A Phase 1 Randomized, Dose Escalation Study to Evaluate the Safety, Reactogenicity and Immunogenicity of an mRNA-based Monovalent Influenza Vaccine Candidate in Healthy Younger and Older Adults
Phase: PHASE1
Conditions: Influenza, Human
Sponsor: GlaxoSmithKline

 

CONFIDENTIAL 
217895 (FLU SV MRNA-003) 
Protocol Amendment 5 Final 
20 June 2023 
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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA (GSK) 
Primary study intervention(s) BIO FLU SV MRNA (GSK4382276A) 
Other study intervention(s) 
GlaxoSmithKline Flu D-QIV (α-RIX-Tetra 
[Belgium]) 
eTrack study number and 
abbreviated title 
217895 (FLU SV MRNA-003) 
EudraCT number 
2022-000489-17 
Date of protocol 
Final: 15 April 2022 
Date of protocol amendment 
Amendment 1 Final: 19 May 2022 
Amendment 2 Final: 08 July 2022 
Amendment 3 Final: 12 January 2023 
Amendment 4 Final: 14 February 2023 
Amendment 5 Final: 20 June 2023 
Title 
A Phase 1 randomized, dose escalation study to 
evaluate the safety, reactogenicity and 
immunogenicity of an mRNA-based monovalent 
influenza vaccine candidate in healthy younger and 
older adults. 
Brief title 
A study on the safety, reactogenicity and immune 
response of a vaccine against influenza in healthy 
younger and older adults. 
Sponsor signatory 
Pascal Peeters, MD 
Senior Director Clinical Project Lead 
Based on GlaxoSmithKline Biologicals SA Protocol WS v17.3 
©2022 GSK group of companies or its licensor. 

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217895 (FLU SV MRNA-003) 
Protocol Amendment 5 Final 
20 June 2023 
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Protocol Amendment 5 Investigator Agreement  
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical 
trial agreement and with any other study conduct procedures and/or study 
conduct documents provided by GSK. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and 
all applicable regulatory requirements. 
• 
That I will comply with the terms of the site agreement. 
• 
To comply with local bio-safety legislation. 
• 
To ensure that all persons assisting me with the study are adequately informed 
about the GSK study intervention and other study-related duties and functions 
as described in the protocol. 
• 
To supervise any individual or party to whom I have delegated study-related 
duties and functions conducted at the study site. 
• 
To ensure that any individual or party to whom I have delegated study-related 
duties and functions conducted at the study site are qualified to perform those 
study-related duties and functions. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if 
required by local regulations, obtain the laboratory’s current certification or 
Quality Assurance procedure manual. 
• 
To co-operate with representative(s) of GSK in the monitoring process of the 
study and in resolution of queries about the data. 
• 
To perform no biological assays on the clinical samples other than those 
described in the protocol or its amendment(s). 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
That I have been informed that certain regulatory authorities require the 
sponsor to obtain and supply, as necessary, details about the investigator(s)’ 
ownership interest in the sponsor or the investigational intervention(s), and 
more generally about their financial ties with the sponsor. GSK will use and 
disclose the information solely for the purpose of complying with regulatory 
requirements. 

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217895 (FLU SV MRNA-003) 
Protocol Amendment 5 Final 
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Hence, I: 
• 
Agree to supply GSK with any necessary information regarding ownership 
interest and financial ties (including those of my spouse and dependent 
children). 
• 
Agree to promptly update this information if any relevant changes occur during 
the study and for 1 year following completion of the study. 
• 
Agree that GSK may disclose any information about such ownership interests 
and financial ties to regulatory authorities. 
• 
Agree to provide GSK with an updated Curriculum Vitae and all other 
documents required by regulatory agencies for this study. 

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217895 (FLU SV MRNA-003) 
Protocol Amendment 5 Final 
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eTrack study number and 
abbreviated title 
217895 (FLU SV MRNA-003) 
EudraCT number 
2022-000489-17 
Date of protocol amendment 
Amendment 5 Final: 20 June 2023 
Title 
A Phase 1 randomized, dose escalation study to 
evaluate the safety, reactogenicity and 
immunogenicity of an mRNA-based monovalent 
influenza vaccine candidate in healthy younger and 
older adults. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 

CONFIDENTIAL 
217895 (FLU SV MRNA-003) 
Protocol Amendment 5 Final 
20 June 2023 
5 
SPONSOR INFORMATION  
1. Sponsor 
GlaxoSmithKline Biologicals SA (GSK)  
2. Sponsor medical expert for the study 
Refer to the local study contact information document. 
3. Sponsor study monitor 
Refer to the local study contact information document. 
4. Sponsor study contact for reporting of Serious Adverse Events (SAEs) 
GSK central back up study contact for reporting SAEs: refer to Section 8.3.3.1. 
Study contact for reporting SAEs: refer to the local study contact information 
document. 
5. GSK Helpdesk for emergency unblinding 
Refer to Section 6.3.5.1. 
 

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217895 (FLU SV MRNA-003) 
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20 June 2023 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
Amendment 5 (20 June 2023): 
This amendment is considered substantial based on the criteria defined in Article 10 (a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it significantly impacts the scientific value of the study.  
Overall rationale for the current Amendment:  
Available data from the
 and 
 dose cohorts in this study show
 
 
 
 
. The aim of the current protocol amendment is to assess the immunogenicity 
of 
 and
 dose levels in order to expand the therapeutic window of this 
monovalent H1 vaccine candidate in younger adults. Data from this amendment will be 
used to further characterize the mRNA platform, and may inform the dose selection for 
future mRNA-based vaccine candidates and/or vaccine combinations. 
List of main changes in the protocol and their rationale:  
Section # and title 
Description of change 
Brief rationale 
4.1. Overall design 
4.3. Justification for dose 
4.3.2. Justification for additional 
doses in YAs, evaluated in 
Amendment 5 
Addition of 2 dose levels to the 
study 
 and 
 
To assess the immunogenicity of 
the monovalent H1 vaccine 
candidate at these dose levels 
1.1. Synopsis  
2.1. Study rationale 
Clarification that only younger 
adults will be enrolled in the
 
and 
 dose cohort 
To be able to compare the 
safety/immunogenicity results  
against the dose levels 
previously tested in this study (all 
previous dose levels were tested 
in this population)  
1.1 Synopsis  
1.3. Schedule of Activities (SoA) 
2.1. Study rationale 
2.3. Benefit/Risk assessment 
4.1. Overall design 
8.2.3.1.1. Staggered enrollment 
of OAs 
Removal of sentinel participants 
for the
 and 
 dose cohort 
As (i) 
 
 
, and (ii) 
 
 have 
showed 
 
 (incidence 
of Grade 3 solicited adverse 
events ranging from 
 
 depending on dose 
group) 
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Section # and title 
Description of change 
Brief rationale 
1.1. Synopsis  
2.1. Study rationale 
4.1. Overall design 
No dose escalation and parallel 
enrollment for the
 and 
 
dose cohort  
 and 
 dose levels are 
 than the 
 and 
 dose levels that have been 
tested previously in this study 
with a
 
 (incidence 
of Grade 3 solicited adverse 
events ranging from
 
 depending on dose 
group) 
1.1. Synopsis  
2.1. Study rationale 
4.1. Overall design 
4.2.1. Choice of active 
comparator 
No active control for the 
 and 
 dose cohort 
The sample size of the currently 
available control group (N=30) is 
already similar to the sample 
size of each additional dose 
group to be tested (N=24). It is 
considered sufficiently large, 
given that the main objective is 
an assessment of 
immunogencity. 
1.3. Schedule of Activities (SoA) 
9.4.1. Sequence of planned 
analyses 
Addition of a planned interim 
analysis upon availability of all 
primary endpoints up to Day 29 
for the 
 and 
 dose cohort 
To allow an interim analysis of 
primary endpoints for this cohort 
8.1.3. Immunological read-outs 
Revision of the number of 
participants included for each 
immunological readout 
To reflect the 9 dose levels 
planned to date and the 
additional number of participants 
planned in the 
 and 
 dose 
cohort 
6.1. Study intervention(s) 
administered 
Addition of the 
and
 Flu 
mRNA vaccines in the study 
intervention table 
To reflect all the dose levels 
used in this study 
4.1. Overall design 
4.2.2. Rationale for study 
blinding 
6.3.5. Blinding and unblinding 
Clarification that the blinding 
level for 
 and 
 dose 
cohort will be single-blind 
Two different Flu mRNA doses 
will be used, therefore the 
persons reconstituting the 
interventions will be aware of the 
dose of the allocated Flu mRNA 
vaccine. This requires unblinding 
the randomization system for this 
cohort and accordingly all users 
of the randomization system will 
be unblinded and only the 
participant will remain blinded 
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217895 (FLU SV MRNA-003) 
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Section # and title 
Description of change 
Brief rationale 
6.3.2. Randomization to study 
intervention 
Clarification that full block sizes 
including active control will be 
shipped for the 
 and 
 
dose cohort, and that the active 
control arm will be blocked at 
randomization. 
Control arm will be blocked as no 
active control is used for the 
 
and 
 dose cohort.  
Since active control and Flu 
mRNA vaccines are already 
present in the same blocks to 
support a previous amendment 
of this study, full block sizes – 
including active control – will be 
shipped to avoid risks of 
potential handling errors at the 
contract manufacturing 
organization. 
 
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217895 (FLU SV MRNA-003) 
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TABLE OF CONTENTS  
PAGE  
SPONSOR INFORMATION ............................................................................................ 5 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 6 
List of main changes in the protocol and their rationale: ........................................... 6 
1. 
PROTOCOL SUMMARY ........................................................................................ 17 
1.1. 
Synopsis (Amended: 20 June 2023) ........................................................... 17 
1.2. 
Schema ...................................................................................................... 20 
1.3. 
Schedule of Activities (SoA)  (Amended: 20 June 2023) ............................. 20 
2. 
INTRODUCTION .................................................................................................... 26 
2.1. 
Study rationale (Amended: 20 June 2023) .................................................. 26 
2.2. 
Background ................................................................................................ 29 
2.3. 
Benefit/Risk assessment ............................................................................. 29 
2.3.1. 
Risk assessment (Amended 20 June 2023) ................................. 30 
2.3.2. 
Benefit assessment ..................................................................... 31 
2.3.3. 
Overall benefit/risk conclusion ..................................................... 32 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ................................................... 32 
4. 
STUDY DESIGN .................................................................................................... 34 
4.1. 
Overall design (Amended: 20 June 2023) ................................................... 34 
4.1.1. 
Enrollment rules (Amended: 20 June 2023) ................................. 38 
4.2. 
Scientific rationale for study design ............................................................. 39 
4.2.1. 
Choice of active comparator (Amended: 20 June 2023) ............... 39 
4.2.2. 
Rationale for study blinding  (Amended: 20 June 2023) ............... 39 
4.3. 
Justification for dose (Amended: 20 June 2023) ......................................... 39 
4.3.1. 
Justification for dose for YAs........................................................ 40 
4.3.2. 
Justification for additional doses in YAs, evaluated in 
Amendment 5 (Amended: 20 June 2023)..................................... 40 
4.3.3. 
Justification for additional doses in YAs, evaluated in 
Amendment 3 .............................................................................. 41 
4.3.4. 
Justification for additional doses in YAs, evaluated in 
Amendment 4 .............................................................................. 41 
4.3.5. 
Justification for dose for OAs ....................................................... 41 
4.4. 
End of Study definition ................................................................................ 41 
5. 
STUDY POPULATION ........................................................................................... 42 
5.1. 
Inclusion criteria .......................................................................................... 42 
5.2. 
Exclusion criteria ......................................................................................... 42 
5.2.1. 
Medical conditions ....................................................................... 43 
5.2.2. 
Prior/Concomitant therapy ........................................................... 43 
5.2.3. 
Other exclusions .......................................................................... 44 
5.3. 
Lifestyle considerations ............................................................................... 44 
5.4. 
Screening failures ....................................................................................... 44 
5.5. 
Criteria for temporarily delaying randomization/study intervention 
administration ............................................................................................. 45 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY .................................. 45 

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6.1. 
Study intervention(s) administered .............................................................. 45 
6.2. 
Preparation, handling, storage, and accountability ...................................... 51 
6.3. 
Measures to minimize bias: randomization and blinding ............................. 51 
6.3.1. 
Participant identification ............................................................... 51 
6.3.2. 
Randomization to study intervention (Amended: 20 June 
2023) ........................................................................................... 51 
6.3.3. 
Intervention allocation to the participant ....................................... 52 
6.3.4. 
Allocation of participants to assay subsets ................................... 52 
6.3.5. 
Blinding and unblinding (Amended: 20 June 2023) ...................... 52 
6.3.5.1. 
Emergency unblinding ................................................ 53 
6.3.5.2. 
Unblinding prior to regulatory reporting of SAEs ......... 53 
6.4. 
Study intervention compliance .................................................................... 54 
6.5. 
Dose modification ....................................................................................... 54 
6.6. 
Continued access to study intervention after the end of the study ............... 54 
6.7. 
Treatment of overdose and management of anaphylaxis ............................ 54 
6.8. 
Concomitant therapy ................................................................................... 54 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 55 
7.1. 
Discontinuation of study intervention ........................................................... 55 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 55 
7.3. 
Lost to follow up .......................................................................................... 56 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 56 
8.1. 
Immunogenicity assessments ..................................................................... 58 
8.1.1. 
Biological samples ....................................................................... 58 
8.1.2. 
Laboratory assays ....................................................................... 59 
8.1.3. 
Immunological read-outs  (Amended: 20 June 2023) ................... 60 
8.1.4. 
Immunological correlates of protection ......................................... 61 
8.2. 
Safety assessments .................................................................................... 61 
8.2.1. 
Pre-intervention administration procedures .................................. 61 
8.2.1.1. 
Collection of demographic data .................................. 61 
8.2.1.2. 
Medical and vaccination history .................................. 61 
8.2.1.3. 
Physical examination .................................................. 61 
8.2.1.4. 
Pre-dosing body temperature ..................................... 62 
8.2.1.5. 
Pregnancy test ........................................................... 62 
8.2.1.6. 
Distribution of eDiary or installing the 
application for devices ................................................ 62 
8.2.1.7. 
Warnings and precautions to administration of 
study intervention ....................................................... 62 
8.2.2. 
Clinical safety laboratory tests ..................................................... 63 
8.2.3. 
Study holding rules and safety monitoring.................................... 63 
8.2.3.1. 
Staggered enrollment and safety monitoring .............. 63 
8.2.3.1.1. 
Staggered enrollment of YAs 
(Amended: 20 June 2023) ...................... 63 
8.2.3.1.2. 
Staggered enrollment of OAs .................. 64 
8.2.3.2. 
Outcome of safety evaluation ..................................... 68 
8.2.3.3. 
Study holding rules ..................................................... 68 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and other 
safety reporting ........................................................................................... 71 
8.3.1. 
Time period and frequency for collecting AE, SAE and 
other safety information ............................................................... 71 

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8.3.2. 
Method of detecting AEs and SAEs, pregnancies and 
other events ................................................................................. 72 
8.3.2.1. 
Clinically significant abnormal laboratory 
findings ....................................................................... 72 
8.3.3. 
Regulatory reporting requirements for SAEs, pregnancies 
and other events .......................................................................... 72 
8.3.3.1. 
Contact information for reporting SAEs, AESIs, 
pregnancies and study holding rules .......................... 74 
8.3.4. 
Treatment of expedited adverse events (SAE/AESI) .................... 74 
8.3.5. 
Participant card ............................................................................ 74 
8.3.6. 
Medical device deficiencies ......................................................... 74 
8.3.6.1. 
Detection, follow up and prompt reporting of 
medical device deficiency ........................................... 75 
8.3.6.2. 
Regulatory reporting of medical device 
deficiency when used as combination product ............ 75 
8.4. 
Pharmacokinetics ....................................................................................... 75 
8.5. 
Genetics ..................................................................................................... 75 
8.6. 
Biomarkers ................................................................................................. 75 
8.7. 
Immunogenicity assessments ..................................................................... 76 
8.8. 
Health outcomes ......................................................................................... 76 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 76 
9.1. 
Statistical hypotheses ................................................................................. 76 
9.2. 
Analysis sets ............................................................................................... 76 
9.3. 
Statistical analyses ..................................................................................... 77 
9.3.1. 
Co-primary safety endpoints ........................................................ 77 
9.3.1.1. 
Analysis of reactogenicity for dose escalation: 
BLRM ......................................................................... 77 
9.3.2. 
Co-primary and secondary immunogenicity endpoints ................. 78 
9.4. 
Interim analyses .......................................................................................... 79 
9.4.1. 
Sequence of planned analyses (Amended: 20 June 2023) .......... 79 
9.4.2. 
Statistical considerations for interim analysis ............................... 80 
9.5. 
Sample size determination .......................................................................... 80 
9.5.1. 
Sample size determination for reactogenicity and safety .............. 80 
9.5.2. 
Sample size determination for immunogenicity ............................ 81 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 81 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 81 
10.1.1. 
Regulatory and ethical considerations ......................................... 81 
10.1.2. 
Financial disclosure ..................................................................... 82 
10.1.3. 
Informed consent process ............................................................ 82 
10.1.4. 
Data protection ............................................................................ 83 
10.1.5. 
Committees structure ................................................................... 83 
10.1.6. 
Dissemination of clinical study data ............................................. 83 
10.1.7. 
Data quality assurance ................................................................ 84 
10.1.8. 
Source documents ....................................................................... 85 
10.1.9. 
Study and site start and closure ................................................... 85 
10.1.10. Publication policy ......................................................................... 86 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 86 
10.2.1. 
Protocol required safety laboratory assessments ......................... 86 

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10.2.2. 
FDA Guidance for industry: Toxicity grading scale for 
healthy adult and adolescent volunteers enrolled in 
preventive vaccine clinical trials (September 2007) ...................... 87 
10.3. 
Appendix 3: AEs: definitions and procedures for recording, 
evaluating, follow up, and reporting............................................................. 88 
10.3.1. 
Definition of an AE ....................................................................... 88 
10.3.1.1. Events Meeting the AE Definition ............................... 88 
10.3.1.2. Events NOT Meeting the AE Definition ....................... 89 
10.3.2. 
Definition of an SAE ..................................................................... 89 
10.3.3. 
Solicited events............................................................................ 90 
10.3.4. 
Unsolicited AEs............................................................................ 91 
10.3.5. 
SAEs related to study participation .............................................. 92 
10.3.6. 
AESIs .......................................................................................... 92 
10.3.6.1. Potential immune-mediated diseases ......................... 92 
10.3.6.2. Other AEs of special interest ...................................... 98 
10.3.7. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as AEs or SAEs ...................................... 99 
10.3.8. 
Events or outcomes not qualifying as AEs or SAEs ..................... 99 
10.3.8.1. Pregnancy .................................................................. 99 
10.3.9. 
Recording and follow up of AEs, SAEs, AESIs and 
pregnancies ................................................................................. 99 
10.3.9.1. Time period for collecting and recording AEs, 
SAEs, AESIs and pregnancies ................................. 100 
10.3.9.2. Follow up of AEs, SAEs, AESIs, pregnancies 
or any other events of interest .................................. 100 
10.3.9.2.1. Follow up during the study .................... 101 
10.3.9.2.2. Follow up after the participant is 
discharged from the study .................... 101 
10.3.9.2.3. Follow up of pregnancies ...................... 101 
10.3.9.3. Updating of SAE, AESI and pregnancy 
information after removal of write access to the 
participant’s eCRF .................................................... 101 
10.3.10. Assessment of intensity and causality ........................................ 102 
10.3.10.1. Assessment of intensity ............................................ 102 
10.3.10.2. Assessment of causality ........................................... 103 
10.3.10.3. Medically attended visits ........................................... 104 
10.3.10.4. Assessment of outcomes.......................................... 105 
10.3.11. Reporting of SAEs, AESIs, pregnancies and other events ......... 105 
10.3.11.1. Events requiring expedited reporting to GSK ............ 105 
10.3.11.2. Back up system in case the electronic reporting 
system does not work ............................................... 105 
10.4. 
Appendix 4: Contraceptive guidance and collection of pregnancy 
information ................................................................................................ 106 
10.4.1. 
Definitions .................................................................................. 106 
10.4.1.1. Woman of childbearing potential (WOCBP) .............. 106 
10.4.1.1.1. Women not considered as women 
of childbearing potential ........................ 106 
10.4.2. 
Contraception guidance ............................................................. 107 
10.4.3. 
Collection of pregnancy information ........................................... 108 
10.4.3.1. Female participants who become pregnant .............. 108 
10.5. 
Appendix 5: Genetics ................................................................................ 108 

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10.6. 
Appendix 6: Definition of medical device AE, adverse device effect 
(ADE), serious adverse device effect (SADE) and unanticipated 
SADE (USADE) ........................................................................................ 108 
10.6.1. 
Definition of medical device AE and ADE................................... 108 
10.6.2. 
Definition of medical device SAE, SADE and USADE ................ 109 
10.6.3. 
Recording and reporting of medical device AE, ADEs, 
SADEs and USADE ................................................................... 109 
10.6.4. 
Reporting of medical device deficiencies for associated 
person ....................................................................................... 110 
10.7. 
Appendix 7: Country-specific requirements ............................................... 110 
10.8. 
Appendix 8: Statistical appendix including model performance and 
data scenarios .......................................................................................... 110 
10.9. 
Appendix 9: Abbreviations and glossary of terms ...................................... 112 
10.9.1. 
List of abbreviations ................................................................... 112 
10.9.2. 
Glossary of terms ....................................................................... 115 
10.10. Appendix 10: Protocol amendment history ................................................ 119 
11. REFERENCES ..................................................................................................... 147 
 

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LIST OF TABLES  
PAGE 
Table 1 
Schedule of Activities (SoA) (Amended: 20 June 2023) ......................... 21 
Table 2 
Intervals between study visits (Amended: 20 June 2023) ....................... 26 
Table 3 
Study objectives, endpoints and estimands ............................................ 32 
Table 4 
Study groups, intervention and blinding (Amended: 20 June 
2023) ...................................................................................................... 38 
Table 5 
Study intervention(s) administered (Amended: 20 June 2023) ............... 46 
Table 6 
Contact information for emergency unblinding ....................................... 53 
Table 7 
Biological samples ................................................................................. 58 
Table 8 
Laboratory assays .................................................................................. 59 
Table 9 
Immunological read-outs  (Amended: 20 June 2023) ............................. 60 
Table 10 
Staggered enrollment and safety monitoring (Amended: 20 June 
2023) ...................................................................................................... 66 
Table 11 
Study holding rules ................................................................................. 69 
Table 12 
Timeframes for collecting and reporting of safety information ................. 71 
Table 13 
Timeframes for submitting SAE, pregnancy and other events 
reports to GSK ....................................................................................... 73 
Table 14 
Contact information for reporting SAEs, AESIs, pregnancies and 
study holding rules ................................................................................. 74 
Table 15 
Analysis sets .......................................................................................... 76 
Table 16 
Posterior probability estimates of Grade 3 solicited event rate 
<18% for different observed numbers of participants with 
Grade 3 solicited event(s) and 95% credibility interval for the rate ......... 80 
Table 17 
Protocol required safety laboratory assessments ................................... 86 
Table 18 
FDA toxicity grading scales for biochemistry parameters 
evaluated in the current study ................................................................ 87 
Table 19 
FDA toxicity grading scales for hematology parameters 
evaluated in the current study ................................................................ 87 
Table 20 
FDA toxicity grading scales for urinalysis parameters evaluated 
in the current study ................................................................................. 88 

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Table 21 
Solicited administration site events......................................................... 90 
Table 22 
Solicited systemic events ....................................................................... 91 
Table 23 
List of potential immune-mediated diseases (pIMDs) ............................. 93 
Table 24 
Intensity scales for solicited events in participants of 6 years of 
age or more .......................................................................................... 102 
Table 25 
Highly effective contraceptive methods ................................................ 107 
Table 26 
Hypothetical data scenarios for study holds ......................................... 111 
 

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LIST OF FIGURES  
PAGE 
Figure 1 
Study design overview (Amended: 20 June 2023) .................................. 34 
 

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1. 
PROTOCOL SUMMARY  
1.1. 
Synopsis (Amended: 20 June 2023)  
Rationale: 
Annual influenza vaccination is currently the most effective mean of controlling 
influenza and preventing its complications and mortality [WHO, 2018]. 
In the United States of America (USA), the Center for Disease Control and Prevention 
(CDC) recommends annual immunization for everyone 6 months and older. Vaccination 
is particularly important for older adults, children younger than 2 years old, pregnant 
women, and individuals of all ages with certain chronic medical conditions [Grohskopf, 
2020]. 
Influenza viruses constantly change their surface glycoproteins that are the targets of 
most immune responses, allowing them to escape pre-existing immunity, a process called 
antigenic drift. Therefore, seasonal influenza vaccines must be reformulated and re-
administered on an annual basis [WHO, 2021]. Currently licensed seasonal influenza 
vaccines are efficacious when they are well-matched with the circulating virus strains. 
Hence, seasonal influenza vaccine effectiveness ranges from only 10% in years when 
vaccine strains are mismatched, to maximum 60% when they are highly matched [CDC, 
2020]. 
Moreover, licensed seasonal influenza vaccines are less effective in older adults, since 
immunity wanes rapidly after immunization. In addition, the egg-based manufacturing 
process that requires strain adaptation is thought to negatively impact the 
immunogenicity [CDC, 2020]. 
New vaccines have been developed to circumvent those hurdles. High-dose vaccines 
[DiazGranados, 2014; Dunkle, 2017a; Dunkle, 2017b], adjuvanted vaccines [Novavax, 
2021] and non-egg-based vaccines [Divino, 2020; Freyn, 2020] have all demonstrated 
improved immunogenicity and/or efficacy over classical egg-based standard-dose 
vaccines. 
However, considering the need to improve supply continuity and to develop a more 
flexible, adaptable vaccine that can provide optimal strain-adapted protection in all age 
groups in a timely manner, GSK in collaboration with CureVac are developing a new 
seasonal flu vaccine based on a messenger RNA (mRNA) platform. The use of an mRNA 
platform circumvents the immunological limitations caused by viral mutations occurring 
during the egg-adaptation process [CDC, 2020a]. The use of an egg-independent 
manufacturing process was also identified as an opportunity to streamline vaccine 
production and improve reliability of supply and ‘surge capacity’, if required [CRS, 
2004]. Finally, cellular immunity might prove enhanced by the use of an mRNA-based 
vaccine as compared to classical split-virion vaccines [Divino, 2020; Wei, 2020]. 

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In this first-time-in-human (FTiH) study, GSK will evaluate a formulation containing 
mRNA sequences encoding 1 antigen (H1N1 hemagglutinin [HA]), encapsulated in lipid 
nanoparticles (LNPs). This vaccine candidate uses a new iteration of the mRNA 
backbone developed by CureVac, in which improvements were made to the untranslated 
regions, expected to increase immunogenicity. Moreover, the mRNA sequences of the 
vaccine candidate contain modified nucleotides (i.e., N1-methyl-pseudouridine [1mψU]). 
 
