE, please email the medical device 
deficiency report form, within 24 hours. See Section 8.4.7 for reporting. 
• 
GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
10.6. 
Appendix 6: Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the TOC. 
Amendment 1 (16 May 2024) 
Overall rationale for the Amendment 
Following the feedback received from the Food and Drug Administration (FDA), the 
protocol has been amended to reflect the use of pausing criteria. 
Summary of changes table of previous amendments: 
Section # and title 
Description of change 
Brief rationale 
8.3.6 Safety monitoring, 
committees, and study pausing 
criteria 
8.3.6.1 Study pausing criteria 
8.4.7 Contact information for 
reporting SAEs, AESIs, 
pregnancies and study pausing 
criteria 
Study pausing criteria have been 
introduced. 
The role of the investigator in the 
monitoring of participants’ safety 
has been clarified. 
Contact information for reporting 
study pausing criteria has been 
added. 
To comply with the recommendations of 
the US FDA to define study pausing 
criteria. 
8.3.1 Physical examination 
Details of physical examination 
assessment at unscheduled site 
visits have been added. 
To specify monitoring of participants’ 
vital signs in case of suspected 
myocarditis or pericarditis.  
 

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11. 
REFERENCES 
References are available upon request. Please note that GSK is not able to provide pdf 
copies in those cases where copyright clearance is still pending or permission has not yet 
been granted. 
Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and 
management of pericardial diseases: The Task Force for the Diagnosis and Management 
of Pericardial Diseases of the European Society of Cardiology (ESC). Endorsed by: The 
European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 
2015;36(42):2921-2964. doi:10.1093/eurheartj/ehv318 
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Signature Page for  222853 TMF-19878380 v1.0
Signature Page for TMF-19878380 v1.0
Reason for signing: Approved
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Date of signature: 24-Sep-2024 14:59:41 GMT+0000
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