 
The present study will comprise an adaptive dose escalation design with staggered 
enrollment using an active control in younger adults (YAs) and older adults (OAs). 
In pivotal clinical trials conducted with the Covid-19 vaccines developed by Moderna 
and Pfizer/BioNTech, the mRNA vaccine was found to be less reactogenic in the older 
age groups (defined as >65 years of age for Moderna and >55 years of age for 
Pfizer/BioNTech) than in the YAs [Baden, 2021; Polack, 2020]. These vaccines also use 
1mψU -containing mRNA technology encapsulated in LNPs, comparable to the vaccine 
candidate assessed in this study. Preliminary Phase 1 data presented by Moderna show a 
similar trend for a candidate mRNA seasonal influenza vaccine, with a higher incidence 
of Grade 3 solicited adverse reactions in YAs when administered high doses of vaccines, 
compared to OAs [Moderna, 2021]. 
The aim of this study is to collect preliminary data to support progression of the clinical 
development with a multivalent influenza vaccine in a larger number of participants. 
Given the higher medical need for an improved influenza vaccine for OAs, a preliminary 
assessment of the immunogenicity and reactogenicity profile in this age group is 
clinically important. 
Based on the data provided above, it is reasonable to hypothesize that a dose considered 
too reactogenic in YAs may be suitable for OAs in terms of reactogenicity and 
immunogenicity. Therefore, it will be important to confirm findings in YAs, also in the 
OA population. The enrollment of OAs, however, will be limited to a single dose level 
and not be initiated prior to establishing a safety database in YAs. 
The methodology used in this study comprises several measures to minimize the risk for 
the study participants, namely: 
1. Initiation of the dose escalation 
 than the dose 
used in the efficacy trial conducted using the previous generation of CureVac mRNA 
Covid-19 vaccine 
 
2. Initiation of the dosing of OAs not until after the review of the safety/reactogenicity 
data reported with the 3 first dose levels administered in YAs by an unblinded Safety 
Review Team (SRT). Note: as the goal of protocol amendments 3, 4 and 5 are to 
further explore the reactogenicity/ immunogenicity profile in YAs (all previous dose 
levels were tested in this population), no OAs will be enrolled in the 
 and 
 
dose cohort, and 
 dose cohort, or in the 
 (and potential 
intermediate doses) dose cohorts. 
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3. Supervision of the dose escalation by SRT. The safety/reactogenicity data reviewed 
by this team cover 8 days of follow up post-dosing (Day 1 to Day 8 included) of all 
participants of the current dose level. This time window is sufficient to ensure a 
reliable evaluation of the reactogenicity of the vaccine, considering that the median 
onset of solicited systemic events after mRNA Covid-19 vaccines administration is 1 
to 2 days, and a median duration of such events is 1 to 2 days [CBER, 2021; CBER, 
2022]. Note: 
, and 
 
have shown a 
 (incidence of Grade 3 
solicited adverse events ranging from 
 depending on dose group), this 
dose escalation step will not be followed for the  and 
 , or the 
 and 
 
dose cohorts, i.e., participants in these cohorts will be enrolled in parallel. 
4. Enrollment of sentinel participants for each dose level, per age group. The 
safety/reactogenicity data for at least 2 days of follow up post-dosing of 6 sentinel 
participants will be reviewed by an SRT before enrolling the 18 remaining 
participants planned in the study group (24 participants/dose level), to reduce the risk 
of unnecessary exposure to a possibly highly reactogenic dose. 
Note: 
, and
 have 
shown a 
 (incidence of Grade 3 solicited 
adverse events ranging from
 depending on dose group), no sentinel 
participants will be included in the additional  and 
 or 
 and 
 dose 
cohorts. 
5. Use of a Bayesian Logistic Regression Model (BLRM) to inform and guide the 
decision to (i) enroll non-sentinel participants and (ii) escalate the dose. 
Reactogenicity data from both sentinel and non-sentinel participants at current and 
all previous dose levels will be used by the BLRM along study progression. 
6. Possibility to assess intermediate dose level in YAs, should the posterior probability 
of the BLRM indicate that the reactogenicity of the upper dose level would be too 
high (adaptive design). 
7. Use of an upper age limit (70 years) for sentinel participants in OA groups. 
8. Enrollment of OAs with no clinically significant co-morbidities. 
GSK’s Flu Dresden- Quadrivalent Influenza Vaccine, hereafter referred to as Flu D-QIV 
and commercially available as α-RIX-Tetra in Belgium was chosen as active control in 
this study. It is indicated for active immunization for the prevention of disease caused by 
influenza A subtype viruses and type B viruses contained in the vaccine. The vaccine is 
approved for use in 6 months of age and older. 
Note: The sample size of the available Control group (N=30) is similar to the sample size 
of each additional dose group to be tested (N=24). As such, we consider the available 
Control group sufficiently large for this phase 1 exploratory and descriptive study and 
will not use an active control for the additional 
 and 
 dose cohort, and and 
 
 dose cohort, where an assessment of immunogenicity is the main objective. However, 
for the additional 
, and their potential intermediate dose cohorts (
and 
 where a safety/reactogenicity assessment is the main objective, Flu D-QIV will 
be reintroduced as active control. 
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Objectives, endpoints and estimands: 
Refer to Section 3 for detailed list of objectives, endpoints and estimands. 
1.2. 
Schema  
See Figure 1 in Section 4. 
1.3. 
Schedule of Activities (SoA)  (Amended: 20 June 2023)  
 

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Table 1 
Schedule of Activities (SoA) (Amended: 20 June 2023)  
Type of contact 
Screening 
visit 
Visit 1 Contact 1† Contact 2 
Visit 2 
Visit 3 
Visit 4 
Visit 5*** Visit 6*** 
Notes 
Timepoints 
Day -28 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 22 
Day 29 
Day 62 
Day 183 
 
Informed consent 
● 
 
 
 
 
 
 
 
 
See Section 10.1.3 for details  
Check inclusion/exclusion criteria 
● 
○ a 
 
 
 
 
 
 
 
Check clinical status before 
randomization and/or 
administration of study 
intervention. 
See Sections 5.1 and 5.2 for 
Inclusion and Exclusion criteria 
Collect demographic data 
● 
 
 
 
 
 
 
 
 
See Section 8.2.1.1 for more 
information 
Medical and vaccination history  
● 
 
 
 
 
 
 
 
 
See Section 8.2.1.2 for more 
information 
Physical examination  
● 
● a 
 
 
○ 
○ 
○ 
○ 
○ 
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 8.2.1.3 for more 
information 
Randomization  
 
○ a 
 
 
 
 
 
 
 
A randomization procedure will be 
used with sentinel, age and dose 
level cohort as stratification factor 
and with study, country, site, and 
flu vaccination history during past 
2 years as minimization factors. 
See Section 6.3 for more 
information 

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Type of contact 
Screening 
visit 
Visit 1 Contact 1† Contact 2 
Visit 2 
Visit 3 
Visit 4 
Visit 5*** Visit 6*** 
Notes 
Timepoints 
Day -28 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 22 
Day 29 
Day 62 
Day 183 
 
Study intervention 
Check contraindications, warnings 
and precautions to study intervention 
administration 
 
○ a 
 
 
 
 
 
 
 
See Section 8.2.1.7 for more 
information 
Check criteria for temporary delay for 
study intervention administration 
 
○ a 
 
 
 
 
 
 
 
See Section 5.5 for more 
information 
Urine pregnancy test (only for female 
participants of childbearing potential) 
● 
●a 
 
 
 
 
 
 
 
Serum pregnancy test can be 
done as per local requirements if 
time allows. 
See Section 8.2.1.4 for more 
information 
Study group and intervention number 
allocation 
 
● a 
 
 
 
 
 
 
 
See Section 6.3 for more 
information 
Body temperature before study 
intervention administration 
 
● a 
 
 
 
 
 
 
 
Fever is defined as temperature 
≥38°C/100.4°F regardless the 
location of measurement. 
The preferred location for 
measuring temperature will be 
axillary. 
See Section 8.2.1.4 for more 
information 
Study intervention administration 
 
● 
 
 
 
 
 
 
 
See Section 6.1 for more 
information 
Post-dose observation period 
 
○ 
 
 
 
 
 
 
 
See Section 6.1 for more 
information 
Recording of administered study 
intervention number 
 
● 
 
 
 
 
 
 
 
 
Distribution of participant card 
 
○ 
 
 
 
 
 
 
 
See Section 8.3.5 for more 
information 
Check participant’s device 
compatibility for eDiary data 
collection 
○ 
○ 
 
 
 
 
 
 
 
See Section 8.2.1.6 for more 
information 

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Type of contact 
Screening 
visit 
Visit 1 Contact 1† Contact 2 
Visit 2 
Visit 3 
Visit 4 
Visit 5*** Visit 6*** 
Notes 
Timepoints 
Day -28 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 22 
Day 29 
Day 62 
Day 183 
 
Training and installing/assigning 
eDiaries  
 
○ 
 
 
 
 
 
 
 
See Section 8.2.1.6 for more 
information 
Review of eDiary data 
 
 
○ 
○ 
○ 
○ 
○ 
 
 
Recording of solicited events 
(Day 1-Day 7 post-dosing) b 
Reporting of unsolicited adverse 
events (Day 1-Day 28 post-
dosing) b 
Completion of 
 
 (Day 3 
and Day 7 post-dosing) b 
See Section 10.3.9 for more 
information 
Return/uninstalling of eDiary 
 
 
 
 
 
 
○ 
 
 
See Section 10.3.9 for more 
information 
Laboratory Assessment 
Blood sampling for routine safety 
panel (~10 mL) 
All participants 
● 
●a  
 
 
● 
 
● 
 
 
If screening occurs within 3 days 
(Day -3 to Day -1) before Visit 1, 
the results of safety lab 
assessments from screening can 
be used as baseline. 
Volume of the blood drawn will 
vary depending on local lab 
requirements. 
See Section 10.2.1 for more 
information 
Urine sampling for routine safety 
panel 
All participants 
● 
● a 
 
 
● 
 
● 
 
 
Volume of urine sample will be 
defined as per local practice. 
See Section 10.2.1 for more 
information. 
Blood sampling for antibody 
determination and characterization 
(~10 mL) 
All participants 
 
● a 
 
 
 
● 
 
●** 
●** 
For this assessment, serum has to 
be isolated from blood. 
See Section 8.1.2 for more 
information 
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Type of contact 
Screening 
visit 
Visit 1 Contact 1† Contact 2 
Visit 2 
Visit 3 
Visit 4 
Visit 5*** Visit 6*** 
Notes 
Timepoints 
Day -28 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 22 
Day 29 
Day 62 
Day 183 
 
Blood sampling 
 
 
(~30mL) * 
subset 
 
● a 
 
 
● 
 
 
●** 
●** 
See Section 8.1.2 for more 
information 
Safety assessments 
Record any concomitant vaccinations 
● 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 6.8 and Table 12 for 
more information. 
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine 
● 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 10.3.9 for more 
information 
Record any concomitant medications 
 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 6.8 and Table 12 for 
more information. 
Recording of unsolicited AEs 
(Day 1-Day 28 post-dosing) 
 
● 
● 
● 
● 
● 
● 
 
 
See Sections 10.3.4 and 10.3.9.1 
for more information 
Recording of SAEs, AESIs and 
pregnancies 
 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 10.3.9 for more 
information 
AEs/SAEs leading to withdrawal from 
the study 
 
● 
● 
● 
● 
● 
● 
● 
● 
See Section 10.3.9 for more 
information 
Study conclusion 
 
 
 
 
 
 
 
 
● 
See Section 4.4 for more 
information 
Investigator sign-off on eCRF 
 
 
 
 
 
● 
● 
 
● 
 
Note: The double-line border after Day 22 (Visit 3) and Day 29 (Visit 4) indicates the schedule of interim analyses. Two initial interim analyses will be conducted upon availability of all 
primary endpoints up to Day 22 for YA participants in the
 and 
 cohorts, respectively and a third interim analysis will be performed upon availability of all primary endpoints up 
to Day 29 for all study participants. Note: additional interim analyses will be performed upon availability of all primary endpoints up to Day 29 for (i) all participants in the  and 
 
dose cohort, (ii) all participants in the 
 and their potential intermediate dose cohorts 
 and 
), and (iii) all participants in the 
 and 
 dose cohort. 
 eDiary: electronic diary (application or electronic device); AE: adverse event; SAE: serious adverse event; 
AESI: adverse event of special interest. 
● 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. 
† Contact 1 (Day 2) will be performed for sentinel participants only. Note that no sentinel participants are included for the
 and 
 or  and 
 dose cohorts. 
* Samples will be collected on sites associated with a 
 Note: for the 
 and their potential intermediate dose cohorts 
 and 
 no blood 
sampling for 
response will be performed. 
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** Sample will be collected only if participants did not receive the standard of care vaccination against seasonal flu since study participation. Note that blood sampling for antibody 
determination and characterization will be limited to Day 1 and Day 22 for the 
 and their potential intermediate dose cohorts 
 and 
). 
*** Visit 5 (Day 62) and Visit 6 (Day 183) will be replaced by a contact if participant have received the standard of care vaccination against seasonal flu prior to this visit and did not 
report any adverse events that would require physical examination on site. Note: No blood sampling will be performed at Day 62 and Day 183 for the 
, and their potential 
intermediate dose cohorts 
 and 
). As such, Visit 5 and Visit 6 will be replaced by a contact for all participants in these cohorts unless they reported any adverse events that 
would require physical examination on site. 
a is used to indicate a study procedure to be performed prior to study intervention administration. 
b is used to indicate a study procedure recorded in eDiary. 
 
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Table 2 
Intervals between study visits (Amended: 20 June 2023)  
Interval 
Planned contact interval  
Allowed interval range 
Screening* → Visit 1  
1-28 days 
1 – 28 days 
Visit 1 → Contact 1** 
20 hours 
18-24 hours 
Visit 1 → Contact 2 
2 days 
2 days† 
Visit 1 → Visit 2 
7 days 
6-8 days 
Visit 1 → Visit 3 
21 days 
20-24 days 
Visit 1 → Visit 4 
28 days 
26-35 days 
Visit 1 → Visit 5*** 
61 days 
54-68 days 
Visit 1 → Visit 6*** 
182 days 
168-196 days 
* Screening visit should take place within 28 days before Visit 1, with sufficient time to receive/review the hematology, 
biochemistry, coagulation and urinalysis results. When applicable, a re-screening visit (including blood and urine 
sample collection, physical examination and re-checking of inclusion/exclusion criteria) may be scheduled at any time 
(but only once to assess eligibility) before Visit 1. All screening procedures need to be performed within 28 days before 
Visit 1. Only laboratory results from the re-screening visit, if it occurs, will be taken into consideration. The participant 
can only be randomized once the investigator receives the results and confirms the eligibility criteria. 
** Contact 1 (Day 2) will be performed for sentinel participants only. Note that no sentinel participants are included for 
the
 and 
 or and 
 dose cohorts. 
*** Visit 5 (Day 62) and Visit 6 (Day 183) will be replaced by a contact if participant have received the standard of care 
vaccination against seasonal flu prior to this visit and did not report any adverse events that would require physical 
examination on site. Note: No blood sampling will be performed at Day 62 and Day 183 for the 
, and 
their potential intermediate dose cohorts (
 and 
 As such, Visit 5 and Visit 6 will be replaced by a contact for 
all participants in these cohorts unless they reported any adverse events that would require physical examination on 
site. 
† For non-sentinel participants, the allowed interval ranges from 1 to 3 days. 
2. 
INTRODUCTION  
2.1. 
Study rationale (Amended: 20 June 2023)  
Annual influenza vaccination is currently the most effective mean of controlling 
influenza and preventing its complications and mortality [WHO, 2018]. 
In the United States of America (USA), the Center for Disease Control and Prevention 
(CDC) recommends annual immunization for everyone 6 months and older. Vaccination 
is particularly important for older adults, children younger than 2 years old, pregnant 
women, and individuals of all ages with certain chronic medical conditions [Grohskopf, 
2020]. 
Influenza viruses constantly change their surface glycoproteins that are the targets of 
most immune responses, allowing them to escape pre-existing immunity, a process called 
antigenic drift. Therefore, seasonal influenza vaccines must be reformulated and re-
administered on an annual basis [WHO, 2021]. Currently licensed seasonal influenza 
vaccines are efficacious when they are well-matched with the circulating virus strains. 
Hence, seasonal influenza vaccine effectiveness ranges from only 10% in years when 
vaccine strains are mismatched, to maximum 60% when they are highly matched [CDC, 
2020]. 
Moreover, licensed seasonal influenza vaccines are less effective in older adults, since 
immunity may wane rapidly after immunization. In addition, the egg-based 
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manufacturing process that requires strain adaptation is thought to negatively impact the 
immunogenicity [CDC, 2020]. 
New vaccines have been developed to circumvent those hurdles. High-dose vaccines 
[DiazGranados, 2014; Dunkle, 2017a; Dunkle, 2017b], adjuvanted vaccines [Novavax, 
2021] and non-egg-based vaccines [Divino, 2020; Freyn, 2020] have all demonstrated 
improved immunogenicity and/or efficacy over classical egg-based standard-dose 
vaccines. 
However, considering the need to improve supply continuity and to develop a more 
flexible, adaptable vaccine that can provide optimal strain-adapted protection in all age 
groups in a timely manner, GSK in collaboration with CureVac are developing a new 
seasonal flu vaccine based on a messenger RNA (mRNA) platform. The use of an mRNA 
platform circumvents the immunological limitations caused by viral mutations occurring 
during the egg-adaptation process [CDC, 2020a]. The use of an egg-independent 
manufacturing process was also identified as an opportunity to streamline vaccine 
production and improve reliability of supply and ‘surge capacity’, if required [CRS, 
2004]. Finally, cellular immunity might prove enhanced by the use of an mRNA-based 
vaccine as compared to classical split-virion vaccines [Divino, 2020; Wei, 2020]. 
In this first-time-in-human (FTiH) study, GSK will evaluate a formulation containing 
mRNA sequences of 1 antigen (H1N1 hemagglutinin [HA]) encapsulated in lipid 
nanoparticles (LNPs). This vaccine candidate uses a new iteration of the mRNA 
backbone developed by CureVac, in which improvements were made to the untranslated 
regions, expected to increase immunogenicity. Moreover, the mRNA sequences of the 
vaccine candidate contain modified nucleotides (i.e., N1-methyl-pseudouridine [1mψU]). 
 
 
The present study will comprise an adaptive dose escalation design with staggered 
enrollment using an active control in younger adults (YAs) and older adults (OAs). 
In pivotal clinical trials conducted with the Covid-19 vaccines developed by Moderna 
and Pfizer/BioNTech, the mRNA vaccine was found to be less reactogenic in the older 
age groups (defined as >65 years of age for Moderna and >55 years of age for 
Pfizer/BioNTech) than in the YAs [Baden, 2021; Polack, 2020]. These vaccines also use 
1mψU -containing mRNA technology encapsulated in LNPs, comparable to the vaccine 
candidate assessed in this study. Preliminary Phase 1 data presented by Moderna show a 
similar trend for a candidate mRNA seasonal influenza vaccine, with a higher incidence 
of Grade 3 solicited adverse reactions in YAs when administered high doses of vaccines, 
compared to OAs [Moderna, 2021]. 
The aim of this study is to collect preliminary data to support progression of the clinical 
development with a multivalent influenza vaccine in a larger number of participants. 
Given the higher medical need for an improved influenza vaccine for OAs, a preliminary 
assessment of the immunogenicity and reactogenicity profile in this age group is 
clinically important. 
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Based on the data provided above, it is reasonable to hypothesize that a dose considered 
too reactogenic in YAs may be suitable for OAs in terms of reactogenicity and 
immunogenicity. Therefore, it will be important to confirm findings in YAs, also in the 
OA population. The enrollment of OAs will be limited to a single dose level and not be 
initiated prior to establishing a safety database in YAs. 
The methodology used in this study comprises several measures to minimize the risk for 
the study participants, namely: 
1. Initiation of the dose escalation with a 
 than the dose 
used in the efficacy trial conducted using the previous generation of CureVac mRNA 
Covid-19 vaccine 
). 
2. Initiation of the dosing of OAs not until after the review of the safety/reactogenicity 
data reported with the 3 first dose levels administered in YAs by an unblinded Safety 
Review Team (SRT).  
Note: As the goals of protocol amendments 3, 4 and 5 are to further explore the 
reactogenicity/immunogenicity profile in YAs (all previous dose levels were tested 
in this population), no OAs will be enrolled in the 
 and 
 dose cohort, and  
and 
 dose cohort, or in the 
, and their potential intermediate dose 
cohorts (
 and 
). 
3. Supervision of the dose escalation by SRT. The safety/reactogenicity data reviewed 
by this team cover 8 days of follow up post-dosing (Day 1 to Day 8 included) of all 
participants of the current dose level. This time window is sufficient to ensure a 
reliable evaluation of the reactogenicity of the vaccine, considering that the median 
onset of solicited systemic events after mRNA Covid-19 vaccines administration is 1 
to 2 days, and a median duration of such events is 1 to 2 days [CBER, 2021; CBER, 
2022].  
Note: 
, and 
 have 
shown a 
 (incidence of Grade 3 solicited 
adverse events ranging from
 depending on dose group) this dose 
escalation step will not be followed for the  and 
 , or the 
 and 
 dose 
cohorts, i.e., participants in these cohorts will be enrolled in parallel. Enrollment of 
sentinel participants for each dose level, per age group. The safety/reactogenicity 
data for at least 2 days of follow up post-dosing of 6 sentinel participants will be 
reviewed by an SRT before enrolling the 18 remaining participants planned in the 
study group (24 participants/dose level), to reduce the risk of unnecessary exposure 
to a possibly highly reactogenic dose. 
Note: 
, and 
 have 
shown a 
 (incidence of Grade 3 solicited 
adverse events ranging from 
 depending on dose group), no sentinel 
participants will be included in the additional 
 and 
 dose cohort and and 
 
 dose cohort. 
4. Use of a Bayesian Logistic Regression Model (BLRM) to inform and guide the 
decision to (i) enroll non-sentinel participants and (ii) escalate the dose. 
Reactogenicity data from both sentinel and non-sentinel participants at current and 
all previous dose levels will be used by the BLRM along study progression. 
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5. Possibility to assess intermediate dose level in YAs, should the posterior probability 
of the BLRM indicate that the reactogenicity of the upper dose level would be too 
high (adaptive design). 
6. Use of an upper age limit (70 years) for sentinel participants in OA groups. 
7. Enrollment of OAs with no clinically significant co-morbidities. 
GSK’s Flu Dresden- Quadrivalent Influenza Vaccine, hereafter referred to as Flu D-QIV 
and commercially available as α-RIX-Tetra in Belgium was chosen as active control in 
this study. It is indicated for active immunization for the prevention of disease caused by 
influenza A subtype viruses and type B viruses contained in the vaccine. The vaccine is 
approved for use in 6 months and older. 
Note: The sample size of the available Control group (N=30) is similar to the sample size 
of each additional dose group to be tested (N=24). As such, we consider the available 
Control group sufficiently large for this phase 1 exploratory and descriptive study and 
will not use an active control for the additional 
 and 
 dose cohort and and 
 
dose cohort, where an assessment of immunogenicity is the main objective. However, for 
the additional 
, and their potential intermediate dose cohorts (
 and 
 
), where a safety/reactogenicity assessment is the main objective, Flu D-QIV will be 
reintroduced as active control. 
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 
and young children, influenza can aggravate existing medical conditions and potentially 
lead to life-threatening complications. During seasonal epidemics, 5-15% of the 
population is typically infected, resulting in 3-5 million cases of severe illness. Up to 
650 000 deaths annually are associated with seasonal influenza [WHO, 2017]. 
Please refer to the current Investigator’s Brochure (IB) for information regarding pre-
clinical studies of Flu Seasonal mRNA. 
2.3. 
Benefit/Risk assessment  
Detailed information about the known and expected benefits and risks and expected 
adverse events of Flu Seasonal mRNA can be found in the IB. 
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Detailed information about the known and expected benefits and risks and expected 
adverse events of Flu D-QIV can be found in the Summary of Product Characteristics 
(SmPC). 
As for any vaccine, administration site (e.g., pain, swelling, redness) and systemic (e.g., 
fever, fatigue, headache, myalgia) post-dosing events may occur within the first 3 days of 
study intervention administration, and are anticipated to resolve within a few days of 
onset. 
2.3.1. 
Risk assessment (Amended 20 June 2023) 
Potential risks 
Data/Rationale for risk 
Mitigation strategy 
All study vaccines 
Hypersensitivity including 
allergic reactions such as 
anaphylaxis 
Acute allergic reactions are serious, 
but rare occurrences estimated in 
the range of 1 to 10 cases per 
million of vaccinations, depending 
on the vaccine studied [Rüggeberg, 
2007]. 
Participants with history of hypersensitivity 
or severe allergic reaction to any previous 
vaccine or any component of the study 
intervention are excluded from the study 
enrollment. 
All participants will remain under 
observation with appropriate medical 
treatment readily available, if needed. 
Participants will be instructed to contact the 
study site immediately for occurrence of 
any possible hypersensitivity reaction within 
1 day following study intervention 
administration. 
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 judgment of the investigator would make 
intramuscular injection unsafe will be 
excluded from study enrollment. 
Flu Seasonal mRNA vaccine 
Due to the lack of 
experience in human 
participants, there is 
currently not enough 
information available about 
the relationship of AEs and 
the administration of the 
Flu Seasonal mRNA 
investigational vaccines 
 
The first sentinel participants in each age 
category (both in Flu mRNA and in Control 
groups) will be dosed in the morning of the 
first day. There will be an interval of at least 
60 minutes between dosing of all sentinel 
participants. 
The next day, if no holding rule has been 
met in the sentinel participants dosed at the 
first day, the remaining sentinel participants 
in each age category (in Flu mRNA and in 
Control groups) will be dosed. 
All the participants (including non-sentinel) 
will be observed on site for 60 minutes after 
dosing. 
Refer to Section 8.2.3.1 for more 
information on safety monitoring. 

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Potential risks 
Data/Rationale for risk 
Mitigation strategy 
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]. The risk of reporting 
facial paralysis following an 
influenza vaccination seems to be 
higher compared with that following 
the administration of other vaccines 
[Kamath, 2020]. 
Although literature is sparse on 
specific mechanism involved, given 
the potential association between 
influenza infection and incidence of 
facial palsy, Bell’s palsy is proposed 
as an important potential risk for this 
candidate vaccine. 
Participants with a recurrent history of 
neurological disorders or seizures, including 
Bell’s palsy, will be excluded from the study 
enrollment. Moreover, pIMDs including 
Bell’s palsy will be collected as AESIs (refer 
to Section 10.3.6). 
Guillain-Barré Syndrome 
(GBS) 
An association between the onset of 
GBS and influenza vaccination was 
suggested in late 70’s during swine 
flu immunization program [Langmuir, 
1979; Schonberger, 1979] and was 
confirmed by results of 39 studies 
published between 1981 and 2014 
[Martín Arias, 2015; Greene, 2012; 
Wise, 2012]. Given the potential 
association, GBS is proposed as an 
important potential risk for this 
candidate vaccine. 
Participants with a recurrent history of 
neurological disorders or seizures, including 
GBS, will be excluded from the study 
enrollment. Moreover, pIMDs including 
GBS will be collected as AESIs (refer to 
Section 10.3.6). 
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 after the procedure. 
The decision to dose the participant will be 
dependent on the clinical judgment of the 
investigator. 
Note: no sentinel participants are included for the
 and
 or 
 and 
 dose cohorts 
2.3.2. 
Benefit assessment  
Participants may gain information and medical advice about their general health status 
through medical evaluations/assessments associated with this study (i.e., physical 
examinations, urine analysis and blood testing [hematology, biochemistry and 
coagulation data]). 
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2.3.3. 
Overall benefit/risk conclusion 
The investigational Flu Seasonal mRNA vaccine is currently in an early stage of clinical 
development and vaccine efficacy, immunogenicity, and safety have not yet been 
demonstrated in humans. Considering the measures to minimize the risk to participants in 
this Phase 1 clinical study, the potential risks are justified by the potential benefits linked 
to the development of this Flu Seasonal mRNA vaccine. 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 3 
Study objectives, endpoints and estimands 
Objectives 
Endpoint(s) and estimand(s) 
Co-primary 
To evaluate the safety and 
reactogenicity profile of the study 
interventions 
Solicited events: 
• 
Percentage of participants reporting each solicited administration site 
and systemic events within 7 days (i.e., from Day 1 to Day 7) after 
study intervention administration 
Unsolicited adverse events (AEs): 
• 
Percentage of participants reporting unsolicited AEs within 28 days 
(i.e., from Day 1 to Day 28) after study intervention administration 
Serious Adverse Events (SAEs) and Adverse Events of Special Interest 
(AESI*): 
• 
Percentage of participants reporting SAEs within 6 months (i.e., from 
Day 1 to Day 183) after study intervention administration 
• 
Percentage of participants reporting AESIs within 6 months (i.e., from 
Day 1 to Day 183) after study intervention administration 
Safety laboratory: 
• 
Percentage of participants reporting a shift from non-clinically 
significant laboratory value on Day 1 (pre-dose) to clinically significant 
abnormal laboratory value on Day 8 (post-dose) or on Day 29 (post-
dose) for hematology, clinical chemistry, coagulation and urine 
analysis.  
To evaluate the humoral immune 
response induced by the study 
interventions 
 antibody titer: 
• 
Geometric mean titers (GMT) at Day 1 and Day 22 
• 
Geometric mean increase (GMI) from Day 1 to Day 22 
• 
 from Day 1 to Day 22 
• 
) at Day 22 
Secondary 
To evaluate the humoral immune 
response induced by the study 
interventions 
 antibody titer**: 
• 
GMT at Day 62 and Day 183 
• 
GMI from Day 1 to Day 62 
• 
GMI from Day 1 to Day 183 
• 
 at Day 62 and Day 183 
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Objectives 
Endpoint(s) and estimand(s) 
 
 
* Refer to Sections 10.3.3 and 10.3.6 for the list of solicited events and events considered as AESI, respectively. 
** Note: for the 
, and their potential intermediate dose cohorts 
 and 
 no analysis for 
 
response will be performed, and humoral immune response determination will be limited to Day 1 and Day 22. 
Details related to attributes of estimand covering intercurrent events, population and 
treatment definition are provided in the Section 9. 
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4. 
STUDY DESIGN  
4.1. 
Overall design (Amended: 20 June 2023)  
Figure 1 
Study design overview (Amended: 20 June 2023)  
  
AE: adverse event; SAE: serious adverse event; AESI: adverse event of special interest; D: day; 
 
 Control: Flu D-QIV (Flu Dresden-Quadrivalent Influenza Vaccine; GlaxoSmithKline; season 
2021-2022 Northern Hemisphere [NH] for the 
 dose cohorts, and season 2022-2023 NH for the 
 
Flu mRNA dose 2 (N = 24)
Control (N = 6)
Flu mRNA dose 1 (N = 24)
Control (N = 6)
Selected dose from YAs (N = 24)
Control (N = 24)
Flu mRNA dose 4 (N = 24)
D1
D183
D1
D183
D1
D183
D1
D183
D1
D183
Control (N = 6)
Control (N = 6)
Flu mRNA dose 3 (N = 24)
Flu mRNA dose 6 (N = 24)
D1
D183
Flu mRNA dose 7 (N = 24)
Flu mRNA dose 8 (N = 24)
D1
D183
Control (N = 6)
D1
D183
Flu mRNA dose 9 (N = 24)
Concomitant vaccinations and SAEs related to study participation or to a concurrent GSK vaccine
(Day -28 - Day 183) 
Solicited events (Day 1 - Day 7)
Unsolicited AEs
(Day 1 - Day 28)
(Day 3 and 7)
Visit 5
D62* , ***
Visit 6
D183 * , ***
Visit 1
D1*
Contact 1
D2 **
Visit 2 
D8*
Visit 3
D22
Visit 4
D29
: Contact
: Study intervention 
administration
: Younger adults
: Older adults
: Blood and urine sampling 
safety
: Blood sampling 
immunogenicity
Screening
D-28 to D-1
Contact 2
D3
SAEs, AESIs, pregnancies, AEs/SAEs leading to withdrawal and concomitant medications
(Day 1 - Day 183) 
Control (N = 6)
Flu mRNA dose 10 (N = 24)
D183
Flu mRNA dose 11 (N = 24)
D1
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 dose cohorts, and their potential intermediate dose cohorts 
 and 
); commercially available as α-RIX-
Tetra in Belgium).  
Doses of study intervention for YAs are coded as follows: dose 1: 
 dose 2: 
 dose 3: 
, dose 4: 
 
dose 6: 
 dose 7: 
, dose 8:
, dose 9: 
 dose 10: 
 dose 11: 
 Potential intermediate 
dose levels 
, and 
 may be evaluated with the total number of dose levels not 
exceeding 12 in YAs and 1 in OAs. In OAs, dose of study intervention will be selected based on safety/reactogenicity 
data up to dose 3 in YAs. Refer to Section 4.3 for more information. Refer to Section 4.3.2, 4.3.4, and 4.3.4 for 
rationale for addition of the
 and their potential intermediate dose 
cohorts (
) respectively. 
* Blood sample for 
 will be collected from a subset of participants. 
 will be assessed in 50% of participants of 
each group (Flu mRNA and Control) to be enrolled at the selected sites.  
Note: for the 
 and their potential intermediate dose cohorts 
) no blood sampling for 
 
response will be performed.  
** Contact 1 (Day 2) will be performed for sentinel participants only. Note that no sentinel participants are included for 
the 
 dose cohorts. 
*** Visit 5 (Day 62) and Visit 6 (Day 183) will be replaced by a contact if participant have received the standard of care 
vaccination against seasonal flu prior to this visit and did not report any adverse events that would require physical 
examination on site. Note: No blood sampling will be performed at Day 62 and Day 183 for the 
, and 
their potential intermediate dose cohorts 
). As such, Visit 5 and Visit 6 will be replaced by a contact for 
all participants in these cohorts unless they reported any adverse events that would require physical examination on 
site. 
Note: Each dose group consists of sentinel and non-sentinel participants, except for the 
 dose 
groups. 
• 
First-time-in-human (FTiH) 
• 
Phase 1 study with adaptive design that will be conducted in the following way: 
− 
Safety of and immune response to 1 formulation at different dose levels of study 
intervention will be assessed in YAs using an active controlled and dose 
escalation design. Unless safety concerns are identified by SRT after dosing 
sentinel participants, remaining participants at the current dose level will be 
administered the study intervention. SRT will also review data from all 
participants from a current dose level and advise on dosing of sentinel 
participants for the next dose level. 
− 
Safety of and immune response to 1 formulation at 1 dose level of study 
intervention will be assessed in OAs using an active control. Unless safety 
concerns are identified by SRT after dosing sentinel participants, remaining 
participants at the current dose level will be administered the study intervention. 
− 
For the additional 
 dose cohorts, no sentinel 
participants will be enrolled; no dose escalation design applies; the dose levels 
in each cohort will be enrolled in parallel; no control vaccine will be used. 
YA  
OA  
Flu mRNA 
Control 
Flu mRNA 
Control 
Sentinel 
participants 
N = 6 /group 
Non-sentinel 
participants 
N = 18/group 
Sentinel 
participants 
N = 3 /group 
Non-sentinel 
participants 
N = 3/group 
Sentinel 
participants 
N = 6 /group 
Non-sentinel 
participants 
N = 18/group 
Sentinel 
participants 
N = 6 /group 
Non-sentinel 
participants 
N = 18/group 
Note: No sentinel participants will be enrolled for the additional
 dose cohorts, hence all 
participants in these cohorts will be considered as non-sentinel. No control vaccine will be used for the 
 
or 
 dose cohorts, where a randomization ratio of 1:1 will be applied between the
 dose levels, 
and between the 
 dose levels, for a total of 48 participants per cohort.  
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• 
Staggered enrollment for the 
 cohorts and their potential 
intermediate dose cohorts 
 refer to Section 8.2.3.1 and Table 10 for 
details.  
• 
Parallel enrollment for the 
, and the 
 dose cohorts. 
• 
Planned (approximate) number of participants to be enrolled is 354: 
− 
306 YA participants (24 participants per dose level and a total number of 42 
participants receiving the active control) 
− 
48 OA participants (24 participants receiving a dose of investigational study 
intervention and 24 participants receiving the active control) 
− 
Due to the adaptive design, the actual number of participants enrolled might be 
lower than the target number or up to 384 participants in case a 12th dose level is 
evaluated in YAs. 
• 
Study intervention: single dose intramuscular (IM) administration of different dose 
levels of the study intervention: 
− 
YAs: 1 formulation at 6 dose levels (
). Depending 
on the reactogenicity/safety findings after dosing with these dose levels, 
potential intermediate dose levels may be assessed (i.e., 
 and 
. Refer to Section 8.2.3.1 for details on dose escalation management.  
Furthermore, 2 additional doses of
 of the vaccine candidate will be 
assessed in 48 YAs under Protocol Amendment 3; and 2 additional doses of 
 
 will be assessed in 48 YAs under Protocol Amendment 5. Refer to 
Section 4.3.2, 4.3.4, and 4.3.4 for rationale for addition of the 
 
, and their potential intermediate dose cohorts 
respectively. In any case, the total number of dose levels assessed will not 
exceed 12. 
− 
OAs: 1 formulation at 1 dose level (up to 
 The dose level will be selected 
after review by SRT of the safety/reactogenicity data obtained in YAs dose 
levels 1 to 3 (up to 
 
• 
Active control: Flu D-QIV (Flu Dresden- Quadrivalent Influenza Vaccine; 
GlaxoSmithKline; season 2021-2022, Northern Hemisphere [NH], commercially 
available as α-RIX-Tetra in Belgium) will be used as the active control for the 
 
, and their potential intermediate dose cohorts in both YAs and OAs, while 
Flu D-QIV season 2022-2023 will be used as active control for the 
, 
and their potential intermediate dose cohorts (
 No active control will 
be used for the 
, or 
 dose cohorts. 
• 
Study groups: 
− 
2 parallel groups, Flu mRNA versus Control in YAs. 
− 
2 parallel groups, Flu mRNA versus Control in OAs. 
− 
For the
 dose cohort: 2 parallel groups, Flu mRNA 
 versus Flu 
mRNA 
 in YAs.  
− 
For the 
 dose cohort: 2 parallel groups, Flu mRNA 
 versus 
Flu mRNA 
 in YAs.  
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A 
 subset will be defined, where 
 will be assessed in 50% of participants of each 
group (Flu mRNA and Control) to be enrolled at the selected sites. 
• 
Note: no 
 response will be assessed for the 
, and their potential 
intermediate dose cohorts (
). 
• 
Method of study intervention allocation: for each dose level and age group 
separately, randomization, using study, country, site and influenza vaccination 
history for the past 2 years as minimization factors for all participants. 
− 
YA participants will be randomized to receive either 1 of the dose levels, or the 
active control. 
− 
OA participants will be randomized to receive either 1 dose level or the active 
control. 
− 
For the 
 dose cohort, YA participants will be randomized to receive 
either the Flu mRNA 
 or 
 dose. 
− 
For the 
 and 
 dose cohort, YA participants will be randomized to 
receive either the Flu mRNA 
 or 
 dose. 
• 
Study type: primary vaccination. 
• 
Level of blinding: for participants and investigators, the study will be observer-blind 
with regards to the study intervention, but open-label with regards to the dose level. 
For the sponsor, the study will be open-label. For the 
, and 
 
dose cohorts, the study will be single-blind. 
• 
Multi-country, multi-center. However, sentinel participants will be preferably 
recruited at a single site. 
• 
Self-contained. 
• 
Aspects of data collection: blood and urine samples, safety events, 
 
 
• 
Intended duration of the study per participant: up to 8 months. 
• 
Method of data collection: 
− 
Standardized electronic Case Report Form (eCRF) 
− 
Solicited AEs, the occurrence of unsolicited AEs and responses to
 will be 
collected using electronic Diary (eDiary). 
• 
Safety monitoring: refer to Section 8.2.3 for the review of safety data by SRT. 
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Table 4 
Study groups, intervention and blinding (Amended: 20 June 2023)  
Study groups 
Number of 
participants 
Age 
(Min-Max) 
Study interventions 
(IM use) 
Blinding 
Visit 1→Visit 6 
YA 
 Flu mRNA dose 1 
24 
18 – 45 years 
Observer-blind*  
Flu mRNA dose 2 
24 
18 – 45 years 
Observer-blind* 
Flu mRNA dose 3 
24 
18 – 45 years 
Observer-blind * 
Flu mRNA dose 4 
24 
18 – 45 years 
Observer-blind * 
Flu mRNA dose 6 
24 
18 – 45 years 
Single-blind* 
Flu mRNA dose 7 
24 
18 – 45 years 
Single-blind*  
Flu mRNA dose 8 
24 
18 – 45 years 
Observer-blind * 
Flu mRNA dose 9 
24 
18 – 45 years 
Observer-blind * 
Flu mRNA dose 10 
24 
18 – 45 years 
Single-blind* 
Flu mRNA dose 11 
24 
18 – 45 years 
Single-blind*  
Control** 
24 
18 – 45 years 
FDQ21A-NH 
Observer-blind* 
Control** 
12 
18 – 45 years 
FDQ22A-NH 
Observer-blind* 
OA 
Selected dose from 
YAs 
24 
60 – 80 years 
Selected dose from YAs*** 
Observer-blind* 
Control 
24 
60 – 80 years 
FDQ21A-NH 
Observer-blind* 
YA: younger adult; OA: older adult; NH: Northern Hemisphere. 
Control: Flu D-QIV (Flu Dresden- Quadrivalent Influenza Vaccine; GlaxoSmithKline; season 2021-2022 NH for the 
 
 dose cohorts, and season 2022-2023 NH for the 
 dose cohorts; commercially available 
as α-RIX-Tetra in Belgium)  
Doses of vaccine candidate are coded as follows: dose 1:
 dose 2: 
 dose 3: 
; dose 4: 
, dose 6: 
 dose 7: 
, dose 8: 
, dose 9: 
, dose 10: 
, dose 11: 
 Potential intermediate dose 
levels 
 may be evaluated with the total number of dose levels not 
exceeding 12 in YAs and 1 in OAs. Refer to Section 4.3.2, 4.3.4, and 4.3.4 for rationale for addition of the 
 
 and their potential intermediate dose cohorts 
 respectively. 
* For participants and investigators, the study will be observer-blind with regards to the study intervention, but open-
label with regards to the dose level. For the sponsor, the study will be open-label. For the 
 and 
 
dose cohorts, the study will be single-blind. Refer to Section 6.3.5 for more information. 
** In YAs, 6 participants are enrolled in the control group per dose level of the investigational study intervention, except 
for the 
 and 
 dose cohorts, where no control vaccine will be used. 
*** Study intervention dose will be selected based on the safety/reactogenicity data obtained up to dose 3 in YAs. 
Refer to Section 4.3 for more information. 
Note: Hereafter, name of the study groups for YAs will be only referred to as Flu mRNA dose 1-11. Details on the study 
intervention administered are shown in Table 5. 
4.1.1. 
Enrollment rules (Amended: 20 June 2023) 
Overall, participants will be enrolled in 2 age categories (YAs and OAs) with at least 
35% of either sex to ensure balance between males and females. Note: To allow a higher 
enrollment flexibility in the study and since sex is not considered an important prognosis 
factor, the sex enrollment rule will not be applied to the additional 
 dose 
cohort, or the 
 and their potential intermediate dose cohorts (
 
).  
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4.2. 
Scientific rationale for study design  
4.2.1. Choice of active comparator (Amended: 20 June 2023)  
To completely characterize the immunogenicity of the candidate vaccine compared with 
a licensed vaccine, Flu D-QIV has been selected as active control in this study. This 
vaccine is indicated for active immunization for prevention of disease caused by 
influenza A subtype viruses and type B viruses contained in the vaccine and is approved 
for use in adults.  
Note: The sample size of the available Control group (N=30) is similar to the sample size 
of each additional dose group to be tested (N=24). As such, we consider the available 
Control group sufficiently large for this phase 1 exploratory and descriptive study and 
will not use an active control for the additional 
 or 
 dose cohorts, 
where an assessment of immunogenicity is the main objective. However, for the 
additional 
, and their potential intermediate dose cohorts (
), 
where a safety/reactogenicity assessment is the main objective, Flu D-QIV will be 
reintroduced as active control. 
4.2.2. 
Rationale for study blinding  (Amended: 20 June 2023) 
 
 the study will be blinded for participants and 
investigators with regards to the formulation (Flu mRNA versus Control) but open-label 
with regards to the dose level.  
For the 
 and 
 dose cohorts, 2 different Flu mRNA doses are to 
be used, therefore the persons reconstituting the interventions will be aware of the dose of 
the allocated Flu mRNA vaccine. This requires unblinding the randomization system for 
this cohort and accordingly all users of the randomization system, including the 
investigator, will be unblinded and only the participant will remain blinded. 
The study will be open-label for the sponsor to allow continuous review of data by the 
SRT for dose level determination and escalation and monitoring of holding rules. 
Please refer to Glossary of terms for the definition of observer-blind and single-blind. 
Further information on blinding and unblinding is provided in Section 6.3. 
4.3. 
Justification for dose (Amended: 20 June 2023)  
Six dose levels 
) and 1 dose level (up to 
) are planned 
to be evaluated in YAs and OAs, respectively, in this study. Depending on the outcomes 
of safety and reactogenicity evaluations, intermediate dose levels (YAs: 
 
; OAs: 
) may be used. Furthermore, 2 additional doses of 
 
of the vaccine candidate will be evaluated in YAs under Protocol Amendment 3, and 2 
additional doses of 
 of the vaccine candidate will be evaluated in YAs 
under Protocol Amendment 5. Refer to Section 4.3.2,  4.3.4, and 4.3.4 for rationale for 
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addition of the 
, and 
 and their potential 
intermediate dose cohorts 
 respectively. The total number of dose levels 
will not exceed 12 in YAs and 1 in OAs. 
4.3.1. 
Justification for dose for YAs  
In the Phase 3 efficacy trial of the Covid-19 vaccine (first generation mRNA vaccine of 
the same platform with unmodified nucleotides) conducted by CureVac in approximately 
20 000 participants, the safety profile of 
 was 
 [Kremsner, 
2021a]. As the reactogenicity profile of modified nucleotides formulations is expected to 
be improved as compared to the unmodified formulations, a starting dose of 
 in YAs 
is considered appropriate. 
For dose escalation in YAs, 
-fold increases will be implemented (option to decrease 
to lower than 
-fold increases with intermediate dose levels). A 
-fold dose 
escalation increase will be implemented for the higher dose levels (i.e., 
). 
Although earlier studies [Aldrich, 2021; Kremsner, 2021b] showed that reactogenicity 
increased even after modest dose increments, dose-finding studies of mRNA vaccines 
based on modified nucleotides have adopted 
 incremental dose escalation schemes: 
10-20-30-100 µg for Pfizer/BioNTech Covid-19 vaccine and 25-100-250 µg for 
Moderna’s Covid-19 vaccine [Jackson, 2020; Walsh, 2020].  
Data from 
, a GSK-sponsored FTiH dose escalation study in 
adults evaluating an investigational SARS-CoV-2 vaccine using the same mRNA 
platform as in the Flu SV mRNA-003 study, have shown a
 
. 
In addition, as competitors’ experience suggests 
 as the maximum tolerable 
dose [Jackson, 2020; Walsh, 2020], and the test vaccines in this study use comparable 
LNPs as the Pfizer/BioNTech Covid-19 vaccine [Walsh, 2020], 
 
 tested in that program. 
4.3.2. 
Justification for additional doses in YAs, evaluated in 
Amendment 5 (Amended: 20 June 2023) 
Available data from the 
 dose cohorts in this study 
 
 
 
 
 In this amendment, we will therefore further 
assess the immunogenicity of 
 dose levels in order to 
 
. Data 
from this amendment will be used to further characterize the mRNA platform, and may 
 
 
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4.3.3. 
Justification for additional doses in YAs, evaluated in 
Amendment 3  
Preliminary immunogenicity data from the 
 cohorts in this study 
suggest that the most immunogenic dose of the study intervention in YAs 
 
 In this amendment, we will therefore further assess the immunogenicity of  
 dose levels in order to better define the optimal dose for this monovalent H1 
vaccine candidate. These data will be used to inform the selection of dose levels of 
influenza vaccine candidates in upcoming clinical studies. 
4.3.4. 
Justification for additional doses in YAs, evaluated in 
Amendment 4   
Available data from the 
 dose cohorts in this study show  
. In addition, data from 
 a GSK-sponsored FTiH dose escalation study in adults 
evaluating an investigational SARS-CoV-2 vaccine using the same mRNA platform as in 
the Flu SV mRNA-003 study, have shown 
 
. The aim of the current protocol amendment is to 
 
 
and specifically to explore the reactogenicity/immunogenicity profile at 
 
and their potential 
 Data from this amendment 
will not only be used to further characterize the mRNA platform, but also to support 
 
 
. 
4.3.5. 
Justification for dose for OAs  
To limit overall exposure in OAs, 
 will be evaluated for 
safety/reactogenicity and immunogenicity for comparison with YAs. Dosing in OAs will 
be initiated after the review of safety/reactogenicity from 
 in YAs. 
The dose level in OAs will be selected from the dose levels evaluated in YAs 
 
and will be limited to dose levels 
 with no safety/reactogenicity 
concerns (including a posterior probability estimate of Grade 3 solicited event rate <18% 
based on the BLRM) in YAs. 
4.4. 
End of Study definition  
A participant is considered to have completed the study if the participant returns for the 
last visit or is available for the last scheduled procedure as described in the protocol. 
End of Study (EOS): Last subject last visit (LSLV) (Visit 6) or Date of the last 
testing/reading released of the Human Biological Samples or imaging data, related to 
primary and secondary endpoints, whichever occurs later. EoS must be achieved no later 
than 8 months after LSLV. EoS cannot be before LSLV. 
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5. 
STUDY POPULATION  
Adherence to the inclusion and exclusion criteria specified in the protocol is essential. 
Deviations from these criteria are not allowed because they can jeopardize the scientific 
integrity, regulatory acceptability of the study or safety of the participant. 
5.1. 
Inclusion criteria  
All participants must satisfy ALL the following criteria at study entry: 
1. A male or female between and including 18 and 45 years of age (YAs) or between 
and including 60 and 80 years of age (OAs) at the time of the study intervention 
administration. The age of sentinel participants in OA category will be limited to 
maximum 70 years. 
2. Healthy or medically stable participants as established by medical history, safety 
laboratory assessments and clinical examination. 
3. Body mass index ≥ 18 kg/m² and ≤ 32 kg/m². 
4. Participants who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g., completion of the eDiary, return for follow up 
visits). 
5. Written informed consent obtained from the participant prior to performing any 
study-specific procedure. 
6. Female participants of non-childbearing potential may be enrolled in the study. Refer 
to Section 10.4.1 for definitions of women of childbearing potential, menarche and 
menopause. 
7. Female participants of childbearing potential may be enrolled in the study if the 
participant: 
− 
has practiced adequate contraception for 28 days prior to study intervention 
administration, and 
− 
has a negative pregnancy test on the day of study intervention administration, 
and 
− 
has agreed to continue adequate contraception for at least 1 month after study 
intervention administration. 
Refer to Section 10.4.1 for definitions of woman of childbearing potential and 
adequate contraception. 
5.2. 
Exclusion criteria  
The following criteria should be checked at the time of study entry. The potential 
participant MUST NOT be included in the study if ANY exclusion criterion applies: 

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5.2.1. 
Medical conditions  
1. Acute or chronic clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by physical examination or review of the 
participant’s medical record. 
2. Any clinically significant* hematological, biochemical, coagulation or urine analysis 
laboratory abnormality. Refer to Section 10.2.1 for the list of safety laboratory 
assessments to be considered in this study. 
* The investigator should use his/her clinical judgment to decide which 
abnormalities are clinically significant. 
3. Current or past malignancy, unless completely resolved without sequelae for 
>5 years. 
4. Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including HIV infection, based on medical history and physical examination (no 
laboratory testing required). 
5. History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the study intervention (including latex, poly-ethylene-glycol, 
egg-protein and aminoglycoside antibiotics). 
6. Recurrent history or uncontrolled neurological disorders or seizures, including 
Guillain-Barré syndrome and Bell’s palsy, with the exception of febrile seizures 
during childhood. 
7. Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe. 
8. Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the participant due to participation in the study. 
9. Significant exposure to persons with influenza or laboratory-confirmed SARS-CoV-
2 within 7 days prior to Visit 1 (Day 1) and for whom a SARS-CoV-2 PCR test has 
not (yet) been confirmed as negative. 
5.2.2. 
Prior/Concomitant therapy   
10. Administration of seasonal influenza vaccine, within 180 days before enrollment or 
planned administration up to Visit 4 (Day 29). 
11. Administration of a vaccine not foreseen by the study protocol in the period starting 
28 days before the study intervention administration, or planned administration 
within 28 days after the study intervention administration*, with the exception of 
vaccines authorized or approved for the prevention of Covid-19 (regardless of the 
type of vaccine). 
*In case emergency mass vaccination for an unforeseen public health threat (e.g., a 
pandemic) is organized by public health authorities outside the routine immunization 
program, the time period described above can be reduced to 7 days, if necessary, for 
that mass vaccination vaccine, provided it is used according to the local 
governmental recommendations and that the Sponsor is notified accordingly. 

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12. 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. 
13. Administration of long-acting immune-modifying drugs within 90 days before 
enrollment or planned use at any time during the study period (e.g., infliximab). 
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. Administration of monoclonal 
antibodies specifically directed against the spike protein of SARS-CoV-2 virus, for 
treatment of Covid-19 disease is allowed. 
15. Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 3 
months prior to the study intervention administration. For corticosteroids, this will 
mean prednisone equivalent ≥ 20 mg/day. Inhaled, topical and intraarticular steroids 
are allowed. 
5.2.3. 
Other exclusions  
16. Pregnant or lactating female. 
17. Female planning to become pregnant or planning to discontinue contraceptive 
precautions within the 1-month post-dosing period. 
18. History of abusive alcohol and/or drug consumption in the past 5 years. 
19. Any study personnel or their immediate dependents, family, or household members. 
20. Participants with extensive tattoos covering deltoid region on both arms that would 
preclude the assessment of local reactogenicity. 
21. Previous enrollment in this study. 
5.3. 
Lifestyle considerations  
Section is not applicable. 
5.4. 
Screening failures  
A screening failure is an individual who consents to participate in this study but is not 
entered in the study/randomized to a study intervention. 
Limited data for screening failures (including informed consent date, demographic data, 
eligibility criteria check, reason for screening failure and any SAEs related to study 
participation or concurrent GSK medication/vaccine) will be collected and reported in the 
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5.5. 
Criteria for temporarily delaying randomization/study 
intervention administration  
For participants who have not been randomized, randomization may be postponed within 
the screening period of 28 days interval until transient conditions cited below are 
resolved. 
For participants who have been randomized, study intervention administration may be 
postponed within the 3 days interval until transient conditions cited below are resolved: 
• 
Acute disease and/or fever at the time of randomization and/or study intervention 
administration. Refer to the SoA (Section 1.3) for definition of fever and preferred 
location for measuring temperature in this study. 
• 
Use of antipyretics and/or analgesics within 24 hours prior to study intervention 
administration, with exception of use of low dose of acetyl salicylic acid for 
prevention of cardiovascular disease. 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY  
Refer to the Glossary of terms for the definition of study intervention. 
6.1. 
Study intervention(s) administered  

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Table 5 
Study intervention(s) administered (Amended: 20 June 2023)  
Study intervention 
name: 
Flu mRNA vaccine 
Study intervention 
formulation: 
Presentation: 
Concentrate for 
dispersion for injection 
(Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for injection 
(Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for injection 
(Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for injection 
(Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Manufacturer: 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
Type: 
Investigational 
Product category: 
Biologic 
Route of 
administration:  
IM 
Location 
Deltoid 
• 
Directionali
ty  
Upper 
• 
Laterality ** 
Non-Dominant 
Number of doses 
to be administered: 
1 
Volume to be 
administered by 
dose ***: 
Refer to the Study Procedures Manual (SPM) for more details 
Packaging and 
labeling: 
Refer to the SPM for more details 
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Study intervention 
name: 
Flu mRNA vaccine 
Study intervention 
formulation: 
Presentation: 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Manufacturer: 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
Type: 
Investigational 
Product category: 
Biologic 
Route of 
administration:  
IM 
Location 
Deltoid 
• 
Directionali
ty  
Upper 
• 
Laterality ** 
Non-Dominant 
Number of doses to 
be administered: 
1 
Volume to be 
administered by 
dose ***: 
Refer to the Study Procedures Manual (SPM) for more details 
Packaging and 
labeling: 
Refer to the SPM for more details 
 
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Study intervention 
name: 
Flu mRNA vaccine 
Study intervention 
formulation: 
Presentation: 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersio
n for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersio
n for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Manufacturer: 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
Type: 
Investigational 
Product category: 
Biologic 
Route of 
administration:  
IM 
Location 
Deltoid 
• 
Directionali
ty  
Upper 
• 
Laterality 
** 
Non-Dominant 
Number of doses to 
be administered: 
1 
Volume to be 
administered by 
dose ***: 
Refer to the Study Procedures Manual (SPM) for more details 
Packaging and 
labeling: 
Refer to the SPM for more details 
 
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Study intervention 
name: 
Flu mRNA vaccine 
Study intervention 
formulation: 
Presentation: 
Concentrate for dispersion 
for injection (Vials) 
Solution for 
dispersion for 
injection 
(Ampoule or 
other) 
Concentrate for dispersion 
for injection (Vials) 
Solution for 
dispersion for 
injection 
(Ampoule or 
other) 
Concentrate for dispersion 
for injection (Vials) 
Solution for 
dispersion for 
injection 
(Ampoule or 
other) 
Manufacturer: 
GSK Biologicals 
B BRAUN**** 
GSK Biologicals 
B BRAUN**** 
GSK Biologicals 
B BRAUN**** 
Type: 
 
Product category: 
Biologic 
Route of 
administration:  
IM 
Location 
Deltoid 
• 
Directionality  
Upper 
• 
Laterality ** 
Non-Dominant 
Number of doses to 
be administered: 
1 
Volume to be 
administered by dose 
***: 
Refer to the Study Procedures Manual (SPM) for more details 
Packaging and 
labeling: 
Refer to the SPM for more details 
 
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Study intervention name: 
FDQ21A-NH† 
FDQ22A-NH‡ 
Study intervention formulation: 
A/Victoria/2570/2019 (H1N1), IVR-215 (15 µg HA); 
A/Tasmania/503/2020 (H3N2), IVR-221 (15 µg HA); 
B/Washington/02/2019 (15 µg HA); B/Phuket/3073/2013 
(15 µg HA); Water for injections 
A/Victoria/2570/2019 (H1N1), IVR-215 (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 
Presentation: 
Suspension for injection (Syringe) 
Suspension for injection (Syringe) 
Manufacturer: 
GSK Biologicals 
GSK Biologicals 
Type: 
Active control 
Active control 
Product category: 
Combination product 
Combination product 
Route of administration:  
IM 
IM 
Location 
Deltoid 
Deltoid 
• 
Directionality  
Upper 
Upper 
• 
Laterality ** 
Non-Dominant 
Non-Dominant 
Number of doses to be administered: 
1 
1 
Volume to be administered by dose ***: 
Refer to the Study Procedures Manual (SPM) for more 
details 
Refer to the Study Procedures Manual (SPM) for more 
details 
Packaging and labeling: 
Refer to the SPM for more details 
Refer to the SPM for more details 
IM: intramuscular; TBD: to be defined. 
† FDQ21A-NH: Flu D-QIV (Flu Dresden- Quadrivalent Influenza Vaccine, GlaxoSmithKline; 2021-2022 NH for the 
 dose cohorts). 
‡ FDQ22A-NH: Flu D-QIV (Flu Dresden- Quadrivalent Influenza Vaccine, GlaxoSmithKline; 2022-2023 NH for the 
, and their potential intermediate dose cohorts (
 
). 
* Potential intermediate dose levels that may be evaluated, with the total number of dose levels not exceeding 12 in YAs and 1 in OAs. 
** The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the study intervention in the non-dominant arm, an injection in the dominant arm may 
be performed. 
*** Refer to the SPM for the volume after reconstitution. 
**** Another manufacturer might be used depending on study site. 
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Study participants must be observed closely for at least 60 minutes after the 
administration of the study intervention. Appropriate medical treatment must be readily 
available during the observation period in case of anaphylaxis, syncope.  
Refer to Section 4 for more information on study groups and enrollment strategy. 
6.2. 
Preparation, handling, storage, and accountability  
The study interventions must be stored in a secured place within the temperature range 
specified on the study intervention’s label. The storage temperature should be 
continuously monitored and recorded with a calibrated (if not validated) temperature 
monitoring device(s). 
Only authorized study personnel should be allowed access to the study interventions. 
Storage conditions will be assessed by a sponsor study contact during pre-study activities. 
Refer to the SPM for more details on storage and handling of the study interventions. 
6.3. 
Measures to minimize bias: randomization and blinding  
6.3.1. 
Participant identification  
Participant identification numbers will be assigned sequentially to the participants who 
have consented to participate in the study, according to the range of participant 
identification numbers allocated to each study center. 
6.3.2. 
Randomization to study intervention (Amended: 20 June 2023)  
Planned (approximate) number of participants to be enrolled is 354: 
• 
306 YA participants (24 participants per dose level and a total number of 42 
participants receiving the active control) 
• 
48 OA participants (24 participants receiving a dose of investigational study 
intervention and 24 participants receiving the active control) 
Due to the adaptive design, the actual number of participants enrolled might be lower or 
higher (up to 384 participants in total) in case a 12th dose level is evaluated in YAs. 
Planned number of participants to be enrolled for the 
 dose cohort is 48 (24 
participants per dose level). Planned number of participants to be enrolled for the 
 
dose cohort is 48 (24 participants per dose level).  
The randomization of supplies within blocks will be performed at GSK, using MATerial 
Excellence (MatEx), a program developed for use in Statistical Analysis System (SAS) 
(Cary, NC, US) by GSK. Entire blocks will be shipped to the study centers/warehouse(s). 
For the 
 dose cohort, the active control arm will be blocked at 
randomization. For the 
 dose cohort, partial block sizes, not including active 
control, will be shipped.  
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To allow GSK to take advantage of greater rates of recruitment than anticipated at 
individual centers in this multi-center study and to thus reduce the overall study 
recruitment period, an over-randomization of supplies will be prepared. 
6.3.3. 
Intervention allocation to the participant  
An automated Internet-based system, Source data Base for Internet Randomization (e.g., 
SBIR) will be used for randomization and for identification of study intervention. 
Once a participant identification number is allocated, the randomization system will 
determine study group and will provide the study intervention number to be used. 
When SBIR is not available, please refer to the SBIR user guide or SPM for specific 
instructions. 
The randomization algorithm will use a stratification procedure accounting for sentinel, 
age and dose level cohort as stratification factor and a minimization procedure accounting 
for study, country, site, and flu vaccination history during past 2 years as minimization 
factors. 
Refer to the SPM for additional information about the study intervention number 
allocation. 
6.3.4. 
Allocation of participants to assay subsets  
A
 subset will be defined, where 
 will be assessed in 50% of participants of each 
group (Flu mRNA and Control). Participants will be enrolled at selected sites.  
Note: no 
 response will be assessed for the 
, and their potential 
intermediate dose cohorts 
). 
6.3.5. 
Blinding and unblinding (Amended: 20 June 2023) 
Data will be collected in an observer-blind manner. The participant and the site personnel 
involved in the clinical evaluation of the participants are blinded while the sponsor and 
other study personnel may be aware of the treatment assignment. To do so, study 
interventions will be prepared and administered by qualified study personnel who will not 
participate in data collection, evaluation, review or the entry of any study endpoint (i.e., 
reactogenicity, safety and immunogenicity). 
However, for the additional 
 dose cohort and
 dose cohort, data 
will be collected in a single-blind manner. The investigator(s) and/or their staff are aware 
of the study intervention assignment, but the participant is not. The study intervention 
will be prepared and administered by qualified study personnel who can be aware of the 
intervention assignment. 
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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. 
6.3.5.1. 
Emergency unblinding  
Unblinding a participant’s individual study intervention number should occur ONLY in 
case of a medical emergency when this information is essential for the clinical 
management or welfare of the participant. 
In case of emergency, the investigator can have unrestricted, immediate and direct access 
to the participant’s study intervention information via an automated Internet-based 
system (e.g., SBIR). The investigator may contact a GSK Helpdesk (refer to Table 6) if 
help is needed to access participant’s study intervention information (i.e., if the 
investigator is unable to access SBIR). 
A physician other than the investigator (e.g., an emergency room physician) or 
participant/participant’s caregiver or family member may also request emergency access 
to the participant’s study intervention information either via the investigator or 
investigator’s back up (preferred option) or via the GSK Helpdesk (back up option). The 
participant card provides contact information for the investigator(s), their back up and 
GSK Helpdesk. 
Table 6 
Contact information for emergency unblinding  
GSK Helpdesk 
Available 24/24 hours and 7/7 days 
The Helpdesk is available by phone, fax and email 
Belgium 
00 800 4344 1111 
Canada 1 833 541 0263 
Spain  
00 800 4344 1111 
Fax: 
 +32 2 401 25 75 
Email: rix.ugrdehelpdesk@gsk.com 
6.3.5.2. 
Unblinding prior to regulatory reporting of SAEs  
GSK Global Safety staff may unblind the intervention assignment for any participant 
with a Suspected Unexpected Serious Adverse Reaction (SUSAR). GSK Global Safety is 
responsible for unblinding the study intervention assignment within the timeframes 
defined for expedited reporting of SAEs (refer to Section 10.3.11.1). For SAEs requiring 
expedited reporting to 1 or more regulatory agencies, a copy of the report containing 
participant’s intervention assignment may be sent to investigators in accordance with 

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local regulations and/or GSK policy. GSK policy requires unblinding of any unexpected 
SAE which is attributable/suspected to be attributable to the study interventions, prior to 
regulatory reporting. 
6.4. 
Study intervention compliance  
Study intervention administration will be performed on site by authorized personnel 
under medical supervision. The date of the dose administration will be recorded in the 
source documents and in the eCRF. 
6.5. 
Dose modification  
Section is not applicable. 
6.6. 
Continued access to study intervention after the end of the 
study  
Section is not applicable. 
6.7. 
Treatment of overdose and management of anaphylaxis  
An overdose is any dose of study vaccine given to a participant that exceeds the planned 
randomized dose for an individual within a given dose group. 
There is no specific treatment recommended for an overdose. 
An overdose is not to be reported as an AE. However, any AEs associated with overdose 
are to be reported in the relevant AE/SAE sections of the eCRF. 
The appropriate medical treatment to be administered for any episodes of anaphylaxis or 
other immediate AEs, including those associated with overdose, will be based on the 
judgment of the medical team/physician attending to the participant. 
6.8. 
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 concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF: 
• 
All concomitant medications, except vitamins and dietary supplements, administered 
during the study (Day 1 to Day 183). 
• 
Any concomitant vaccination administered in the period starting 28 days before 
study intervention administration and ending at the last study visit (Day -28 to Day 
183). 

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• 
All concomitant medication which may explain/cause/be used to treat an SAE/AESI 
including vaccines/products, as defined in Sections 8.3.1 and 10.3.9.1. These must 
also be recorded in the Expedited Adverse Event report. 
• 
Prophylactic medication (i.e., medication administered in the absence of any 
symptom and in anticipation of a reaction to the vaccination). 
The Local Medical Lead (LML) 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  
Section is not applicable. 
7.2. 
Participant discontinuation/withdrawal from the 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 at that time. 
A participant is considered to have withdrawn from the study if no new study procedure 
has been performed or no new information has been collected for them since the date of 
withdrawal/last contact.  
From an analysis perspective, a study ‘withdrawal’ refers to any participant who did not 
return for the concluding visit planned in the protocol. 
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow up. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. 
The primary reason for study withdrawal will be documented in the eCRF, based on the 
list below: 
• 
AEs requiring expedited reporting to GSK (refer to Section 10.3.11.1 for the details) 
• 
Unsolicited non-serious adverse events 
• 
Solicited AEs 
• 
Withdrawal by participant, not due to an AEs* 

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• 
Physician decision 
• 
Migrated/Moved from the study area 
• 
Lost to follow up  
• 
Sponsor study/site termination 
• 
Other (specify) 
*If a participant is withdrawn from the study because the participant has withdrawn 
consent and the reason for withdrawal was provided, the investigator must document this 
reason in the eCRF. 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE until the event 
is resolved (see Section 10.3.9.2). 
7.3. 
Lost to follow up  
Participants will be considered ‘lost to follow up’ if they fail to return for scheduled visits 
and cannot be contacted by the study site. 
Please refer to the SPM for a description of actions to be taken before considering the 
participant lost to follow up. 
8. 
STUDY ASSESSMENTS AND PROCEDURES  
Protocol waivers or exemptions are only permitted when necessary for the management 
of immediate safety concerns for the participant. 
Immediate safety concerns should be discussed with the sponsor as soon as they occur or 
when the study team becomes aware of them. The purpose of this communication is to 
determine if the participant(s) should discontinue the study intervention. 
Study procedures and their timing are summarized in the SoA (Section 1.3). 
All screening evaluations must be completed and the results reviewed before confirming 
that potential participants meet all eligibility criteria. When applicable, a re-screening 
visit (including blood and urine sample collection, physical examination and re-checking 
of inclusion/exclusion criteria) may be scheduled at any time (but only once to assess 
eligibility) before Visit 1 (Day 1). 
The investigator will maintain a log of all participants screened. All relevant information, 
such as confirmation of eligibility and reasons for screening failure will be mentioned in 
this screening log. 
The SPM provides the investigator and site personnel with detailed administrative and 
technical information that does not impact participant safety. 

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In exceptional situations (e.g., pandemic) and if allowed by local regulation, the 
following procedures can be performed remotely/virtually, provided approved tools and 
infrastructures are used, as per local requirements (refer to the Glossary of terms for the 
definitions of telemedicine, remote and virtual visits): 
• 
Safety follow up may be performed by telemedicine which will use secure video 
conferences, phone calls, and a web portal and/or mobile application as a way of 
communicating with the participant and monitoring the participant’s progress. In 
addition, qualified study staff/health care professionals (HCPs) may also identify 
AEs and report them to the investigator for evaluation. 
• 
If allowed by local regulation, blood samples may be collected remotely* by 
qualified study staff/HCPs. Blood samples should be collected only if they can be 
processed in a timely manner and appropriately stored until the intended use. 
*It is the investigator’s responsibility to ensure that the alternate location for 
collection of samples meets the International Council for Harmonization (ICH) GCP 
requirements, such as adequate facilities to perform study procedures/data 
collection, appropriate training of the staff and documented delegation of 
responsibilities in this location. This location should be covered by proper insurance 
for the conduct of study by investigator/study staff at a site other than the designated 
study site. 
Details of how these visits will be conducted are outlined in the SPM. 
Study participants may decide to assign a caregiver to help them fulfilling the study 
procedures. Please refer to the Glossary of terms for the definition of a caregiver. 
A caregiver can be appointed by the participant at any time during the study, when the 
participant feels it is necessary. Caregiver should receive the caregiver information letter 
before providing support to the study participant. Ideally, a single caregiver should be 
appointed by the participant but, in some situations, it may happen that several caregivers 
will support a study participant throughout the conduct of the study. This should be 
recorded in the source documents. However, every effort should be done to ensure that 
only one caregiver enters the data into eDiary to allow for timely completion. 
Caregivers may help the study participants perform some study procedures such as 
receiving or making phone call(s) to site staff, planning study visits, transcribing 
responses to eDiaries, 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. 
During the screening visit, the site staff should inform the participant of the possibility of 
appointing a caregiver. Then at subsequent study visit(s), the site staff should check again 
with the participant if he/she wishes to appoint a caregiver or if there were or will be 
changes of caregiver. 
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8.1. 
Immunogenicity assessments  
Biological samples will be used for research planned in the protocol and for purposes 
related to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. 
Findings in this or future studies may make it desirable to use samples acquired in this 
study for research not planned in this protocol. In this case, all participants in countries 
where this is allowed will be asked to give consent to allow GSK or a contracted partner, 
to use the samples for further research. The further research will be subject to prior 
IEC/IRB approval, if required by local legislation. 
Information on further research and its rationale can be obtained from GSK. 
Sample testing will be done in accordance with the recorded consent of the individual 
participant. 
By default, collected samples will be stored for a maximum of 20 years. This storage 
period begins when the last participant performs the last study visit. This timeline can be 
adapted based on local laws, regulations or guidelines requiring different timeframes or 
procedures. In all cases, the storage period should be aligned with participant’s consent. 
These additional requirements must be formally communicated to, discussed and agreed 
with GSK. 
8.1.1. 
Biological samples  
Approximate maximum volumes of blood collected from each participant in each subset 
over the duration of the study are summarized in Table 7. 
Refer to SoA (Section 1.3) for details of volumes collected for different assessments. 
Table 7 
Biological samples  
Sample 
type 
Quantity* 
Unit 
Timepoint 
Subset name** 
Blood 
200  
mL 
Screening 
Participants in 
 subset 
Day 1 
Day 8 
Day 22 
Day 29 
Day 62 
Day 183 
Blood 
80 
mL 
Screening 
Other participants 
Day 1 
Day 8 
Day 22 
Day 29 
Day 62 
Day 183 
Urine 
As per local practice 
Screening 
All participants 
Day 1 
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Day 8 
Day 29 
 
*Approximate maximum total volume collected throughout the study. 
** Refer to Section 6.3.4 for subset description. 
Note: for the
 and their potential intermediate dose cohorts (
), no blood sampling for 
 response will be performed, and blood sampling for antibody determination and characterization will be limited to 
Day 1 and Day 22. For the participants in these cohorts, the total quantity of blood collected will be approximately 60 
mL. 
8.1.2. 
Laboratory assays  
All laboratory testing will be performed at GSK laboratory or in a laboratory designated 
by GSK, with the exception of the routine blood and urine panel for safety monitoring 
which will be performed by the site’s local laboratory according to their standard 
practices. 
Table 8 
Laboratory assays  
Test 
Classification 
System 
Component 
Challenge 
Method 
Laboratory * 
Humoral 
Immunity 
(Antibody 
determination 
and 
characterization) 
Serum 
 
 
GSK** or 
GSK 
designated 
laboratory 
GSK** 
or GSK 
designated 
laboratory 
Ab: antibody; 
. 
* Refer to the list of clinical laboratories for details. 
** GSK laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; CLS may 
designate testing to GSK Research laboratories in Rixensart, Belgium; Rockville, USA; Siena, Italy 
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. 
Additional exploratory testing to characterize the immune response of the 
vaccine/vaccine components or to characterize the disease may be performed on the 
serum and 
 if deemed necessary for accurate interpretation of the 
data and/or should such test(s) become available in the GSK Biologicals’ laboratory, or a 
laboratory designated by GSK Biologicals. These additional assays may not be 
represented in the objectives/endpoints of the study protocol. Serum/
 might also be 
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used for other Influenza-related assay development/validation purpose outside of this 
protocol. 
8.1.3. 
Immunological read-outs  (Amended: 20 June 2023)  
Table 9 
Immunological read-outs  (Amended: 20 June 2023)  
Blood sampling timepoint 
Subset name* No. participants 
Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 1 (Day 1) 
Pre-dose 
All enrolled 
participants 
354 
Participants in 
subset 
147 
Visit 2 (Day 8) 
Post-dose  Participants in 
 subset 
147 
Visit 3 (Day 22) 
Post-dose  
All enrolled 
participants 
354 
Visit 5 (Day 62) 
Post-dose  
All enrolled 
participants 
294 
Participants in 
 subset 
147 
Visit 6 (Day 183) 
Post-dose  
All enrolled 
participants 
294 
Participants in 
 subset 
147 
* Refer to Section 6.3.4 for subset description. 
Ab: antibody; 
. 
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8.2. 
Safety assessments  
The investigator(s) and their designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE. The investigator and designees 
are responsible for following up AEs that are serious, considered related to the study 
intervention or the study, or that caused the participant’s withdrawal from the study. 
8.2.1. 
Pre-intervention administration procedures  
8.2.1.1. 
Collection of demographic data  
Record demographic data such as year of birth, sex, race and ethnicity in the participant’s 
eCRF. 
8.2.1.2. 
Medical and 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 and flu 
vaccination history for the past 2 years in the eCRF. 
8.2.1.3. 
Physical examination  
During the screening visit and prior to dosing at Visit 1 (Day 1), the investigator will 
perform a physical examination of the participant including assessment of resting vital 
signs: systolic/diastolic blood pressure, pulse oximetry, heart rate and respiratory rate 
after at least 10 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 his/her medical judgment to ensure that the 
participant meets all the inclusion/exclusion criteria. 
Treatment of any abnormality observed during physical examination must be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
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Physical examination at each study visit after the dosing visit, will be performed only if 
the participant indicates during questioning that there might be some underlying 
pathology(ies) or if deemed necessary by the investigator or delegate. 
8.2.1.4. 
Pre-dosing body temperature  
The body temperature of each participant needs to be measured prior to the study vaccine 
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. 
8.2.1.5. 
Pregnancy test  
Only women with negative pregnancy test result at the screening visit will be included in 
the study. The study intervention may only be administered if the pregnancy test result is 
negative at Visit 1 (Day 1). 
Female participants of childbearing potential must perform a urine pregnancy test before 
the administration of the study intervention. If time allows, serum pregnancy test can be 
done as per local requirements. 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. 
Refer to Section 10.4.3.1 for the information on study continuation for participants who 
become pregnant during the study. 
8.2.1.6. 
Distribution of eDiary or installing the application for devices  
Participants will be encouraged to bring their own devices at screening visit, or if not 
feasible, at Visit 1 (Day 1). The study staff will check the compatibility of participant’s 
device (e.g., smart phone or tablet) with respect to eDiary application. 
At Visit 1 (Day 1), participant will download the eDiary application on his/her own 
electronic device or will receive an electronic device to record information related to 
his/her health and participation in the study. The participant will also be trained on the 
use of eDiary. 
The same procedures should apply to a caregiver, if identified by the study participant. 
Refer to Section 8.3.1 for details of collection of safety information and Section 10.3.9 
for guidelines. 
8.2.1.7. 
Warnings and precautions to administration of study intervention  
Warnings and precautions to administration of study intervention must be checked at 
Visit 1 (Day 1), as specified in SoA (Section 1.3). 

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Refer to the approved product label/package insert. 
8.2.2. 
Clinical safety laboratory tests  
Refer to Section 10.2.1 for the list of clinical laboratory safety assessments required by 
the protocol. These assessments must be conducted according to the clinical laboratory 
manual and the SoA (Section 1.3). 
Analyses will be performed at the local laboratory using local standards, and the results 
will be encoded by the investigator into the eCRF. 
Laboratory data will be graded according to the FDA Guidance for Industry “Toxicity 
Grading Scale for Healthy Adults and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials” dated September 2007 [FDA, 2007]. These laboratory values 
serve as guidelines and are dependent upon institutional normal parameters. Institutional 
normal reference ranges should be provided to demonstrate that they are appropriate. 
Only clinically significant laboratory findings, as judged by the investigator, should be 
reported as AE. 
8.2.3. 
Study holding rules and safety monitoring  
Safety monitoring is specified in the SoA (Section 1.3), Section 8.2.3.1 and Table 11. 
8.2.3.1. 
Staggered enrollment and safety monitoring  
During this study, recruitment will be progressive to allow careful monitoring of the 
participants. At each dose level, early participants in each group will be referred to as 
‘sentinel participants’. Enrollment of sentinel and non-sentinel participants will be 
managed as described below. Refer to Table 10 for a visual representation of the process. 
8.2.3.1.1. Staggered enrollment of YAs (Amended: 20 June 2023)  
Enrollment of sentinel and non-sentinel participants in YA for each dose level: 
• 
Sentinel participants will be the first 9 participants (6 in Flu mRNA group and 3 in 
Control group) to be randomized at each dose level and will be enrolled over 2 days. 
− 
In the morning of the first day, the first 3 sentinel participants (2 in Flu mRNA 
group and 1 in Control group) will be dosed. There will be an interval of at least 
60 minutes between dosing of each of the 3 sentinel participants. A safety follow 
up contact with each sentinel participant in each dose group will be performed 
approximately 20 hours post-dosing and prior to dosing of the next sentinel 
participants. 
− 
The second day, the next 6 sentinel participants (4 in Flu mRNA group and 2 in 
Control group) can be dosed, if no holding rule has been met in the sentinel 
participants dosed the first day. 

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• 
After at least 2 days of follow up of sentinel participants, all available safety data 
will be analyzed, and the BLRM will be run. Results will be provided to and 
reviewed by the SRT during scheduled meetings. The SRT will decide whether to 
allow the dosing of non-sentinel participants at the current dose level. Screening 
procedures may be initiated prior to SRT meeting to facilitate the enrollment of 
remaining participants. 
• 
If obtaining favorable decision from SRT, non-sentinel participants at the current 
dose level will be dosed without restriction. 
• 
After 8 days of follow up of non-sentinel participants (Day 1 to Day 8 included), all 
safety data collected until this point (from both sentinel and non-sentinel 
participants) will be analyzed and the BLRM will be run. Results will be provided to 
and reviewed by the SRT during scheduled meetings. The SRT will decide whether 
to allow the initiation of dosing of new sentinel participants at the next higher (or 
intermediate) dose level (until the maximum dose level of 
 has been reached 
and/or a maximum of 8 dose levels have been tested in sentinel participants). 
Screening procedures may be initiated prior to SRT meeting to facilitate the 
enrollment of sentinel participants at the next dose level. 
• 
Note: No sentinel participants will be enrolled for the additional 
 dose 
cohort, or 
 dose cohort. The rationale for this is that 
 
 have showed a 
 (incidence of Grade 
3 solicited AEs ranging from 
 depending on dose group), and 
 
. The 
 dose cohorts will be 
enrolled in parallel.  
• 
All the participants will be observed on site for 60 minutes after dosing. 
8.2.3.1.2. Staggered enrollment of OAs  
Enrollment of sentinel and non-sentinel participants in OA for 1 dose level: 
• 
Enrolled of OAs will be initiated once the analysis of safety data (for 8 days follow 
up post-dosing) for 3 dose levels in YAs is completed and an OA dose level has been 
recommended by the SRT. Refer to Section 4.3 for dose justification. 
• 
Sentinel participants will be the first 12 participants (6 in Flu mRNA group and 6 in 
Control group) to be randomized and will be enrolled over 2 days. The age of 
sentinel participants will be limited to maximum 70 years. 
− 
In the morning of the first day, the first 4 sentinel participants (2 in Flu mRNA 
group and 2 in Control group) will be dosed. There will be an interval of at least 
60 minutes between dosing of each of the 4 sentinel participants. A safety follow 
up contact with each sentinel participant will be performed approximately 20 
hours post-dosing and prior to dosing of the next sentinel participants. 
− 
The second day, the next 8 sentinel participants (4 in Flu mRNA group and 4 in 
Control group) can be dosed, if no holding rule has been met in the sentinel 
participants dosed the first day. 
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• 
After at least 2 days of follow up of sentinel participants, all available safety data 
will be analyzed, and the BLRM will be run. Results will be provided to and 
reviewed by the SRT during scheduled meetings. The SRT will decide whether to 
allow the dosing of non-sentinel participants at the current dose level. Screening 
procedures may be initiated prior to SRT meeting to facilitate the enrollment of 
remaining participants. 
• 
If obtaining favorable decision from SRT, non-sentinel participants at the current 
dose level will be dosed without restrictions.  
• 
All the participants will be observed on site for 60 minutes after dosing. 
 

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Table 10 
Staggered enrollment and safety monitoring (Amended: 20 June 2023) 
YA 
 
 
Dose 1 
Control 
 
 
 
 
 
 
 
 
2 p* 
1 p* 
 
 
 
 
 
 
 
 
1 day follow up** 
 
 
 
 
 
 
 
 
4 p* 
2 p* 
 
 
 
 
 
 
 
 
2 days follow up 
 
 
 
 
 
 
 
 
SRT review*** 
 
 
 
 
 
 
 
 
18 
3 
 
 
 
 
 
 
 
 
8 days follow up 
 
 
 
 
 
 
 
 
SRT review**** 
 
 
 
 
 
 
 
 
 
 
Dose 2 
Control 
 
 
 
 
 
 
 
 
2 p* 
1 p* 
 
 
 
 
 
 
 
 
1 day follow up** 
 
 
 
 
 
 
 
 
4 p* 
2 p* 
 
 
 
 
 
 
 
 
2 days follow up 
 
 
 
 
 
 
 
 
SRT review*** 
 
 
 
 
 
 
 
 
18 
3 
 
 
 
 
 
 
 
 
8 days follow up 
 
 
 
 
 
 
 
 
SRT review**** 
 
 
 
 
 
 
 
 
 
 
Dose 3 
Control 
 
 
 
 
 
 
 
 
2 p* 
1 p* 
 
 
 
 
 
 
 
 
1 day follow up** 
 
 
 
 
 
 
 
 
4 p* 
2 p* 
 
 
 
 
 
 
 
 
2 days follow up 
 
 
 
 
 
 
 
 
SRT review*** 
 
 
 
 
 
 
 
 
18 
3 
 
 
 
 
 
 
 
 
8 days follow up 
 
 
 
 
 
 
 
 
SRT review***** 
 
 
OA 
 
 
 
 
 
 
Dose 4 
Control 
Selected dose 
from YAs 
Control 
 
 
 
 
 
 
2 p* 
1 p* 
2 p* 
2 p* 

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1 day follow up** 
1 day follow up** 
 
 
 
 
 
 
4 p* 
2 p* 
4 p* 
4 p* 
 
 
 
 
 
 
2 days follow up 
2 days follow up 
 
 
 
 
 
 
SRT review*** 
SRT review*** 
 
 
 
 
 
 
18 
3 
18 
18 
Dose 8 
Control 
 
 
 
2 p* 
1 p* 
 
 
 
1 day follow up** 
 
 
 
4 p* 
2 p* 
 
 
 
2 days follow up 
 
 
 
SRT review*** 
 
 
 
18 
3 
 
 
 
8 days follow up 
 
 
 
SRT review**** 
 
 
 
 
 
Dose 9 
Control 
 
 
 
2 p* 
1 p* 
 
 
 
1 day follow up** 
 
 
 
4 p* 
2 p* 
 
 
 
2 days follow up 
 
 
 
SRT review*** 
 
 
 
18 
3 
 
 
 
8 days follow up 
 
 
 
SRT review**** 
 
 
P: participant; SRT: Safety Review Team. Dose 1-4 and dose 8 and 9: Flu mRNA dose 1-4 and 8 and 9. Potential intermediate dose levels may be evaluated with the total number of 
doses not exceeding 12 in YAs and 1 in OAs. 
* Sentinel participants 
** Participants will be followed-up to the next day post-dosing. If any holding rule is met or any Grade 3 AE is reported within follow up post-dosing period, the SRT will be consulted 
before continuation of enrollment of the next sentinel participants. 
*** Safety review of at least 2-days post-dosing data from sentinel participants by SRT to decide on enrollment of non-sentinel participants. 
**** Safety review of 8-days post-dosing data from all sentinel and non-sentinel participants by SRT to decide on enrollment of sentinel participants for next dose level in YAs. 
***** Safety review of 8-days post-dosing data from all sentinel and non-sentinel participants by SRT to decide on enrollment of sentinel participants for next dose level in YA and 
enrollment of sentinel OAs. 
Refer to Section 10.1.5 for the definition and roles of the SRT. 

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8.2.3.2. 
Outcome of safety evaluation  
Outcome of safety evaluations will be documented and provided in a written way to the 
investigator. Refer to Appendix 1 on Safety Oversight of Phase I study for more details. 
8.2.3.3. 
Study holding rules  
The safety holding rules are defined in the Table 11. Holding rules 1a-d will be assessed 
by the investigator on a continuous basis. Meeting any of these holding rules will trigger 
a hold of study intervention administration irrespective of number of participants enrolled 
and/or timing of the event. Holding rules 2a-c will be assessed by the SRT during the 
safety evaluations on unblinded data. 
Of note, no formal holding rules will be applied for other safety data such as non-life-
threatening SAEs, missed visits due to study intervention related AEs, Grade 1 and Grade 
2 solicited and unsolicited AEs in the 7-day follow up period (Day 1 to Day 7) and 
unsolicited AEs collected from Day 8 to Day 28 after study intervention administration. 
However, if available, these data will also be reviewed by the SRT to allow an overall 
assessment of the benefit/risk ratio of study intervention administration. 

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Table 11 
Study holding rules  
Holding 
rule 
Events, per dose and per individual study group 
Number of participants to 
pause dosing in all groups, 
pending further evaluation 
by the SRT 
1a 
Death or any life-threatening SAE regardless of causality 
≥ 1 
1b 
Any non-life-threatening SAE that cannot reasonably be attributed to a 
cause other than study intervention administration as per Investigator 
or Sponsor assessment 
≥ 1 
1c 
Any withdrawal from the study (by investigator or participant request) 
due to a Grade 3 AE that cannot reasonably be attributed to a cause 
other than study intervention administration 
≥ 1 
1d 
Any administration site or systemic solicited AE leading to 
hospitalization, or necrosis at the injection site, each with an event 
onset within the 7-day (Day 1-7) post-dosing period 
≥ 1 
2a 
Any Grade 3 solicited local or systemic AE in an investigational vaccine 
group, within the 7-day (Day 1-7) post-dosing period 
BLRM 
2b 
Any occurrence in an investigational vaccine group, of a same or 
similar Grade 3 unsolicited AE, including events with an identical 
MedDRA High Level Term and events assessed as clinically similar, 
and that cannot reasonably be attributed to a cause other than study 
intervention administration, within the 7-day (Day 1-7) post-dosing 
period 
≥ 2 
2c 
Any Grade 3 unsolicited AE that can be reasonably attributed to the 
study intervention administration as per Investigator or Sponsor 
assessment, with an event onset within the 7-day (Day 1-7) post-
dosing period 
OR 
Any Grade 3 or above abnormality in pre-specified hematological or 
biochemical laboratory parameters* that are reported as AEs with onset 
within the 8-day (Day 1-8) post-dosing period 
≥ 3 
* Grading of laboratory parameters will be based on the FDA Guidance for Industry “Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”. 
Rule 2a will be analyzed on a regular basis and reviewed during the scheduled SRT 
meetings to manage (i) initiation of dosing of non-sentinel participants at current dose 
level (ii) initiation of randomization of the sentinel participants at the next dose level in 
YAs (iii) initiation of randomization of the sentinel participants in OA age group (see 
Section 8.2.3.1). The adaptive BLRM evaluates the posterior probability for the 
percentage of severe solicited events at the current and the next dose levels (Section 
10.8). A greater than 50% posterior probability that the percentage is below the 18% (i.e., 
the maximal tolerable rate), will be favorable to progress with the enrollment of non-
sentinel participants in the current dose or sentinel participants in the next dose. 
More details on the composition, objectives, and responsibilities of the SRT, and the 
schedule and conduct of the SRT meetings will be described in the Appendix 1 on Safety 
Oversight of Phase I study. 

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If the investigator becomes aware of a holding rule being met, he/she must suspend 
administration of the study intervention and inform GSK immediately (e.g., holding rules 
1a-1d). Refer to 8.3.3.1 for contact information. GSK will inform the investigator if 
holding rules 2a-2c are met. 
The following communication sequence must be followed, when an investigator becomes 
aware of a holding rule (1a-1d) being met: 
• 
The concerned site staff have to put study intervention administration on hold. 
• 
The concerned site staff must immediately inform their local GSK contact defined in 
Section 8.3.3.1. 
• 
Local GSK contact will immediately inform the study Clinical Research and 
Development Lead (CRDL) and LML. The study CRDL will ensure that other sites 
are notified. 
• 
All informed site staff will confirm to their local contact that action has been taken 
providing appropriate documentation to GSK. 
• 
GSK Central will further evaluate the case with the SRT and GSK Global Safety 
Board (GSB) and will take the decision to stop or to restart the study intervention 
administration or to amend the protocol. All site staff will be informed about that 
final decision by their local GSK contact. 
The following communication sequence must be followed when a holding rule (2a-2c) is 
being met: 
• 
The study CRDL will ensure that all LMLs and local GSK contacts are notified upon 
meeting holding rules 2a-2c. 
• 
The LMLs and local GSK contacts will inform all the sites of their country that a 
holding rule is met. Following this notification, the study intervention administration 
should be put on hold. 
• 
All informed site staff will confirm to their local contact that action has been taken 
providing appropriate documentation to GSK. 
• 
GSK Central will further evaluate the case with the SRT and GSK GSB and will take 
the decision to stop or to restart the study intervention administration or to amend the 
protocol. All site staff will be informed about that final decision by their local GSK 
contact. 

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8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
other safety reporting  
8.3.1. 
Time period and frequency for collecting AE, SAE and other 
safety information  
Table 12 
Timeframes for collecting and reporting of safety information  
Event 
Pre- 
dose* 
D-28 to 
D-1 
Dose 
D1 
 
 
 
 
 
Study 
conclusion 
 
 
D7 
D28 
 
D183 
SAEs related to study 
participation**  
or concurrent GSK 
medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record any concomitant 
vaccinations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration site and 
systemic solicited events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to 
withdrawal from the 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record any concomitant 
medications  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AESIs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D: Day 
* i.e., consent obtained 
** 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. 
The investigator or designee will record and immediately report all SAEs in enrolled 
participants to the sponsor or designee via the Expedited AE Reporting Form. Reporting 
should, under no circumstances, occur later than 24 hours after the investigator becomes 

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aware of an SAE, as indicated in Section 10.3.11. The investigator will submit any 
updated SAE data to the sponsor within 24 hours of it being available. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting periods defined in Table 12. Investigators are not obligated to actively seek AEs 
or SAEs from former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and 
if the investigator considers the event to be reasonably related to the study intervention, 
the investigator will promptly notify the study contact for reporting SAEs mentioned in 
the Table 14. 
8.3.2. 
Method of detecting AEs and SAEs, pregnancies and other 
events  
Detection and recording of AE/SAE/AESI/pregnancies are detailed in Section 10.3.9. 
Assessment of AE/SAE intensity, causality and outcome are described in Section 
10.3.10. 
Open-ended and non-leading verbal questioning of participants is the preferred method of 
acquiring information related to an AE/SAE/AESI/pregnancy. 
8.3.2.1. 
Clinically significant abnormal laboratory findings  
The investigator must review the laboratory report, document that the review occurred, 
and record any clinically relevant changes occurring during the study in the AE section of 
the eCRF. Clinically significant abnormal laboratory findings are those which are not 
associated with an underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition. 
• 
All clinically significant abnormal laboratory test values reported during the study 
should be repeated until the values return to normal/baseline, or until they are no 
longer considered significantly abnormal by the investigator or LML. Refer to 
Section 10.3.7 for more information on clinically abnormal laboratory assessments 
that qualify as an AE or SAE. 
• 
If such values do not return to normal/baseline after an interval judged reasonable by 
the investigator, the etiology of the abnormal value should be identified, and the 
sponsor notified. 
8.3.3. 
Regulatory reporting requirements for SAEs, pregnancies and 
other events  
Once an investigator (or designee) becomes aware that a study participant has 
experienced an SAE/AESI/pregnancy, it must be reported to GSK using the required 
documentation and within the timeframes mentioned in Table 13. This is essential for 
GSK to meet legal obligations and ethical responsibilities for participant safety and the 
safety of a study intervention under clinical investigation. 

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For SAEs/AESIs, the investigator must always provide an assessment of causality at the 
time of the initial report, as defined in the Section 10.3.10.2. 
Local regulatory requirements and sponsor policy for preparation of an investigator 
safety report of SUSAR must be followed. These reports will be forwarded to 
investigators as necessary. 
The sponsor has the legal responsibility to notify local authorities/regulatory agencies 
about the safety of an investigational study intervention. The sponsor will comply with 
country-specific regulatory requirements related to safety reporting to the regulatory 
authority, IRB/IEC and investigators. 
Please refer to Section 10.3.11 for further details regarding the reporting of 
SAEs/AESIs/pregnancies. 
Table 13 
Timeframes for submitting SAE, pregnancy and other events reports 
to GSK  
Type of event 
Initial reports 
Follow up of relevant information on a 
previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* ‡ ‡‡ 
paper/electronic Expedited 
Adverse Events Report 
24 hours* 
paper/electronic Expedited 
Adverse Events Report 
Pregnancies  
24 hours* 
paper pregnancy notification 
report/electronic pregnancy 
report  
24 hours * 
paper pregnancy follow up 
report/electronic pregnancy 
report  
AESIs  
24 hours** ‡, ‡‡  paper/electronic Expedited 
Adverse Events Report 
24 hours* 
paper/electronic Expedited 
Adverse Events Report 
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
**Timeframe allowed once the investigator determines that the event meets the protocol definition of an AESI. 
‡ Paper Expedited Adverse Events 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. 

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8.3.3.1. 
Contact information for reporting SAEs, AESIs, pregnancies and study 
holding rules  
Table 14 
Contact information for reporting SAEs, AESIs, pregnancies and 
study holding rules   
Study contact for questions regarding 
SAEs, AESIs, pregnancies  
Study contact for reporting of study 
holding rules  
Refer to the local study contact 
information document 
If a holding rule is met, the investigator 
must immediately inform the LML 
Back up study contact for reporting 
SAEs, AESIs, pregnancies 
Available 24/24 hours and 7/7 days: 
Back up study contact for escalation of 
holding rules  
GSK Global Safety 
Refer to the local study contact 
information document 
Canadian sites only: 
Fax: 1 866 903 4718 
Outside Canada sites: 
Fax: +32 2 656 80 09 
Email address: ogm28723@gsk.com 
 
8.3.4. 
Treatment of expedited adverse events (SAE/AESI)  
Any medication administered for the treatment of an SAE/AESI should be recorded in 
the Expedited Adverse Event Report of the participant’s eCRF screen (refer to Section 
10.3.11.1). 
8.3.5. 
Participant card  
The investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
always keep the participant card in 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. 
8.3.6. 
Medical device deficiencies  
Some study groups have study interventions that are combination products constituted of 
a device and biologic product (e.g., pre-filled syringes). Refer to the Glossary of terms for 
the definition of combination product and medical device deficiency. 

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8.3.6.1. 
Detection, follow up and prompt reporting of medical device deficiency  
The investigator is responsible for the detection, documentation and prompt reporting of 
any medical device deficiency occurring during the study to GSK. This applies to any 
medical device provided for the conduct of the study. 
Device deficiencies will be reported to GSK within 24 hours after the investigator 
determines that the event meets the protocol definition of a device deficiency. Refer to 
Section 10.6 for definitions and details on recording and reporting of these events. 
The investigator will ensure that follow up includes any additional investigations to 
elucidate the nature and/or relatedness of the device deficiency to the incident. 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator and reported to GSK within 24 hours. 
Medical device deficiencies and any associated AE/SAEs for associated person (i.e., 
spouse, caregiver, site staff) will also be collected. The associated person will be 
provided with a safety reporting information and authorization letter. 
Follow up applies to all participants, including those who discontinue study intervention 
or the study, and associated persons. 
8.3.6.2. 
Regulatory reporting of medical device deficiency when used as 
combination product  
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study to GSK. GSK has a legal responsibility to notify 
appropriate regulatory authorities and other entities about safety information linked to 
medical devices being used in clinical studies. Refer to section 10.6.3 for details of 
reporting. 
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 
linked to the reporting of device deficiencies to the IRB/IEC. 
8.4. 
Pharmacokinetics  
Pharmacokinetics are not evaluated in this study. 
8.5. 
Genetics  
Genetics are not evaluated in this study. 
8.6. 
Biomarkers  
This section is not applicable. 

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8.7. 
Immunogenicity assessments  
Immunogenicity is described in Section 8.1. 
8.8. 
Health outcomes  
Health outcomes data (e.g., 
data) will be collected as an outcome of this study. This 
data will be collected in the eDiary. Statistical analyses must be adjusted for protocol-
mandated procedures, tests, and encounters. 
 
 
 
 
 All participants of the study 
are expected to complete the 
 as part of the eDiary. If necessary, the 
 may be 
administered by an interviewer (e.g., a caregiver). Interviewer instructions are provided 
in the 
 on how to record the participant’s answers exactly as reported and without 
any interpretation from the interviewer. 
9. 
STATISTICAL CONSIDERATIONS  
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% cIs. 
9.2. 
Analysis sets  
Table 15 
Analysis sets  
Analysis set 
Description 
Screened 
All participants who were screened for eligibility  
Enrolled  
All participants who entered the study (who were randomized or received study 
intervention or underwent a post-screening study procedure). 
Note: screening failures (who never passed screening even if rescreened) and 
participants screened but never enrolled into the study (met eligibility but not 
needed) are excluded from the Enrolled analysis set as they did not enter the 
study 
Exposed Set (ES) 
All participants who received a study intervention. Analysis per group is based on 
the study intervention administered 
Per Protocol Set (PPS)  
All eligible participants who received a dose of study intervention as per protocol, 
had 
 results pre- and post-dose, without intercurrent 
conditions (influenza disease) that may interfere with immunogenicity and without 
prohibited concomitant medication/vaccination before Day 22. The analysis will be 
done according to the study intervention that participants received. Results from 
blood sample deviating from the dosing/blood draw intervals (refer to Table 2) as 
well as results obtained after intercurrent conditions (influenza disease) that may 
interfere with immunogenicity or after prohibited concomitant 
medication/vaccination during this period will be excluded from the PPS. 
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9.3. 
Statistical analyses  
The statistical analysis plan (SAP) will be finalized prior to the first subject first visit 
(FSFV) 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, i.e., the primary endpoints. 
The co-primary and secondary endpoints are described in Section 3. The primary 
analyses of immunogenicity endpoints will be based on the per protocol set (PPS). The 
analysis of safety endpoints will be based on the ES. All analyses will be done separately 
for OAs and YAs, unless specified otherwise. 
9.3.1. 
Co-primary safety endpoints 
The percentage of participants reporting each individual solicited administration site 
event (any grade, Grade 2 or 3, Grade 3 and medically attended events) and solicited 
systemic event (any grade, Grade ≥2, Grade ≥3 and medically attended events) within the 
7-day follow up period (i.e., Day 1-Day 7 post-dose) will be tabulated for each group. 
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 preferred term (PT). The percentage of 
participants with any unsolicited AEs within the 28-day follow up period (i.e., Day 1-Day 
28 post-dose) with its exact 95% confidence interval (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, and with at least 1 report of 
AESI respectively, classified by the MedDRA SOC and PT and reported from Dose 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-Day 28 post-dose) will be summarized by group. 
9.3.1.1. 
 Analysis of reactogenicity for dose escalation: BLRM  
An adaptive BLRM guided by the escalation with overdose control (EWOC) principle 
will be used to inform on the dose escalation part of the study. The use of Bayesian 
response adaptive models for Phase 1 studies has been advocated by the European 
Medicines Agency (EMA) adopted guideline on small populations [EMA, 2006] and by 
Rogatko et al., 2007 [Rogatko, 2007] and is 1 of the key elements of the FDA’s Critical 
Path Initiative. 

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The dose escalation will be based on a modified version of the 2-parameter BLRM 
described by Neuenschwander et al., 2008 [Neuenschwander, 2008] and will account for 
all doses and age groups. The modification will be the addition of age-specific slope to 
account for a potential difference in safety profile between the 2 age groups. This 
approach allows the results of 1 age group to inform the decisions in the other group, 
which increases statistical power. The decisions will still be done separately for each age 
group, but this approach allows the use of all the available information as well as the 
assessment of whether there is a relevant difference in the solicited Grade 3 event rate 
between groups. 
Standardized dose level will be used such that 1 of the doses (d*) equals 1, e.g., doses are 
rescaled as d/d*. Consequently, α is equal to the odds of the probability of intolerance at 
d*. This model was shown to be fit for purpose in the context of Phase I mRNA vaccine 
dose range [Walsh, 2020; Kremsner, 2021b]. The prior distribution will be updated after 
each group of participants with all the data available in the Safety Set from the current 
study. Once updated, the distribution summarizes the posterior probability that the true 
Grade 3 solicited event rate for each dose level lies in the following categories: 
• 
0% to <18%: targeted tolerance; and 
• 
≥18% to 100%: intolerance. 
The EWOC principle mandates that any dose of the study vaccine candidates that has 
more than a 50% chance of being in the intolerance category is not considered for the 
next dose administrations [Neuenschwander, 2008; Babb, 1998]. 
Section 10.8 provides additional details on the model and data scenarios. 
A clinical synthesis of the available safety and reactogenicity information (including 
symptoms that are not Grade 3), and, if available, laboratory values as well as the 
recommendations from the Bayesian model and the SRT will be used to determine the 
dose level(s) for the next group at a dose escalation teleconference. The frequency of 
each safety event associated to holding rules (see Table 11) will be tabulated by study 
group (i.e., by dose level). Individual data will also be available. 
9.3.2. 
Co-primary and secondary immunogenicity endpoints  
The group difference between the investigational study intervention and control group 
(pooled for YAs) will be assessed at each dose level separately as follows: 
• 
At each post-dosing timepoint and in each age group separately, the 2-sided CI for 
group GMT ratio between Flu mRNA dose and (over) the control group (pooled 
across dose cohorts for YAs) will be derived from an ANCOVA model on log10 
transformed concentration. The ANCOVA model will be based on the data from all 
age groups and will include group (i.e., each of the Flu mRNA doses and the 
(pooled) control group), country, flu vaccination history and log-transformed 
concentration 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. Concentrations below the assay cut-off will be replaced by half the assay 
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• 
For a given age group, the 2-sided 95% CI on group difference in 
 between a 
mRNA dose and (minus) the control group (pooled across dose cohorts for YAs) will 
be computed at day 22 based on the method of Miettinen and Nurminen [Miettinen, 
1985]. 
• 
The percentage of participants achieving 
, defined as having post-dose 
 for 
 will be 
summarized by age group with associated exact 95% CI. 
Abbreviation/term 
Definition 
GMI 
The geometric mean of the ratios of the post-dose 
 over the Day 1 
. 
The percentage of dosed participants who have either a 
pre-dose 
 and 
a post-dose 
 or a pre-dose 
 and at least a 4-fold increase 
in post-dose 
 
The percentage of dosed participants with a 
. 
9.4. 
Interim analyses  
9.4.1. 
Sequence of planned analyses (Amended: 20 June 2023)  
In addition to the analyses detailed below, safety analyses will be conducted to support 
SRT decisions as described in Section 8.2.3. 
Two initial interim analyses will be conducted upon availability of all primary endpoints 
up to Day 22 for YA participants in the 
 cohorts, respectively. An interim 
analysis will be performed upon availability of all primary endpoints up to Day 29 for all 
study participants in the 
 cohorts.  
Additional interim analyses will be performed upon availability of all primary endpoints 
up to Day 29 for (i) all participants in the 
 dose cohort,(ii) all participants in 
the 
, and and their potential intermediate dose cohorts (
) and 
(iii) all participants in the 
 dose cohort,. 
For all interim analyses, the GSK study team will have access to all unblinded individual 
data while the investigator, participants and site personnel will remain blinded. 
An analysis with all primary and secondary endpoints obtained until the last visit (Visit 6 
[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 later and described in an annex report. 
Tertiary analyses deemed futile due to the other study results will not be analyzed nor 
reported. 
Note: If there is a delay in availability of the immunogenicity data, leading to a window 
between 2 analyses shorter than what is planned at the time of protocol writing, statistical 
analyses may be combined. 
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9.4.2. 
Statistical considerations for interim analysis  
As this study is descriptive and each analysis will be completed on expected final 
immunogenicity data, there will be no type I error adjustment for the different analyses. 
9.5. 
Sample size determination  
Enrolled participants who withdraw from the study will not be replaced. 
9.5.1. 
Sample size determination for reactogenicity and safety  
The study is designed to provide a reasonable precision for the rate of Grade 3 solicited 
events and to describe the safety profile of an mRNA-based monovalent seasonal 
influenza vaccine. 
For each dose cohort, it is expected that up to 24 participants will be enrolled per age 
group. Assuming a maximum acceptable rate of Grade 3 solicited events of 18%, it is 
possible to calculate the probability of a lower true Grade 3 solicited event rate given a 
different number of participants with Grade 3 solicited event(s). Table 16 provides the 
estimate and 95% credibility interval for a given observed number of participants for a 
sample size of 24 participants per age group in a dose level cohort (assuming a Beta 
[0.5,0.5] prior distribution). For example, if 4 participants report Grade 3 solicited 
event(s) among 24 exposed participants, the posterior probability that the true Grade 3 
solicited event rate is <18% is 54.5%. 
Table 16 
Posterior probability estimates of Grade 3 solicited event rate <18% 
for different observed numbers of participants with Grade 3 solicited 
event(s) and 95% credibility interval for the rate  
Number of participants with 
Grade 3 solicited event(s) 
Estimate (95% credibility interval) in 
% 
Probability Grade 3 solicited 
event rate <18% 
0 
2 (0 - 9.8) 
99.8 
1 
6 (0.5 - 17.9) 
97.6 
2 
10 (1.8 - 24.1) 
89.9 
3 
14 (3.6 - 29.7) 
74.8 
4 
18 (5.9 - 34.9) 
54.5 
A further description of the BLRM, including prior, hypothetical data scenarios of 
number of Grade 3 solicited events that could occur in the actual study, and the decision 
guides are presented in Section 10.8. 

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9.5.2. 
Sample size determination for immunogenicity  
The primary objective is to explore how the different dose levels of mRNA-based 
monovalent seasonal influenza vaccine compare to standard of care control group. 
The sample size is based on clinical considerations to inform dose regimen decisions for 
continued clinical development. With 24 participants in each dose level cohort and age 
group, a 10% unevaluable rate for immunogenicity results, and a standard deviation of 
0.61 for log10-transformed titer, assuming that all doses will progress with enrollment, 
the ratio of the upper limit of a 2-sided 95% CI and the point estimate of the group GMT 
ratio between a mRNA dose level and the control group (pooled across dose cohorts for 
YAs) is 2.5. 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1. 
Appendix 1: Regulatory, ethical, and study oversight 
considerations  
10.1.1. 
Regulatory and ethical considerations  
• 
This study will be conducted in accordance with the protocol and with: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator for review and 
approval. These documents will be signed and dated by the investigator before the 
study is initiated. 
• 
Any protocol amendments will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• 
The investigator will be responsible for the following: 
− 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. 
− 
Notifying the IRB/IEC of SAE(s) or other significant safety findings as required 
by IRB/IEC procedures. 

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− 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
10.1.2. 
Financial disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study. 
10.1.3. 
Informed consent process  
The investigator(s) or their representative(s) must fully explain the nature of the study to 
the participant and answer all questions regarding the study. 
Participant must be informed that their participation is voluntary. 
Freely given and written informed consent must be obtained from each participant prior 
to participation in the study. 
The content of the informed consent form must meet the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. If a 
caregiver is assigned by the participant to help with the study procedures, the caregiver 
must receive an information letter that describes his/her roles prior to supporting study 
participant. 
Participants must be re-consented if a new version of the ICF(s) or an ICF addendum is 
released during their participation in the study. 
A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF, only if there are changes 
to the original ICF. If there are no changes to the original ICF, participants should 
confirm that they still agree to be part of the study. This information should be captured 
in the participant source document. 

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10.1.4. 
Data protection  
Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets transferred to the sponsor will contain only the identifier. Name and 
any other information which would identify the participant will not be transferred. 
GSK will ensure protection of the personal data of the investigator and site staff which is 
collected within the framework of and for the purpose of the study. 
The participants must be informed that: 
• 
Their personal study-related data will be used by the sponsor in accordance with 
local data protection law. 
• 
Their medical records may be examined by Clinical Quality Assurance auditors or 
other authorized personnel appointed by the sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 
The participants must be notified about their rights regarding the use of their personal 
data in accordance with the data privacy section of the ICF. 
10.1.5. 
Committees structure  
The SRT will be an internal team, with representatives from both GSK and CureVac. 
The role of the SRT in deciding dose escalation is described in Section 8.2.3.1. In 
addition, the SRT will review safety and immunogenicity data during the planned interim 
analyses and whenever any study holding rules are met (Section 8.2.3.3). According to its 
charter, the SRT may also recommend to permanently stop enrollment in a group. Based 
on SRT review and recommendations, the sponsor may drop dose groups at any time 
during the study if an unfavorable safety profile is observed in that group or based on 
safety or immunogenicity data from other groups. 
More details on the composition, objectives, and responsibilities of the SRT, and the 
schedule and conduct of the SRT meetings will be described in the Appendix 1 on Safety 
Oversight of Phase I study. 
10.1.6. 
Dissemination of clinical study data  
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocols summaries prior to 
study start and target results summaries submission within 12 months of primary/study 
completion date. Where external regulations require earlier disclosure, GSK will follow 
those timelines. 
Where required by regulation, summaries will also be posted on applicable national or 
regional clinical study registers. 

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Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK will also provide the investigator 
with the full summary of the study results. The investigator is encouraged to share the 
summary results with the study participants, as appropriate. 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
GSK intends to make anonymized patient-level data from this study available to external 
researchers for scientific analyses or to conduct further research that can help advance 
medical science or improve patient care. This helps ensure the data provided by study 
participants are used to maximum effect in the creation of knowledge and understanding. 
10.1.7. 
Data quality assurance  
The investigator should maintain a record of the location(s) of their respective essential 
documents, including source documents (see Glossary of terms for the exact definition of 
essential and source documents). The document storage system used during the study and 
for archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval. 
Essential study documents may be added or removed where justified (in advance of study 
initiation) based on their importance and relevance to the study. When a copy is used to 
replace an original document (e.g., source documents, case report form [CRF]), the copy 
should fulfill the requirements for certified copies (see Glossary of terms for the exact 
definition of certified copies). 
All participant data related to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
The investigator must maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the site’s study participants (see 
Glossary of terms for the exact definition of source documents) that supports information 
entered in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies for such review and inspection. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data (see Glossary of terms for the exact definition of 
source documents). 
Study monitors will perform ongoing source data verification to confirm that data entered 
in the eCRF by authorized site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data must be traceable, not obscure 

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the original entry, and be fully explained if necessary (e.g., via an audit trail). The safety 
and rights of participants must be protected, and the study conducted in accordance with 
the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
Quality tolerance limits (QTLs) will be pre-defined in the Study Management Plan to 
identify systematic issues that can impact participant safety and/or the reliability of study 
results. These pre-defined parameters will be monitored during the study. Important 
deviations from the QTLs and remedial actions taken will be summarized in the Clinical 
Study Report (CSR). 
Study records and source documents pertaining to the conduct of this study, including 
signed ICFs, must be retained by the investigator for 25 years from issuance of the final 
CSR/equivalent summary unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
10.1.8. 
Source documents  
Source documents provide evidence to establish the existence of the participant and 
substantiate the integrity of collected data. The investigator should maintain a record of 
the location(s) of their source documents. 
Data transcribed into the eCRF from source documents must be consistent with those 
source documents; any discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
Definitions of what constitutes source data and documents can be found in the Glossary 
of terms. 
10.1.9. 
Study and site start and closure  
First act of recruitment 
The start of study is defined as FSFV at a country-level. 
Study/Site termination 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at its sole discretion, provided there is sufficient notice given to 
account for all participants safe exit from study. 
Regular closure of study sites will occur upon study completion. A study site is 
considered closed when all required data/documents and study supplies have been 
collected and a study site closure visit has been performed. 

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The investigator may initiate study site closure at any time, provided there is reasonable 
cause and enough notice in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow up. 
10.1.10. 
Publication policy  
GSK aims to submit the results of the study for publication in searchable, peer reviewed 
scientific literature within 18 months from the LSLV for interventional studies and 
follows the guidance from the International Committee of Medical Journal Editors 
(ICMJE). 
10.2. 
Appendix 2: Clinical laboratory tests  
10.2.1. 
Protocol required safety laboratory assessments  
Table 17 
Protocol required safety laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
White Blood Cell (WBC) count with differential: Lymphocytes, 
Neutrophil, Eosinophils, Basophils, Monocytes 
Red Blood Cell (RBC) count 
Platelet count 
Hemoglobin 
Hematocrit 
Clinical chemistry/Biochemistry 
Creatinine, CRP, BUN/Urea, AST, ALT, cardiac troponin (Troponin I 
and/or Troponin T)  
Coagulation 
INR  
Urinalysis* 
Leukocytes, Blood, Proteins, Glucose, Ketones, Bilirubin, 
Urobilinogen, Nitrite, Specific gravity, pH 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; CRP: C-reactive protein; 
INR: international normalized ratio. 
*Urinalysis will be done by dipstick. 
The tests detailed in Table 17 will be performed by the local laboratory. 

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10.2.2. 
FDA Guidance for industry: Toxicity grading scale for healthy 
adult and adolescent volunteers enrolled in preventive vaccine 
clinical trials (September 2007)  
The laboratory values provided in the tables below serve as guidelines and are dependent 
upon institutional normal parameters. Institutional normal reference ranges should be 
provided to demonstrate that they are appropriate. 
Table 18 
FDA toxicity grading scales for biochemistry parameters evaluated 
in the current study  
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Blood Urea Nitrogen 
BUN mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires dialysis  
Liver Function Tests –ALT, 
AST 
increase by factor  
1.1 – 2.5 x ULN  
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
ULN is the upper limit of the normal range. 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as potentially life-threatening (Grade 4). For example, a low sodium value that falls within a 
Grade 3 parameter (125-129 mE/L) should be recorded as a Grade 4 hyponatremia event if the participant had a new 
seizure associated with the low sodium value. 
Table 19 
FDA toxicity grading scales for hematology parameters evaluated in 
the current study  
Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-
Threatening 
(Grade 4) 
Hemoglobin (Female) - 
gm/dL  
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL  12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm
3 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
> 25,000 
WBC Decrease - cell/mm
3 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Lymphocytes Decrease - 
cell/mm
3 
750 – 1 000 
500 – 749 
250 – 499 
< 250 
Neutrophils Decrease - 
cell/mm
3 
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils - cell/mm
3 
650 – 1 500 
1,501 – 5,000 
> 5,000 
Hypereosinophilic 
Platelets Decreased - 
cell/mm
3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000 
< 25,000 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 

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Table 20 
FDA toxicity grading scales for urinalysis parameters evaluated in 
the current study  
Urine * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-
Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or 
dialysis 
Glucose 
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia 
Blood (microscopic) – red 
blood cells per high power 
field (rbc/hpf) 
1 - 10 
11 – 50 
> 50 and/or 
gross blood 
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion 
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
10.3. 
Appendix 3: AEs: definitions and procedures for recording, 
evaluating, follow up, and reporting  
10.3.1. 
Definition of an AE  
An AE is any untoward medical occurrence (an unfavorable/unintended sign - including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) in a clinical 
study participant that is temporally associated with the study intervention. The AE may or 
may not be considered related to the study intervention. 
10.3.1.1. 
Events Meeting the AE Definition    
• 
Significant or unexpected worsening or exacerbation of the condition/indication 
under study. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after administration of the study 
intervention even though they may have been present before study start. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug, disease or other 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either the 
study intervention or a concurrent medication. 
• 
Signs or symptoms temporally associated with administration of the study 
intervention. 
• 
Signs, symptoms that require medical attention (e.g., hospital stays, physician 
visits and emergency room visits). 
• 
Significant failure of an expected pharmacologic or biological action. 

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• 
Pre- or post- intervention events that occur as a result of protocol-mandated 
procedures (i.e., invasive procedures, modification of participant’s previous 
therapeutic regimen). 
• 
Clinically significant abnormal laboratory findings or other abnormal assessments 
that are present at baseline and significantly worsen following the start of the study 
will also be reported as AEs or SAEs. 
• 
AEs to be recorded as solicited AEs are described in the Section 10.3.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
10.3.1.2. 
Events NOT Meeting the AE Definition    
• 
Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
• 
Pre-existing conditions or signs and/or symptoms present in a participant before 
the study intervention administration. These events will be recorded in the medical 
history section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
10.3.2. 
Definition of an SAE  
An SAE is any untoward medical occurrence that: 
a. 
Results in death. 
b. Is life-threatening 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the participant was at risk of death at the time of the event. It does not refer 
to an event, which hypothetically might have caused death, had it been more 
severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 

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other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
d. Results in disability/incapacity 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza like illness, and accidental trauma 
(e.g., sprained ankle) which may interfere or prevent everyday life functions but 
do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth. 
f. 
 defect in the offspring of a study participant. 
g. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy). 
h. Other situations 
Medical or scientific judgment must be exercised in deciding whether reporting is 
appropriate in other situations. Important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition should be considered 
serious. Examples of such events are invasive or malignant cancers; intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias; and convulsions that do not result in hospitalization. 
10.3.3. 
Solicited events  
a. Solicited administration site events 
The following administration site events will be solicited: 
Table 21 
Solicited administration site events  
Pain  
Redness  
Swelling  
Lymphadenopathy* 
* Lymphadenopathy, defined as localized axillary, cervical or supraclavicular swelling or tenderness ipsilateral to the 
injection arm 

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b. Solicited systemic events 
The following systemic events will be solicited: 
Table 22 
Solicited systemic events  
Fever 
Headache 
Myalgia 
Arthralgia 
Fatigue 
Chills 
Note: Participants will be instructed to measure and record the axillary temperature in the 
evening. If additional temperature measurements are taken at other times of the day, 
participants will be instructed to record the highest temperature in the eDiary. 
10.3.4. 
Unsolicited AEs  
An unsolicited AEs is an AEs that was either not included in the list of solicited events or 
could be included in the list of solicited events but with an onset outside the specified 
period of follow up for solicited events. Unsolicited AEs must have been communicated 
by a participant who has signed the informed consent or through his/her caregiver. 
Unsolicited AEs include both serious and non-serious AEs. The participants will be 
instructed to report the occurrence of unsolicited AEs using the eDiary from Day 1 to 
Day 28. If the participant is unable to fill out the eDiary, he/she may contact the site 
directly. 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, or an emergency room visit, or visit to/by a health care 
provider). Upon notification from eDiary system to the investigator of the occurrence of 
unsolicited AEs that are medically attended or perceived as a concern by the participant, 
the site should contact the participant to collect the safety information. Refer to the SPM 
for details. 
Unsolicited AEs that are not medically attended or perceived as a concern by the 
participant will be collected during an interview with the participant and by review of 
available medical records at the next scheduled visit/contact or earlier, if deemed 
necessary by the investigator or delegate. 
As of Day 29, the participants will be instructed to contact the site as soon as possible to 
report medically attended event(s), as well as any events that, though not medically 
attended, are of participant’s concern. Detailed information about reported unsolicited 
AEs will be collected by qualified site personnel and documented in the participant’s 
records. 

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10.3.5. 
SAEs related to study participation  
Any SAEs related to study participation (e.g., SAEs due to study mandated procedures or 
invasive tests) should be reported as per Section 8.3.3. 
10.3.6. 
AESIs  
10.3.6.1. 
Potential immune-mediated diseases  
Potential immune-mediated diseases (pIMDs) are a subset of AESIs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune etiology. AEs that need to be recorded and 
reported as pIMDs include those listed in Table 23. Refer to Section 10.3.9.1 for 
reporting details. 
The investigator(s) must exercise their medical/scientific judgment to determine whether 
other diseases have an autoimmune origin (i.e., pathophysiology involving systemic or 
organ-specific pathogenic autoantibodies) and should also be recorded as a pIMD. 
When there is enough evidence to make any of the diagnoses mentioned in Table 23, the 
AE must be reported as a pIMD. Symptoms, signs or conditions which might (or might 
not) represent the above diagnoses, should be recorded and reported as AEs but not as 
pIMDs until the final or definitive diagnosis has been determined, and alternative 
diagnoses have been eliminated or shown to be less likely. 
To facilitate the documentation of pIMDs in the eCRF, a pIMD standard questionnaire 
and a list of PTs and PT codes corresponding to the above diagnoses will be available to 
investigators at study start. 
Once a pIMD is diagnosed (serious or non-serious) in a study participant, the investigator 
(or designate) must complete, date and sign an electronic Expedited Adverse Events 
Report. 

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Table 23 
List of potential immune-mediated diseases (pIMDs)  
Medical Concept 
Additional Notes 
Blood disorders and coagulopathies 
Antiphospholipid syndrome 
 
Autoimmune aplastic anemia 
 
Autoimmune hemolytic anemia 
• 
Includes warm antibody hemolytic anemia and cold antibody hemolytic 
anemia 
Autoimmune lymphoproliferative 
syndrome (ALPS) 
 
Autoimmune neutropenia  
 
Autoimmune pancytopenia 
 
Autoimmune thrombocytopenia 
• 
Frequently used related terms include: “autoimmune thrombocytopenic 
purpura”, “idiopathic thrombocytopenic purpura (ITP)”, “idiopathic 
immune thrombocytopenia”, “primary immune thrombocytopenia”. 
Evans syndrome 
 
Pernicious anemia 
 
Thrombosis with 
thrombocytopenia syndrome 
(TTS) 
 
Thrombotic thrombocytopenic 
purpura 
• 
Also known as “Moschcowitz-syndrome” or “microangiopathic 
hemolytic anemia” 
Cardio-pulmonary inflammatory disorders 
Idiopathic 
Myocarditis/Pericarditis 
Including but not limited to: 
• 
Autoimmune / Immune-mediated myocarditis 
• 
Autoimmune / Immune-mediated pericarditis 
• 
Giant cell myocarditis 
Idiopathic pulmonary fibrosis 
Including but not limited to: 
• 
Idiopathic interstitial pneumonia (frequently used related terms include 
“Interstitial lung disease”, “Pulmonary fibrosis”, “Immune-mediated 
pneumonitis”) 
• 
Pleuroparenchymal fibroelastosis (PPFE) 
Pulmonary alveolar proteinosis 
(PAP) 
• 
Frequently used related terms include: “pulmonary alveolar 
lipoproteinosis”, “phospholipidosis” 
Endocrine disorders 
Addison’s disease 
 
Autoimmune / Immune-mediated 
thyroiditis  
Including but not limited to: 
• 
Hashimoto thyroiditis (autoimmune hypothyroidism, lymphocytic 
thyroiditis) 
• 
Atrophic thyroiditis 
• 
Silent thyroiditis 
• 
Thyrotoxicosis 

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Medical Concept 
Additional Notes 
Autoimmune diseases of the 
testis and ovary 
• 
Includes autoimmune oophoritis, autoimmune ovarian failure and 
autoimmune orchitis 
Autoimmune hyperlipidemia 
 
Autoimmune hypophysitis 
 
Diabetes mellitus type I 
 
Grave's or Basedow’s disease 
• 
Includes Marine Lenhart syndrome and Graves' ophthalmopathy, also 
known as thyroid eye disease (TED) or endocrine ophthalmopathy 
Insulin autoimmune syndrome 
 
Polyglandular autoimmune 
syndrome 
• 
Includes Polyglandular autoimmune syndrome type I, II and III 
Eye disorders 
Ocular Autoimmune / Immune-
mediated disorders 
Including but not limited to: 
• 
Acute macular neuroretinopathy (also known as acute macular outer 
retinopathy) 
• 
Autoimmune / Immune-mediated retinopathy 
• 
Autoimmune / Immune-mediated uveitis, including idiopathic uveitis 
and sympathetic ophthalmia 
• 
Cogan's syndrome: an oculo-audiovestibular disease 
• 
Ocular pemphigoid 
• 
Ulcerative keratitis 
• 
Vogt-Koyanagi-Harada disease 
Gastrointestinal disorders 
Autoimmune / Immune-mediated 
pancreatitis 
 
Celiac disease 
 
Inflammatory Bowel disease  
Including but not limited to: 
• 
Crohn’s disease 
• 
Microscopic colitis 
• 
Terminal ileitis 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
Hepatobiliary disorders 
Autoimmune cholangitis 
 
Autoimmune hepatitis 
 
Primary biliary cirrhosis 
 
Primary sclerosing cholangitis 
 
Musculoskeletal and connective tissue disorders  
Gout 
• 
Includes gouty arthritis 
Idiopathic inflammatory 
myopathies 
Including but not limited to: 
• 
Dermatomyositis 

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Medical Concept 
Additional Notes 
• 
Inclusion body myositis 
• 
Immune-mediated necrotizing myopathy 
• 
Polymyositis 
Mixed connective tissue disorder 
 
Polymyalgia rheumatica (PMR) 
 
Psoriatic arthritis (PsA) 
 
Relapsing polychondritis 
 
Rheumatoid arthritis  
Including but not limited to: 
• 
Rheumatoid arthritis associated conditions 
• 
Juvenile idiopathic arthritis 
• 
Palindromic rheumatism 
• 
Still's disease 
• 
Felty’s syndrome 
Sjögren’s syndrome 
 
Spondyloarthritis 
Including but not limited to: 
• 
Ankylosing spondylitis 
• 
Juvenile spondyloarthritis 
• 
Keratoderma blenorrhagica 
• 
Psoriatic spondylitis 
• 
Reactive Arthritis (Reiter's Syndrome) 
• 
Undifferentiated spondyloarthritis 
Systemic lupus Erythematosus  
• 
Includes Lupus associated conditions (e.g. Cutaneous lupus 
erythematosus, Lupus nephritis, etc.) or complications such as 
shrinking lung syndrome (SLS) 
Systemic Scleroderma (systemic 
sclerosis) 
• 
Includes Reynolds syndrome (RS), systemic sclerosis with diffuse 
scleroderma and systemic sclerosis with limited scleroderma (also 
known as CREST syndrome) 
Neuroinflammatory/neuromuscular disorders 
Acute disseminated 
encephalomyelitis (ADEM) and 
other inflammatory 
demyelinating variants  
Includes the following: 
• 
Acute necrotizing myelitis 
• 
Bickerstaff's brainstem encephalitis 
• 
Disseminated necrotizing leukoencephalopathy (also known as 
Weston-Hurst syndrome, acute hemorrhagic leuko-encephalitis, or 
acute necrotizing hemorrhagic encephalomyelitis) 
• 
Myelin oligodendrocyte glycoprotein antibody-associated disease 
• 
Neuromyelitis optica (also known as Devic’s disease) 
• 
Noninfective encephalitis / encephalomyelitis / myelitis 
• 
Postimmunization encephalomyelitis  
Guillain-Barré syndrome (GBS) 
• 
Includes variants such as Miller Fisher syndrome and the acute motor 
and sensory axonal neuropathy (AMSAN) 

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Medical Concept 
Additional Notes 
Idiopathic cranial nerve 
palsies/paresis and 
inflammations (neuritis), 
including Bell’s palsy 
Including but not limited to: 
• 
Cranial nerve neuritis (e.g., Optic neuritis) 
• 
Idiopathic nerve palsies/paresis (e.g., Bell’s palsy) 
• 
Melkersson-Rosenthal syndrome 
• 
Multiple cranial nerve palsies/paresis  
Multiple sclerosis (MS) 
Includes the following: 
• 
Clinically isolated syndrome (CIS) 
• 
Malignant MS (the Marburg type of MS) 
• 
Primary-progressive MS (PPMS) 
• 
Radiologically isolated syndrome (RIS) 
• 
Relapsing-remitting MS (RRMS) 
• 
Secondary-progressive MS (SPMS) 
• 
Uhthoff's phenomenon  
Myasthenia gravis 
• 
Includes ocular myasthenia and Lambert-Eaton myasthenic syndrome 
Narcolepsy 
• 
Includes narcolepsy with or without presence of unambiguous 
cataplexy 
Peripheral inflammatory 
demyelinating neuropathies and 
plexopathies 
Including but not limited to: 
• 
Acute Brachial Radiculitis (also known as Parsonage-Turner 
Syndrome or neuralgic amyotrophy) 
• 
Antibody-mediated demyelinating neuropathy 
• 
Chronic idiopathic axonal polyneuropathy (CIAP) 
• 
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), 
including atypical CIDP variants (e.g. multifocal acquired 
demyelinating sensory and motor neuropathy also known as Lewis-
Sumner syndrome) 
• 
Multifocal motor neuropathy (MMN)  
Transverse myelitis (TM) 
• 
Includes acute partial transverse myelitis (APTM) and acute complete 
transverse myelitis (ACTM) 
Renal disorders 
Autoimmune / Immune-mediated 
glomerulonephritis  
Including but not limited to: 
• 
IgA nephropathy 
• 
IgM nephropathy 
• 
C1q nephropathy 
• 
Fibrillary glomerulonephritis 
• 
Glomerulonephritis rapidly progressive 
• 
Membranoproliferative glomerulonephritis 
• 
Membranous glomerulonephritis 
• 
Mesangioproliferative glomerulonephritis 
• 
Tubulointerstitial nephritis and uveitis syndrome 

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

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Medical Concept 
Additional Notes 
• 
Necrotizing vasculitis 
• 
Polyarteritis nodosa 
• 
Single organ cutaneous vasculitis, including leukocytoclastic vasculitis, 
hypersensitivity vasculitis and acute hemorrhagic edema of infancy 
(AHEI) 
• 
Wegener's granulomatosis  
Other (including multisystemic) 
Anti-synthetase syndrome 
 
Capillary leak syndrome 
• 
Frequently used related terms include: “systemic capillary leak 
syndrome (SCLS)” or “Clarkson's Syndrome” 
Goodpasture syndrome 
• 
Frequently used related terms include: “pulmonary renal syndrome” 
and “anti-Glomerular Basement Membrane disease (anti-GBM 
disease)” 
Immune-mediated enhancement 
of disease 
• 
Includes vaccine associated enhanced disease (VAED and VAERD). 
Frequently used related terms include “vaccine-mediated enhanced 
disease (VMED)”, “enhanced respiratory disease (ERD)”, “vaccine-
induced enhancement of infection”, “disease enhancement”, “immune 
enhancement”, and “antibody-dependent enhancement” 
Immunoglobulin G4 related 
disease 
 
Langerhans' cell histiocytosis 
 
Multisystem inflammatory 
syndromes 
Including but not limited to: 
• 
Kawasaki’s disease 
• 
Multisystem inflammatory syndrome in adults (MIS-A) 
• 
Multisystem inflammatory syndrome in children (MIS-C)  
Overlap syndrome 
 
Raynaud’s phenomenon 
 
Sarcoidosis 
• 
Includes Loefgren syndrome 
Susac's syndrome 
 
10.3.6.2. 
Other AEs of special interest  
The following events are considered as AESI in this study. 
• 
Severe hypersensitivity reactions within 24 hours after study intervention 
administration 
• 
Myocarditis/Pericarditis 
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. 

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10.3.7. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as AEs or SAEs  
In the absence of a diagnosis, abnormal laboratory findings assessments described in 
Table 17 or other abnormal results the investigator considers clinically significant will be 
recorded as an AE or SAE, if they meet the definition of an AE or SAE (refer to Sections 
10.3.1 and 10.3.2). 
The investigator(s) must exercise their medical and scientific judgment in deciding 
whether an abnormal laboratory finding, or other abnormal assessment is clinically 
significant. 
10.3.8. 
Events or outcomes not qualifying as AEs or SAEs  
10.3.8.1. 
Pregnancy  
Female participants who become pregnant after administration of the study intervention 
may continue the study at the discretion of the investigator. 
While pregnancy itself is not considered an AE or SAE, any abnormal pregnancy 
outcome or complication or elective termination of a pregnancy for medical reasons will 
be recorded and reported as an SAE. Please refer to Section 10.3.2 for definition of SAE. 
10.3.9. 
Recording and follow up of AEs, SAEs, AESIs and pregnancies  
The participants will be instructed to contact the investigator immediately should they 
experience any signs or symptoms they perceive as serious. 
When an AE/SAE occurs, it is the investigator’s responsibility to review all 
documentation (e.g., hospital progress notes, laboratory and diagnostics reports) related 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE on the paper Expedited Adverse Events Report/in eCRF. The investigator may 
not send photocopies of the participant’s medical records to GSK instead of appropriately 
completing the paper Expedited Adverse Events Report/eCRF. 
There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all participant identifiers will be blinded on copies of the medical 
records prior to submission to GSK. 
The investigator will attempt to establish a diagnosis pertaining to the event, based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE instead of individual signs/symptoms. 
Electronic Diary (eDiary) will be used in this study to capture solicited administration 
site or systemic events and inform the site staff of the occurrence of an unsolicited event. 
The participant/caregiver should be trained on how and when to complete the eDiary. 

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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. 
Collect and verify completed eDiary during discussions with the participant on all 
contacts and visits up to Day 29. eDiary device should be returned to the site after the end 
of the relevant data collection period on Day 29 (Visit 4). If eDiary application was 
installed on participant’s/caregiver’s own device, it must be uninstalled after Day 29. 
Any unreturned eDiary will be sought from the participant through telephone call(s) or 
any other convenient procedure. 
Refer to the SPM for more information regarding the use of eDiary. 
10.3.9.1. 
Time period for collecting and recording AEs, SAEs, AESIs and 
pregnancies  
All solicited events that occur within 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. 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. 
All unsolicited AEs that occur within 28 days after administration of the study 
intervention (Day 1 to Day 28) must 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. 
SAEs related to study participation or to a concurrent GSK medication/vaccine will be 
collected from the time the consent is obtained until the participant is discharged from the 
study. 
The time period for collecting and recording SAEs and AESIs will begin at the day of 
study intervention administration (Day 1) and will end 6 months after (study end [Day 
183]). 
all AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study intervention until the participant is discharged from 
the study. 
See Section 10.3.9 for instructions on reporting of pregnancies. 
10.3.9.2. 
Follow up of AEs, SAEs, AESIs, pregnancies or any other events of 
interest  
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. All SAEs 

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and AESIs (as defined in the Section 10.3.6), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow up. 
Other non-serious AEs must be followed for 6 months (until Day 183) or until the 
participant is lost to follow up. 
10.3.9.2.1. Follow up during the study  
AEs/AESIs documented at a previous visit/contact and defined as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study or the participant is lost to follow up. 
If a participant dies during their participation in the study or during a recognized follow 
up period, GSK will be provided with any available post-mortem findings, including 
histopathology. 
10.3.9.2.2. Follow up after the participant is discharged from the study  
The investigator will provide any new or updated relevant information to GSK on a 
previously reported SAE/AESI using a paper/electronic Expedited Adverse Events 
Report and/or pregnancy report as applicable. The investigator is obliged to perform or 
arrange for the conduct of supplemental clinical examinations/tests and/or evaluations to 
elucidate the nature and/or causality of the SAE/AESI as fully as possible. 
10.3.9.2.3. Follow up of pregnancies  
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the paper pregnancy follow up 
report/electronic pregnancy report and the Expedited Adverse Events Report if 
applicable. Generally, the follow up period does not need to be longer than 6 to 8 weeks 
after the 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 10.3.11. 
10.3.9.3. 
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 faxed to the study contact for reporting SAEs (refer to Section 
8.3.3.1 or to GSK Global Safety department within the defined reporting timeframes 
specified in the Table 13). 

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10.3.10. 
Assessment of intensity and causality  
10.3.10.1. Assessment of intensity  
The intensity of the following solicited AEs will be assessed as described: 
Table 24 
Intensity scales for solicited events in participants of 6 years of age 
or more  
Adult 
Event 
Intensity grade 
Parameter 
Pain at administration site 
0 
None 
 
1 
Mild: Any pain neither interfering with nor preventing 
normal everyday activities. 
 
2 
Moderate: Painful when limb is moved and interferes with 
everyday activities. 
 
3 
Severe: Significant pain at rest. Prevents normal 
everyday activities. 
Redness at administration site 
Greatest surface diameter in mm 
Swelling at administration site 
Greatest surface diameter in mm  
Lymphadenopathy* 
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 
Temperature** 
Temperature in °C/°F 
Headache 
0 
None 
 
1 
Mild: Headache that is easily tolerated 
 
2 
Moderate: Headache that interferes with normal activity 
 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
None 
 
1 
Mild: Fatigue that is easily tolerated 
 
2 
Moderate: Fatigue that interferes with normal activity 
 
3 
Severe: Fatigue that prevents normal activity 
Myalgia 
0 
None 
 
1 
Mild: Myalgia present but does not interfere with activity 
 
2 
Moderate: Myalgia that interferes with normal activity 
 
3 
Severe: Myalgia that prevents normal activity 
Arthralgia 
0 
None 
 
1 
Mild: Arthralgia present but does not interfere with 
activity 
 
2 
Moderate: Arthralgia that interferes with normal activity 
 
3 
Severe: Arthralgia that prevents normal activity 
 
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 
* Defined as localized axillary, cervical or supraclavicular swelling or tenderness ipsilateral to the administration arm. 
** Refer to the SoA (Section 1.3) for the definition of fever and the preferred location for temperature measurement. 

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The maximum intensity of local administration site redness/swelling, and fever will be 
scored at GSK as follows: 
 
Redness/Swelling 
Fever 
0: 
< 25 mm 
< 38.0°C (100.4°F) 
1: 
≥ 25 - ≤ 50 mm 
≥ 38.0°C (100.4°F) - ≤ 38.4°C (101.1°F) 
2: 
≥ 51 - ≤ 100 mm 
≥ 38.5°C (101.2°F) - ≤ 38.9°C (102.0°F) 
3: 
> 100 mm 
≥ 39.0°C (102.1°F) 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgment. 
The intensity should be assigned to 1 of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the participant, causing 
minimal discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities. In 
adults/adolescents, such an AE would, for example, prevent 
attendance at work/school and would necessitate the 
administration of corrective therapy. 
An AE that is assessed as Grade 3 (severe) should not be confused with an SAE. Grade 3 
is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets 1 of the pre-defined 
outcomes as described in the Section 10.3.2. 
10.3.10.2. Assessment of causality  
The investigator must assess the relationship between study intervention and the 
occurrence of each unsolicited AE/SAE using clinical judgment. Where several different 
interventions were administered, the investigator should specify, when possible, if the 
unsolicited AE/SAE could be causally related to a specific intervention. When a causal 
relationship to a specific study intervention cannot be determined, the investigator should 
indicate the unsolicited AE/SAE to be related to all interventions. 
Alternative possible causes, such as the natural history of underlying disease, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study intervention will be considered and investigated. The investigator will also consult 
the IB and/or SmPC and/or Prescribing Information for marketed products while making 
their assessment. 

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Causality should be assessed by the investigator using the following question: 
Is there a reasonable possibility that the unsolicited AE may have been caused by the 
study intervention? 
YES 
: 
There is a reasonable possibility that the study intervention contributed 
to the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study intervention. There are other, more likely 
causes and administration of the study intervention is not suspected to 
have contributed to the AE. 
If an event meets the criteria to be determined ‘serious’ (see Section 10.3.2), additional 
examinations/tests will be performed by the investigator to determine ALL possible 
contributing factors for each SAE. 
Possible contributing factors include: 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the study intervention, if applicable. 
• 
An error in study intervention administration. 
• 
Other cause (specify). 
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important to 
record an assessment of causality for every event before submitting the Expedited 
Adverse Events Report to GSK. 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. The investigator(s) may change their opinion of causality after receiving 
additional information and update the SAE information accordingly. 
10.3.10.3. Medically attended visits  
For each solicited and unsolicited AE the participant experiences, the participant will be 
asked if they received medical attention (defined as unscheduled visit to or from medical 
personnel for any reason, including emergency room visits). This information will be 
recorded in the in the participant’s diary (for solicited AEs) and in the participant’s eCRF 
as part of normal AE reporting (for unsolicited AEs). Medical attention received for 
SAEs/AESIs will have to be reported using the normal AE reporting process in the eCRF. 

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10.3.10.4. Assessment of outcomes  
The investigator will assess the outcome of all serious and non-serious unsolicited AEs 
recorded during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
10.3.11. 
Reporting of SAEs, AESIs, pregnancies and other events  
10.3.11.1. Events requiring expedited reporting to GSK  
Once an investigator becomes aware that an SAE has occurred in enrolled participant, the 
investigator (or designee) must complete a paper Expedited Adverse Events 
Report/information in the electronic Expedited Adverse Events Report within 24 hours, 
even if the investigator does not have complete information on the SAE. It must be 
completed as thoroughly as possible, with all available details of the event. 
The SAE report must be updated within 24 hours of the receipt of updated information on 
the SAE. The investigator will always provide an assessment of causality at the time of 
the initial report. 
Refer to the Table 13 for the details on timeframes for reporting of 
SAEs/AESIs/pregnancies. 
Refer to Section 10.3.11.2 for information on back up systems in case the electronic 
reporting system does not work. 
10.3.11.2. Back up system in case the electronic reporting system does not work  
If the electronic reporting system does not work, the investigator (or designee) must fax 
or email a completed, dated and signed paper Expedited Adverse Events Report to the 
study contact for reporting SAEs (refer to Sponsor Information) or to GSK Global Safety 
department within 24 hours of becoming aware of the SAE. 
Investigator (or designee) must complete the electronic Expedited Adverse Events Report 
within 24 hours after the electronic reporting system is working again. The information 
reported through the electronic SAE reporting system will be considered valid for 
regulatory reporting purposes. 

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10.4. 
Appendix 4: Contraceptive guidance and collection of 
pregnancy information  
10.4.1. 
Definitions  
10.4.1.1. 
Woman of childbearing potential (WOCBP)  
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
10.4.1.1.1. Women not considered as women of childbearing potential  
• 
Premenarchal 
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. 
Additional evaluation should be considered if a participant’s fertility status is unclear 
(e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention. 
• 
Premenopausal female with ONE of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
− 
Current bilateral tubal ligation or occlusion 
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview. 
• 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use a 
non-hormonal, highly effective contraception method if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 

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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 
25). 
Table 25 
Highly effective contraceptive methods  
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.* 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation 
− 
Oral 
− 
Intravaginal 
− 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
− 
Injectable 
− 
Oral (if allowed by local regulation or if it is part of standard medical practice in the 
country) 
Highly Effective Methods That Are User Independent  
− 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
− 
Intrauterine device (IUD) 
− 
Intrauterine hormone-releasing system (IUS) 
− 
Bilateral tubal occlusion/ligation. 
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used.)  
Male partner sterilization prior to the female participant’s entry into the study, and this male is the 
sole partner for that participant, 
(The information on the male sterility can come from the site personnel’s review of the 
participant’s medical records; medical examination and/or semen analysis, or medical history 
interview provided by her or her partner). 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.)  
*Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects in clinical studies 

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10.4.3. 
Collection of pregnancy information  
10.4.3.1. 
Female participants who become pregnant  
Refer to Sections 8.3.1, 8.3.2, 10.3.9.1, 10.3.9.2 and 10.3.9.3 for further information on 
detection, recording, reporting and follow up of pregnancies. 
Since this is a single dose study, a female participant who becomes pregnant during 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. 
10.5. 
Appendix 5: Genetics  
Not applicable. 
10.6. 
Appendix 6: Definition of medical device AE, adverse device 
effect (ADE), serious adverse device effect (SADE) and 
unanticipated SADE (USADE)  
10.6.1. 
Definition of medical device AE and ADE  
• 
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 considered related to a medical device or not. 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 medical device. This definition includes events related to the medical device 
or comparator and events related to the procedures involved. 
• 
An ADE is an AE related to the use of a medical device. This definition includes any 
AE resulting from: 
− 
insufficient or inadequate instructions for use (i.e., user error), or 
− 
any malfunction of a medical device, or 
− 
intentional misuse of the medical device. 

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10.6.2. 
Definition of medical device SAE, SADE and USADE  
A medical device SAE is any SAE 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. 
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 a serious adverse event. 
• 
Any device deficiency that might have led to an SAE if appropriate action had not 
been taken or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome has 
not been identified in the current version of the IB. 
10.6.3. 
Recording and reporting of medical device AE, ADEs, SADEs and 
USADE  
• 
Any device deficiency must be reported to GSK within 24 hours after the 
investigator determines that the event meets the definition of a device deficiency. 
• 
Refer to paper ‘Medical device or combination product with device 
deficiency/incident report form’ for details on transmission of this information to the 
sponsor. 
• 
GSK will review all device deficiencies, 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. 
• 
If required or in case of any issues refer to the general safety contacts for SAE/AE 
reporting in Section 8.3.3.1. 

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10.6.4. 
Reporting of medical device deficiencies for associated person  
• 
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 safety reporting information and 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 should be reported using the medical device deficiency 
report form. 
• 
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. 
• 
Contacts for Medical device Deficiency reporting can be found in the medical device 
deficiency report form. 
10.7. 
Appendix 7: Country-specific requirements  
Not applicable. 
10.8. 
Appendix 8: Statistical appendix including model 
performance and data scenarios  
Study holding rules will be applied independently to each dose group. Rule 2a relates to 
any Grade 3 solicited events in an investigational group, with an event onset within the 7-
day (Days 1 to 7) post-dose period. The threshold of the holding decision is determined 
by a mixed BLRM, described below: 
logit(pi(d)) = log(α) + β1*log(d/d*) + β2*age group 
where 
• 
pi(d) represents the probability of having a Grade 3 solicited event at dose d 
• 
logit(p) = log(p/(1-p)) 
• 
d* = 
 is the reference dose 
• 
α is the intercept parameter 
• 
β1 is a dose effect 
• 
β2 is age group effect. 
CCI

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Since no prior information is available, the uncertainty about the dose-tolerance 
relationship (parameters α and β1) is expressed by a mixture of 2 bivariate normal 
distributions as follows: 
1. 80% weight for minimally informative component: log(α) ≈ normal (mean= -1.516, 
var=1) and log(β1) ≈ normal (mean= -1.553, var=1), a priori assuming 10% and 18% 
Grade 3 solicited event rate at 
, respectively. 
2. 20% weight for toxicity component: log(α) ≈ normal (mean= -0.708, var=1) and 
log(β1) ≈ normal (mean= -1.143, var=1), a priori assuming 15% and 33% Grade 3 
solicited event rate at 
, respectively. 
The age group parameter, β2, will be assigned a half-normal prior, normal (mean = 0, var 
= 0.25) with β2<0 to reflect a priori lower adverse reaction (AR) rate in the OA group. 
A zero covariance between priors is assumed. 
Holding rule 2a will be based on a greater than 50% posterior probability that the Grade 3 
solicited event rate ≥ 18% at the next dose. This will be applied by dose. 
Hypothetical scenarios that illustrate when a study hold could occur is presented in Table 
26. 
Table 26 
Hypothetical data scenarios for study holds  
Scenario 
Age group 
Dose 
#Events 
#Participants CD – P(OD) Next Dose ND – P(TD) ND – P(OD) 
1 
YA 
0 
24 
0 
0.990 
0.010 
0 
24 
0 
0.976 
0.024 
0 
24 
0 
0.959 
0.041 
0 
24 
0 
NA 
 
 
OA 
0 
24 
0 
0.998 
0.002 
0 
24 
0 
0.996 
0.004 
0 
24 
0 
0.989 
0.011 
0 
24 
0 
NA 
 
 
2 
YA 
 0 
24 
0 
0.990 
0.010 
 3 
24 
0.026 
0.706 
0.294 
 5 
24 
0.607* 
0.104 
0.896* 
 8 
24 
0.999* 
NA 
 
 
OA 
 0 
24 
0 
0.998 
0.002 
 3 
24 
0.002 
0.877 
0.123 
 5 
24 
0.270 
0.259 
0.741* 
 8 
24 
0.975* 
NA 
 
 
3 
YA 
0 
24 
0 
0.990 
0.010 
0 
24 
0.002 
0.922 
0.078 
4 
24 
0.764* 
0.023 
0.977* 
9 
24 
1* 
NA 
 
 
OA 
0 
24 
0 
0.999 
0.001 
2 
24 
0 
0.974 
0.026 
9 
24 
0.565* 
0.050 
0.950* 
14 
24 
1* 
NA 
 
 
*Holding rule met, i.e., ND – P(OD) >0.5 
CD = Current dose; NA = not applicable; ND = Next dose; P(TD) = Probability of target dose; and P(OD) = Probability 
of overdose. 
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When fitting the model, 0 events (#events) are replaced by 1 event (i.e., assume 1 event in the younger adult group); 
this is done to prevent results from being overinfluenced by rates of events (=0%) being on the boundary of the 
parameter space. 
Rows in red should not be in the table since the holding rule would have been met at the previous dose; however, the 
rows are included for illustration purposes only. 
10.9. 
Appendix 9: Abbreviations and glossary of terms  
10.9.1. 
List of abbreviations  
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate aminotransferase 
BLRM 
Bayesian Logistic Regression Model  
BUN 
Blood Urea Nitrogen 
CDC 
Center for Disease Control and Prevention 
CRDL 
Clinical Research and Development Lead  
CSR 
Clinical Study Report  
eCRF 
electronic Case Report Form  
EoS 
End of Study 
EWOC 
Escalation with Overdose Control  
FDA 
Food and Drug Administration, United States of 
America 
FSFV 
First Subject First Visit 
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FTiH 
First-Time-in-Human 
GCP 
Good Clinical Practice 
GMI 
Geometric Mean Increase 
GMT 
Geometric Mean Titers 
GSB 
GSK Global Safety Board 
GSK 
GlaxoSmithKline 
GSK-
GSK
HA 
Hemagglutinin  
HCP 
Health Care Professional 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
ICS 
Intracellular Cytokine Staining 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LLOQ 
Lower Limit of Quantification  
LML 
Local Medical lead 
LNP 
Lipid Nanoparticles 
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LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
OA 
Older Adult 
PCD 
Primary Completion Date 
PI 
Prescribing Information 
pIMD 
Potential Immune-Mediated Disease 
PPS 
Per Protocol Set 
PT 
Preferred Term 
QTL 
Quality Tolerance Limit 
RNA 
Ribonucleic Acid 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SBIR 
Source data Base for Internet Randomization  
SDV 
Source Document Verification 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SPM 
Study Procedures Manual 
SRT 
Safety Review Team 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
USADE 
Unanticipated Serious Adverse Device Effect 
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VCSP 
Vaccines Clinical Safety and Pharmacovigilance 
WHO 
World Health Organization 
WOCBP 
Woman of Childbearing Potential 
YA 
Younger Adult 
10.9.2. 
Glossary of terms  
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation participant, temporally associated with the 
use of a medicinal product, whether or not considered 
related to the medicinal product. 
An adverse event (AE) can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal 
product. For marketed medicinal products, this also 
includes failure to produce expected benefits (i.e., lack 
of efficacy), abuse or misuse. 
Blinding: 
A procedure in which 1 or more parties to the study are 
kept unaware of the intervention assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
study, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a serious adverse 
event. 
In a single-blind study, the investigator(s) and/or their 
staff are aware of the intervention assignment, but the 
participant is not.  
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. Refer to 
Section 6.3.5 for more information on blinding applied 
in this study. 
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 

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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. 
Child in care: 
A child who has been placed under the control or 
protection of an agency, organization, institution or 
entity by the courts, the government or a government 
body, acting in accordance with powers conferred on 
them by law or regulation. The definition of a child in 
care can include a child cared for by foster parents or 
living in a care home or institution, provided that the 
arrangement falls within the definition above. The 
definition of a child in care does not include a child who 
is adopted or has an appointed legal guardian. 
Combination product: 
Combination product comprises any combination of 
− 
drug 
− 
device 
− 
biological product 
Each drug, device and biological product included in a 
combination product is a constituent part.  
eDiary 
Electronically registered 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. 
Enrollment: 
The process of registering a participant into a clinical 
study by assigning participant identification number 
after signing the ICF. 
Essential documents: 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of 
the data produced 
eTrack: 
GSK’s tracking tool for clinical studies. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
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Immunological correlate of 
protection: 
A correlate of risk that has been validated to predict a 
certain level of protection from the targeted endpoint. 
Intervention: 
Term used throughout the clinical study to denote a set 
of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a participant. 
Intervention number: 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Invasive medical device 
EEC directive 93/42/EEC defines an invasive medical 
device as ‘A device which, in whole or in part, 
penetrates inside the body, either through a body orifice 
or through the surface of the body’ 
Investigational vaccine 
A pharmaceutical form of an active ingredient being 
tested in a clinical study, including a product with a 
marketing authorization when used in a way different 
from the approved form, or when used for an 
unapproved indication, or when used to gain further 
information about an approved use. 
Synonym: Investigational Medicinal Product 
Investigator: 
A person responsible for the conduct of the clinical 
study at a study site. If a study is conducted by a team of 
individuals at a study site, the investigator is the 
responsible leader of the team and may be called the 
principal investigator. 
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified 
individual or party to perform those study-related duties 
and functions 
Medical device deficiency: 
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 information 
supplied by the manufacturer. 
Participant: 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the 
study intervention (vaccine(s)/product(s)/control). 
Synonym: subject 

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Participant number: 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Primary completion date: 
The date that the final participant was examined or 
received an intervention for the purpose of final 
collection of data for all primary outcomes, whether the 
clinical study was concluded according to the pre-
specified protocol or was terminated. 
Randomization: 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Remote visit: 
This term refers to the visit conducted in the place other 
than the study site. 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
Solicited event: 
Events to be recorded as endpoints in the clinical study. 
The presence/occurrence/intensity of these events is 
actively solicited from the participant or an observer 
during a specified follow up period following study 
intervention administration. 
Source data: 
All information in original records and certified copies 
of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or 
certified copies). 
Source documents: 
Original legible documents, data, and records (e.g., 
hospital records, clinical and office charts, laboratory 
notes, memoranda, participants' diaries or evaluation 
checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, participant files, and records 
kept at the pharmacy, laboratories and at medico-
technical departments involved in the clinical study). 
Study intervention: 
Any investigational or marketed product(s) or placebo 
intended to be administered to a participant during the 
study. 

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Study monitor: 
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
Telemedicine: 
The use of electronic information and 
telecommunications technologies (both video-based and 
audio-only) to facilitate remote health care delivery, 
patient and professional health-related education, public 
health and health administration. 
Unsolicited adverse event: 
Any AE reported in addition to those solicited during the 
clinical study. Also, any ‘solicited’ symptom with onset 
outside the specified period of follow up for solicited 
symptoms will be reported as an unsolicited AE. 
Virtual visit: 
This term refers to study visits conducted using 
multimedia or technological platforms. 
10.10. 
Appendix 10: Protocol amendment history  
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the table of contents (TOC). 
DOCUMENT HISTORY 
Document 
Date of issue 
Amendment 5 
20 June 2023 
Amendment 4 
14 February 2023 
Amendment 3 
12 January 2023 
Amendment 2 
08 July 2022 
Amendment 1 
19 May 2022 
Final protocol 
15 April 2022 
 

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Amendments summary of changes table: 
Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
Amendment 1 
19 May 2022 
Title page 
‘Observer-blind’ was removed from the title of 
the study 
To avoid confusion: the study remains 
observer-blind for the study participant and 
investigator, but will be open-label for the 
sponsor 
1.1 Synopsis 
Rationale for the study has been updated 
The description of methodology used in this 
study and measures to minimize the risk for 
the study participants have been updated to 
reflect the study design revisions based on 
recommendations from the Belgian 
Competent Authority 
1.3 Schedule of Activities (SoA) 
Contact 3 (Day 29) has been transformed into a 
visit to enable sample collection for safety 
laboratory assessments. Numbering of visits 
has been adjusted throughout the document. 
Modifications made based on the 
recommendation from the Belgian Competent 
Authority 
Urine analysis was added into the list of safety 
assessments. 
Possibility to replace Visit 5 and 6 by a contact 
has been added. 
To reduce burden on study participants and 
improve compliance and participants 
retention 
 
Table 2 ‘Intervals between study visits’ has 
been updated 
To reflect updated schedule of study visits 
and contacts 
2.1. Study rationale 
Updated to align with Section 1.1 Synopsis 
The description of methodology used in this 
study and measures to minimize the risk for 
the study participants were aligned with 
synopsis 

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Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
2.3.1. Risk assessment 
Wording for mitigation strategy applicable to Flu 
Seasonal mRNA vaccine has been updated 
Updated to reflect the changes in safety 
follow up strategy for younger adults (YAs) 
versus older adults (OAs) implemented 
based on the recommendations from the 
Belgian Competent Authority 
2.3.2. Benefit assessment 
3. Objectives, endpoints, and 
estimands 
4.1 Overall design 
5.2.1. Medical conditions 
8. Study assessments and 
procedures 
8.1.1. Biological samples 
8.1.2. Laboratory assays 
Table 17 Protocol required safety 
laboratory assessments 
Urinalysis was added into the list of safety 
assessments made at different timepoints of 
the study 
To comply with the recommendation from the 
Belgian Competent Authority  

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Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
4.1. Overall design 
Table 5 Study intervention(s) 
administered 
8.2.3.1. Staggered enrollment and 
safety monitoring 
8.2.3.2. Outcome of safety evaluation 
8.2.3.3. Study holding rules 
9.3.1.1. Analysis of reactogenicity for 
dose escalation: Bayesian logistic 
regression model 
9.4.1. Sequence of planned analyses 
10.1.5. Committees structure 
Wording of several sections has been modified 
to implement following changes in study 
design: 
Dose escalation in YAs will depend on 
safety/reactogenicity data from all (sentinel and 
non-sentinel) participants at a given dose level 
Enrollment of OAs will start only after a 
reasonable database (i.e., from several dose 
levels in YAs) is available 
Only 1 dose will be assessed in OA. This dose 
will be assessed after the doses of 
 
 are evaluated in YAs 
To maximize the efficiency of the review of the 
safety data by the sponsor, the blinding is 
maintained for the investigator and participants, 
but the study becomes open-label for the 
sponsor. This alleviates the need for an internal 
Safety Review Committee (iSRC) and 
therefore, the safety data will be reviewed in an 
unblinded fashion by the Safety Review Team 
(SRT), in line with GSK processes. 
Several sections of the document have been 
updated to comply with the recommendations 
from the Belgian Competent Authority and to 
enhance safety of participants 
4.3. Justification for dose 
Wording on dose selection for OAs has been 
updated 
To limit overall exposure in OAs to 
investigational study intervention 
6.3.2. Randomization to study 
intervention 
Table 9 Immunological read-outs 
Total number of participants in the study has 
been updated 
To limit overall exposure in OAs to 
investigational study intervention 
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Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
9.3.2. Co-primary and secondary 
immunogenicity endpoints 
9.5.1. Sample size determination for 
reactogenicity and safety 
9.5.2. Sample size determination for 
immunogenicity 
4.2.2. Rationale for study blinding 
6.3.5. Blinding and unblinding 
Blinding was updated to open-label for the 
sponsor 
To maximize the efficiency of the safety data 
review by SRT for providing 
recommendations on dosing of non-sentinel 
participants at the current dose level, dose 
escalation for the next dose level in YAs and 
selection of dose for OAs 
5.1. Inclusion criteria 
Safety laboratory assessments were added 
To comply with the recommendation from the 
Belgian Competent Authorities 
Prior/Concomitant therapy 
Timing for administration of seasonal influenza 
vaccine has been changed  
To avoid biased reporting of AEs due to 
seasonal flu vaccination and its impact on 
safety and immunogenicity data within time 
period for collection of unsolicited adverse 
events 
6.8. Concomitant therapy 
Time-periods for recording of administration of 
concomitant medications and vaccinations 
have been updated 
To align with study design and GSK process 
8.2.1.5. Pregnancy test 
Wording updated to include pregnancy test at 
screening 
To clarify that 2 pregnancy tests will be 
required prior to enrollment and study 
intervention administration 

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Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
10.2.1. 
Protocol required safety 
laboratory assessments (Table 17) 
Troponin I and/or Troponin T was added as 
options for cardiac troponin assessment 
To allow flexibility for local labs when 
performing this assessment 
10.2.2. FDA Guidance for Industry: 
Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine 
Clinical Trials (September 2007) 
Table 20 was added  
To provide FDA toxicity grading scales for 
urinalysis parameters evaluated in the study 
10.3.10.1. Assessment of intensity 
Scales for redness, swelling and fever 
measurements have been updated  
To align with FDA toxicity grading scales. 
Amendment 2 
08 July 2022 
5.1. Inclusion criteria 
‘Before entering the study‘ was removed from 
inclusion criterion N°2 to clarify that this 
inclusion criterion will be checked along with all 
other eligibility criteria prior to enrolment/study 
intervention administration 
To comply with the recommendation from the 
Belgian Competent Authorities  
6.7. Treatment of overdose 
Section title and content were modified to 
include the management of anaphylaxis  
To comply with the recommendation from the 
Canadian Competent Authorities 
7.2. Participant 
discontinuation/withdrawal from the 
study 
Additional wording was added to provide a 
more exhaustive list of criteria for participant’s 
withdrawal from the study 
To comply with the recommendation from the 
Canadian Competent Authorities 
10.2.1. 
Protocol required safety 
laboratory assessments (Table 17) 
Urea has been added as option for clinical 
chemistry/biochemistry assessment 
To allow flexibility for local labs when 
performing this assessment 
10.3.10.1 Assessment of intensity 
(Table 24) 
Definition of Grade 0 for ‘Fatigue’ has been 
updated from ‘Normal’ to ‘None’ 
Grading aligned with current GSK standard 
definition and definition of grading provided in 
the participant diary 

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Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
Amendment 3 
12 January 2023 
4.1. Overall design 
4.3. Justification for dose 
4.3.2. Justification for additional 
doses in YAs, evaluated in 
Amendment 3 
Addition of 2 dose levels to the study 
 
 
To define the optimal dose for the 
monovalent H1 vaccine candidate 
1.1. Synopsis  
2.1. Study rationale 
Clarification that only younger adults will be 
enrolled in the
 dose cohort 
To optimize the dose level in younger adults 
(all previous dose levels were tested in this 
population)  
 
1.1 Synopsis  
1.3. Schedule of Activities (SoA) 
2.1. Study rationale 
2.3. Benefit/Risk assessment 
4.1. Overall design 
8.2.3.1.1. Staggered enrollment of 
OAs 
Removal of sentinel participants for the 
 
 dose cohort 
As (i) 
 
 dose cohorts, and 
(ii) 
 have showed a 
 
 (incidence 
of Grade 3 solicited adverse events ranging 
from 
 depending on dose group) 
 
1.1. Synopsis  
2.1. Study rationale 
4.1. Overall design 
No dose escalation and parallel enrollment for 
the 
 dose cohort  
 dose levels are 
than the 
 dose levels that have been 
tested previously in this study with a 
 
 (incidence 
of Grade 3 solicited adverse events ranging 
from 
 depending on dose group) 
 
1.1. Synopsis  
2.1. Study rationale 
4.1. Overall design 
4.2.1. Choice of active comparator 
No active control for the
 dose 
cohort 
The sample size of the available control 
group (N=30) is already similar to the sample 
size of each additional dose group to be 
tested (N=24) 
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Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
 
1.3. Schedule of Activities (SoA) 
9.4.1. Sequence of planned analyses 
Addition of a planned interim analysis upon 
availability of all primary endpoints up to Day 
29 for the 
 dose cohort 
To allow an interim analysis of primary 
endpoints for this cohort 
 
1.3. Schedule of Activities (SoA) 
Expansion of the allowed interval range for Visit 
1 → Contact 2 for non-sentinel participants 
To provide more flexibility for study sites to 
ensure participant compliance with study 
procedures 
 
5.2.2. Prior/Concomitant therapy 
“Previous enrollment in this study” added to the 
exclusion criteria 
To mitigate the risk of having the same 
participant enrolling more than once in the 
study 
 
8.1.2. Laboratory assays 
8.1.3. Immunological read-outs 
Replacement of cell-propagated 
 
with 
 
 
Due to strain production issue, the 
 
strain was used for the validation of the 
 
assay instead of the 
 strain. Both 
strains are per WHO recommendation 
considered as “like virus” and belong to the 
same clade/sub-clade, i.e., 
 
 
8.1.3. Immunological read-outs 
Revision of the number of participants included 
for each immunological readout 
To reflect the 5 dose levels enrolled to date 
and the additional number of participants 
planned in the
 dose cohort 
 
6.1. Study intervention(s) 
administered 
Addition of the 
 Flu mRNA vaccine in the 
study intervention table 
To reflect all the dose levels used in this 
study 
 
4.1. Overall design 
4.2.2. Rationale for study blinding 
6.3.5. Blinding and unblinding 
Clarification that the blinding level for 
 
 dose cohort will be single-blind 
Two different Flu mRNA doses will be used, 
therefore the persons reconstituting the 
interventions will be aware of the dose of the 
allocated Flu mRNA vaccine. This requires 
unblinding the randomization system for this 
cohort and accordingly all users of the 
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Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
randomization system will be unblinded and 
only the participant will remain blinded 
 
10.8. Appendix 8: Statistical appendix 
including model performance and 
data scenarios 
Correction of a typographical error for the mean 
of the second component of the mixture prior 
from -0.143 to -1.143. 
An updated description of the prior of the age 
group parameter to reflect what was actually 
used for the hypothetical data scenario in Table 
26 
To account for feedback received from FDA 
statistician 
 
10.9.2. Glossary of terms 
Single-blind definition added to the Glossary 
Since the blinding level for 
 dose 
cohort will be single-blind 
 
8.2.1.1. Collection of demographic 
data 
Clarification that year of birth, and not date of 
birth, is recorded in the participant’s eCRF 
To correct for error in protocol that date of 
birth is collected in the eCRF 
 
8.3.3. Regulatory reporting 
requirements for SAEs, pregnancies 
and other events 
Administration and systemic solicited events 
and Unsolicited events were removed from 
Table 13 
As these are not events that would require 
expedited reporting within 24 hours unless 
they meet the definition of SAE or AESI as 
per section 8.3.3. and Appendix 3 
 
6.3.2. Randomization to study 
intervention 
Clarification that partial block sizes without 
active control will be shipped for the 
 
 dose cohort 
As no active control is used for the 
 
 dose cohort 
Amendment 4 
14 February 2023 
4.1. Overall design 
4.3. Justification for dose 
4.3.2. Justification for additional 
doses in YAs, evaluated in 
Amendment 4 
Addition of 2 dose levels 
), and 
2 potential intermediate dose levels (
 
) to the study 
To widen the dose range of the monovalent 
Flu Seasonal mRNA vaccine candidate in 
younger adults, and explore the 
reactogenicity/immunogenicity profile at 
these dose levels 
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Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
8.2.3.1 Staggered enrolment and 
safety monitoring 
1.1. Synopsis  
2.1. Study rationale 
Clarification that only younger adults will be 
enrolled in the 
 and their 
potential intermediate dose cohorts (
 
 
To allow comparisons of 
reactogenicity/immunogenicity between dose 
levels in younger adults, as all previous dose 
levels were also tested in this population 
4.4. Enrollment rules 
Removal of the enrolment rule for sex  
To allow a higher enrollment flexibility in the 
study and since sex is not considered an 
important prognosis factor. The study 
conclusions are not expected to be impacted 
by sex distribution. 
1.1. Synopsis  
2.1. Study rationale 
4.1. Overall design 
4.2.1. Choice of active comparator 
New active control (Flu seasonal QIV vaccine 
2022-2023) for the 
, and their 
potential intermediate dose cohorts (
 
) 
Added due to expiry of the previous active 
control (Flu seasonal QIV vaccine 2021-
2022) 
1.3. Schedule of Activities (SoA) 
3. Objectives, Endpoints, and 
Estimands 
4.1. Overall design 
6.3.4 Allocation of participants to 
assay subsets 
8.1.1. Biological samples 
No blood sampling for 
response for 
 
 and their potential intermediate 
dose cohorts (
) 
As safety/reactogenicity assessment is the 
main objective for these additional dose 
cohorts, immunogenicity endpoints will be 
restricted to the most critical (Day 1 and Day 
22 antibody determination). 
1.3. Schedule of Activities (SoA) 
3. Objectives, Endpoints, and 
Estimands 
4.1. Overall design 
Removal of blood sampling at Day 62 and Day 
183 
As safety/reactogenicity assessment is the 
main objective for these additional dose 
cohorts, immunogenicity endpoints will be 
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Document 
Date of issue 
Section # and title 
Description of change 
Brief rationale 
8.1.1. Biological samples 
restricted to the most critical (Day 1 and Day 
22 antibody determination). 
1.3. Schedule of Activities (SoA) 
9.4.1. Sequence of planned analyses 
Addition of a planned interim analysis upon 
availability of all primary endpoints up to Day 
29 for the 
, and their potential 
intermediate dose cohorts (
) 
To allow an interim analysis of primary 
endpoints for these dose cohorts. 
8.1.3. Immunological read-outs 
Revision of the number of participants included 
for each immunological readout 
To reflect the additional number of 
participants planned in the 
 
dose cohorts, as well as the changes in blood 
sampling schedule for these cohorts 
6.1. Study intervention(s) 
administered 
Addition of the 
 Flu 
mRNA vaccine and new active control (Flu 
seasonal QIV vaccine 2022-2023) in the study 
intervention table 
To reflect all the Flu mRNA dose levels and 
control vaccines used in this study 
8.2.3.2. Outcome of safety evaluation 
8.2.3.3. Study holding rules 
10.1.5. Committees structure 
Replacement of term SRT charter with 
Appendix 1 on Safety Oversight of Phase I 
study 
This Appendix 1 on Safety Oversight of 
Phase I study has replaced the SRT charter 
and contains same information. 
9.3.1. Co-primary safety endpoints 
Addition of grade 4 (grade ≥ 3) solicited 
systemic events (fever) 
To make it clearer that Grade 4 solicited 
systemic events as defined by FDA’s Toxicity 
Grading Scale for Healthy Adults and 
Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, in particular fever, are 
captured and accounted for in this study. 
5.2. Exclusion criteria 
5.2.3. Other exclusions 
Exclusion criteria “Previous enrollment in this 
study” moved to number 21 under “Other 
exclusions”. 
To avoid needing to implement eCRF coding 
changes that would impact already enrolled 
study participants 
 
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Detailed description of the current Protocol amendment: 
Sections 1.1. Synopsis  
[…] 
2. Initiation of the dosing of OAs not until after the review of the safety/reactogenicity 
data reported with the 3 first dose levels administered in YAs by an unblinded Safety 
Review Team (SRT). Note: as the goal of protocol amendments 3, and 4 and 5 are to 
optimizefurther explore the reactogenicity/ immunogenicity profile the dose level 
between 
 and to explore the reactogenicity/immunogenicity profile of 
 
 dose cohorts respectively in YAs (all previous dose levels were tested in 
this population), no OAs will be enrolled in the 
 dose cohort, 
 
 dose cohort, or in the 
 dose 
cohorts 
 
[…]  
3. Supervision of the dose escalation by SRT. The safety/reactogenicity data reviewed 
by this team cover 8 days of follow up post-dosing (Day 1 to Day 8 included) of all 
participants of the current dose level. This time window is sufficient to ensure a 
reliable evaluation of the reactogenicity of the vaccine, considering that the median 
onset of solicited systemic events after mRNA Covid-19 vaccines administration is 1 
to 2 days, and a median duration of such events is 1 to 2 days [CBER, 2021; CBER, 
2022]. Note: 
 
 have shown a 
 (incidence of 
Grade 3 solicited adverse events ranging from 
 depending on dose 
group), this dose escalation step will not be followed for the 
 , or the 
 
 dose cohorts, i.e., participants in these cohorts will be enrolled in parallel. 
[…] 
Note: 
, and 
 
have shown a 
 (incidence of Grade 3 solicited 
adverse events ranging from 
 depending on dose group), no sentinel 
participants will be included in the additional 
 or 
 dose cohorts. 
[…] 
Note: The sample size of the available Control group (N=30) is similar to the sample size 
of each additional dose group to be tested (N=24). As such, we consider the available 
Control group sufficiently large for this phase 1 exploratory and descriptive study and 
will not use an active control for the additional 
 dose cohort, and 
 
 dose cohort, where an assessment of immunogenicity is the main objective. However, 
for the additional 
, and their potential intermediate dose cohorts (
 
), where a safety/reactogenicity assessment is the main objective, Flu D-QIV will 
be reintroduced as active control. 
Section 1.3. 
Schedule of Activities (SoA) 
Table 1 
Schedule of Activities (SoA) 
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[…] 
Note: The double-line border after Day 22 (Visit 3) and Day 29 (Visit 4) indicates the schedule of interim analyses. Two 
initial interim analyses will be conducted upon availability of all primary endpoints up to Day 22 for YA participants in 
the
 cohorts, respectively and a third interim analysis will be performed upon availability of all primary 
endpoints up to Day 29 for all study participants. Note: additional interim analyses will be performed upon availability of 
all primary endpoints up to Day 29 for (i) all participants in the 
 dose cohort and, (ii) all participants in the 
 and their potential intermediate dose cohorts (
 and (iii) all participants in the 
 
dose cohort. 
; eDiary: electronic diary (application or 
electronic device); AE: adverse event; SAE: serious adverse event; AESI: adverse event of special interest. 
● 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. 
† Contact 1 (Day 2) will be performed for sentinel participants only. Note that no sentinel participants are included for 
the 
 or 
 dose cohorts. 
* Samples will be collected on sites associated with a 
. Note: for the 
 and their 
potential intermediate dose cohorts (
 no blood sampling for
 response will be performed. 
** Sample will be collected only if participants did not receive the standard of care vaccination against seasonal flu 
since study participation. Note that blood sampling for antibody determination and characterization will be limited to 
Day 1 and Day 22 for the 
, and their potential intermediate dose cohorts (
). 
*** Visit 5 (Day 62) and Visit 6 (Day 183) will be replaced by a contact if participant have received the standard of care 
vaccination against seasonal flu prior to this visit and did not report any adverse events that would require physical 
examination on site. Note: No blood sampling will be performed at Day 62 and Day 183 for the 
, and 
their potential intermediate dose cohorts 
). As such, Visit 5 and Visit 6 will be replaced by a contact for 
all participants in these cohorts unless they reported any adverse events that would require physical examination on 
site. 
a is used to indicate a study procedure to be performed prior to study intervention administration. 
b is used to indicate a study procedure recorded in eDiary. 
[…] 
Table 2 
 Intervals between study visits 
[…] 
* Screening visit should take place within 28 days before Visit 1, with sufficient time to receive/review the hematology, 
biochemistry, coagulation and urinalysis results. When applicable, a re-screening visit (including blood and urine 
sample collection, physical examination and re-checking of inclusion/exclusion criteria) may be scheduled at any time 
(but only once to assess eligibility) before Visit 1. All screening procedures need to be performed within 28 days before 
Visit 1. Only laboratory results from the re-screening visit, if it occurs, will be taken into consideration. The participant 
can only be randomized once the investigator receives the results and confirms the eligibility criteria. 
** Contact 1 (Day 2) will be performed for sentinel participants only. Note that no sentinel participants are included for 
the 
 or 
 dose cohorts. 
*** Visit 5 (Day 62) and Visit 6 (Day 183) will be replaced by a contact if participant have received the standard of care 
vaccination against seasonal flu prior to this visit and did not report any adverse events that would require physical 
examination on site. Note: No blood sampling will be performed at Day 62 and Day 183 for the 
, and 
their potential intermediate dose cohorts (
). As such, Visit 5 and Visit 6 will be replaced by a contact for 
all participants in these cohorts unless they reported any adverse events that would require physical examination on 
site. 
† For non-sentinel participants, the allowed interval ranges from 1 to 3 days. 
[…] 
Section 2.1. Study rationale 
[…] 
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Note: As the goals of protocol amendments 3 and 4 and 5 are to further optimize the 
dose level between 
 and to explore the reactogenicity/immunogenicity profile of 
 dose cohorts respectively in YAs (all previous dose levels were tested in 
this population), no OAs will be enrolled in the 
 dose cohort, and 
 
 dose cohort, or in the 
 and their potential intermediate dose cohorts (
 
). 
 […] 
Note: 
, and 
 
have shown a 
 (incidence of Grade 3 solicited 
adverse events ranging from 
 depending on dose group this dose escalation 
step will not be followed for the 
 , or the 
 dose cohorts, i.e., 
participants in these cohorts will be enrolled in parallel.), this dose escalation step will 
not be followed for the 
 dose groups will be enrolled in parallel. […] 
Note: 
 and 
 
have shown a 
 (incidence of Grade 3 solicited 
adverse events ranging from 
 depending on dose group), no sentinel 
participants will be included in the additional or 
 dose cohort and 
 
 dose cohort. 
[…] 
Note: The sample size of the available Control group (N=30) is similar to the sample size 
of each additional dose group to be tested (N=24). As such, we consider the available 
Control group sufficiently large for this phase 1 exploratory and descriptive study and 
will not use an active control for the additional 
 dose cohort and 
 
dose cohort, where an assessment of immunogenicity is the main objective. However, for 
the additional 
, and their potential intermediate dose cohorts (
 
), where a safety/reactogenicity assessment is the main objective, Flu D-QIV will be 
reintroduced as active control. 
Section 2.3.1. Risk assessment 
[…] 
Note: no sentinel participants are included for the 
 or 
 dose cohorts 
[…] 
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Section 4.1  
Overall design 
Figure 1  
Study design overview 
Old figure: 
 
 
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New figure: 
 
AE: adverse event; SAE: serious adverse event; AESI: adverse event of special interest; D: day; 
 
; Control: Flu D-QIV (Flu Dresden-Quadrivalent Influenza Vaccine; GlaxoSmithKline; season 
2021-2022 Northern Hemisphere [NH] for the 
 dose cohorts, and season 2022-2023 NH for the 
 
 dose cohorts, and their potential intermediate dose cohorts 
); commercially available as α-RIX-
Tetra in Belgium).  
Doses of study intervention for YAs are coded as follows: dose 1: 
, dose 2: 
, dose 3: 
, dose 4: 
 
dose 6:
, dose 7: 
, dose 8: 
, dose 9: 
, dose 10: 
, dose 11: 
 Potential intermediate 
dose levels 
 may be evaluated with the total number of dose levels not 
exceeding 1012 in YAs and 1 in OAs. In OAs, dose of study intervention will be selected based on 
safety/reactogenicity data up to dose 3 in YAs. Refer to Section 4.3 for more information. Refer to Section 4.3.2, 4.3.4, 
Flu mRNA dose 2 (N = 24)
Control (N = 6)
Flu mRNA dose 1 (N = 24)
Control (N = 6)
Selected dose from YAs (N = 24)
Control (N = 24)
Flu mRNA dose 4 (N = 24)
D1
D183
D1
D183
D1
D183
D1
D183
D1
D183
Control (N = 6)
Control (N = 6)
Flu mRNA dose 3 (N = 24)
Flu mRNA dose 6 (N = 24)
D1
D183
Flu mRNA dose 7 (N = 24)
Flu mRNA dose 8 (N = 24)
D1
D183
Control (N = 6)
D1
D183
Flu mRNA dose 9 (N = 24)
Concomitant vaccinations and SAEs related to study participation or to a concurrent GSK vaccine
(Day -28 - Day 183) 
Solicited events (Day 1 - Day 7)
Unsolicited AEs
(Day 1 - Day 28)
(Day 3 and 7)
Visit 5
D62* , ***
Visit 6
D183 * , ***
Visit 1
D1*
Contact 1
D2 **
Visit 2 
D8*
Visit 3
D22
Visit 4
D29
: Contact
: Study intervention 
administration
: Younger adults
: Older adults
: Blood and urine sampling 
safety
: Blood sampling 
immunogenicity
Screening
D-28 to D-1
Contact 2
D3
SAEs, AESIs, pregnancies, AEs/SAEs leading to withdrawal and concomitant medications
(Day 1 - Day 183) 
Control (N = 6)
Flu mRNA dose 10 (N = 24)
D183
Flu mRNA dose 11 (N = 24)
D1
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and 4.3.4 for rationale for addition of the 
 and 
 and their potential 
intermediate dose cohorts 
) respectively. 
* Blood sample for
 will be collected from a subset of participants. 
will be assessed in 50% of participants of 
each group (Flu mRNA and Control) to be enrolled at the selected sites.  
Note: for the 
 and their potential intermediate dose cohorts (
) no blood sampling for 
 
response will be performed.  
** Contact 1 (Day 2) will be performed for sentinel participants only. Note that no sentinel participants are included for 
the 
 dose cohorts. 
*** Visit 5 (Day 62) and Visit 6 (Day 183) will be replaced by a contact if participant have received the standard of care 
vaccination against seasonal flu prior to this visit and did not report any adverse events that would require physical 
examination on site. Note: No blood sampling will be performed at Day 62 and Day 183 for the 
, and 
their potential intermediate dose cohorts (
). As such, Visit 5 and Visit 6 will be replaced by a contact for 
all participants in these cohorts unless they reported any adverse events that would require physical examination on 
site. 
Note: Each dose group consists of sentinel and non-sentinel participants, except for the 
 dose 
cohorts. 
[…] 
For the additional 
 dose cohorts, no sentinel participants 
will be enrolled; no dose escalation design applies; 
 the dose levels in each 
cohort will be enrolled in parallel; no control vaccine will be used. 
[…] 
Note: No sentinel participants will be enrolled for the additional 
 dose cohorts, hence all 
participants in thatthese cohorts will be considered as non-sentinel. No control vaccine will be used for the 
 
 dose cohorts, where a randomization ratio of 1:1 will be applied between the
 dose 
levels, and between the 
 dose levels, for a total of 48 participants per cohort.  
[…] 
• 
Parallel enrollment for the 
, and the 
 dose cohorts. 
• 
Planned (approximate) number of participants to be enrolled is 306354: 
− 
258306 YA participants (24 participants per dose level and a total number of 42 
participants receiving the active control) 
− 
48 OA participants (24 participants receiving a dose of investigational study 
intervention and 24 participants receiving the active control) 
− 
Due to the adaptive design, the actual number of participants enrolled might be 
lower than the target number or up to 336384 participants in case a 10th 12th 
dose level is evaluated in YAs. 
[…] 
Furthermore, 2 additional doses of 
 of the vaccine candidate will be assessed 
in 48 YAs under Protocol Amendment 3; and 2 additional doses of 
 will be 
assessed in 48 YAs under Protocol Amendment 5. Refer to Section 4.3.2, and 4.3.4, and 
4.3.4for rationale for addition of the 
, and 
their potential intermediate dose cohorts respectively. In any case, the total number of 
dose levels assessed will not exceed 1012. 
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[…] 
Flu D-QIV season 2022-2023 will be used as active control for the 
and 
their potential intermediate dose cohorts (
 No active control will be used 
for the 
 dose cohorts. 
[…] 
• 
Study groups: 
− 
2 parallel groups, Flu mRNA versus Control in YAs. 
− 
2 parallel groups, Flu mRNA versus Control in OAs. 
− 
For the 
 dose cohort: 2 parallel groups, Flu mRNA
 versus Flu 
mRNA 
 in YAs. 
− 
For the 
 dose cohort: 2 parallel groups, Flu mRNA 
 versus 
Flu mRNA 
 in YAs. 
[…] 
• 
Level of blinding: for participants and investigators, the study will be observer-blind 
with regards to the study intervention, but open-label with regards to the dose level. 
For the sponsor, the study will be open-label. For the 
, and 
 
dose cohorts, the study will be single-blind. 
[…] 
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Table 27 
Study groups, intervention and blinding 
Study groups 
Number of 
participants 
Age 
(Min-Max) 
Study interventions 
(IM use) 
Blinding 
Visit 1→Visit 6 
YA 
 Flu mRNA dose 1 
24 
18 – 45 years 
Observer-blind*  
Flu mRNA dose 2 
24 
18 – 45 years 
Observer-blind* 
Flu mRNA dose 3 
24 
18 – 45 years 
Observer-blind * 
Flu mRNA dose 4 
24 
18 – 45 years 
Observer-blind * 
Flu mRNA dose 6 
24 
18 – 45 years 
Single-blind* 
Flu mRNA dose 7 
24 
18 – 45 years 
Single-blind*  
Flu mRNA dose 8 
24 
18 – 45 years 
Observer-blind * 
Flu mRNA dose 9 
24 
18 – 45 years 
Observer-blind * 
Flu mRNA dose 10 
24 
18 – 45 years 
Single-blind* 
Flu mRNA dose 11 
24 
18 – 45 years 
Single-blind*  
Control** 
24 
18 – 45 years 
FDQ21A-NH 
Observer-blind* 
Control** 
12 
18 – 45 years 
FDQ22A-NH 
Observer-blind* 
OA 
Selected dose from 
YAs 
24 
60 – 80 years 
Selected dose from YAs*** 
Observer-blind* 
Control 
24 
60 – 80 years 
FDQ21A-NH 
Observer-blind* 
YA: younger adult; OA: older adult; NH: Northern Hemisphere. 
Control: Flu D-QIV (Flu Dresden- Quadrivalent Influenza Vaccine; GlaxoSmithKline; season 2021-2022 NH for the 
 
 dose cohorts, and season 2022-2023 NH for the 
 dose cohorts; commercially available 
as α-RIX-Tetra in Belgium)  
Doses of vaccine candidate are coded as follows: dose 1: 
; dose 2: 
; dose 3: 
 dose 4: 
, dose 6: 
, dose 7: 
 dose 8: 
, dose 9: 
 dose 10: 
 dose 11: 
. Potential intermediate dose 
levels 
) may be evaluated with the total number of dose levels not 
exceeding 1012 in YAs and 1 in OAs. Refer to Section 4.3.2,and 4.3.4, and 4.3.4 for rationale for addition of the 
 
 and their potential intermediate dose cohorts (
) 
respectively. 
* For participants and investigators, the study will be observer-blind with regards to the study intervention, but open-
label with regards to the dose level. For the sponsor, the study will be open-label. For the 
, and 
 
dose cohorts, the study will be single-blind. Refer to Section 6.3.5 for more information. 
** In YAs, 6 participants are enrolled in the control group per dose level of the investigational study intervention, except 
for the
, and 
 dose cohorts, where no control vaccine will be used. 
*** Study intervention dose will be selected based on the safety/reactogenicity data obtained up to dose 3 in YAs. 
Refer to Section 4.3 for more information. 
Note: Hereafter, name of the study groups for YAs will be only referred to as Flu mRNA dose 1-119. Details on the 
study intervention administered are shown in Table 5. 
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[…] 
Section 4.1.1 Enrollment rules 
Overall, participants will be enrolled in 2 age categories (YAs and OAs) with at least 
35% of either sex to ensure balance between males and females. Note: To allow a higher 
enrollment flexibility in the study and since sex is not considered an important prognosis 
factor, the sex enrollment rule will not be applied to the additional 
 dose 
cohort, or the 
, and their potential intermediate dose cohorts (
 
).  
[…] 
Table 28 
Study groups, intervention and blinding (Amended:20 June 2023)  
Study groups 
Number of 
participants 
Age 
(Min-Max) 
Study interventions 
(IM use) 
Blinding 
Visit 1→Visit 6 
YA 
 Flu mRNA dose 1 
24 
18 – 45 years 
Observer-blind  
Flu mRNA dose 2 
24 
18 – 45 years 
Observer-blind 
Flu mRNA dose 3 
24 
18 – 45 years 
Observer-blind  
Flu mRNA dose 4 
24 
18 – 45 years 
Observer-blind  
Flu mRNA dose 6 
24 
18 – 45 years 
Single-blind 
Flu mRNA dose 7 
24 
18 – 45 years 
Single-blind  
Flu mRNA dose 8 
24 
18 – 45 years 
Observer-blind 
Flu mRNA dose 9 
24 
18 – 45 years 
Observer-blind  
Control** 
24 
18 – 45 years 
FDQ21A-NH 
Observer-blind 
Control** 
12 
18 – 45 years 
FDQ22A-NH 
Observer-blind* 
OA 
Selected dose from 
YAs 
24 
60 – 80 years 
Selected dose from YAs*** 
Observer-blind 
Control 
24 
60 – 80 years 
FDQ21A-NH 
Observer-blind 
YA: younger adult; OA: older adult; NH: Northern Hemisphere. 
Control: Flu D-QIV (Flu Dresden- Quadrivalent Influenza Vaccine; GlaxoSmithKline; season 2021-2022 NH for the
, 
 dose cohorts, and season 2022-2023 NH for the 
 dose cohorts; commercially available as α-
RIX-Tetra in Belgium)  
Doses of vaccine candidate are coded as follows: dose 1: 
 dose 2: 
; dose 3: 
; dose 4: 
 dose 6: 
, dose 7: 
, dose 8: 
, dose 9: 
, dose 10: 
, dose 11: 
. Potential intermediate dose 
levels 
 may be evaluated with the total number of dose levels not 
exceeding 12 in YAs and 1 in OAs. Refer to Section 4.3.2, 4.3.4, and 4.3.4 for rationale for addition of the 
 
 and their potential intermediate dose cohorts 
) 
respectively. 
* For participants and investigators, the study will be observer-blind with regards to the study intervention, but open-
label with regards to the dose level. For the sponsor, the study will be open-label. For the 
 
 dose cohorts, the study will be single-blind. Refer to Section 6.3.5 for more information. 
** In YAs, 6 participants are enrolled in the control group per dose level of the investigational study intervention, except 
for the 
 dose cohorts, where no control vaccine will be used. 
*** Study intervention dose will be selected based on the safety/reactogenicity data obtained up to dose 3 in YAs. 
Refer to Section 4.3 for more information. 
Note: Hereafter, name of the study groups for YAs will be only referred to as Flu mRNA dose 1-11. Details on the study 
intervention administered are shown in Table 5. 
Section 4.2.1 Choice of active comparator 
[…] 
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Note: The sample size of the available Control group (N=30) is similar to the sample size 
of each additional dose group to be tested (N=24). As such, we consider the available 
Control group sufficiently large for this phase 1 exploratory and descriptive study and 
will not use an active control for the additional 
 dose cohorts, 
where an assessment of immunogenicity is the main objective. However, for the 
additional 
, and their potential intermediate dose cohorts (
), 
where a safety/reactogenicity assessment is the main objective, Flu D-QIV will be 
reintroduced as active control. 
[…] 
Section 4.2.2 Rationale for study blinding 
[…] 
For the 
 dose cohorts, 2 different Flu mRNA doses are to 
be used, therefore the persons reconstituting the interventions will be aware of the dose of 
the allocated Flu mRNA vaccine. This requires unblinding the randomization system for 
this cohort and accordingly all users of the randomization system, including the 
investigator, will be unblinded and only the participant will remain blinded. 
[…] 
Section 4.3 
Justification for dose  
Six dose levels (
) and 1 dose level (up to 
 are planned 
to be evaluated in YAs and OAs, respectively, in this study. Depending on the outcomes 
of safety and reactogenicity evaluations, intermediate dose levels (YAs: 
 
; OAs:
) may be used. Furthermore, 2 additional doses of 
 
of the vaccine candidate will be evaluated in YAs under Protocol Amendment 3, and 2 
additional doses of 
 of the vaccine candidate will be evaluated in YAs 
under Protocol Amendment 5. Refer to Section 4.3.2,  4.3.4, and 4.3.4 for rationale for 
addition of the 
, and 
 and their potential 
intermediate dose cohorts (
) respectively. The total number of dose levels 
will not exceed 10 12 in YAs and 1 in OAs. 
Section 4.3.2 Justification for additional doses in YAs, evaluated in Amendment 5 
Available data from the 
 dose cohorts in this study show  
 
 
 
. In this amendment, we will therefore further 
assess the immunogenicity of 
 dose levels in order to expand the 
therapeutic window of this monovalent H1 vaccine candidate in younger adults. Data 
from this amendment will be used to further characterize the mRNA platform, and may 
inform the dose selection for future mRNA-based vaccine candidates and/or vaccine 
combinations. 
[…] 
Section 6.1. 
Study intervention(s) administered 
Table 5 
 
Study intervention(s) administered
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Study intervention 
name: 
Flu mRNA vaccine 
Study intervention 
formulation: 
Presentation: 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Manufacturer: 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
Type: 
Investigational 
Product category: 
Biologic 
Route of 
administration:  
IM 
Location 
Deltoid 
• 
Directionali
ty  
Upper 
• 
Laterality ** 
Non-Dominant 
Number of doses to 
be administered: 
1 
Volume to be 
administered by 
dose ***: 
Refer to the Study Procedures Manual (SPM) for more details 
Packaging and 
labeling: 
Refer to the SPM for more details 
 
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Study intervention 
name: 
Flu mRNA vaccine 
Study intervention 
formulation: 
Presentation: 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Manufacturer: 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
Type: 
Investigational 
Product category: 
Biologic 
Route of 
administration:  
IM 
• 
Location 
Deltoid 
• 
Directionali
ty  
Upper 
• 
Laterality ** 
Non-Dominant 
Number of doses to 
be administered: 
1 
Volume to be 
administered by 
dose ***: 
Refer to the Study Procedures Manual (SPM) for more details 
Packaging and 
labeling: 
Refer to the SPM for more details 
 
 
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Study intervention 
name: 
Flu mRNA vaccine 
 
Study intervention 
formulation: 
Presentation: 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersio
n for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersio
n for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Concentrate for 
dispersion for 
injection (Vials) 
Solution 
for 
dispersion 
for 
injection 
(Ampoule 
or other) 
Manufacturer: 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN***
* 
GSK Biologicals 
B 
BRAUN**
** 
Type: 
Investigational 
Product category: 
Biologic 
Route of 
administration:  
IM 
Location 
Deltoid 
• 
Directional
ity  
Upper 
• 
Laterality 
** 
Non-Dominant 
Number of doses to 
be administered: 
1 
Volume to be 
administered by 
dose ***: 
Refer to the Study Procedures Manual (SPM) for more details 
Packaging and 
labeling: 
Refer to the SPM for more details 
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Study intervention 
name: 
Flu mRNA vaccine 
Study intervention 
formulation: 
Presentation: 
Concentrate for dispersion 
for injection (Vials) 
Solution for 
dispersion for 
injection (Ampoule 
or other) 
Concentrate for dispersion 
for injection (Vials) 
Solution for 
dispersion for 
injection 
(Ampoule or 
other) 
Concentrate for dispersion 
for injection (Vials) 
Solution for 
dispersion for 
injection 
(Ampoule or 
other) 
Manufacturer: 
GSK Biologicals 
B BRAUN**** 
GSK Biologicals 
B BRAUN**** 
GSK Biologicals 
B BRAUN**** 
Type: 
 
Product category: 
Biologic 
Route of 
administration:  
IM 
Location 
Deltoid 
• 
Directional
ity  
Upper 
• 
Laterality 
** 
Non-Dominant 
Number of doses to 
be administered: 
1 
Volume to be 
administered by 
dose ***: 
Refer to the Study Procedures Manual (SPM) for more details 
Packaging and 
labeling: 
Refer to the SPM for more details 
 
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Study intervention name: 
FDQ21A-NH† 
FDQ22A-NH‡ 
Study intervention formulation: 
A/Victoria/2570/2019 (H1N1), IVR-215 (15 µg HA); 
A/Tasmania/503/2020 (H3N2), IVR-221 (15 µg HA); 
B/Washington/02/2019 (15 µg HA); B/Phuket/3073/2013 (15 
µg HA); Water for injections 
A/Victoria/2570/2019 (H1N1), IVR-215 (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 
Presentation: 
Suspension for injection (Syringe) 
Suspension for injection (Syringe) 
Manufacturer: 
GSK Biologicals 
GSK Biologicals 
Type: 
Active control 
Active control 
Product category: 
Combination product 
Combination product 
Route of administration:  
IM 
IM 
Location 
Deltoid 
Deltoid 
• 
Directionality  
Upper 
Upper 
• 
Laterality ** 
Non-Dominant 
Non-Dominant 
Number of doses to be administered: 
1 
1 
Volume to be administered by dose ***: 
Refer to the Study Procedures Manual (SPM) for more details 
Refer to the Study Procedures Manual (SPM) for more details 
Packaging and labeling: 
Refer to the SPM for more details 
Refer to the SPM for more details 
IM: intramuscular; TBD: to be defined. 
† FDQ21A-NH: Flu D-QIV (Flu Dresden- Quadrivalent Influenza Vaccine, GlaxoSmithKline; 2021-2022 NH for the 
 dose cohorts). 
‡FDQ22A-NH: Flu D-QIV (Flu Dresden- Quadrivalent Influenza Vaccine, GlaxoSmithKline; 2022-2023 NH for the 
, and their potential intermediate dose 
cohorts (
). 
* Potential intermediate dose levels that may be evaluated, with the total number of dose levels not exceeding 12 in YAs and 1 in OAs. 
** The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the study intervention in the non-dominant arm, an injection in the dominant arm may 
be performed. 
*** Refer to the SPM for the volume after reconstitution. 
**** Another manufacturer might be used depending on study site 
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[…] 
Section 6.3.2 Randomization to study intervention  
• 
Planned (approximate) number of participants to be enrolled is 306354: 
− 
258306 YA participants (24 participants per dose level and a total number of 42 
participants receiving the active control) 
− 
48 OA participants (24 participants receiving a dose of investigational study 
intervention and 24 participants receiving the active control) 
− 
Due to the adaptive design, the actual number of participants enrolled might be 
lower or higher (up to 336384 participants in total) in case a 10th 12th dose level 
is evaluated in YAs. 
Planned number of participants to be enrolled for the 
 dose cohort is 48 (24 
participants per dose level). Planned number of participants to be enrolled for the 
 
 dose cohort is 48 (24 participants per dose level).  
The randomization of supplies within blocks will be performed at GSK, using MATerial 
Excellence (MatEx), a program developed for use in Statistical Analysis System (SAS) 
(Cary, NC, US) by GSK. Entire blocks will be shipped to the study centers/warehouse(s). 
For the 
 dose cohort, the active control arm will be blocked at 
randomization. For the 
 dose cohort, partial block sizes, not including active 
control, will be shipped. 
To allow GSK to take advantage of greater rates of recruitment than anticipated at 
individual centers in this multi-center study and to thus reduce the overall study 
recruitment period, an over-randomization of supplies will be prepared. 
[…] 
Section 6.3.5. Blinding and unblinding 
[…] 
However, for the additional 
 dose cohort and 
 dose cohort, data 
will be collected in a single-blind manner. The investigator(s) and/or their staff are aware 
of the study intervention assignment, but the participant is not. The study intervention 
will be prepared and administered by qualified study personnel who can be aware of the 
intervention assignment. 
[…] 
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Section 8.1.3. Immunological read-outs 
Table 9 
Immunological read-outs 
Blood sampling timepoint 
Subset name* No. participants 
Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 1 (Day 1) 
Pre-dose 
All enrolled 
participants 
306354 
Participants in 
 subset 
123147 
Visit 2 (Day 8) 
Post-dose  Participants in 
subset 
123147 
Visit 3 (Day 22) 
Post-dose  
All enrolled 
participants 
306354 
Visit 5 (Day 62) 
Post-dose  
All enrolled 
participants 
246294 
Participants in 
 subset 
123147 
Visit 6 (Day 183) 
Post-dose  
All enrolled 
participants 
246294 
Participants in 
 subset 
123147 
* Refer to Section 6.3.4 for subset description. 
Ab: antibody; 
. 
[…] 
Section 8.2.3.1.1. Staggered enrollment of YAs 
[…] 
• 
Note: No sentinel participants will be enrolled for the additional 
 dose 
cohort, or 
 dose cohort. The rationale for this is that all dose cohorts, 
including the higher dose levels 
, and upto 
 have showed a 
 
(incidence of Grade 3 solicited AEs ranging from 
 depending on dose group), and no safety signal has been observed. The 
 , and 
 dose groups cohorts will be enrolled in parallel.  
[…] 
P: participant; SRT: Safety Review Team. Dose 1-4 and dose 8 and 9: Flu mRNA dose 1-4 and 8 and 9. Potential 
intermediate dose levels may be evaluated with the total number of doses not exceeding 12 in YAs and 1 in OAs. 
[…] 
Section 9.4.1. Sequence of planned analyses 
[…] 
Additional interim analyses will be performed upon availability of all primary endpoints 
up to Day 29 for (i) all participants in the 
 dose cohort,(ii) all participants in 
the 
 and their potential intermediate dose cohorts (
). and 
(iii) all participants in the 
 dose cohort,  
[…] 
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11. 
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Signature Page for  217895 TMF-16223720 v2.0
Signature Page for TMF-16223720 v2.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 23-Jun-2023 10:59:07 GMT+0000
PPD